Controlled Drug Delivery

DRUGS AND THE PHARMACEUTICAL SCIENCES

A Series of Textbooks and Monographs

Edited by
James Swarbrick
School of Pharmacy
University of North Cam Una
Chape/ Hill, North Carolina

Volume 1. P H A R M A C O K I N E T I C S , Milo Gibaldi and Donald Perrier

(out of print)

Volume 2. GOOD M A N U F A C T U R I N G PRACTICES FOR

P H A R M A C E U T I C A L S : A PLAN FOR T O T A L Q U A L I T Y
C O N T R O L , Sidney H. Willig, Murray M. Tucker man, and
William S. Hitchings IV (out of print)

Volume 3. M I C R O E N C A P S U L A T I O N , edited by J R. Nixon

Volume 4. DRUG M E T A B O L I S M : CHEMICAL A N D B I O C H E M I C A L

ASPECTS, Bernard Testa and Peter Jenner

Volume 5. NEW DRUGS: DISCOVERY A N D DEVELOPMENT,

edited by Alan A. Rubin

Volume 6. SUSTAINED A N D C O N T R O L L E D RELEASE DRUG D E L I V E R Y

SYSTEMS, edited by Joseph R. Robinson

Volume 7. M O D E R N PHARMACEUTICS, edited by Gilbert S.

Banker and Christopher T Rhodes

Volume 8. PRESCRIPTION DRUGS IN SHORT SUPPLY: CASE

HISTO RIES, Michael A. Sch wartz

Volume 9. A C T I V A T E D C H A R C O A L : A N T I D O T A L A N D OTHER
M E D I C A L USES, David O. Cooney

Volume 10. CONCEPTS IN D R U G M E T A B O L I S M (in t w o parts), edited

by Peter Jenner and Bernard Testa

Volume 1 1 . P H A R M A C E U T I C A L A N A L Y S I S : M O D E R N METHODS
(in two parts), edited by James i/V. Munson
Volume 12. TECHNIQUES OF S O L U B I L I Z A T I O N OF DRUGS,
edited by Samuel H. Yalkowsky

Volume 13. ORPHAN DRUGS .edited by Fred E. Karch

Volume 14. NOVEL DRUG DELIVERY SYSTEMS: FUNDAMENTALS,

DEVELOPMENTAL CONCEPTS, BIOMEDICAL ASSESSMENTS,
edited by Yie W. Chien

Volume 15. PHARMACOKINETICS, Second Edition, Revised and Expanded,

Milo Gibaldi and Donald Perrier

Volume 16. GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICALS:

A PLAN FOR TOTAL QUALITY CONTROL, Second Edition,
Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman,
and William S. Hitchings IV

Volume 17. FORMULATION OF VETERINARY DOSAGE FORMS, edited by

Jack Blodinger

Volume 18. DERMATOLOGICAL FORMULATIONS: PERCUTANEOUS

ABSORPTION, Brian W. Barry

Volume 19. THE CLINICAL RESEARCH PROCESS IN THE PHARMACEUTICAL

INDUSTRY, edited by Gary M. Matoren

Volume 20. MICROENCAPSULATION AND RELATED DRUG

PROCESSES, Patrick B. Deasy

Volume 21. DRUGS AND NUTRIENTS: THE INTERACTIVE

EFFECTS, edited by Daphne A. Roe and T. Colin
Campbell

Volume 22. BIOTECHNOLOGY OF INDUSTRIAL ANTIBIOTICS,

Erick J. Vandamme

Volume 23. PHARMACEUTICAL PROCESS VALIDATION,

edited by Bernard T. Loft us and Robert A. Nash

Volume.24. ANTICANCER AND INTERFERON AGENTS:

SYNTHESIS AND PROPERTIES, edited by Raphael
M. Ottenbrite and George B. Butler

Volume 25. PHARMACEUTICAL STATISTICS: PRACTICAL AND

CLINICAL APPLICATIONS, Sanford Bolton

Volume 26. DRUG DYNAMICS FOR ANALYTICAL, CLINICAL, AND BIOLOGICAL

CHEMISTS, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael
J. Gudzinowicz
Volume 27. MODERN ANALYSIS OF ANTIBIOTICS, edited by Adorjan Aszalos

Volume 28. SOLUBILITY AND RELATED PROPERTIES, Kenneth C. James

Volume 29. CONTROLLED DRUG DELIVERY: FUNDAMENTALS AND
APPLICATIONS, Second Edition, Revised and Expanded,
Joseph R. Robinson and Vincent H. L. Lee

Other Volumes in Preparation

Controlled Drug Delivery
Fundamentals and Applications

SECOND EDITION,
REVISED AND EXPANDED

Edited by

Joseph R. Robinson Vincent H. L. Lee

SCHOOL OF PHARMACY SCHOOL OF PHARMACY
UNIVERSITY OF WISCONSIN UNIVERSITY OF SOUTHERN CALIFORNIA
MADISON, WISCONSIN LOS ANGELES, CALIFORNIA

M A R C E L

MARCEL DEKKER, INC. N E W YORK • BASEL

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In memory of our fathers,
and to our mothers
 Preface to the Second Edition

Controlled drug delivery is the phasing of drug administration to

the needs of a condition at hand so that an optimal amount of drug
is used to cure or control the condition in a minimum time. Research
in controlled drug delivery during the past decade has led to increas-
ingly sophisticated means to sustain drug delivery. It has also stim-
ulated greater awareness among the pharmaceutical industry, the
regulatory agencies, the health care profession, and the public at
large of the therapeutic advantages of controlled drug delivery sys-
tems. Presently, the majority of these systems are based on syn-
thetic polymers of some sort that differ in the degree of erodibility,
swellability, and sensitivity to the biological environment in which
they are placed. These polymers have been used to fabricate sys-
tems such as microcapsules and nanoparticles for implantation, hy-
drogels for oral and parenteral drug delivery, the osmotic pump for
oral drug delivery, and patches for transdermal drug delivery.
Clearly, in order to fully utilize the potential of polymers in the
broad area of drug delivery, it is necessary to understand their
fundamental physical, chemical, and biological properties.
When the first edition of this text was written a decade ago,
liposomes were considered by many to be the answer to drug delivery
optimization in virtually all routes of drug administration. Research
since then has revealed that liposomes in particular and microparticu-
late carriers in general would probably have their greatest impact in

iv
 Preface to the Second Edition I v

targeting drugs for diseases affecting the reticuloendothelial system,

to which these carriers are directed, as well as for diseases involv-
ing blood cells in the systemic circulation, to which these carriers
are confined.
The frustrations associated with targeting drugs to specific sites
in the body using systems such as liposomes have led to research
to seek alternative carriers, such as insulin, that are biological in
nature and capable of exiting the circulation by virtue of their ability
to cross endothelial barriers via endocytosis and transcytosis. Par-
allel research has focused on other biological carriers such as mono-
clonal antibodies and certain glycoproteins that can recognize specific
determinants at their target cells. While these approaches are still
at their early stages of development and their role in controlled
drug delivery is therefore still uncertain, it is clear that the area
of controlled drug delivery is increasingly being based on molecular
biology.
The area of controlled drug delivery is also becoming broader
in scope in terms of routes of administration. Traditionally, con-
trolled drug delivery systems were developed primarily for the oral
route and, to some extent, for the parenteral route. Recently,
there has been an explosion in research on drug delivery via the
skin, due primarily to the success of several transdermal devices in
sustaining drug delivery to the systemic circulation. Meanwhile, a
better understanding of the potential therapeutic role of biologically
active peptides and of their susceptibility to inactivation in the gas-
trointestinal tract has stimulated research in delivering these substan-
ces systemically via the nasal, buccal, rectal, and vaginal routes, the
so-called unconventional routes. In the short term, there will be
a need to fabricate systems perhaps more sophisticated than those
now available to deliver peptides via these routes as well as paren-
teral routes. In the long term, it will be necessary to understand
the biochemistry and cell biology of these uncoventional routes, since
these may affect drug delivery system design. At the same time,
there will be a need to seek means to deliver these peptides orally.
This would require an enormous leap in our understanding of gross
physiology and cellular physiology, as well as of immunology of the
digestive system. Research has already begun in this area as exem-
plified by the bioadhesion approach, whose initial aim is to prolong
the residence time of drugs in the gastrointestinal tract.
With this background in mind, we have organized the book into
three parts. Part I deals with the fundamentals of controlled drug
delivery. These include biological considerations of selected routes
of drug administration (Chapter 1), theory of mass transfer (Chap-
ter 2), fundamentals of polymer science (Chapter 3), use of polymers
in controlled drug release (Chapter 4), pharmacokinetic/pharmacody-
namic basis of controlled drug delivery (Chapter 5), bioavailability
vi I Preface to the Second Edition

assessment and dosing considerations of controlled drug delivery

systems (Chapter 6), and regulatory assessment of such systems
(Chapter 7). Part II deals with the design and fabrication of tech-
nology-based controlled release drug delivery systems. These in-
clude novel chemical approaches (Chapter 8), oral products (Chapter
9), parenteral products (Chapter 10), implantable systems (Chapter
11), and transdermal systems (Chapter 12). Finally, Part III deals
with several biochemical and molecular biology approaches to con-
trolled drug delivery. These include microparticulate drug carriers
(Chapter 13), selective endocytosis of macromolecular drug carriers
(Chapter 14), and antibodies (Chapter 15).
With the possible exception of Chapters 6, 9, 10, and 11, this
edition of the text is not a mere updating of the first edition. Rath-
er, it is a companion to the first edition. It is the work of an inter-
disciplinary panel of scientists, reflecting the nature of controlled
drug delivery research today and certainly in the foreseeable future.
In reviewing the manuscripts, we recognized some overlaps among a
few chapters but chose to retain these overlaps since they were
viewed from a subtly different perspective by the respective authors.
Thus, we consider these overlaps a strength rather than a weakness
of this book.
As stated in the preface of the first edition, this book will ful-
fill our expectations if it creates further interest in the area of con-
trolled as well as targeted drug delivery, provides a framework by
which the pharmaceutical scientists can begin assessing the candidacy
of a specific drug for controlled and targeted release, and serves as
a plan of attack in formulating an appropriate drug delivery system.

Joseph R. Robinson
Vincent H. L. Lee
 Preface to the First Edition

Great strides have been made in the management of diseases through

the intervention of drugs over the past 50 years, as judged by the
introduction and success of immunizing agents, antibiotics, steroids,
tranquilizers, and many other drugs. These accomplishments in drug
development have not been matched by a similar growth in the area
of drug delivery. Clearly, unless a drug can be delivered to its
target area at a rate and concentration that both minimize side effects
and maximize therapeutic effects, the drug will not be maximally
beneficial to the patient and, in the extreme, an otherwise useful
drug may be discarded.
For accessible target tissues it is possible to directly titrate the
patient on the basis of biological response, and temporal administra-
tion of drug in these situations is straightforward. However, the
reality of the situation is that the desired target tissue, when identi-
fied, is usually well removed from the site of administration so that
drug placement becomes difficult, especially when control over the
time course of therapy is desired. Adding to the complexity of drug
localization at the target tissue is the problem of drug behavior in
the dosage form and body proper, as well as reliance on the patient
to administer drug in the correct amount at the right time.
Over the years there has been available a variety of drug modi-
fications and dosage forms with which we have attempted to control

VII
viii / Preface to the First Edition

the time course and specificity of drugs in the body; these have been
identified by various names, such as "prodrug," "controlled release,"
"sustained release," "prolonged release," and "timed release." In each
of these types of drug delivery there has been some degree of con-
trol over the temporal pattern of drug placement in the target tissue.
However, a maximization of therapy has generally not been achieved.
To maximize drug utilization, it is necessary to deliver drug to the
target tissue in the correct amount at the proper time to elicit the
desired response. Moreover, drug delivery must be continued at a
rate such that the condition in question is cured or controlled in a
minimum time with the fewest side effects. Thus, an appropriate
definition of controlled drug release is as follows: It is the phasing
of drug administration to the needs of the condition at hand so that
an optimal amount of drug is used to cure or control the condition
in a minimum time. In some situations this might mean that drug is
delivered more promptly for short periods of time and in other cases
it would mean prolongation of drug levels. In the latter category
we employ the terms "sustained release" and "prolonged release"
interchangeably; this designates only one aspect of controlled release,
namely, to produce protracted levels of drug in the body. Actually,
controlled drug delivery is the desired effect of all drug delivery
systems, and all presently fabricated sustained and prolonged drug
delivery systems provide some degree of control, albeit incomplete.
Thus, whereas second-generation sustained release products have
made significant advances over their first-generation counterparts,
none of the commercially available systems presently on the market
is in truth a controlled drug delivery system; some are just better
than others.
The present text was designed to fulfill a perceived need to pro-
vide a comprehensive picture of the sustained release drug product
area. Admittedly, there are numerous review articles, chapters, and
a few texts devoted to one or more topics in the sustained release
drug or chemical area, but a current and comprehensive treatment
appears to be lacking.
To accomplish this task, I have organized the book in the follow-
ing manner. The principal chapters describing the various physical,
chemical, and bioengineering approaches to the preparation of sus-
tained release drug products are Chapters 3, 4, 6, and 7. The
various physiological, drug-related, and formulation constraints on
the design of these products are described in Chapters 1 and 2,
the early part of Chapter 3, and Chapter 5. Chapters 1, 2, and
3 focus primarily on the physiological and drug-related constraints,
and Chapter 5 deals with parenteral drug and formulation biocom-
patibility considerations. Thus, the first seven chapters provide a
description of the problems and potential approaches of sustained
release drug product preparation. I have elected to place those
 Preface to the First Edition I ix

chapters with modest amounts of mathematics at the end of the text.

Thus, Chapter 8 deals with pharmacokinetic considerations in the
design of sustained release drug products, and Chapter 9 describes
the very important area of dosing considerations.
The text will fulfill my expectations if it creates interest in the
area of controlled drug delivery, provides a framework by means of
which the pharmaceutical scientist can begin to assess a specific drug
as to its candidacy for a sustained release system, and serves as a
plan of attack in formulating an appropriate drug delivery system.
Thus, the book is aimed at those interested in understanding the
principles of sustained and controlled drug delivery systems.

Joseph R. Robinson
 Contents

Preface to the Second Edition

Preface to the First Edition
Contributors

Part I
FUNDAMENTALS OF C O N T R O L L E D RELEASE
DRUG DELIVERY

1. Influence of Drug Properties and Routes of D r u g

Administration on the Design of Sustained and
Controlled Release Systems

Vincent H. K. Li, Vincent H. L. Lee, and

Joseph R. Robinson

I. Introduction
II. Terminology
III. Rationale of .Sustained/Controlled D r u g Delivery
IV. Factors Influencing the Design and Performance
of Sustained/Controlled Release P r o d u c t s
xii I Contents

V. Physicochemical P r o p e r t i e s of a D r u g Influencing
Design and Performance 12
VI. Biological Factors Influencing Design and
Performance of S u s t a i n e d / C o n t r o l l e d Release
Products 15
VII. Selected Routes of D r u g Administration 36
VIII. Drug Targeting 56
IX. Conclusions 59
References 61

2. Theory of Mass T r a n s f e r 95

Ronald R. Burnette

I. Introduction 96
II. Random Walk I n t e r p r e t a t i o n of Diffusion 96
III. Fick's First and Second Law 97
IV. Passive Diffusion T h r o u g h a Membrane—The
Partition Coefficient 113
V. Passive Diffusion T h r o u g h a Membrane—The
Stagnant Diffusion Layer 119
VI. Application of Fick's Second Law to t h e
Determination of t h e N o n - S t e a d y - S t a t e
Output Flux T h r o u g h the Skin 127
VII. Application of Fick's First Law to the
Determination of D r u g Release from a
Polymeric Matrix or Ointment 130
VIII. Diffusion with Simultaneous Reaction 135
IX. Additional Concerns in Diffusional Mass
Transport 135
References 136

3. Fundamentals of Polymer Science 139

Jorge Heller

I. Introduction 140
II. Polymer Classification and Polymerization
Mechanisms 141
III. Polymerization Methods 152
IV. Polymer Fabrication 156
V. Polymer P r o p e r t i e s 164
VI. Polymer Characterization 169
 Contents I xiii

4. Use of Polymers in Controlled Release of Active

Agents 179

Jorge Heller

I. Diffusion-Controlled Devices 180

II. Solvent-Controlled Devices 187
III. Chemically Controlled Devices 191
References 210

5. Pharmacokinetic/Pharmacodynamic Basis of Controlled

D r u g Delivery 213

B . Michael Silber, Meir Bialer, and Avraham Yacobi

I. Introduction 213
II. Review of General Principles 219
III. Summary 240
References 241

6. Dosing Considerations and Bioavailability Assessment

of Controlled D r u g Delivery Systems 253

Peter G. Welling and Michael R. Dobrinska

I. Introduction 254
II. A d v a n t a g e s of Controlled Release Dosage Forms 255
III. Disadvantages of Controlled Release Dosage
Forms 257
IV. Compounds That Are Unsuitable for Controlled
Release 259
V. In Vitro Considerations 262
VI. In Vivo Considerations 263
VII. Bioavailability T e s t i n g 284
VIII. Conclusions 288
References 289

7. Regulatory Assessment 293

Jerome Philip Skelly and William H. Barr

I. Introduction 294
II. Terminology 294
III. Rationale for Controlled Release Dosage Forms 296
xiv I Contents

IV. Potential Pharmacodynamic Problems with

Continuous Release P r o d u c t s 298
V. Ideal I n p u t Function 299
VI. Potential Bioavailability Problems of Oral
Controlled Release P r o d u c t s 304
VII. Dissolution Rate Assessment 309
VIII. Biopharmaceutic Considerations in t h e
Regulatory Assessment of Controlled
Release P r o d u c t s 321
References 332

Part II
DESIGN AND F A B R I C A T I O N OF TECHNOLOGY BASED
C O N T R O L L E D RELEASE DRUG DELIVERY SYSTEMS

8. Novel Chemical Approaches for Sustained D r u g

Delivery 337

Nicholas Bodor and Thorsteinn Loftsson

I. Introduction 337
II. Prodrugs 339
III. Classical P r o d r u g s as Chemical Delivery
Systems 340
IV. Sustained Chemical Delivery Systems 342
V. Sustained Delivery of Natural Soft Drugs 343
VI. Brain-Specific Sustained Chemical Delivery
Systems 357
VII. Conclusions 368
References 369

9. Design and Fabrication of Oral Controlled Release

D r u g Delivery Systems 373

Ho-Wah Hui, Vincent H. L. Lee, and Joseph R.

Robinson

I. Introduction 373
II. Design and Fabrication of Oral Systems 375
III. Summary 420
References 421
 Contents I xv

10. Parenteral Products 433

Sau-Hung Spence Leung, Vincent H. L. Lee, and

Joseph R. Robinson

I. Introduction 434
II. Major Routes of P a r e n t e r a l Administration 435
III. Biopharmaceutics of Sustained /Controlled
Release P a r e n t e r a l D r u g P r o d u c t s 437
IV. Biocompatibility of Polymeric Material 440
V. S u s t a i n e d / C o n t r o l l e d P a r e n t e r a l Dosage Forms 442
VI. Summary 464
References 465

11. Implantable Therapeutic Systems 481

Yie W. Chien

I. Introduction 482
II. Historical Development 482
III. Approaches to Development of Implantable
T h e r a p e u t i c Systems 484
IV. Benefits of Controlled D r u g Administration
Via Implantation 509
V. Medical Aspects of Implantation 512
References 516

12. Transdermal Therapeutic Systems 523

Yie W. Chien

I. Introduction 524
II. Skin as a Site for D r u g Infusion 524
III. Fundamentals of Skin Permeation 528
IV. Approaches to Development of T r a n s d e r m a l
T h e r a p e u t i c Systems 532
V. Kinetic Evaluation of T r a n s d e r m a l T h e r a p e u t i c
Systems 538
VI. Formulation Design and Optimization 547
References 549
xv i I Contents

Part I I I
B I O C H E M I C A L AND MOLECULAR BIOLOGY APPROACHES
TO C O N T R O L L E D DRUG DELIVERY

13. Microparticulate D r u g C a r r i e r s : Liposomes,

Microspheres, and Cells 555

Rudy L. Juliano

I. Introduction 556
II. P r e p a r a t i o n of D r u g Containing Microparticulates 557
III. In Vivo B a r r i e r s to Microparticulate Distribution 561
IV. Selected Examples of D r u g Delivery with
Microparticulate C a r r i e r s 566
V. Summary 571
References 572

14. Selective Endocytosis of Macromolecular D r u g C a r r i e r s 581

Ruth Duncan

I. Introduction 582
II. Mechanisms for Achieving Selective C a p t u r e 596
III. Use of Selective Endocytosis for D r u g
Targeting 604
IV. Conclusions 606
References 607

15. Antibodies for Drug Delivery 623

Karl Erik Hellstrom, Ingegerd Hellstrom, and

Gary E. Goodman

I. Introduction 624
II. Tumor Antigens Defined by Monoclonal
Antibodies 624
III. D r u g - A n t i b o d y Conjugates 633
IV. Conclusions 641
References 642

Author Index 655

Subject Index 703
 Contributors

William H. Barr, P h a r m . D . , P h . D . Department of Pharmacy and

P h a r m a c e u t i c s , Virginia Commonwealth University/Medical College of
Virginia, Richmond, Virginia

Meir Bialer, P h . D . * Pharmacodynamics D e p a r t m e n t , Medical R e s e a r c h

Division, American Cyanamid C o r p o r a t i o n , Pearl R i v e r , New York

Nicholas Bodor, P h . D . Department of Medicinal C h e m i s t r y , College

of Pharmacy, University of Florida, Gainesville, Florida

Ronald R. B u r n e t t e , P h . D . , P h a r m . D . , M . S . School of P h a r m a c y ,
University of Wisconsin, Madison, Wisconsin

Yie W. Chien, P h . D . Controlled D r u g Delivery Research C e n t e r ,

College of P h a r m a c y , R u t g e r s — T h e State University of New J e r s e y ,
Piscataway, New J e r s e y

Michael R. D o b r i n s k a , P h . D . Department of D r u g Metabolism, Merck

Sharp & Dohme Research L a b o r a t o r i e s , West Point, Pennsylvania

^Current affiliation: Department of P h a r m a c y , School of Pharmacy,

The Hebrew University of J e r u s a l e m , J e r u s a l e m , Israel

xvh
xviii I Contributors

Ruth Duncan, B . S c , P h . D . Department of Biological Sciences,

University of Keele, Keele, S t a f f o r d s h i r e , England

Gary E. Goodman, M . S . , M.D. Tumor I n s t i t u t e , Swedish Hospital

Medical C e n t e r , Seattle, Washington

J o r g e Heller, P h . D . Polymer Sciences D e p a r t m e n t , SRI I n t e r n a t i o n a l ,

Menlo P a r k , California

I n g e g e r d Hellstrom, M.D. ONCOGEN, S e a t t l e , Washington

Karl Erik Hellstrom, M.D. ONCOGEN, Seattle, Washington

Ho-Wah Hui, P h . D . * School of Pharmacy, University of Wis-

c o n s i n , Madison, Wisconsin

Rudy L. J u l i a n o , P h . D . Department of Pharmacology, University of

Texas Medical School, Houston, Texas

Vincent H. L. Lee, P h . D . Department of P h a r m a c e u t i c s , School of

P h a r m a c y , University of Southern California, Los A n g e l e s , California

S a u - H u n g S. L e u n g , M . S . School of Pharmacy, University of Wis-

consin , Madison, Wisconsin

Vincent H. K. Li, M . S . School of P h a r m a c y , U n i v e r s i t y of Wisconsin,

Madison, Wisconsin

T h o r s t e i n n Loftsson, M . S . , P h . D . t Department of Medicinal Chemis-

t r y , College of P h a r m a c y , U n i v e r s i t y of Florida, Gainesville, Florida

J o s e p h R. Robinson, P h . D . School of Pharmacy, University of Wis-

c o n s i n , Madison, Wisconsin

B . Michael Silber, P h . D . Pharmacodynamics D e p a r t m e n t , Medical

Research Division, American Cyanamid Company, Pearl R i v e r , New York

^Current affiliation: Pharmaceutical P r o d u c t s Division, Abbott L a b -

oratories, North Chicago, Illinois
tCurrent affiliation: Department of Pharmacy, University of Iceland,
Rekjavik, Iceland
 Con trib u tors I x ix

Jerome Philip Skelly, P h . D . Division of Biopharmaceutics, C e n t e r

for D r u g s and Biologies, Food and D r u g Administration, Rockville,
Maryland

Peter G. Welling, P h . D . , D . S c . Department of Pharmacokinetics and

D r u g Metabolism, W a r n e r - L a m b e r t / P a r k e - D a v i s Pharmaceutical R e s e a r c h
Division, Ann A r b o r , Michigan

Avraham Yacobi, P h . D . Pharmacodynamics D e p a r t m e n t , Medical Re-

s e a r c h Division, American Cyanamid Company, Pearl R i v e r , New York
Controlled Drug Delivery
I
Fundamentals of Controlled Release
Drug Delivery
1
Influence of Drug Properties and Routes of Drug
Administration on the Design of Sustained and
Controlled Release Systems
VINCENT H. K. LI and JOSEPH R. ROBINSON / University of Wis-
c o n s i n , Madison, Wisconsin

VINCENT H. L. LEE / University of S o u t h e r n California, Los

A n g e l e s , California

I. Introduction 4
II. Terminology 5
III. Rationale of S u s t a i n e d / C o n t r o l l e d D r u g Delivery 7
IV. F a c t o r s Influencing t h e Design and Performance of
S u s t a i n e d / C o n t r o l l e d Release P r o d u c t s 9
V. Physicochemical P r o p e r t i e s of a D r u g Influencing
Design and Performance 12
A. Aqueous Solubility 13
B. Partition Coefficient and Molecular Size 14
C. D r u g Stability 14
D. Protein B i n d i n g 15
VI. Biological Factors Influencing Design and Performance
of S u s t a i n e d / C o n t r o l l e d Release P r o d u c t s 15
A. Absorption 16
B. Distribution 18
C. Metabolism 23
D. Duration of Action 26
E. Side Effects 30
F. Margin of Safety 31

3
4 / Li et al.

G. Role of Disease State 33

H. Role of Circadian Rhythm 35
V I I . Selected R o u t e s of D r u g Administration 36
A. Parenteral 37
B . Oral 40
C. B uccal /Sublingual 42
D . Rectal 43
E. Nasal 44
F . Pulmonary 45
G. Vaginal 49
H. I n t r a u t e r i n e 51
I. Transdermal 53
J . Ocular 55
VIII. D r u g Targeting 56
I X . Conclusions 59
References 61

I. INTRODUCTION

In recent years, considerable attention has been focused on the

development of new drug delivery systems. This is evidenced by
the spate of books [1-8] and review articles [9-18] published on
this subject. There are a number of reasons for the intense interest
in new systems. First, recognition of the possibility of repatenting
successful drugs by applying the concepts and techniques of con-
trolled release drug delivery systems, coupled with the increasing
expense in bringing new drug entities to market, has encouraged
the development of new drug delivery systems. Second, new systems
are needed to deliver the novel, genetically engineered pharmaceuti-
cals, i . e . , peptides and proteins, to their sites of action without in-
curring significant immunogenicity or biological inactivation. Third,
treating enzyme deficient diseases and cancer therapies can be im-
proved by better targeting. Finally, therapeutic efficacy and safety
of drugs, administered by conventional methods, can be improved by
more precise spatial and temporal placement within the body, thereby
reducing both the size and number of doses.
If one were to conceptualize the ideal drug delivery system, two
prerequisites would come to mind. First, it should deliver drug at
a rate dictated by the needs of the body over the period of treat-
ment. This may necessitate delivery at a constant rate for drugs
that have a clear relationship between steady state plasma levels and
the resultant therapeutic response, or at a variable rate for drugs
 Influence of Drug Properties on Design I 5

which need either a series of peaks and valleys or act on a rhythmn.

Second, it should channel the active entity solely to the site of action.
This may necessitate delivery to specific receptors, as in the case of
Hi and H2 antagonists, localization to tumor cells, as required by
most cancer treatments, or to specific areas of the body as for ar-
thritis or gout. At present, no available drug delivery systems can
achieve all these lofty goals. Conventional dosage forms, including
prolonged-release dosage forms, are unable to control either the rate
or site of action. While rate-controlled release drug delivery systems
are capable of delivering a drug at some predetermined rate either
systemically or locally for a specific period of time, they do so with
virtually no control over the fate of the drug once it enters the body.
Targeted drug delivery systems, on the other hand, while capable
of achieving site specific delivery, are usually unable to control the
release kinetics of drug in a predictable manner. To date, their
usefulness is limited to systemic administration.
This chapter will describe those factors influencing the design
of sustained/controlled drug delivery systems with particular empha-
sis on limitations imposed by the intrinsic physicochemical and biologi-
cal properties of a drug candidate and by the route of administration.

II. TERMINOLOGY

Before initiating a discussion of sustained and controlled release

dosage forms, it is necessary to provide a short explanation of termi-
nology used because there is considerable confusion in this area.
The general consensus is that controlled release denotes systems
which can provide some control, whether this be of a temporal or
spatial nature, or both, of drug release in the body. In other words,
the system attempts to control drug concentrations in the target tis-
sue or cells. Thus, prolonged release or sustained release systems,
which only prolong therapeutic blood or tissue levels of the drug for
an extended period of time, cannot be considered as controlled r e -
lease systems by this definition. They are distinguished from rate-
controlled drug delivery systems, which are able to specify the re-
lease rate and duration in vivo precisely, on the basis of simple in
vitro tests [15]. Drug targeting, on the other hand, can be con-
sidered as a form of controlled release in that it exercises spatial
control of drug release within the body. Since rate-controlled r e -
lease and drug targeting represent totally separate delivery ap-
proaches, they will be discussed separately in this chapter.
In general, controlled delivery attempts to:

1. Sustain drug action at a predetermined rate by maintaining

a relatively constant, effective drug level in the body with
6 I Li et a/.

concomitant minimization of undesirable side effects associated

with a sawtooth kinetic pattern
2. Localize drug action by spatial placement of a controlled
release system (usually rate-controlled) adjacent to or in the
diseased tissue or organ
3. Target drug action by using carriers or chemical derivatiza-
tion to deliver drugs to a particular "target" cell type

In practice, very few of the applied systems embrace all of these

actions. In most cases, the release system creates constant concen-
tration of drug within the body over an extended period of time.
The assumption is that there is a steady state drug levels in plasma
and in target tissues or cells are correlated. Ideally, it is desirable
to place the drug at the target, be it a tissue, a population of cells,
or receptors, leaving the rest of the body drug free. Obviously,
this would be quite difficult, especially if the target is sheltered
from systemic circulation by various barriers. For example, drug
targeting to the brain via systemic administration is severely limited
by selectivity of the blood-brain barrier.
In order to maintain a constant drug level in either plasma or
target tissue, release rate from the controlled release system should
be equal to the elimination rate from plasma or target tissue. The
most conventional method to achieve a constant plasma level is the
use of intravenuous infusion. However, this would be inconvenient
for most therapeutic situations so that other noninvasive routes, such
as the oral or transdermal route, are preferred.
Various designations such as "smart" [19], "targeted" [20],
"intelligent" [15], "novel" [6], and "therapeutic" [21], have been
given to controlled release systems. Therapeutic systems have also
been used interchangeably with rate-controlled release systems.
These usually operate on an advanced engineering system-control
approach, consisting of a logic element with or without a sensor.
Three types of therapeutic systems are available, namely, passive
preprogrammed, active preprogrammed, and active self-programmed
[22] . Most rate-controlled release systems fall in the category of
passive preprogrammed, in which the release rate is predetermined
and is irresponsive to the external biological environment. Examples
of active preprogrammed are few and include most metered insulin
pumps, whose release rate can be altered by a source external to
the body [23]. The active, self-programmed therapeutic systems
modulate release rate of the drug in response to information, regis-
tered by a sensor, on the changing biological environment such as
blood sugar level in diabetes [24] . In our view, the term therapeutic
system, while helpful for marketing purposes, is inappropriate as a
substitute for controlled release systems since non-controlled release
systems are therapeutic systems also.
 Influence of Drug Properties on Design I 7

ZERO-ORDER CONTROLLED RELEASE

.SUSTAINED RELEASE

TIME

Fig. 1 Plasma drug concentration-profiles for conventional tablet

or capsule formulation, a sustained release formulation, and a zero-
order controlled release formulation.

Figure 1 shows comparative blood drug level profiles obtained

from administration of conventional, controlled as well as prolonged
release dosage forms. Thus, the conventional tablet or capsule pro-
vides only a single and transient burst of d r u g . As long as the
amount of drug is above the minimum effective concentration, a phar-
macological response is observed. Problems occur when the therapeu-
tic range is very narrow or when the peak is greater than the upper
limit of this range. Indeed, one of the main purposes of controlled
release is to improve safety and minimize side effects of the drug by
reducing fluctuations in drug level. Prolonged-release dosage forms
also reduce fluctuations in plasma drug levels by slowing down the
absorption rate due to slower drug release rate. In many cases,
this is achieved by intermittently releasing a small burst of drug
over a prolonged period of time as in the case of repeat-action dos-
age forms.

III. R A T I O N A L E OF S U S T A I N E D / C O N T R O L L E D
DRUG DELIVERY

The basic rationale for controlled drug delivery is to alter the phar-
macokinetics and pharmacodynamics of pharmacologically active moieties
by using novel drug delivery systems or by modifying the molecular
structure and/or physiological parameters inherent in a selected route
of administration. It is desirable that the duration of drug action
become more a design property of a rate-controlled dosage form, and
less, or not at all, a property of the drug molecule's inherent kinetic
properties. Thus, optimal design of controlled release systems
8 I Li et al.

necessitates a thorough understanding of the pharmacokinetics and

pharmacodynamics of the drug.
As mentioned earlier, the primary objectives of controlled drug
delivery are to ensure safety and to improve efficacy of drugs as well
as patient compliance. This is achieved by better control of plasma
drug levels and less frequent dosing. For conventional dosage forms,
only the dose (D) and dosing interval ( T ) can vary and, for each
drug, there exists a therapeutic window of plasma concentration, be-
low which, therapeutic effect is insufficient, and above which unde-
sirable or toxic side effects are elicited. As an index of this window,
the therapeutic index TI can be used. This is often defined as the
ratio of median lethal dose (LD50) to median effective dose (ED50).
Alternatively, it can be defined as the ratio of maximum drug concen-
tration (C* m a x ) in blood that can be tolerated to the minimum concen-
tration (C* m i n ) needed to produce an acceptable therapeutic response.
Table 1 lists the therapeutic indices of a variety of drugs in plasma
in humans.
For drugs whose disposition show pronounced linear, one-compart-
ment characteristics, Theeuwes and Bayne [25] have demonstrated the
following relationship between dosing interval (x) and therapeutic
index (TI). Thus,

T < t 1 / 2 ( l n TI)/ln 2 (1)

where t^/2 is the half-life. Since the therapeutic index for most
drugs is around 2, it will be necessary to dose the patients at inter-
vals shorter than the half-life. Such inconvenient regimens often
result in reduced compliance and inadequate treatment. For drugs
with pronounced multicomp art mental characteristics, a better estimate
of the dosing interval may be obtained by replacing t i / 2 with 0.693*
(MRT), where MRT is the mean residence time. In such cases, the
drug must be given even more frequently than suggested by Eq. (1).
In general, the dosing interval may be increased either by modi-
fying the drug molecule to decrease the rate of elimination (k e j) or
by modifying the release rate of a dosage form to decrease the rate
of absorption ( k a ) . Both approaches seek to decrease fluctuations
in plasma levels during multiple dosing, allowing the dosing interval
to increase without either overdosing or underdosing. When attempt-
ing to extend the dosing interval by decreasing the rate of absorp-
tion, the formulator will be confronted with the physiological con-
straint of a finite residence time at the absorption site. For example,
an effective absorption time for orally administered drugs is about
9-12 h r . If the rate of absorption decreases too much, some of the
unabsorbed drug will pass into the large intestine, where absorption
is slower and more variable and where bacterial degradation of the
drug may occur. Thus, drugs with half-lives of 6 hr or less and
 Influence of Drug Properties on Design I 9

Table 1. Usual Ranges of Therapeutic Serum Concentrations and

Terminal Half-Lives in Humans

Therapeutic serum
Drug concentrations a Terminal
substance (C* . to C* ) half-lives 0
min max
Digit oxin 14-30 yg/liter 6.3-11.3 days
Digoxin 0.9-2 yg/liter 1.4-2.2 days
Lidocaine 1.5-5 mg/liter 1.2-1.7 hr
Lithium 0.5-1.3 mEq 14.2-24.1 hr
Nortriptyline 50-140 yg/liter 18.2-35.0 hr
Phenytoin 10-20 mg/liter 18.7-27.6 hr
Procainamide 4-8 mg/liter 2.5-4.7 hr
Propranolol 20-50 yg/liter 1.1-9.9 hr
Quinidine 2-5 mg/liter 3.0-16.0 h r
Salicylates 150-300 mg/liter 2.9-22 hr
Theophylline 10-20 mg/liter 5.3-8.3 h r

"Data were obtained from Koch-Weser [26] .

Data were obtained from Pagliaro and Benet [27] ,

possessing therapeutic indices less than 3 must be given no less

frequently than every 12 hr [28]. Unless gastrointestinal transit
time can be lengthened, once-daily oral dosing may prove to be dif-
ficult to achieve for drugs with such extremely short half-lives [28] .
For other routes of administration, where residence time is less of a
problem, dosing intervals can be lengthened to months or even years.
For example, implants containing contraceptives may be effective for
a year or two.
In summary, only when the rate-limiting step resides in the drug
delivery system, and not in physiological constraints, can control
over drug administration be achieved.

IV. FACTORS INFLUENCING T H E DESIGN A N D PERFORMANCE

OF S U S T A I N E D / C O N T R O L L E D RELEASE PRODUCTS

To establish criteria for the design of controlled release products,

a number of variables must be considered.
10 I Li et al.

1. Drug properties: The physiochemical properties of a drug,

including stability, solubility, partitioning characteristics,
charge, and protein binding propensity, play a dominant
role in the design and performance of controlled release
systems.
2. Route of drug delivery: The area of the body in which drugs
will be applied or administered can be restrictive on the basis
of technological achievement of a suitable controlled release
mechanism or device. At times, the drug delivery system, in
certain routes of administration, can exert a negative influ-
ence on drug efficacy, particularly during chronic adminis-
tration, and hence other routes of administration should be
considered. Performance of the controlled release systems
may also be influenced by physiological constraints imposed
by the particular route, such as first-pass metabolism, GI
motility, blood supply, and sequestration of small foreign
particles by the liver and spleen.
3. Target sites: In order to minimize unwanted side effects, it
is desirable to maximize the fraction of applied dose reaching
the target organ or tissue. This can be partially achieved
by local administration or by the use of carriers. However,
the absorptive surfaces of most routes are impermeable to
macromolecules or other targeted delivery systems, thereby
necessitating either intravascular or intraarterial administration.
4. Acute or chronic therapy: Consideration of whether one ex-
pects to achieve cure or control of a condition and the ex-
pected length of drug therapy are important factors in de-
signing controlled release systems. Attempts to generate a
one year contraceptive implant presents significantly differ-
ent problems in design than does an antibiotic for acute in-
fection. Moreover, long term toxicity of rate-controlled drug
delivery systems is usually different from that of conventional
dosage forms [29].
5. The disease: Pathological changes during the course of a
disease can play a significant role in the design of a suitable
drug delivery system. For example, in attempting to design
an ocular controlled-release product for an external inflamma-
tion, the time course of changes in protein content in ocular
fluids and in the integrity of the ocular barriers would have
to taken into consideration. Sometimes, one can take advan-
tage of the unique manifestations of the disease state. For
example, the higher plasminogen activator levels in some tumor
cells can lead to preferential bioconversion of peptidyl pro-
drugs in these cells [30-32]. Similarly, the higher tyrosin-
ase level in melanoma cells has been demonstrated to allow
targeting to and preferential bioconversion of 2, 4-dihydrox-
phenylalanine in them [33].
 Influence of Drug Properties on Design I 11

6. The patient: Whether the patient is ambulatory or bedridden,

young or old, obese or gaunt, e t c . , can influence the design
of a controlled release product. An implant or intramuscular
injection of a drug to a bedridden patient with little muscle
movement may perform in a manner significantly different from
that of an ambulatory patient. Some of these factors repre-
sent individual patient variation and cannot be controlled by
the research scientist while others must be considered. For
example, single unit controlled release products are particu-
larly prone to intra- and inter-subject variation because of
variabilities in individual GI motility [34] .

While all of these variables are important in the design of con-

trolled and targeted release delivery systems, our discussion will
center on drug properties and routes of administration as they relate
to controlled release drug delivery in general. In particular, this
chapter is concerned with increasing the visibility of some of the
detrimental or prohibitive factors in the design of controlled release
system. The release mechanism and the applicability of the various
approaches (physical, chemical, and biological) used in the design of
individual controlled release system will be discussed in Chapters
8-15.
To establish a basis for discussion of the influence of drug prop-
erties and the route of administration on sustained/controlled release
product design, it is worthwhile focusing on:

1. Behavior of the drug in its delivery system

2. Behavior of the drug and its delivery system in the body

The first of these two elements is concerned with the ways in

which drug properties can influence release characteristics from its
delivery system. For conventional drug delivery systems, the rate-
limiting step in drug availability is usually absorption of drug across
a biological membrane such as the gastrointestinal wall (Scheme 1). In
a sustained/controlled release product, one aims for release of drug

Drug release Absorption

(Dru (Drug) (Dr
^ D o s a f f e form ~ ~ S o l u t i o n at ~ * V g ) Target area
absorption
site Elimination

Scheme 1

from the dosage form as the rate-limiting step instead. Thus, drug
availability is controlled by the kinetics of drug release rather than
12 I Li et al.

absorption. Consequently, the associated rate constant(s) for drug

release from the dosage form are smaller than the absorption rate
constant and kinetically the process appears as shown in Scheme 2.

Drug release
(Drug)^ „ • (Drug)™ . *- Elimination
to &
Dosage form Target area
Scheme 2

To control drug release one can employ a variety of approaches, such

as dissolution, diffusion, swelling, osmotic pressure, complexation,
ion-exchange, and magnetic field, each of these will be amplified on
in subsequent chapters. The interplay between physiochemical prop-
erties of a drug and characteristics of its delivery system determines
the temporal release pattern that is observed.
The second element, behavior of the drug and its delivery system
in the body, is extremely complex, involving the fate of drug during
transit to the target area as well as its fate while in the biophase.
Availability of drug to its target will depend on its pharmacokinetics
as well as that of its carrier. In the case of drug targeting, the
carrier is used to alter the pharmacokinetics of drug in the body.
The influence of physiological constraints on the fate of the delivery
system in the body is usually negative, for example, oral absorption
is usually limited by GI transit time of the delivery system.
From the previous discussion, it is clear that the formulation and
performance of sustained/controlled release dosage forms have roots
in the physicochemical properties of the drug and its carrier. The
pharmacokinetics and pharmacodynamics, to a large extent, are de-
rived functions of the intrinsic properties of the drug. Thus, devel-
opment and assessment of a sustained/controlled drug delivery system
requires a rather complete knowledge of the intrinsic properties of a
drug and the ways in which it can influence the design of sustained/
controlled release systems. Oftentimes, undesirable physiochemical
and biological properties can be altered by suitable chemical modifica-
tion, by use of a carrier, or perhaps can be altered by suitable
chemical modification, by use of a carrier, or perhaps by administra-
tion via another route. The first approach will be discussed in Chan-
ter 9, while the other two approaches will be briefly discussed in this
chapter and further amplified upon in subsequent chapters.

V. PHYSICOCHEMICAL PROPERTIES OF A DRUG INFLUENCING

DRUG PRODUCT DESIGN AND PERFORMANCE

The performance of a drug in its release pattern from the dosage

form as well as in the body proper is a function of its properties.
 Influence of Drug Properties on Design I 13

These properties can at times prohibit/restrict placement of the drug

in a sustained/controlled release form, restrict the route of drug ad-
ministration, and significantly modify performance for one reason or
another. Most of the time these properties are restrictive rather than
prohibitive, making sustained/controlled release product design more
difficult. For the purpose of this discussion, it is convenient to de-
scribe the properties of a drug as being either physiochemical or bio-
logical. Obviously, there is no clear distinction between these two
since the biological properties of a drug are a function of its physi-
cochemical properties. By our definition, physiochemical properties
are those that can be determined from in vitro experiments. Biologi-
cal properties will be those that result from typical pharmacokinetic
studies on the absorption, distribution, metabolism, and excretion
(ADME) characteristics of a drug as well as those resulting from
pharmacological studies.

A. Aqueous Solubility

Since drugs must be in solution before they can be absorbed, com-

pounds with very low aqueous solubility usually suffer oral bioavail-
ability problems because of limited gastrointestinal transit time of the
undissolved drug particles and limited solubility at the absorption
site. Unfortunately, for many compounds, the site of maximum ab-
sorption will also be the area in which the drug is least soluble. For
example, tetracycline dissolves to a greater extent in the stomach
than in the intestine, although it is best absorbed in the intestine
[35]. Such drugs may be poor candidates for sustained/controlled
release systems, unless the system is capable of retaining the drug
in the stomach and gradually releasing it to the small intestine or
unless the solubility is made higher and independent of the external
environment by encapsulating the drug with an acid (if the drug is
a weak base) or a base (if the drug is a weak acid) in a membrane
system. Examples of other drugs which are limited in absorption by
their dissolution rate are digoxin [36], warfarin [37], griseofulvin
[38] , and salicylamide [39] . Although the action of a drug can be
prolonged by making it less soluble, this may occur at the expense
of inconsistent and incomplete bioavailability.
The choice of mechanism for oral sustained/controlled release sys-
tems is limited by aqueous solubility of the drug. Diffusional systems
will be poor choices for slightly soluble drugs since the driving force
for diffusion, the concentration in aqueous solution, will be low. In
contrast, such drugs may be effectively incorporated in matrix systems.
In selecting polymer coatings for sustained/controlled systems,
the dissolution rate of a drug must be considered. Some antiobiotics
and high molecular weight drugs may have reasonably good to excel-
lent aqueous solubility, but very slow dissolution rates. On the
positive side, the slow dissolution rate of such compounds can be
74 / Li et al.

utilized to achieve sustained/controlled drug release by incorporation

in a matrix system. On the negative side, dissolution-limited bio-
availability may occur.
Aqueous solubility also limits the loading efficiency of drugs into
a variety of carriers such as liposomes, erythrocytes, and other mi-
croparticles. Most water-soluble drugs tend to leak out from such
carriers readily.

B. Partition Coefficient and Molecular Size

Partition coefficient and molecular size influence not only the permea-
tion of a drug across biological membranes, but also diffusion across
or through a rate-controlling membrane or matrix. Following admin-
istration, the drug must traverse a variety of membranes to gain
access to the target area. Drugs with extremely high partition coef-
ficient ( i . e . , very oil-soluble) readily penetrate the membranes but
are unable to proceed further, while drugs with excessive aqueous
solubility, i . e . , low oil/water partition coefficients cannot penetrate
the membranes. A balance in the partition coefficient is needed to
give an optimum flux for permeation through the biological and rate-
controlling membranes. Hansen and Dunn [40] as well as Fujita et
al. [41] have shown that, for many body tissues, such as the gas-
trointestinal tract, skin, and blood-aqueous barrier of the eye, the
optimum n-octanol/water partition coefficient at which maximum flux
occurs is approximately 1000.
The ability of a drug to diffuse through membranes, its so called
diffusivity, is related to its molecular size by the following equation:

Log D = -S v log V + k v = -s M log M + 1^

where D is diffusivity, M is molecular weight, V is molecular volume,

and s v , SJVI, k v , and k]yj are constants in a particular medium. In
general, the denser the medium, the smaller the diffusivity. For
drugs of intermediate molecular weight (150-400), diffusivities through
flexible polymers are typically of the order of 10"^ cm2 s e c - 1 .

C. D r u g Stability
The stability of a drug in the environment to which it is exposed is
another physicochemical factor to be considered in the design of sus-
tained/controlled release systems. Drugs that are unstable in the
stomach can be placed in a slowly soluble form or have their release
delayed until they reach the small intestine. However, such a strate-
gy would be detrimental for drugs that either are unstable in the
small intestine or undergo extensive gut-wall metabolism, as evidenced
 Influence of Drug Properties on Design I 15

by decreased bioavailability when these drugs are administered from

a sustained release dosage form [42,43]. To achieve better bioavail-
ability and controlled release of drugs that are unstable in the small
intestine, a different route of administration should be chosen. Con-
trolled release of nitroglycerin is a good example. On the positive
side, the presence of metabolizing enzymes at the site of administra-
tion or along the pathway to the target area can sometimes be utilized
in controlled drug delivery. Chapter 8 will describe some of these
approaches.

D. Protein Binding

It is well known that many drugs bind to plasma proteins with a con-
comitant influence on the duration of drug action [44-48]. Since
blood proteins are for the most part recirculated and not eliminated,
drug protein binding can serve as a depot for drug producing a pro-
longed release profile, especially if a high degree of drug-binding
occurs. This aspect of prolonged drug activity has been described
in the literature [49]. There are, however, other drug-protein in-
teractions that have a bearing on drug performance. Levine [50] has
shown that quaternary ammonium compounds bind to mucin in the GI
tract. Drugs bound to mucin may increase absorption, if the bound
drug act as a depot. However, if degradation and/or washing of the
drug further down the GI tract occurs, binding of drug to mucin may
result in a reduction of free drug available for absorption. The issue
of drug and vehicle interaction with the mucin layer and its influence
on extent and duration of drug absorption has been reviewed [51] .

VI. BIOLOGICAL FACTORS INFLUENCING DESIGN AND

PERFORMANCE OF S U S T A I N E D / C O N T R O L L E D
RELEASE PRODUCTS

The design of a sustained/controlled release product should be based

on a comprehensive picture of drug disposition. This would entail
a complete examination of the ADME characteristics of a drug follow-
ing multiple dosing. Unfortunately, an imcomplete picture of a drug's
disposition is usually the case and decisions are generally made on
this basis. The biological parameters that form the basis of controlled
release product design will be described in Chapters 5 and 6.
Every pharmacokinetic property and biological response parameter
has a useful range for the design of sustained/controlled release
products, outside of which sustained/controlled release product de-
sign becomes difficult or impossible. Presumably, with unlimited
technological capability and strategic placement of a drug in the
body, all of these limitations could be circumvented but this capability
16 I Li et al.

is usually not available and thus constraints are generally imposed.

In the following discussion, it is assumed that the level of drug in
blood or body tissue parallels biological activity of the drug.

A. Absorption

To maintain constant blood or tissue level of drug, it must be uni-

formly released from the controlled release system and then uniformly
absorbed. It would be desirable to have the released dose completely
absorbed as well but this is not a prohibitive consideration. Usually,
the rate-limiting step in drug delivery from a controlled release pro-
duct is release from the dosage form rather than absorption. Thus,
rapid drug absorption, relative to drug release from a dosage form,
is expected but this is not always the case. In addition, variation
in both the extent and rate of drug absorption can occur, particularly
with orally administered drugs.
The fraction of drug absorbed from a single noncontrolled dose
of drug can sometimes be quite low for a variety of reasons, such as
drug degradation due to solvolysis or metabolism, binding of drugs
to proteins, physical loss, or perhaps site- or dose-dependent absorp-
tion. Nevertheless, as long as the drug is uniformly absorbed, albeit
incomplete, a successful controlled release product can be generated.
As stated earlier it is preferable, but not essential, to have the drug
completely absorbed. The development of the controlled release ocu-
lar system, Ocusert^, is an excellent illustration of dealing with this
problem. Pilocarpine is usually absorbed across the cornea to the
extent of about 1% from an applied dose, the extensive loss due to
drainage and absorption into nontarget tissues [52,53]. However,
despite the low fraction of dose absorbed, a controlled release product
was prepared that in fact significantly improved the low bioavailability
problem and was able to maintain a constant level of drug in the tar-
get tissues for extended periods of time [54].
When considering orally administered drugs, significant loss prior
to appearance in the systemic circulation can occur through hydroly-
tic degradation in the contents of the GI tract [55], metabolism by
the intestinal flora [56] , and metabolism during its transit across the
GI wall [57] . Metabolism at the site of administration is a potential
problem for all routes of administration, as is hydrolytic degradation.
However, some routes, such as the GI tract, possess a relatively
rich supply of metabolizing enzymes whereas other, such as the pre-
corneal portion of the eye, have few. Hydrolytic and metabolic reac-
tions are usually first order in drug concentrations, but fortunately
degradation is primarily restricted to drugs in solution, and thus
drugs in the solid state or in solid dosage forms are protected from
degradation. Indeed, placement of a labile drug in a sustained or
controlled release drug delivery system can sometimes improve the
 Influence of Drug Properties on Design I 17

fraction of dose absorbed. The extent of this protection, hence im-

proved bioavailability, is at times difficult to predict a priori and
thus it is sometimes necessary to rely on empirical manipulations of
the release rate after obtaining blood or tissue drug levels with a
prototype controlled release system.
If the drug were erratically absorbed, as might occur in a route
of administration with variable absorptive surface, such as the GI
tract, design of a controlled release product would be more difficult
or prohibitive. With respect to the oral route, it is well known that
the absorptive character of the different segments of the GI tract
varies [58], which in turn can influence the amount and rate of ab-
sorption for certain drugs. The oral anticoagulant dicumarol [59],
the quaternary ammonium compounds hexamethonium and decamethonium
[60] , and the aminoglycosides such as gentamicin and kanamycin [61]
are examples of such drugs. Similarly, drugs absorbed by specialized
transport processes and drugs at special sites of the GI tract are
also poor candidates for controlled release products. Riboflavin is
absorbed by an active transport process, a process which is satur-
able [62] , and is preferentially absorbed in the upper part of the
GI tract [63]. Consequently, unless this drug can be localized at
the absorptive site one expects a gradation in absorption for this drug
but this is not necessarily prohibitive. Indeed, riboflavin has been
formulated in various sustained release multivitamin preparations.
However, Morrison et al. [63] found that such preparations provided
no demonstrable advantages over conventional preparations.
Iron is another drug which is not uniformly well absorbed along
the length of the GI tract. The greatest uptake of drug occurs at
the upper part of the duodenum with significantly reduced absorptive
capacity in the lower segment of the intestine [64-66] . Middleton
et al. [67] found that iron given in divided doses, a situation analo-
gous to a sustained release product, was only 68% as available as the
same amount of drug taken as a single dose. Sustained release iron
products have been evaluated by several investigators and the results
are equivocal. Crosland-Taylor et al. [68] found that absorption of
iron from sustained release tablets was extremely variable. Bothwell
et al. [69] reported that the amount of iron absorbed from Spansules1*
was a function of the rate at which drug was released; significant
reduction in the amount of iron absorbed occurred in the Spansules R
with slow release rates. On the other hand, Baird et al. [70] found
that iron formulated in a wax matrix sustained release product was as
well absorbed as conventional ferrous sulfate tablets. Indeed, Web-
ster [71], Callender [72], and Bent ley and Jacobs [73] detected no
significant differences in the elevation of hemoglobin levels in iron-
deficient anemic patients taking the sustained release Gradumet R and
nonsustained release ferrous sulfate products. These studies, to-
gether with others [74-76], leave in doubt the appropriateness of
18 / Li et al.

some commercially available sustained release iron preparations. Never-

theless, they indicate that the selection of sustaining mechanisms has
an important bearing on ultimate biological response.
When considering the problem of variable absorption rates, it is
necessary to cite intramuscular injections as a route of administration
with significant difficulties in this regard. Aside from the large in-
dividual variation with this route of administration, due to muscle
mobility, water content, tissue integrity, e t c . , there is the additional
problem of tissue insult upon initial injection and further changes in
the tissue from repeated injection, all of which can change the release
and absorption pattern of a drug.
A more prohibitive aspect of the absorption process via the oral
route is the magnitude of the absorption rate constant. For single
nonsustained doses, a minimum absorption rate constant of 0.25 h r " l
to 0.35 h r " 1 is necessary for 95% of the administered dose to be ab-
sorbed, assuming that the GI transit time is between 10 and 12 h r .
To formulate drugs at the lower limit of absorption rate constants
into controlled or sustained release systems, the desired rate constant
of release from the dosage form would have to be even lower, result-
ing in decreased bioavailability. As the GI transit time is finite, a
suitable controlled release system, giving a high fraction of dose ab-
sorbed, can be difficult to design. In addition, the rate constant
of release based on absorption considerations may be very different
from that based on biological half-life considerations so that a com-
promise is achieved generating less than ideal release rates. In es-
sence, oral drugs which are slowly absorbed are poor candidates for
sustained dosage forms primarily because drug availability is limited
by GI transit time. An example of a slowly absorbed drug is iron.
Other problems relative to the design of a sustained release iron
dosage form have already been described.

B. Distribution

The distribution of drugs into tissues can be an important factor in

the overall drug elimination kinetics since it not only lowers the con-
centration of circulating drug but it also can be rate limiting in its
equilibration with blood and extracellular fluid. One aspect of this
distribution is binding of drug to tissues and proteins in blood. An
extensive discussion of this phenomenon can be found in a series of
papers by Kruger-Thiemer et al. [77-81]. In general, the bound
portion of a drug can be considered inactive and unable to cross
membranes. At high binding one sees prolonged drug action.
The apparent volume of distribution of a drug is frequently used
to describe the magnitude of distribution, including binding, within
the body. Conceptually, this pharmacokinetic parameter can be
viewed as a proportionality constant relating plasma or serum concen-
tration of drug to total amount of drug in the body. Since rate
 Influence of Drug Properties on Design I 19

processes are driven by concentration and not amount, it is this

quantity in which we are interested. Physiological interpretation of
the apparent volume of distribution is difficult in the one-compartment
kinetic system and even more difficult in cases where multicompart-
ment kinetics are operative. Indeed, in the absence of definitive
studies, it should probably be treated as a proportionality constant
or "fudge factor" rather than a specific physiological parameter. Un-
like drugs that follow one-compartment kinetics, those with multicom-
partment kinetics usually do not equilibrate with various tissues in-
stantaneously. Consequently, the apparent volume of distribution
assumes different values depending on the time course of drug dis-
position. Thus, one has to be cautious in interpreting the numerical
values of apparent volumes of distribution in the literature.
For design of sustained/controlled release products one would like
to have as much information on drug disposition as possible but, in re-
ality, decisions are usually based on only a few pharmacokinetic param-
eters, one of which is the apparent volume of distribution. The appar-
ent volume of distribution influences the concentration and amount of
drug either circulating in the blood or in target tissues. It can also in-
fluence the elimination kinetics of a drug. Unfortunately, the influ-
ence is frequently not a predictable one because of difficulties in in-
terpreting apparent volume of distribution. Nevertheless, the mag-
nitude of apparent volume of distribution can be used as a guide for
additional studies and for some a priori comments concerning drug
dosing and hence the need for a prolonged release system. These
a priori comments are made in conjunction with consideration of other
pharmacokinetic parameters, such as amount of drug in the various
compartments and elimination constants for removal of drug from these
compartments.
The total apparent volume of distribution for a drug at steady
state can be calculated from Eqs. (2-4):

S = [(k
V 12+k21)/k21]Vp (2)

Vdextrap = [(a - 3)/k 2 1 - 3)]V (3)

Vdarea = V d ss + [(k el - 3)/k 21 ]V (4)

where V^ss, Vdextrap., and Vdarea are apparent volumes of distri-

bution at steady state—Vdextrap, is that obtained by the extrapola-
tion method, Vdarea is that obtained by the area method, Vp is the
volume of the central compartment, a is the fast disposition constant,
3 is the slow disposition constant, k e i is the constant for elimination
of drug from the central compartment, ki2 is the constant for dis-
tribution of drug from the central to peripheral compartment, and
20 I Li et al.

k2i is that from the peripheral to central compartment. Riegelman

et al. [82] demonstrated that the best estimate of total drug volume
at steady state is V^ss, while V^extrap. and V^area tend to over-
estimate this parameter.
While V^ss can be used to correctly estimate amount of drug in
the body when amount of drug in the peripheral compartment is at a
maximum, it tends to underestimate or overestimate amount of drug
in the body at other times during the time course of drug disposition.
This observation has been elaborated upon by Gibaldi et al. [83],
who proposed the use of V^area instead of V^ss to estimate amount
of drug in the body.
To avoid ambiguity inherent in apparent volume of distribution as
an estimator of amount of drug in the body, and noting that the same
parameter does not differentiate relative distribution of drug in two
or more compartments, one can use the T/P ratio as defined in Eq.
(5) to describe relative amount of drug in the central and peripheral
compartments at steady state. Provided amount of drug in the cen-
tral compartment (P) is known, the amount of drug in the peripheral
compartment (T) and hence total amount of drug in the body can be
calculated:

T/P = k 1 2 / ( k 2 1 - 3) (5)

where ki2> k 2 i , and 3 are as defined previously. Note that one

cannot infer from the T/P ratio the physical state of the drug, such
as the extent of binding, in the two compartments. The model merely
assumes that distribution between the two compartments is controlled
by two first-order constants, k^2 and k21- Moreover, it implies that
the amount of drug transferred to the tissues increases proportionally
with dose without limit. In view of this shortcoming of the model,
DiSanto and Wagner [84] proposed a nonlinear model to describe dis-
position kinetics of drugs in tissues.
From the preceding discussion it can be seen that the distribution
characteristics of a drug can be described by the volume of distri-
bution at steady state and the T/P ratio. However, one should be
aware of the fundamental difference between the two parameters;
namely, Vdss estimates the extent of distribution in the body, while
the T/P ratio estimates the relative distribution of drug between com-
partments. One cannot predict a priori the magnitude of volume of
distribution at steady state from the T/P ratio, and vice versa. In-
deed, Table 2 shows that the two parameters behave independently
of each other. As examples, the T/P ratio for procainamide is about
10 times that for pentobarbital although the Vdss for both drugs is
about the same. Similarly, while the T/P ratio for procainamide is
larger than that for digoxin, the volume of distribution at steady
state of procainamide is less than that of digoxin.
 Influence of Drug Properties on Design I 27

Table 2 Relationship Between Apparent Volume

of Distribution at Steady State (V^ss) and T/P
Ratio

Vdss
Drug T/P (liters) Ref.

Amoxicillin 1.04 22 91
Cefazolin 2.20 9 92
Diazepam 2.85 130 93
Digoxin 4.31 500 94
Furosemide 0.96 5 95
Meperidine 2.04 289 96
Metolazone 2.71 113 97
Pentobarbital 1.30 63 98
Pivampicillin 1.16 13 99
Procainamide 14.35 62 100
Sulfisoxazole 0.60 11 101
Theophylline 0.97 40 102
Tobramycin 1.78 34 103,104
Tolbutamide 0.27 24 105
Trimethoprim 1.24 12 106

Presently, there are insufficient data to allow one to gauge the

relative importance of the two parameters in terms of contribution to
approximating drug distribution characteristics. Presumably one can
use volume of distribution at steady state as a starting point. Noting
that the 95% confidence interval on the average value for volume of
distribution of drugs at steady state is about 35 ± 1 liters, volumes
of distribution exceeding total body water volume (about 50 liters in
a 70-kg man) would suggest extensive tissue accumulation and/or
binding of drugs. Table 3 lists some examples of such drugs. Pro-
vided that drug elimination is rate-limited by the release of drug from
tissue binding sites and that drug is released from the tissues to
give concentrations exceeding the threshold level or within the thera-
peutic range, one can probably assume that such drugs are inherently
sustained. Naturally, in the absence of information on binding con-
stants and extent of binding, one should be cautious in asserting
22 / L i et al.

Table 3 Examples of D r u g s with A p p a r e n t Volumes of Distribution

L a r g e r Than Total Body Water Volume (52 l i t e r s )

V s '1/2,6 TBCb
Drug (liters) (hr) (ml/min) Ref.

Chlorphentermine 213 40 62 107

Clindamycin 83 2.8 342 108,109
Diazepam 130 30.8 49 93
Digoxin 500 34 170 94
Lidocain 120 1.8 110
Meperidine 289 3.2 96
Metolazone 113 19.8 66,97
Ouabain 1430 24-74 230-690 111
Pentobarbital 63 22 98
Phenytoin 54 21.3 112,113
Practolol 151 114
Procainamide 62 2.7 265 100
Propranolol 182 3.3 115,116
Quinidine 146 7.2 117,118
Tetracycline 100 9.6 120 119,120

Terminal l o n g - l i n e a r half-life.
b
T o t a l body clearance = V d s s (0.693/t ).

t h e above a s s u m p t i o n . As shown in Table 3, t h e 3 half-lives ( t i / 2 , ^ )

of lidocaine a n d metolazone differ b y a factor of 10 although they have
similar volumes of d i s t r i b u t i o n at s t e a d y s t a t e . A similar p a t t e r n is
o b s e r v e d in t h e p a i r s quinidine-diazepam, p e n t o b a r b i t a l - p r o c a i n a m i d e ,
and c h l o r p h e n t e r m i n e - p r o p r a n o l o l . It follows t h a t Vdss and t i / 2 , 3 are
not r e l a t e d l i n e a r l y . A possible solution to t h i s dilemma is to u s e total
body clearance at s t e a d y s t a t e as defined in E q . (6) to g a u g e t h e im-
p o r t a n c e of t i s s u e b i n d i n g in d r u g elimination k i n e t i c s .

Total body clearance at s t e a d y state = V d s s ( 0 . 6 9 3 / t /2 ) (6)

Consider t h e lidocaine-metolazone example in t h i s l i g h t . Lidocaine

with a clearance of 820 ml/min p r o b a b l y e x p e r i e n c e s less t i s s u e
 Influence of Drug Properties on Design I 23

binding than metolazone with a clearance of 66 ml/min and hence

would be cleared from the body at a faster rate. Furthermore, from
the standpoint of need for sustained drug delivery, lidocaine would
be a more likely candidate than metolazone.
Presently, while it is recognized that the disposition of many
drugs follows multicompartment kinetics, dose calculations for sus-
tained release products are based primarily on one-compartment ki-
netic considerations. Whether such an approach represents a good
approximation to the more complex multicompartment kinetics situation
has yet to be proven. Nevertheless, it should be pointed out that
implicit in such an approach is the assumption that tissue distribution
in the additional compartments has minimal influence on dose consid-
erations. According to this approach, for a given therapeutic con-
centration of drug, the dose would be similar for drugs with similar
volumes of distribution. This assumption hold only when the rela-
tive distribution of the two drugs between compartments is similar.
The error introduced would be especially pronounced in the extreme
case where the active sites of the two drugs reside in different com-
partments. In order to minimize this error, one may have to incor-
porate the T/P ratio into sustaining dose considerations for drugs
exhibiting multicompartment kinetics.
In summary, no conclusion can be made on the relative impor-
tance of volume of distribution at steady state and the T/P ratio in
estimating the distribution characteristics of a drug. Undoubtedly,
both parameters contribute to this aspect of drug disposition. Per-
haps mention should be made of the use of T/P ratio in conjunction
with total body clearance at steady state to gain further insight into
drug disposition. Table 4 gives an example of how this can be done.

C. Metabolism
Metabolism of a drug can either inactivate an active drug or convert
an inactive drug to an active metabolite. Metabolic alteration of a
drug can occur in a variety of tissues, some of which are richer in
enzymes than others. For example, the organ most responsible for
metabolism is the liver and thus the greatest metabolic conversion
occurs after a drug has been absorbed into the general circulation.
Clearly, for optimal bioavailability, the route of drug administration
may be dictated by the drug's metabolic pattern.
Metabolism of a drug will be reflected in the elimination constant
of a drug or by the appearance of metabolite. It is possible to in-
corporate this pharmacokinetic property into the design of a con-
trolled release product, provided that the rate and extent of meta-
bolism are predictable and that the rate constant(s) for the process
are not too large. Undoubtedly, complex metabolic patterns would
make the design much more difficult, particularly when biological
activity is wholely or partly due to a metabolite, as is the case in
24 I Li et al.

Table 4 Use of T / P Ratio and Total Body Clearance at Steady State

to Estimate D r u g Disposition C h a r a c t e r i s t i c s

T/P Total body

ratio8 clearance0 Disposition c h a r a c t e r i s t i c s 0

High High Little a n d / o r weak t i s s u e b i n d i n g

High Low Extensive and/or strong tissue binding;
possible e x t e n s i v e a n d / o r s t r o n g plasma
protein binding
Low Low Strong tissue binding; extensive and/or
s t r o n g plasma p r o t e i n b i n d i n g
Low High Little or weak plasma protein b i n d i n g

A v e r a g e T / P ratio i s 1.
^ A v e r a g e total body clearance at s t e a d y s t a t e is about 80 ml/min.
c
A s s u m e t h a t elimination of d r u g o c c u r s primarily in t h e central com-
partment.

isosorbide 2 , 5 - d i n i t r a t e [ 8 5 ] . T h e r e a r e , h o w e v e r , two a r e a s of con-

c e r n relative to metabolism t h a t significantly r e s t r i c t s u s t a i n e d release
p r o d u c t d e s i g n . F i r s t , if a d r u g , upon chronic administration, i s
capable of e i t h e r i n d u c i n g or i n h i b i t i n g enzyme s y n t h e s i s , it will be
a poor candidate for a s u s t a i n e d release p r o d u c t b e c a u s e of t h e dif-
ficulty of maintaining uniform blood levels of d r u g . Second, if t h e r e
is a variable blood level of d r u g t h r o u g h e i t h e r intestinal (or o t h e r
t i s s u e ) metabolism or t h r o u g h a f i r s t - p a s s effect, t h i s also will make
p r e p a r a t i o n of a s u s t a i n e d release p r o d u c t difficult. Since most of
t h e s e p r o c e s s e s a r e s a t u r a b l e , t h e fraction of d r u g lost would b e
d o s e - d e p e n d e n t and one would anticipate a significant r e d u c t i o n in
bioavailability if a d r u g is slowly r e l e a s e d over a period of time.
T h e r e a r e some excellent examples of t h e s e metabolic d r u g p r o b -
lems in t h e l i t e r a t u r e . Hydralazine is metabolized b y t h e intestinal
wall a n d / o r t h e liver d u r i n g a b s o r p t i o n , although it is well a b s o r b e d
[ 8 6 ] . In c o n t r a s t , bromocriptine is incompletely a b s o r b e d , t h e poor
bioavailability of which is f u r t h e r r e d u c e d b y first p a s s metabolism
in t h e liver r e s u l t i n g in an absolute bioavailability of only 6% [ 8 7 ] .
Likewise, only 23-30% of an orally administered dose of levopoda
r e a c h e s the systemic circulation as intact d r u g [88] a n d t h e plasma
level after an oral dose is about 20% of t h a t after an i n t r a v e n o u s
dose [ 8 9 ] . Abrams [89] s t a t e d t h a t t h e orally administered dose of
t h e d r u g was completely a b s o r b e d and a t t r i b u t e d t h e r e d u c t i o n in
bioavailability to metabolism of t h e d r u g d u r i n g its first p a s s t h r o u g h
t h e l i v e r . In addition, Sandler et al. [90,91] r e p o r t e d t h a t levodopa
 Influence of Drug Properties on Design I 25

was metabolized by gut microbial flora, thus constituting an additional

route of loss of drug prior to absorption. The metabolism of levo-
dopa by the gut flora was shown to occur mostly in the portion of
the GI tract distal to the duodenum [91]. This would significantly
reduce the amount of drug available for absorption from oral sustained
release products, since a substantial portion of the dose released past
the duodenum would be lost. This may be one of the reasons for the
findings of Woods et al. [92] and Curzon et al. [93] that as far as
duration of action was concerned, Brocadopa Temtabs (a sustained
release levodopa product) provided no advantage over the standard
form of levodopa.
Perrier and Gibaldi [94] predicted that due to a first-pass effect,
a maximum of about 41% of an oral dose of propoxyphene would reach
the systemic circulation, provided the entire dose was released, ab-
sorbed, and not metabolized during its transit through the intestinal
wall. Their experimental results indicated that only 18% of a 65-mg
dose, 28% of a 130-mg dose, and 33% of a 195-mg dose reached the
systemic circulation, implying that bioavailability was dose dependent.
Provided that this dose-dependent bioavailability could be predicted,
a sustained release delivery system could be generated although it
makes the sustained dosage form candidacy of propoxyphene less
desirable.
Dose-dependent bioavailability behavior has also been demonstrated
for salicylamide [57,95,96], which is metabolized during its passage
through the intestinal wall. Barr and Riegelman [57,95] showed that
as much as 60% of the drug administered in a small dose that appeared
in blood was in the glucuronide form. Johansson et al. [97] obtained
similar results with alprenolol. They showed that the metabolism of
drug during its passage through the intestinal wall was more complete
when it was administered in a sustained release form than in conven-
tional tablets. However, these investigators claimed that this increase
in drug loss was not enough to render sustained release tablets un-
suitable. This would be in accord with our expectation that as long
as the extent of metabolism is constant, albeit extensive, a suitable
sustained release product can be generated. It does, however, sug-
gest that some manipulation of the dosage form release rate may be
needed to accommodate this metabolism. Wagner et al. have derived
an equation to calculate variation of systemic availability with input
rate [98].
One final example centers on nitroglycerin. The effectiveness
of the oral route of administering nitroglycerin as opposed to the sub-
lingual route was the focus of several studies and reviews [99-109]
and a conflicting picture emerged. Historically, the argument against
the oral route of administration is that nitroglycerin is extensively
metabolized during its first pass through the liver [99,100], but
recently this has been challenged [109]. Nonetheless, Friend et al.
[101] found that nitroglycerin in doses of 2 mg orally four times
26 J Li et al.

daily exerted no observable effect in angina pectoris, an effect that

was indistinguishable from that of a placebo. Similarly, Bogaert et al.
[102] detected no significant fall in blood pressure after oral admin-
istration of nitroglycerin despite high plasma levels of the drug. No
explanation was offered for this observation. Other studies [103-107],
in contrast, indicated that nitroglycerin was absorbed from the GI
tract in sufficient quantities to bring about peripheral vasodilation.
Since sustained release nitroglycerin products are available on the
market, one can assume improved performance against angina attacks
for these systems. Indeed, Turner [103] and others [104-106,110,
111] found that sustained release products gave a duration of action
longer than oral nonsustained tablets. This observation is not incom-
patible with the view that nitroglycerin is extensively metabolized
during first pass through the liver, as long as metabolism is constant.
However, it is incompatible with reports on lack of biological activity
via the oral route. The role of prolonged act on nitroglycerin pro-
ducts in angina pectoris therapy will be evaluated subsequently from
the standpoint of therapeutic need.
Based on the few examples just cited, controlled release systems
for drugs which are extensively metabolized is possible as long as
the rate of metabolism is not too great nor metabolism variable with
the oral and other routes. It is reasonable to assume that a con-
trolled release product can be made as long as the metabolism remains
predictable.

D. Duration of Action

The biological half-life and hence duration of action of a drug obvi-

ously play a major role in the process of considering a drug for con-
trolled release. Factors influencing the biological half-life of a drug
include its elimination, metabolism, and distribution patterns. Dittert
[112] has stated that most drugs have half-lives of elimination in the
range of 1-20 h r . Drugs with short half-lives require frequent dos-
ing on order to minimize fluctuations in blood levels accompanying
conventional oral dosage regimens [113]. Therefore, controlled re-
lease dosage forms would appear very desirable for such drugs. At
present, the lower limit of the biological half-life needed for controlled
release products has not been defined. Basic pharmacokinetic prin-
ciples (Chapter 5) suggest that for a given steady-state drug con-
centration, the zero-order rate of release of a drug from its dosage
form is directly proportional to its rate of elimination. Thus, for a
drug with a very short half-life, the desired rate of release will be
quite large. For a modest duration of time over which the drug is
to be released, this large rate of release in turn will lead to a pro-
hibitively large dose, so that the upper limit imposed on the size of
the tablet, capsule, or other dosage form may be exceeded. Table 5
 Influence of Drug Properties on Design I 27

Table 5 Ratio of S u s t a i n i n g Dose to Immediate

Release Dose, $m/$i> a s a Function of t i / 2 and
I n t e n d e d D u r a t i o n of R e l e a s e 8

h/2
(hr) Td = 6 h r Td = 8 h r Td = 12 h r

1 4.6 5.54 8.32

2 2.08 2.77 4.16
3 1.39 1.85 2.77
4 1.04 1.39 2.08
5 0.83 1.11 1.66
6 0.69 0.92 1.39
7 0.59 0.79 1.19
8 0.52 0.69 1.04
9 0.46 0.62 0.92
10 0.42 0.55 0.83

HBased on a one-compartment open model.

shows t h e ratio of s u s t a i n i n g dose <2>m to immediate release dose $i

as a function of t h e biological half-life of d r u g and i n t e n d e d d u r a t i o n
of release T ^ . Table 6 lists t h e maximum size D of t h e controlled r e -
lease dosage u n i t . Table 7 lists some examples of d r u g s with e x t r e m e -
ly s h o r t h a l f - l i v e s .
To d a t e , t h e numerical value of biological half-life which makes
a d r u g a good candidate for controlled release has not been e s t a b -
l i s h e d . Heimlich et a l . [114] q u o t e d a value of about 4 h r . For a
d r u g with such a half-life, t h e ratio of s u s t a i n i n g dose to immediate
release dose is approximately 2 if t h e d u r a t i o n of i n t e n d e d release is
12 h r (Table 5 ) . Moreover, for this duration of i n t e n d e d r e l e a s e ,
it would be possible to formulate a controlled release dose unit of 1
g even if t h e immediate release dose (minimum effective dose) is 325
mg (Table 6 ) . C o n s i d e r i n g t h i s c r i t e r i o n alone, propranolol ( t i / 2 =
4 h r ) [120,121], p r o p o x y p h e n e ( t i / 2 = 3 h r ) [122], and procainamide
( t i / 2 = 3 h r ) [123] would be b o r d e r l i n e c a n d i d a t e s for p r o l o n g e d r e -
lease p r o d u c t s . As an i l l u s t r a t i o n , Koch-Weser et al. [124,125] s u g -
g e s t e d t h a t dose of procainamide must be administered e v e r y 3 h r
to p r e v e n t fluctuations of plasma level b y more t h a n 50%. S u s t a i n e d
release formulations of procainamide a r e available a n d have been shown
28 I Li et al.

Table 6 Maximum Value of t h e Ratio of S u s t a i n i n g to

Immediate Release Dose, $ m / $ i , as a Function of Initial
Dose Dj and Size of t h e S u s t a i n e d Release Unit D a

($ /$.)max
m 1

Di (mg) D = 1000 mg D = 500 mg D = 250

5 199 99 49
10 99 49 24
25 99 19 9
50 19 9 4
75 12.3 5.7 2.3
100 9 4 1.5
125 7 3 1
250 3 1 0
325 2 0.5 -
500 1 - -
1000 - - -

Based on a one-compartment open model.

b
C * m / * i ) m a x = ° / D i " *•

Table 7 Examples of D r u g s with

Extremely Short Half-Lives

Half-life
Drug (min) Ref.

Ampicillin 100 115

Cephalexin 54 116
Cloxacillin 90 115
Furosemide 29.5 117
Levodopa 45 89
Penicillin G 45 118
Propylthiouracil 63 119
 Influence of Drug Properties on Design / 29

to be capable of e i t h e r maintaining t h e r a p e u t i c plasma level or mini-

mizing t h e fluctuations in plasma level over an 8-hr period [123,126,
127] . In e s s e n c e , assuming a d u r a t i o n of release of 6, 8, or 12 h r ,
d r u g s with half-lives between 4 a n d 6 h r and whose minimum effective
doses a r e in t h e r a n g e of 125-325 mg will impose little problem insofar
as dose size i s c o n c e r n e d .
It should be pointed out t h a t t h e duration of action of many d r u g s ,
such as monoamine oxidase i n h i b i t o r s [128] a n d c o r t i c o s t e r o i d s [129,
130] , i s longer t h a n t h a t s u g g e s t e d b y t h e i r biological h a l f - l i v e s . As
a case in p o i n t , it i s t h e p e r s i s t e n c e of antiinflammatory effects of
c o r t i c o s t e r o i d s t h a t forms t h e b a s i s for a l t e r n a t e - d a y dosing schedule
and this is u n r e l a t e d to t h e biological half-life as shown in Table 8.
This dosage regimen h a s t h e additional a d v a n t a g e of minimizing a d r e -
nal s u p p r e s s i o n side effects f r e q u e n t l y associated with chronic c o r t i -
costeroid t h e r a p y [131]. T h u s , it is p r o b a b l y justified to assume
t h a t s u s t a i n e d release c o r t i c o s t e r o i d s a r e u n n e c e s s a r y from t h e s t a n d -
point of t h e r a p y , u n d e s i r a b l e from t h e point of view of side effects
[ 1 3 2 ] , and unphysiological from t h a t of t h e diurnal v a r i a t i o n s in Cor-
tisol s e c r e t i o n s [ 1 3 3 , 1 3 4 ] . In fact, s u s t a i n e d release formulations of
prednisolone sodium p h o s p h a t e a n d methylprednisolone have b e e n
shown to be equally effective as conventional t a b l e t s , offering no
a d v a n t a g e s over t h e l a t t e r [ 1 3 5 , 1 3 6 ] ,
Similarly, t h e r e is little r e a s o n to p r e p a r e s u s t a i n e d release formu-
lations for d r u g s with long biological h a l f - l i v e s . Nelson [137] has
indicated t h a t if t h e r e are no appreciable differences in effectiveness
when a d r u g is given as a single l a r g e dose p e r day or in s e v e r a l
smaller doses t h r o u g h o u t t h e d a y , t h e t h e r a p e u t i c n e e d for a p r o -
longed action dosage form would b e doubtful. P h e n y l b u t a z o n e is
such a d r u g . Due to e x t e n s i v e p r o t e i n b i n d i n g , its r a t e of metabo-
lism is relatively slow, r e s u l t i n g in a biological half-life of about 72
h r [ 1 3 9 ] . Para-aminosalicylic acid [140] and t h e p h e n o t h i a z i n e s [141]
belong to the same c a t e g o r y as p h e n y l b u t a z o n e . Examples of o t h e r
d r u g s with long biological half-lives a r e shown in Table 9. S u r p r i s -
i n g l y , s u s t a i n e d release p r o d u c t s for d r u g s with i n t r i n s i c a l l y long
biological half-lives a r e available. As e x p e c t e d , little or not t h e r a -
p e u t i c a d v a n t a g e s have been d e m o n s t r a t e d in t h e s e p r o d u c t s over

Table 8 Biological Half-Life and D u r a t i o n of Antiinflam-

matory Effects of Selected Corticosteroids

Half-life Duration
Drug (hr) (hr) Ref.

Methylprednisolone 3.3 24-36 138

Prednisone 1.0 36 131
30 I Li et al.

Table 9 Examples of D r u g s with Long Biological

Half-Lives

Drug Half-life Ref.

Bishydroxycoumarin 27 h r 151
Chlordiazepoxide 15 h r 152
Chlorphentermine 41 h r 153
Chlorpropamide 36 h r 154,155
Diazepam 54 h r 156
20 h r 157
Ethchlorvynol 24 h r 158
Digitoxin 5-7 d a y s 159
28 d a y s 160
Digoxin 34 h r 159,161
Guanethidine 9-10 d a y s 162
Meprobamate 11.3 h r 163
Phenytoin 22 h r 164
Warfarin 52 h r 165

conventional t a b l e t s or c a p s u l e s . Notable examples a r e meprobamate

[ 1 4 2 ] , amitripyline [ 1 4 3 - 1 4 5 ] , a n d p h e n o t h i a z i n e s [ 1 4 6 - 1 5 0 ] .

E. Side Effects

It is believed t h a t for some d r u g s , t h e incidence of side effects is

a function of plasma c o n c e n t r a t i o n s [166]. Theoretically, t h e inci-
dence of side effects can be minimized b y controlling t h e c o n c e n t r a -
tion at which t h e d r u g e x i s t s in plasma at any given time, and hence
controlled release formulations a p p e a r to offer a solution to this p r o b -
lem. Nau et a l . [167] a n d Sikic et al. [168] d e m o n s t r a t e d t h a t the
toxic effects of valproic acid and bleomycin, r e s p e c t i v e l y , were ame-
liorated upon administering t h e s e d r u g s as a c o n s t a n t infusion t h a n
as a b o l u s . Eckstein et a l . [169] r e p o r t e d t h a t Brocadopa T e m t a b s ,
a controlled release form of levodopa, lowered t h e incidence of d r u g -
i n d u c e d d y s k i n e s i s , and the p a t i e n t s in the s t u d y seemed to be able
to tolerate a l a r g e r daily dose of t h e d r u g . On t h e other h a n d , a
s u s t a i n e d release p r o d u c t of prednisolone p r o d u c e d adrenocortical
s u p p r e s s i o n to a d e g r e e i n d i s t i n g u i s h a b l e from t h a t p r o d u c e d b y the
same dose given in conventional t a b l e t s [ 1 3 5 ] . Moreover, an attempt
 Influence of Drug Properties on Design I 31

to reduce the incidence of drowsiness due to chlorpheniramine maleate

by dispensing the drug in a porous matrix was unsuccessful [1701.
Thus, the success or failure of these specific products to minimize
side effects would appear to be related to the type and success of
preparing a controlled release product.
The technique of controlled release has been more widely used to
lower the incidence of GI side effects than that of systemic side ef-
fects and appears to produce more satisfactory results. Drugs that
are prone to cause gastric irritation include aspirin [171], ferrous
sulfate [172], potassium chloride [173], nitrofurantoin, and several
others. It is postulated that by slowing the rate at which these
drugs are released, the likelihood of GI irritation would be reduced
due to a smaller amount of drug exposed to the GI mucosa at any
given time [174]. Such is the case with sustained release ferrous
sulfate products [71,74,76] and an aminophylline sustained release
preparation [175]. In contrast, two cases of gastric bleeding follow-
ing the ingestion of Bayer's Timed-Release Aspirin were reported
[176] . The extent of gastric bleeding relative to that due to conven-
tional aspirin tablets was not quantitated, however. Nevertheless,
this observation suggests that controlled release preparations are
not foolproof against GI side effects.
One of the common complaints of oral potassium therapy is gastric
irritation associated with its use [176]. To circumvent this problem,
enteric coated tablets are usually prepared, but this has led to another
problem, namely, intestinal erosion and stenosis due to a high local
concentration of potassium ions released in the intestine [177-181] .
Placement of potassium chloride in a controlled release system, such
as a wax matrix (Slow-K), programmed to release its contents over
4-6 hr appears to be a satisfactory solution [182-185]. Moreover,
it has been shown that such tablets are as bioavailable as their non-
sustained counterparts [184], Utilizing the same principles as Slow-
K, a sustained release form of sodium chloride (Slow-Na) has been
formulated. The incidence of side effects such as nausea and vomit-
ing is claimed to be less than that in a tablet or capsule [186,187],
and the formulation has been used to treat and to prevent acute
and chronic deficiency in athletes and in patients on maintenance
sodium therapy. In summary, it would appear that drug properties
can induce local and systemic side effects which can often be circum-
vented by placement in a suitable controlled release system. The
specific controlled release mechanism employed depends on the drug
property inducing side effects.

F. Margin of Safety
Among the indices used to describe the margin of safety of a drug
[188-190], the therapeutic index as defined in Eq. (7) is the most
widely used:
32 I Li et al.

T h e r a p e u t i c i n d e x = Median toxic dose/median effective dose

= TD50/ED5Q (7)

However, t h i s ratio p r o v i d e s no information on (a) t h e n a t u r e of t h e

d i s t r i b u t i o n of toxicity and e f f e c t i v e n e s s , (b) t h e size of doses p r o -
d u c i n g t h e r a p e u t i c and toxic effects, and (c) plasma or serum d r u g
c o n c e n t r a t i o n s c o r r e s p o n d i n g to toxic and t h e r a p e u t i c l e v e l s . Con-
s e q u e n t l y , it can only be u s e d as a c r u d e estimate of t h e r e l a t i v e
safety of a d r u g . As might be e x p e c t e d and as i l l u s t r a t e d in Table
10, t h e r e is wide variation in t h e t h e r a p e u t i c index for various d r u g s .
In g e n e r a l , t h e l a r g e r t h e r a t i o , t h e safer is the d r u g ; in p a r t i c u l a r ,
a d r u g i s c o n s i d e r e d to be relatively safe if its t h e r a p e u t i c i n d e x
e x c e e d s 10 [ 1 9 0 ] . However, since t h e definition of t h e r a p e u t i c i n d e x
is relative r a t h e r t h a n a b s o l u t e , t h e toxic a n d t h e r a p e u t i c effects have
to be clearly defined. Decisions on margin of safety of a d r u g p e r -
h a p s can be b e t t e r made on t h e b a s i s of its t h e r a p e u t i c index in com-
bination with t h e r a n g e of plasma concentration within which t h e d r u g
is c o n s i d e r e d to be t h e r a p e u t i c a l l y safe a n d effective. This a p p r o a c h
has been v e r y valuable as a t h e r a p e u t i c guide in monitoring d r u g
t h e r a p y , especially for d r u g s with n a r r o w t h e r a p e u t i c indices a n d a
n a r r o w r a n g e of t h e r a p e u t i c c o n c e n t r a t i o n , such as t h e cardiac gly-
cosides and a n t i a r r h y t h m i c (Table 11) [ 2 6 , 1 1 3 ] .
In d e s i g n i n g controlled or s u s t a i n e d release systems for d r u g s
with n a r r o w t h e r a p e u t i c i n d i c e s , it is imperative t h a t t h e d r u g release
p a t t e r n be p r e c i s e so t h a t t h e plasma concentration achieved is within
t h e t h e r a p e u t i c a l l y safe a n d effective r a n g e . However, a p r e c i s e r e -
lease p a t t e r n b y itself is not sufficient to e n s u r e attainment of such

Table 10 T h e r a p e u t i c Indices of Selected

Drugs

Therapeutic
Drug index Ref.

Aprobarbital 5.3 191

C hlorp h e n i r amine 1400 192
Digitoxin 1.5-2.0 193
Diphenhydramine 2300 192
Penicillin MOO 193
Phenobarbital 2.6 191
Tripelennamine 19,000 192
 Influence of Drug Properties on Design I 33

Table 11 Examples of Drugs with

Narrow Ranges of Therapeutic Plasma
Concentration at Steady State

Range of therapeutic
Drug concentration

Digoxin 0.02-2 yg/liter

Digitoxin 14-30 yg/liter
Lidocaine 1.5-4 mg/liter
Lithium 0.5-1.3 mEq/liter
Phenytoin 10-20 yg/liter
Procainamide 4-8 mg/liter
Propranolol 20-50 yg/ml
Quinidine 2-5 mg/liter
Theophylline 10-16 yg/ml

Source: Refs. 26,113.

plasma levels. There are other factors, such as patient variability

and the very important drug accumulation upon multiple dosing fac-
tors (Chapter 6), that can potentially alter plasma drug level. Con-
sidering all these factors it is obvious that the design of sustained
release system for drugs with narrow therapeutic indices can be dif-
ficult. Nevertheless, it is conceivable that an unfavorable therapeutic
index can be overcome by suitable manipulation of prolongation mech-
amisms. Indeed, it is the same narrow therapeutic index that makes
it desirable to precisely control drug concentration.

G. Role of Disease State

Strictly speaking, disease state and circadian rhythm are not drug
properties. However, in a few instances they are equally important
as drug properties in considering a drug for controlled release. In-
deed, it is not unusual for a disease state to act as a stimulus for
development of a controlled release drug delivery system. A case in
point is rheumatoid arthritis, for which aspirin is still the drug of
choice [194] . Normally, aspirin would not be considered to be a
likely candidate for sustained release because its biological half-life
is 6 hr [195]. However, a sustained release product would be ad-
vantageous to maintain therapeutic concentrations, particularly
34 J Li et al.

throughout the night, thus alleviating morning stiffness [196]. Note

that a limitation to formulating a sustained release aspirin preparation
is the size of a dose, which necessitates the taking of two sustained
release tablets to obtain the desired degree and duration of relief.
The results of several studies indicated that sustained release aspirin
tablets in the proper dosage provided and maintained blood levels at
therapeutic concentration over 8-10 hr, a duration that was about
twice as long as that provided by nonsustained release tablets [196-
198].
Among the therapeutic armamentarium in peptic ulcer management
are belladonna alkaloids and synthetic anticholinergics. Although the
usefulness of this class of drugs in this disease state is controversial
[199] , they are sometimes prescribed as adjuncts to therapy by virtue
of their ability to decrease gastric secretion of acid and pepsin induced
by vagal stimulation [200]. Since belladonna alkaloids are relatively
short-acting [201], a sustained release dosage form may be helpful
to exercise continuous control on gastric acid and pepsin secretion.
Burness [202] and Resse et al. [201 found that sustained release
belladonna preparations employing the Spansule^ principle appeared
to maintain therapeutic plasma concentrations of alkaloids from 8 to
12 hr, but they did not measure gastric acid and pepsin output.
Kasich [203] as well as Alp and Grant [204] reported similar findings
with hexocyclium. In contrast, Bachrach [43] found that the prolonged
acting forms Antrenyl Prolonged1*, Prantal Repetabs R , Banthine Pro-
longed^, and Probanthine Prolonged** did not sufficiently extend the
duration of action of drug and he attributed this observation to the
design of the products concerned.
Angina pectoris is another disease state that probably would be
benefited by sustained release medications. In spite of the dispute
over the efficacy of nitroglycerin when administered by the oral route,
sustained release nitroglycerin preparations are available. Similar to
the situation with the orally administered nonsustained products, there
are conflicting reports on the value of sustained release nitroglycerin
products in controlling the symptoms of angina pectoris. One reason
that may account for this confusion is the high incidence of placebo
response to prophylaxis of angina pain [205] . The findings of Russek
et al. [107] and Pilkington and Purves [104] supported the argument
that a sustained release ntiroglycerin preparation was of questionable
value in conferring propylaxis to those patients suffering from the
typical short attacks of angina pectoris. They based their conclusions
on the findings of studies employing sustained release ntiroglycerin
preparations containing from 6 to 10 times the dose normally used sub-
lingually. However, Winsor et al. [105], Hirshleifer [106], Turner
[103], Wendkos and Meshulam [110], and Preti et al. [ I l l ] obtained
results contrary to those of Russek and Pilkington. They found
that the sustained release nitroglycerin preparations used in their
 Influence of Drug Properties on Design / 35

studies not only reduced the incidence and severity of angina attacks
but also lowered the nitroglycerin requirements. Kamil and Klinger
[206] as well as Feinblatt and Ferguson [207] reported similar find-
ings with pentaerythritol tetranitrate, another drug used in angina
pectoris. The conflicting nature of the above reports suggests that
additional studies are warranted to establish the role of sustained
release preparations as a prophylactic aid in angina pectoris. Per-
haps the acute and fleeting nature of angina attacks [205] , the large
placebo effect [205], and the development of tolerance with chronic
administration of long-acting oral nitrate preparations [208] should
be major consideration in the design and interpretation of such stud-
ies. An interesting statement on the need for prolonged action forms
of nitrates in the prophylactic treatment of angina pectoris was made
by Wilson [209]. He noted that prophylaxis carries with it the dan-
ger of obscuring the warning symptoms of pain, eventually leading
to over-exertion with potentially harmful results.

H. Role of Circadian Rhythm

Several biological processes and disease states have been shown to
be influenced by circadian rhythm [210]. As examples, acute myo-
cardial insufficiency occurs most commonly around 4:00 a.m. [211]
and epileptic seizures have the highest incidence in the morning
[212]. Liver enzyme activity [248], blood pressure [213,214], and
intraocular pressure [215] also follow a circadian rhythm. As a re-
sult, the response to certain drugs also follows a circadian rhythm.
These include digitalis glycosides, diuretics, and psychoactive drugs
such as the amphetamines, barbiturates, carbamazepine, ethyl alcohol,
and chlordiazepoxide [211,212,216-218].
The disease of asthma follows a circadian rhythm, with most of
the attacks occuring before bedtime [219]. This observation is postu-
lated to be related to a low Cortisol level at that time [211] . It was
found that the highest Cortisol level occurred between 12 midnight
and 4:00 a.m. [211], Like many other diurnal variations, this vari-
ation in Cortisol levels makes the design of a controlled release dos-
age form much more difficult. Foremost among the limitations is
GI transit time. Methylprednisolone has been made available in a
prolonged action product (Medrol MeduleR). In one study [219],
such a product was shown to produce the same duration of relief of
rheumatoid arthritis as the same dose administered as a conventional
tablet.
Although circadian variations of corticosteroid levels is well
known, there is some uncertainty as to whether diurnal variations
in glucose and insulin levels exist. Jarrett and Keen [220] reported
that in diabetics, the diurnal variation in glucose appeared not to
exist, or when it did, it was to a lesser extent. Prior to the reports
36 I Li et al.

of Jarrett and Keen [220], Hayner et al. [221], Freinkel et al. [222],
and Faiman and Morrhouse [223] obtained results opposite to those of
the former investigators, that is, a diurnal variation in blood glucose
existed in the diabetic but not in the normal subject, with blood glu-
cose levels significantly higher in the morning than in the afternoon.
Freinkel et al. [222] also found that, in normal subjects, insulin level
was higher in the morning than in the afternoon. Rigas et al. [224]
postulated that insulin synthesis and storage proceeded to a greater
extent during the night than during the day, thus accounting for
Freinkel's observations on diurnal variation in insulin levels. Theo-
retically, once diurnal variations in blood glucose and/or insulin are
established, controlled release oral hypoglycemic products could be
designed to release their contents in accordance with circadian rhythm.
However, the fluctuation in blood glucose levels in diabetics is not
controlled solely by diurnal variations but also by such variables as
diet and exercise [225], Conceivably, the net result of interaction
of these two influences is to diminish the importance of circadian
rhythm in dosage form design.
Perhaps the classes of drugs that would benefit the most from in-
corporation of circadian rhythm into their dosing regimen are the
chemotherapeutic agents and peptide hormones. That the timing of
chemotherapy is possible in conferring greater specificity is based on
the assumption that, unlike malignant tissues, normal tissues are un-
der more stringent circadian control. Hrushesky [226] demonstrated
that during the course of treatment of ovarian cancer patients with
a combination of adriamycin and cisplatin, administration of adriamycin
in the morning and cisplatin in the evening caused fewer complications
than a regimen in which the order of dosing of these drugs was re-
versed. The secretion of neuropeptides and peptide hormones like
LHRH, parathyroid hormone, and growth hormone is also under cir-
cadian control [227]. Thus, the treatment of conditions by a number
of these substances, notably LHRH [228-230], parathyroid hormone
[231], and triiodothyronine [232] has been found to benefit more
from intermittent, periodic administration than from constant infusion,
in part because a constant tissue level of these substances may lead
to down regulation of their receptors [233-237] . The net effect of
circadian regulation of these substances is to make the design of a
controlled release system for such substances more challenging, as
exemplified by a prototype delivery device programmed to release
melatonin, a pineal gland hormone, in a periodic fashion [238].

VII. SELECTED ROUTES OF DRUG ADMINISTRATION

The route of administration has a significant impact on the therapeu-

tic outcomes of a drug [239,240] . In controlled and sustained drug
 Influence of Drug Properties on Design I 37

delivery system design, the parenteral and oral routes have received
by far the most attention, although transdermal route is gaining at-
tention recently. At the same time, advances in biotechnology have
made possible an increasing number of peptides and proteins which,
by virtue of the biophysical and biochemical properties, have made
specific demands on the route of delivery as well as on the design of
delivery systems. Thus, routes which were of minor importance as
ports of drug delivery in the past have assumed added importance in
peptide and protein delivery. These include the buccal, rectal, nasal,
pulmonary, vaginal, intrauterinal, and ocular routes. The purpose
of this section is to present an overview of the physiological con-
straints inherent in each of the routes mentioned above.

A. Parenteral
Strictly speaking, parenteral products are all systems administered
outside of the GI tract. However, parenteral routes are more common-
ly restricted to injectables such as subcutaneous, intramuscular, intra-
peritoneal, intrathecal, and intraventricular sites.

1. Intravenous /Intraarterial
The intravenous route is attractive because drugs are placed directly
into the blood with the associated potential to give an immediate bio-
logical response. However, sustaining blood concentrations of drugs
given by intravenous injection poses a considerably challenge. Al-
though continuous intravenous infusion can be tailored to maintain
a constant and sustained drug level within a therapeutic concentration
range during the entire treatment period, such a mode of drug ad-
ministration necessitates continuous hospitalization during treatment
and requires frequent drug level monitoring.
There are several reasons for the lack of commercial sustained
release intravenous products. Aside from the irretrievable nature of
such injected drugs, there are the issues of biocompatibility and
limitations on the size of injected drugs. Thus, wishing to avoid
blockage of small capillaries requires that only very small particles
be employed as physical systems for intravenous injections. However,
the reticuloendothelial system, consisting primarily of liver, spleen,
lung, and bone marrow, sequesters "foreign" substances out of the
blood stream rapidly, thus making it difficult to sustain drugs via
this route.
Numerous attempts to provide either prolongation of drug release
or spatial placement of drug, a very desirable attribute for cancer
chemotherapy, have been made. Each appears to suffer from one or
more deficiencies. Thus, loaded red blood cells, where a drug is
38 I Li et a/.

placed within a red blood cell, offers a number of attractive features,

the most notable being biocompatability and a duration akin to the
half-life of a red blood cell, i . e . , 30 days. However, such factors
as loading capacity of red blood cells for drug, damage to the cell
during drug loading resulting in sequestration by the reticuloendo-
thelial system, and lack of control of drug release from the red blood
cell have reduced the therapeutic utility of such systems for controlled
drug delivery. Liposomes and other particulate systems suffer from
similar shortcomings, which will be discussed in Chapter 13.
In general, depot-type parenteral controlled drug release formula-
tions duplicate the benefits of continuous intravenous infusion without
its potential discomfort. Various techniques have been used [241-245],
including viscous vehicles, suspension, sparingly soluble derivatives
and biodegradable microspheres. Biodegradable microspheres are par-
ticularly attractive because labile drugs such as peptides and proteins
are protected by and released at a controlled, efficacous rate for de-
sired periods of time from this delivery system. These microspheres
can also be utilized to direct drugs to certain organs through capil-
lary blockade [243,246]. Its success depends on the size of the
microspheres used and on the mode of administration (intravenous or
intraarterial). Microspheres with a diameter exceeding 25 ym upon
intraarterial administration can be entrapped temporarily in the first
capillary bed encountered. In contrast, microspheres greater than
7 ym in diameter when given intravenously will be trapped in the
lungs by mechanical filtration, while smaller ones will be cleared by
the reticuloendothelial system [247] . The key to a reproducible de-
gree of occlusion for a given dose appears to be due to lack of a
tendency of microspheres to aggregate. However, the use of blockage
incurs the risk of irreversible cellular damage. The brain can only
tolerate a few minutes of anoxia, in comparison to the majority of
organs which can tolerate a 20-40-min "shutdown."

2. Intramuscular /Subcutaneous
Next to oral administration, injection into subcutaneous or muscular
tissues is the most commonly used and acceptable route of drug ad-
ministration. These routes of administration are most useful either
when the disease state or the pharmacokinetic properties of a drug
preclude oral dosing, or prolonged drug action is desired. The
latter can be achieved in a number of ways [241,248], including re-
duction of aqueous solubility, gelling of the oily vehicle, use of bio-
degradable systems, implants, or a combination of these. All of these
approaches aim to decrease the release rate of a drug from its dosage
form and will be discussed further in Chapter 10. A major factor
that needs to be considered during development of biodegradable sys-
tems and implants is biocompatibility of the polymers. Release rate
from implants may decrease with time when a fibrous envelope is
 Influence of Drug Properties on Design I 39

formed around the system as a result of bioincompatibility [249] . In

addition, for biodegradable systems as exemplified by poly(ortho
esters), it is imperative that breakdown products of the polymer be
nontoxic [250] .
In general, drugs are assumed to be absorbed at the same rate
when given intramuscularly and subcutaneously and the sites are
often considered bioequivalent [251,252]. However, subtle differences
between these two modalities of drug administration do exist. The
vascularity in the subcutaneous tissue is poorer than that of muscle
tissue [253] and thus may lead to slower absorption unless there is
compensation with an increase in surface area. Moreover, lymphatic
vessels of subcutaneous tissue are mainly found in the connective
tissue, whereas those of the muscular tissue usually exist where
facial planes enter muscles [253].
Unlike intravenous injections, subcutaneous and intramuscular
injections require an absorption step before a drug reaches the sys-
temic circulation. However, since absorption from subcutaneous and
muscle tissue does not involve passage through an epithelial layer
and the tissues are well supplied with capillary and lymphatic vessels,
absorption from these routes is usually faster relative to the oral
route. Depending on its physicochemical properties, the rate-limiting
step in drug absorption from aqueous solution may be either drug
diffusion in the connective tissue [254,255] or blood flow through
and around the injection site [247,256-260]. Therefore, any factor
that influences the above two parameters should influence the absorp-
tion rate. For example, vasoconstrictors such as epinephrine reduce
the subcutaneous absorption of a number of drugs, whereas hyaluroni-
dase which digests connective tissues markedly increases drug absorp-
tion from both muscle and subcutaneous tissues [254] . Probably due
to differences in blood flow, absorption is most rapid following injec-
tions into the deltoid muscle and least so when injected into the glu-
teal muscle [247]. In contrast, the absorption rate of drugs adminis-
tered intramuscularly does not seem to be affected by the water con-
tent of connective tissues [254] .
Recently, intramuscular and subcutaneous absorption from aqueous
solutions [259-265], oil solutions [251,266], and aqueous suspensions
[267,268] has been examined. Absorption from aqueous and oil solu-
tions follows first-order kinetics. Absorption rate decreases with
increasing volume, probably because of mechanical compression of the
adjacent capillary bed and because of a smaller area-to-volume ratio
[257] . Moreover, absorption rate was found to be inversely related
to molecular size for water soluble compounds and directly proportion-
al to partition coefficient for lipophilic compounds [258]. Low molecu-
lar weight compounds are readily absorbed via the capillaries, while
high molecular weight compounds appear to be absorbed primarily
via lymphatic vessels [255] . Inclusion of adjuvants such as serum
40 J Li et al.

albumin was found to increase subcutaneous absorption of high molec-

ular weight compounds, but the mechanism is unknown [269].
For oil solutions, absorption rate depends on partitioning between
the oil and the aqueous medium in the connective tissue, with little
dependence on viscosity. Clearance of oily vehicles following intra-
muscular and subcutaneous injections has been studied in albino rab-
bits [270]. It was found to be independent of the injection site.
However, clearance was mainly via capillary vessels whereas clearance
via lymphatic uptake or phagocytosis by cells was found to be insig-
nificant. In the case of suspensions, the absorption rate increases
with decreasing particle size, probably due to an increase in lateral
spread of the particles in the connective tissue [267,268]. Phagocy-
tosis appears unimportant except for exceedingly fine drug particles.

B. Oral

The oral route is by far the most popular route of drug administra-
tion. Nevertheless, current knowledge on mechanisms of drug ab-
sorption, GI transit and the microenvironment of the GI tract is still
incomplete. In addition, oral administration is also beset with inher-
ent physiological constraints such as chemical degradation in the
stomach, gastric empyting, intestinal motility, mucosal surface area,
specific absorption sites, and metabolic degradation during passage
through the mucosa and subsequently the liver. Adding to these
constraints is the commonly substantial intra- and intersubject vari-
ability associated with some of these factors. Generally, these factors
cannot be controlled and hence severely limit the design of oral drug
delivery systems.
The duration of a drug after oral administration is mainly a func-
tion of drug-releated properties such as rate of absorption and clear-
ance as well as residence time of the delivery system at the absorp-
tion site. Most sustained release drug delivery systems developed
thus far are aimed at slowing the apparent absorption rate by reduc-
ing drug release rate from the dosage form. However, these systems
will have only limited utility in oral controlled administration of drugs
unless they can remain in the vicinity of the absorption site for the
life time of drug delivery.
The residence time of most sustained/controlled release dosage
forms is primarily determined by gastric emptying and intestinal
motility. Gastric emptying is influenced by factors such as auto-
nomic and hormonal activity, and volume, composition, viscosity,
osmolality, pH, caloric value, temperature of stomach contents as
well as by many drugs [271]. The human/canine stomach behaves
differently in the fed and fasted states [272]. During the fed state,
fluids and solid particles smaller than 2 mm are discharged together
whereas solid particles larger than 2 mm, including pellets and tablets
are retained until arrival of the next phase III of the migrating motor
 Influence of Drug Properties on Design I 47

complex (MMC) [273], In the fasted state, gastric emptying patterns

of fluids depend on the volume administered. A lag phase is com-
monly observed for volumes of fluid less than 100 ml. The onset of
discharge depends on the phase activity of the stomach, and fluid
is discharged before the suspended particles. In contrast, large
volumes of fluids (>200 ml) are discharged immediately, as in the
fed state, and the square root of volume v s . times or an exponential
relationship is usually observed.
Motility of the small intestine during digestion consists mainly of
segmental contractions, whose purpose is to mix its contents. Distal
propulsion also occurs, but its mechanism is unknown [272], Distal
propulsion in fasted state occurs mainly in phase III of the MMC.
Liquids are spread out over the entire small intestine quite
quickly following ingestion. It has been found that the transit of
liquids and solids are similar in the small intestine, so that differ-
ences in their GI transit time are primarily due to differences in
gastric emptying time. Studies in humans have shown a surprising
consistency of small intestinal motility in that, irrespective of dosage
form, it takes approximately three hours for substances to traverse
the small intestine. The methodology of studying GI transit has
been summarized by Hoffman et al. [272].
It is generally assumed that the desirable site of absorption is
the proximal and mid small intestine, the transit time of most delivery
systems in which is only 2-3 hr long [272]. Consequently, a sus-
tained release formulation of about 12-hr duration or longer can only
be achieved by slowing gastric emptying. Several approaches have
been proposed for prolongation of GI transit time. These include
flotation tablets and capsules (U.S. patent #4,140,755), unfolding of
stratified medicated sheet (BE patent #867,692), bioadhesive polymers
[274,275], certain fatty acids [276], and certain drugs such as pro-
pantheline. However, the use of drugs is generally considered un-
desirable because of potential side effects.
An important issue relative to oral controlled release products is
the animal species that is used during the design phase of these
systems. Although our understanding of the anatomical and physio-
logical aspects of all animals is rudimentary, there are certain species
which seem to be preferred. The beagle dog is a frequently utilized
animal for this purpose, in spite of marked differences in its transit
time and GI pH relative to human subjects. Transit time of dosage
forms in the dog is only two-thirds of that in humans, analogous to
that in a young child, aged 1-3. This can be an important consid-
eration for those systems that require drug absorption for an extended
time. Thus, for such systems, dogs will show incomplete absorption.
The second issue is GI pH. Some workers have found (a) a higher
pH in the stomach as compared to humans and (b) an acid pH ex-
tending over a larger segment of the small intestine of the beagle
42 I Li et al.

dog. As an alternative animal species to obviate this pH problem

some pharmaceutical firms routinely employ the cynomolgus monkey as
well as rodents. Here, a word of caution regarding the use of ro-
dents as test animals is in order. The rat has a portion of its stom-
ach in keratinized form with unknown stomach emptying of oral con-
trolled release dosage forms. Moreover, both the rat and the rabbit
eat their own feces, thereby rendering the composition of stomach
contents and the associated influence of this composition on drug re-
lease and stomach emptying somewhat uncertain.
In summary, because of limited residence time and possible exis-
tence of an absorption window for some drug, control of GI transit
time and site-specific release through specific binding of the drug
delivery system to the absorption site are attractive approaches to
controlled oral administration. With some exceptions, targeting of
drugs is not the primary concern for most orally administered drugs.
Rather, the aim is to increase the amount of drug delivered to, with
concommitant prolongation in, the general circulation. For this rea-
son, most systems employed are of the sustained release type. In
cases where systems are used to target a drug, the site of absorption
rather than the site of action is targetted. The assumption is that
by increasing drug concentration at the absorption site, the amount
of drug reaching the site of action will increase correspondingly.
This is exemplified by colon drug delivery [277-279].

C. Buccal /Sublingual
Drugs can be absorbed from the oral cavity through the oral mucosa
either sublingually (under the tongue) or buccally (between the cheek
and gingiva). In general, rapid absorption from these routes is ob-
served because of the thin mucous membrane and rich blood supply.
For highly hydrophilic drugs (log P < 2), which also suffer from ex-
tensive presystemic elimination and require a rapid onset of action,
sublingual or buccal administration may offer advantages over oral
administration. After absorption, drug is transported through the
deep lingual vein or facial vein which then drains into the general
circulation via the jugular vein. Thus, the buccal and sublingual
routes can be used to bypass hepatic T,first-passTT elimination. Lym-
phatic uptake of drug also occurs, but is less common [280].
Drug absorption into the oral mucosa is mainly via passive dif-
fusion into the lipoidal membrane [281-283]. Compounds with favorable
oil-to-water partition coefficients are readily absorbed through the
oral mucosa. Since the mean pH of saliva is 6.0, adequate absorp-
tion through the oral mucosa occurs if the pK a is greater than 2 for
an acid or less than 10 for a base. An oil-water partition coefficient
range of 40-2000 is considered optimal for drugs to be absorbed
sublingually [284,285]. Compounds administered by either the buccal
 Influence of Drug Properties on Design I 43

or sublingual routes include steroids, barbiturates, papain, trypsin,

and streptokinase-streptodornase [282]. Besides transcellular diffu-
sion, there is evidence that water-soluble molecules with a molecular
volume of less than 80 cm3/mole cross primarily through membrane
pores and large water-soluble molecules pass paracellularly [285].
Regardless of polarity, large molecules are poorly absorbed [286, 287].
Conventional buccal and sublingual dosage forms are typically
short acting because of limited contact time between the dosage form
and the oral mucosa. Since sublingual administration of drugs inter-
feres with eating, drinking, and talking, this route is generally con-
sidered unsuitable for prolonged administration. On the other hand,
the duration of buccal drug administration can be prolonged with
saliva-activated adhesive troches without the problems of sublingual
administration [288]. Unfortunately, the buccal nitroglycerin adhesive
troche has yet to be met with commercial success [289] .

D. Rectal

The rectal route is commonly used as an alternative when oral admin-

istration is inconvenient because of inability to swallow or because of
gastrointestinal side effects such as nausea, vomiting and irritation.
More important, rectal drug administration has the advantage of mini-
mizing or avoiding hepatic first pass metabolism [290,291]. For in-
stance, the rectal bioavailability of lidocaine in man is 65%, as com-
pared to an oral bioavailability of 30% [291].
The human rectum is about 15-20 cm long. In the resting state
the rectum does not have any active motility. Normally the rectum
is empty and contains only 2-3 ml of inert mucous fluid (pH 7-8)
which has no enzymatic activity or buffering capacity. There are
no villi or micrivilli on the rectal mucosa and thus, a very limited
surface area (200-400 cm^) is available for absorption. The internal
volume of the rectum depends on the pressure exerted on the rectum
by the surrounding organs. This pressure, together with motility,
affects spreading of a dosage form.
Both blood and lymphatic vessels are abundant in the submucosal
region of the rectal wall. The upper veins drain into the portal cir-
culation, while the lower and middle veins drain directly into the
inferior vena cava. However, there are extensive anastomoses among
these veins, so that a clear-cut anatomical differentiation cannot be
made. Nevertheless, systemic bioavailability seems to depend on the
site of absorption in the rectum [292], rectal motility [293], as well
as animal species [291].
In general, absorption occurs at a slower rate and to a lesser
extent than after oral drug administration with a particular dose
[294] . Drug absorption from the rectum is assumed to occur by
mechanisms similar to those operating in other parts of the GI tract,
44 / Li et al.

i . e . , passive diffusion [295,296]. For poorly water-soluble drugs,

the rectal absorption rate is determined by the release surface area
rather than by drug concentration in the dosage form. Absorption
from aqueous and alcoholic solutions is in general much faster than
that from suppository, which is often very much dependent on the
particle size of the active ingredient as well as on the nature of the
suppository base, surfactants and other addditives [294-298].
Recently, some non-surfactant adjuvants, such as the salicylates,
have been found to enhance rectal absorption of water-soluble drugs
[298-301] and high molecular weight drugs like insulin, heparin, and
gastrin [302-304]. Some peptides, such as N-acyl derivatives of col-
lagen peptide [305], have also been found to exert a self-enhancing
effect [306]. Apparently, a high local concentration and/or simul-
taneous absorption of the adjuvants are required to alter membrane
permeability, thereby assuring rapid drug absorption in the rectum
[300,304], Membrane permeability enhancement by non-steroidal anti-
inflammatory drugs is reversible [307] whereas that by surfactant
adjuvants and chelating agents is not [308] .
Design of rectal controlled release drug delivery systems is likely
to be limited by some inherent problems of the rectal area, including
interruption of absorption by defecation and, in certain parts of the
world, lack of patient acceptance of this route. Only a limited num-
ber of compounds given rectally have been shown as effective as when
given orally [309]. Thus, this route may serve as an alternative
pathway to oral administration for compounds that undergo extensive
first-pass metabolism or for high molecular weight/enzymatically sen-
sitive compounds such as insulin and heparin.

E. Nasal
For many years, the nasal route was used primarily for local action
on the nasal mucosa. Despite its use in systemic delivery of desmo-
pressin and vasopressin, its use as an alternate route for poorly ab-
sorbed oral drugs seems to have been ignored until recently. A
variety of drugs including propranolol [310] , testosterone [311] ,
naloxone [312], buprenorphrine [312], ergotamine tartrate [313],
clofilium tosylate [314], cromolyn sodium [315], meclizine [316], as
well as endogenous hormones such as luteinizing-hormone-releasing
hormone [317], tetracosactrin [318], oxytocin [319], ACTH [320],
insulin [321-324], and enkephalins [325], have been shown to be
absorbed nasally in animals and humans. By virtue of relatively
rapid drug absorption, possible bypassing of presystemic clearance,
and relative ease of administration, delivery of drugs by the nasal
route offers an attractive alternative for administering systemically
active drugs.
The anatomy of the nasal cavity is described in detail elsewhere
[326,327]. The thickness and vascularity of the mucous membrane
 Influence of Drug Properties on Design I 45

lining the nasal cavity depends on location. The mucous membrane

is thickest and most vascular in the upper regions and over the sep-
tum, whereas it is very thin on the floor of the nasal cavity and in
the sinuses. The surface area of the nasal cavity is increased by
the sinuses, where most drug absorption occurs [328]. The absorp-
tive surface area is further increased by the microvilli in the mucous
membrane. The vascular bed of the nasal mucosa provides rapid ab-
sorption with little metabolizing capacity. The pH of nasal mucosal
surface is reported to be around 7.4 [328].
Dosage forms must deposit and remain in the nasal cavity suffici-
ently long for effective absorption to occur. Aerosol and particulate
dosage forms should contain particles greater than 4 ym to minimize
their passage into the lung [329] , where mucociliary clearance will
remove most particulate materials. However, before nasal delivery
can be a viable alternative route for systemic drug absorption, it
will be necessary to have a better understanding of how to control
particle deposition within the nasal cavity reproducibly, how drug
and particle interact with mucus, and how certain disease states of
the nasal mucosa may affect the rate and extent of drug absorption.

F. Pulmonary
Delivery of medication to the respiratory tract for localized therapy
of respiratory diseases is commonly accomplished via the airways be-
cause of their enormous surface area and accessibility [330] . The
respiratory tract consists of a nasopharyngeal region, a tracheo-
bronchial region, and lungs (bronchioles and alveoli). The diameter
of the dichotomous branchings of the bronchial tree decreases in the
distal parts of the respiratory tract, with a simultaneous increase in
total cross-sectional area and the total surface area [331]. Thus,
the flow in the central airway is rapid and turbulent, whereas flow
in the peripheral airways is smooth and laminar [332] . The total sur-
face area of alveoli in an adult is about 35 m2 during expiration and
about 100 m2 during deep inspiration [333] . Thus, most solute ex-
change takes place at the alveolar level.
For purposes of discussion of the deposition and clearance of
inhaled aerosols, the airways can be divided into three functional
regions [334] (Fig. 2):

1. Nasopharyngeal region—cavity to entrance of trachea

2. Tracheobronchial region—trachea to terminal bronchioles
3. Pulmonary region—bronchioles to alveoli, no ciliated cells

In general, prediction of the site of deposition of an aerosolized

drug is difficult because airway sizes and anatomy differ from person
to person and appear to be influenced by pathological changes.
46 / Li et al.

Naso pharyngeal:
particles greater Pharynx
than 5^im deposited
Larynx
Tracheo bronchial1
particles between Trachea
2 and 5 ^m deposited Primary bronchi
in this region Secondary bronchi
Pulmonary: Terminal bronchioles
particles less than
2>um deposited by Respiratory
bronchioles
diffusion and random Alveolar duct
capture.
Alveoli

Fig. 2 Disposition of particles in various regions of the respiratory

tree.

Moreover, alterations in regional ventilation that result from lung

disease can influence the site at which a drug is deposited [335-337].
Deposition of aerosolized particles is mediated by a variety of mechan-
isms, depending on particle size, shape, density, charge and hygro
scopicity [338,339]. The geometry of the airways and physiological
factors such as breathing patterns, air flow dynamics in the respira-
tory tract, and variations of the relative humidity and temperature
inside the airways also influence deposition. The influence of particle
size on aerosol deposition is depicted in Figure 3 [340] .
Therapeutic aerosols are typically polydispersed with sizes ranging
from 1 to 10 ym (341). These particles are small enough to be carried
down the respiratory tract with inspired air [342] . Large particles
(>5 ym) are usually deposited via inertial impaction on the upper
airways, where air velocity is high [341]. Pathological changes usu-
ally increase the inertial impact by narrowing the airways [339,341].
Moderate size particles ( 1 - 5 ym) can sediment out of the air stream
under the force of gravity. Deposition by sedimentation occurs pre-
dominantly in the lower levels of the airways, where air velocity is
low [341]. Thus, peripheral deposition of aerosols is maximized by
inhaling slowly, followed by a period of breath holding [339]. For
submicron particles, diffusion becomes important. All particles smal-
ler than about 10 ym in diameter are deposited to some extent in the
pulmonary region of the lung upon inhalation, while deposition of
particles smaller than 0.01 ym is usually negligible because of diffu-
sional deposition in the nasopharyneal and tracheobronchial regions.
Thus, the efficiency of deposition of intermediate size particles
[0.02-1.0 ym] is less compared to larger and smaller sizes.
Particulate material deposited in the respiratory tract may eventu-
ally be cleared by mucociliary action and/or the lymphatic system
 Influence of Drug Properties on Design I 47

and/or may be transferred to the blood [340,343] (Fig. 4). The

physiocochemical characteristics of aerosols, site of deposition, and
respiratory physiology are important determinants of clearance.
Soluble deposited particles, on the other hand, are cleared via ab-
sorption into the blood stream. Clearance of insoluble particles de-
posited on the ciliated regions of the respiratory tract is mainly
via mucociliary transport [335,342,343], whereas those deposited on
the non-ciliated surfaces of the pulmonary region may be phagocy-
tized by macrophages [344,345] or may leak into the interstitium [346],
which may then be translocated to a lymph node [347] . The mechan-
isms of deposition and clearance are summarized in Table 12.
Once the aerosolized drug particles deposit on the alveolar sur-
face, they must cross the alveolar-capillary barrier before reaching
the systemic circulation. Both alveolar epithelium and pulmonary
capillary endothelium are continuous, but the former has more tight
junctions than the latter [348-350]. Physiological measurements give
an equivalent pore radius of 8-10 A for alveolar epithelium and 20-
200 A for capillary endothelium [351,352]. Thus, the alveolar epithe-
lium has a much lower permeability to liquids and solutes than the
pulmonary endothelium. Of special interest is the large number of
pinocytotic, lamellar vesicles, many of which discharge their content

100 r-

Alveolar and
terminal airway
^ 801— deposition
/ Mouth breathing

iZ 60
o
Q.
Q 40

20
2 '•/. ••"
/
0 1 2 4 6 8 10
%
Submicron
range PARTICLE DIAMETER (/xm)

Fig. 3 Effect of particle size on deposition of particles in various

regions of the respiratory t r e e . The curves indicate the proportion
of total material of any particle size likely to deposit upon an internal
surface: __•_•_> nasal compartment; , tracheobronchial com-
partment; , pulmonary compartment. (From Ref. 340.)
 AIRBORNE PARTICLES

Nasal
l . Mouth breathing

Oral

f
— / \
Mucociliary escalator L^— Pharyngeal
7 0 % deposition ^"v
(10-30/im)
L
astrointestinal tract

Tracheobronchial Blood
Urn—
6 % deposition (depending on
(10/im) solubility)
J
Lower airways 8 lungs
2 4 % deposition
(5/im -lower airways) Lymph
nodes
(< 1 /Am -alveolar
1 ^ parenchyma) Peribronchial
and
subpleural
lymphatic
T Macrophages •-Interstitial
H
channels
space

EXCRETION
Residue

Fig. 4 The ultimate distribution of particulate material inhaled and de-

posited in airways and lungs, as affected by lung clearance mechanisms.
The figures in individual compartments represent the proportions that
are typically likely to be deposited of an inhalable dust of uniform par-
ticle size distribution. Solid arrows indicate major routes, and dotted
arrows indicate minor routes of particle distribution. (From Ref. 340.)

Table 12 Deposition and Clearance of Inhaled Aerosols

Region Deposition Clearance

Nasopharyngeal Impaction Mucociliary

Diffusion Sneezing
Interception Blowing
Attraction Dissolution

Tracheobronchial Impaction Mucociliary

Diffusion Coughing
Settling Dissolution
Interception
Attraction

Pulmonary Diffusion Dissolution

Settling Phagocytes
Attraction Lymph flow
Interception
 Influence of Drug Properties on Design I 49

into the capillary lumen [353,354]. These vesicles contain enzymes

for metabolism of adenine nucleotide and angiotensin I [354]. The
basal lamina subtending the cellular layers offer a substantial barrier
to the penetration of large molecules [355] .
In general, drug absorption from the lung is considerably faster
than from the intestine [356] . However, the nature of drug transport
from the pulmonary epithelium to blood is poorly understood. Results
to date reveal that, the absorption rate of small lipophilic molecules
is related to the oil/water partition coefficient [357], whereas the ab-
sorption rate of some organic cations and anions as well as neutral,
hydrophilic saccharide molecules appears to be related to molecular
size, suggesting diffusion through aqueous membrane pores [357].
While large hydrophilic molecules such as aminoglycoside antibiotics
are poorly absorbed [357] , others such as phenol red [358] and crom-
olyn sodium [359] appear to be better absorbed when compared to
oral absorption. However, this is primarily the result of a saturable
carrier-type transport process in the pulmonary epithelium [358,359].
For drugs used for local treatment of pulmonary disorders, it is
desirable that the drug exert a local effect with minimal systemic ab-
sorption [360,361]. Successful use of inhaled corticosteroids in the
treatment of asthma with minimal systemic side effects was due to
metabolism of the drug prior to entry into the circulation [362] . It
appears that presystemic metabolism of drugs delivered by the intra-
bronchial route may differ quantitatively from their metabolism follow-
ing systemic administration [363,364]. Besides metabolism, the lung
can also bind and accumulate drugs, especially basic d r u g s . This
binding is mostly reversible [365] and can prolong duration of the
drug in the body.
In summary, the efficiency of delivery of drugs via the airways
is relatively poor in man. As much as 90% of the instilled dose may
impact in the mouth and pharynx or be swallowed without ever reach-
ing the lung. Thus, success of pulmonary delivery will depend on a
number of factors. First, drugs used in aerosols must be quite po-
ent but with negligible systemic side-effects. Second, the drug must
be able to gain access to its target site. Third, drug must bind to
tissue components thereby providing a high local concentration for
prolonged periods. Finally, better aerosol delivery from nebulizers
is needed to enhance the amount of drug reaching the lung. Never-
theless, controlled delivery of drugs to the respiratory area is useful
mainly for localized treatment of inflammation or cancer. It is unlikely
that this route will supplant the oral or intravenous routes to achieve
systemic effects.

G. Vaginal
Intravaginal controlled release drug administration of steroidal com-
pounds or spermicidal agents is aimed at obtaining contraception for
50 1 Li et al.

prolonged periods with minimal systemic side effects. In general,

most steroids are readily absorbed so that their bioavailability after
intravaginal administration is higher than from oral administration be-
cause of a reduced first-pass metabolism [366,367]. Recently, the
vaginal route has also been investigated for peptide and protein drug
delivery [368,369].
The human vagina is a fibromuscular tube 4 to 6 in. long, directed
upward and backward, extending from the vulva to the lower part of
the uterine cervix. It is in the form of a collapsed tube under nor-
mal conditions. The vagina is drained by a rich plexus, which em-
pties into internal iliac veins [370]. Blood supply to the vagina is
via uterine and pedendal arteries, which arise from the iliac artery.
The vagina consists of three principal layers: an outer fibrous
layer, a middle muscular layer, and the epithelial layer. The epitheli-
al layer consists of lamina propria and a surface epithelium [370] ,
which is composed of noncornified, stratifeid squamous cells. The
vaginal epithelium is essentially devoid of glands, but its surface is
kept moist by a cervical secretion, whose composition and volume
varies with age, stage of menstrual cycle, and degree of sexual ex-
citement [371] . After puberty, the pH of vaginal fluid varies between
4 and 5 depending on the stage of the cycle and location [372] . Cells
of the superficial mucosal layer contain a high level of glycogen,
which is metabolized to lactic acid (pK a = 3.79) in the vaginal canal
to maintain the vaginal pH on the acidic side. The pH is lowest
around the anterior fornix and highest around the cervix.
Higuchi et al. have developed an in situ method to study vaginal
abosrption in the rabbit [373] and monkey [374]. The absorption
rates of a series of unbranched aliphatic alcohols from methanol to
octanol in the rabbit vagina were found to be first-order and increased
with increasing chain length [375]. The barrier of absorption appears
to consist of an aqueous diffusion layer in contact with the membrane,
which in turn is composed of parallel lipoidal and aqueous pore path-
ways [376]. For drugs with high membrane permeability, vaginal
absorption is determined by permeability of the aqueous diffusion
layer; whereas for drugs with low membrane permeability, such as
testosterone and hydrocortisone, vaginal absorption is determined by
membrane permeability. Similar results were obtained with alcohols
in the monkey [374] and 1-alkanoic acids in the rabbit [376]. No
correlation between vaginal membrane permeability and menstrual cycle
was found in the monkey [377]. However, at ovulation, the monkey's
vaginal permeability is several-fold lower than that of the noncyclic
rabbit [378].
Two major types of intravaginal controlled release systems are
available: vaginal rings [379-386] and microcapsules [387-390]. The
rationale for vaginal ring steroid-releasing systems is based on the
observation that steroids readily penetrate the vaginal mucosa [391]
 Influence of Drug Properties on Design I 51

and that the vagina can accomodate foreign bodies of reasonable size
with minimal discofort for an extended period of time. There are
two common types of vaginal rings: homogeneous [380] and shell [385].
Burst effect of drug release on insertion and a declining release rate
after extended wear are commonly observed with homogenous rings.
Shell rings apparently minimize the burst effect and are able to main-
tain a steady drug release rate. For most vaginal rings, the rate of
vaginal drug absorption shortly after insertion is controlled by either
an aqueous hydrodynamic diffusion layer or by the vaginal wall. At
later times, the rate of vaginal absorption is determined by the drug
release rate from the ring [392].
Reported problems associated with the use of vaginal rings are:
erosion of the vaginal wall, ring expulsion, interference with coitus,
unpleasant ring odor, and difficulty with storage and sanitation [393],
These problems are usually the major causes for discontinued use of
vaginal rings and, because of these problems, vaginal rings have re-
ceived only moderate acceptance.
A potential intravaginal contraceptive system free of most of the
aforementioned problems is the biodegradable microsphere. The ratio-
nale for its development is that inert particles have been demonstrated
to be able to migrate from the vagina across the cervix into the fallopi-
an tube or the perimetrial lining of the uterus without causing erosion
of the vaginal wall by virtue of its small size [294,295] .
Microspheres for intracervical administration have also received
attention. Small doses of progesterone can be released locally to alter
the structure of the cervical mucus so as to interfere with sperm
migration [396] . In addition, a medicated intracervical system has
been tested [397] . The rationale for its development is that contrac-
tility is less severe in the lower segment of the uterus, especially the
cervix. This system still incurs the problems of expulsion and pos-
sibility of infection and does not offer enough advantages over exist-
ing intravaginal or intrauterinal systems to be worth pursuing.

H. Intrauterine
The effectiveness of nonmedicated intrauterine devices (IUDs) is pri-
marily dependent on the relationship of the device morphology (size,
shape, and area) to uterine geometry [398]. The human uterus is a
pear-shaped, muscular structure, about 3 in. in length and about 2
in. wide, consisting of a body, fundus, isthmus, and cervix. Its
wall has three layers: an external peritoneal layer (perimetrium) , a
middle muscular layer (myometrium), and an inner mucous membrane
(endometrium). This organ undergoes dynamic changes in the size
and shape of its various segments during different phases of the
menstrual cycle [399]. Lack of structural adaptability and unfavor-
able geometry of the device may lead to clinical complications such
52 / Li et ah

as expulsion, bleeding, infection, perforation, and pain. It appears

that the mode of action of nonmedicated systems originates promptly
in the uterus, disappears rapidly, is not affected by menstruation
and does not interfere with the normal estrogen-progesterone balance
[400],
The objectives in the development of medicated IUDs are to enhance
their contraceptive effectiveness with concomitant reduction in pain
and bleeding. These objectives are achieved by using small devices
and the incorporation of antifertility agents such as steroids and/or
antifibrinolytic agents-proteinase inhibitors such as aminocaproic acid,
tranexamic acid and aprotonin, and/or antiprostaglandins.
Since the contraceptive action of the medicated device lies mainly
with the antifertility agent itself but not with the structural features
of the device, the geometry and size should be designed for minimal
clinical complications. The T or 7 configurations came closest to the
ideals set forth above [ 401] . The major contraceptive agents employed
in medicated IUDTs include copper, progresterone and levonorgestrel.
The most extensively studied IIJD's have been Progestasert R and
Cu-7^.
The concept of continuous intrauterine administration of proges-
terone is based on these observations: (a) local effect of progester-
one on the uterus might reduce the incidence of expulsion and bleed-
ing provoked by the inert device, (b) the estrogenic component of
oral contraceptives is not essential for contraception, and (c) progestin-
only mini-pills provide adequate contraception, possibly by preventing
blastocyte implantation without inhibiting ovulation. The ProgestasertR
system is a T-shaped progesterone-containing drug delivery system
enclosed by a rate-limiting membrane. It releases 65 yg/day for a
period of 1 year.
Cu-7R is a polypropylene 7-shaped device with 89 mg of copper
wire surrounding the vertical arm, giving a surface area of 200 mm^
of copper, which is released at 9.87 yg/day for up to 40 months.
The exact mechanism by which copper works as a contraceptive agent
is unclear. Copper is known to be cytotoxic if present in sufficiently
high concentrations [402]. It interferes with implantation of the fetus
in rats [403], enhances the spermatocidal and spermatodepressive
action of the IUD [404] , and inhibits the binding of estrogen and
progesterone to their receptors [404] .
Levonorgestrel-releasing IUDs have also been studied clinically.
Since levonorgestrel is effective at concentrations lower than those
required with progesterone, the system can have a life time of about
7 years. Furthermore, it is believed that levonorgestrel offers a
balance of estrogenic and progestational activity, which may lessen
intermenstrual bleeding [405].
Future research in intrauterine controlled drug administration
will depend on increased understanding of reproductive physiology
 Influence of Drug Properties on Design I 53

so that contraception can be achieved by interference with pertinent

reproductive processes at the right time with minimal side effects.
Future research will most likely focus on minimizing intermenstrual
bleeding and pain, searching for longer duration systems as well as
self-regulating drug delivery systems. An example of a self-
regulating system may be one that utilizes human chorionic antibodies
as a sensor, so that drug delivery will occur only when an egg has
undergone fertilization, but not at other times [406].

I. Transdermal
The skin is one of the most extensive and readily accessible organs
of the human body. It covers an area of about 2 m2 and at any
point in time is in contact with about one-third of all blood circulating
through the body [407]. Skin consists of three tissue layers: epi-
dermis, dermis, and hypodermis (subcutaneous tissue). The rate-
limiting step in percutaneous absorption of most drugs appears to be
passage through the stratum corneum [408-414] . The pathway of
drug movement through this layer is believed to be mainly transcellu-
lar, although the paracellular pathway may become important for small
molecular weight compounds [408] . In addition to being a diffusion
barrier, the stratum corneum also serves as a reservoir for compounds
such as corticosteroids, griseofulvin and many other drugs. While
drugs are carried away by the capillary network upon reaching the
subcutaneous tissue, there is evidence that certain drugs such as
thyroxin, 3-methoxypsoralen, estradiol and corticosteroids, remain
in this layer for an extended period of time [415-417]. Such locali-
zation of drugs may prove desirable for exerting local effects in deep-
er tissues of the skin or for prolonged release of drugs.
In the past, topically applied dermatological drugs were used for
localized treatment of skin diseases only. Recently, due to a better
understanding of the anatomy and physiology of the skin as well as
a more thorough understanding of percutaneous absorption, the limited
permeability of human skin has also been utilized for systemic drug
administration.
There are several advantages to the transdermal route provided
the drug is absorbed in sufficient quantity to exert a systemic effect.
Thus, it is possible to:

1. Avoid hepatic "first-pass" metabolism and gastrointestinal

incompatibility of drugs
2. Provide controlled administration for drugs with narrow thera-
peutic indices, thereby reducing side effects or inadequate
dosing
3. Allow utilization of drugs with short biological half-lives
4. Enhance therapeutic efficacy
54 I Li et al.

5. Reduce frequency of dosing

6. Improve patient compliance
7. Permit relatively abrupt termination of drug effect by removal
of the patch from the skin surface

These advantages aside, systemic drug absorption from ointments

or creams is commonly unpredictable, partly because of variability in
skin permeation and partly because of the difficulty in delivering a
dose reliably. The use of rate-controlled tranddermal drug delivery
systems appears to minimize these two problems. However, because
of the relatively low permeability of skin by most drugs, these systems
are only applicable for highly potent drugs which permeate the skin
rapidly, which cause no irritation to the skin, and which are relative-
ly stable to enzymes present in the epidermis. The additional require-
ment is that the drug delivery system rather than the skin acts as
the rate-limiting step in the overall transport process [418]. Drugs
such as scopolamine [419], nitroglycerin [420,421], and clonidine [422]
have been administered in this fashion.
The low skin permeability of most drugs necessitates the use of
penetration enhancers such as dimethyl sulfoxide [423], urea [424],
and, more recently, Azone R [425,526]. One of the major difficulties
associated with penetration enhancers is lack of specificity. This,
coupled with a lack of understanding of their mechanism of action,
limits the rational design and use of penetration enhancers.
Occlusion has been shown to enhance drug absorption across the
skin. It appears to do so partly by increasing hydration of the
stratum corneum and partly by raising the temperature of the skin
surface. However, the contribution of changes in blood flow due to
this treatment is still unclear [412].
Ion-pair formation between a carrier molecule and an anionic drug
has been proposed to enhance penetration [427] . This approach takes
advantage of the pH gradient that exists across the stratum corneum
and the hydrophilic nature of the viable epidermis. Another approach
to improve penetration of poorly absorbed molecules is the use of
prodrugs [428-430]. In this case, the metabolic activity of the skin
is used to transform prodrugs to active drugs. With a better under-
standing of metabolizing enzymes in the skin, the use of prodrugs
can be an attractive approach. Theoretical considerations suggest
that this is a useful approach in enhancing drug permeation [431,432].
One factor that has not been extensively studied is the influence
of pathological states in skin permeability. Bronaugh and Stewart
[316], Scott et al. [433], as well as Flynn et al. [434], have con-
ducted studies on drug absorption through abnormal and damaged
skin. A better understanding of percutaneous absorption through
diseased skin is needed for effective treatment of cutaneous diseases.
 Influence of Drug Properties on Design I 55

J. Ocular

For treatment of many disease affecting the external eye and anterior
segment of the eye, topical instillation is preferred over systemic ad-
ministration because a high drug concentration at the absorbing mem-
brane can be obtained, thereby maximizing drug delivery to the af-
fected tissues while minimizing systemic side effects. However, topi-
cal application of drugs to the eye is impeded significantly by effici-
ent ocular physiological protective mechanisms, such as drainage, tear
turnover, limited permeability of corneal membranes to most drugs,
and aqueous humor turnover. Typically, drug from an instilled aque-
ous solution is essentially eliminated from the precorneal area within
1-2 min of application [435] , so that less than 3% of an applied dose
penetrates into the aqueous humor following topical instillation of an
aqueous solution [436]. The duration of drug action is, therefore,
brief, and frequent dosing is needed.
The duration of drug action in the eye can be extended by two
approaches: (a) reducing drainage through the use of viscosity-
enhancing agents, suspensions, emulsions, ointments, erodible and
nonerodible matrices [437] and (b) improving corneal drug penetration
through the use of ionophores [438], ion-pairs [439], liposomes [440],
and prodrugs [441]. For low viscosity solutions, the improvement
in ocular bioavailability is usually modest [442-444]. Suspensions
and emulsions suffer from the same problem as low viscosity solutions
in that the contact time, though lengthened, is still relatively brief.
Moreover, in the case of suspensions, the solid particles must dissolve
slow enough to offer an advantage over a saturated solution [455].
The release rate of drug is usually rapid from swollen hydrophilic
matrices such as soft contact lenses. Release rate from lipophilic
ointments can be slower, but these systems suffer from the problem
of blurring vision thus reducing their use to night time medication.
The use of ion-pair and ionophores is limited to a small group of drugs
and their improvement is still considered moderate [438,439]. Lipo-
somes appear to be able to enhance the absorption of large, hydro-
philic molecules [446-450] and may prove to be useful in delivering
macromolecules such as peptides and proteins. Their usefulness in
delivering lipophilic molecules seems to depend on the way the drugs
are incorporated into the liposomes [446,447,450] . The use of lipo-
somes in ocular drug delivery has been reviewed [440].
Prodrugs can be used to improve ocular bioavailability by enhanc-
ing corneal penetration, protecting the parent compound from meta-
bolism, or decreasing its elimination. Recently, the first ophthalmic
prodrug, dipivalyl epinephrine, was marketed under the trade name
Propine-^. With improved corneal penetration characteristics, a much
lower dose of epinephrine is needed, thereby reducing side-effects.
Via a different mechanism to affect ocular drug absorption, systems
56 I Li et al.

such as OcusertR [451] and erodible matrices [452], which provide

controlled drug delivery to the conjunctival sac, are able to reduce
fluctuations commonly observed with pulse-entry systems, thereby
allowing the use of drugs with very short biological half-lives. More-
over, systems such as Ocusert R do optimize precorneal delivery of
drug. Unfortunately, patient acceptance of these systems is unsatis-
factory partly because they are easily expelled during sleep.
In summary, the currently available ocular drug delivery systems
are far from ideal. Future research should be directed toward con-
trolled delivery to the absorbing surface with minimization of non-
productive loss. Since eye-drops are the most acceptable dosage form,
it appears that the ideal dosage form should be of low viscosity but
reside near the absorbing surface for an extended period of time and
release its drug in a controlled manner.

VIII. DRUG TARGETING

The objective of drug targeting is to achieve a desired pharmacological

response at a selected site without undesirable interactions at other
sites. This is especially important in cancer chemotherapy and en-
zyme replacement treatment. At present, drug targeting is achieved
by one of two approaches. The first approach involves chemical modi-
fication of the parent compound to a derivative which is activated only
at the target site [453,454]. The second approach utilizes carriers
such as liposomes [455,456], microspheres [457], nanoparticles [458],
antibodies [459-461], cellular carriers (erythrocytes and lymphocytes)
[462,463] , and macro molecules [464,465] to direct the drug to its site
of action.
There are a variety of strategies to modify the chemical structure
of drug molecules, the most common being the prodrug approach and
the most sophisticated being the chemical delivery system approach
(Chapter 8). A prodrug is an inactive chemical derivative of a par-
ent compound that is activated predictably in vivo to the active drug
species, but, with few exceptions [466], it cannot achieve site-specific
delivery [467], In contrast, a chemical delivery system involves
transformation of the active drug by synthetic means into an inactive
derivative which, when placed in the body, will undergo several pre-
dictable enzymatic transformations principally at its site of action.
This approach has proven to be successful in local delivery of drugs
to the eye, brain and testes [454,468].
Because of impermeability of the GI tract to most macromolecules
and instability of the drug-carrier complex in the hostile environment
of the GI tract, administration of large drug-carrier complexes is
restricted to intravenous or intraarterial injections or to direct in-
jection into the target tissue such as a tumor. At present, the major
 Influence of Drug Properties on Design I 57

obstacle of drug targeting using macromolecular and particulate car-

riers is rapid sequestration of intravascularly administered drug car-
riers by mononuclear phagocytes of the reticuloendothelial system
(RES) [469-470] . Because of rapid clearance, only a small fraction of
the injected carrier untimately reaches the target, if at all. The ap-
proaches have been attempted to alleviate this problem. The first
involves blocking the RES prior to administering the drug carrier
[471,472]. However, paralysis of the RES is undesirable especially
in cancer patients. Without the first-line defense mechanism of the
RES against infectious agents, these cancer patients will be at risk
to infections.
A second approach is to impart specificity to the drug carrier
by coupling specific ligands onto its external surface. These include
desialylated fetulin [427], erthyrocyte membrane glycoproteins [473,
474], heat aggregated immunoglobulins [475], monoclonal antibodies
[460], and native immunoglobulins [476]. So far, none of these
strategies has proven to be successful due to difficulties in preserv-
ing the recognition ability in vivo and avoiding triggering any im-
munological response.
Another obstacle in targeting particulate drug carriers is the
vascular system itself. This subject has been carefully reviewed by
Poste [477] as well as by Poznansky and Juliano [478]. In order
for a drug carrier to be able to recognize the target, it must first
extravasate. The vascular endothelium of most tissues and organs,
being continuous with an effective pore diameter of 2 nm, is essenti-
ally impermeable to molecular assemblages such as liposomes (0.025-
5.0 pm) and nanoparticles (<1 urn). Significant extravasation of the
structures in this size range is only possible at those sites with a
discontinuous endothelium, notably in the sinusoids of the liver and
spleen, where the effective pore diameter is approximately 100 nm,
Thus, most particulate matter is confined to the general circulation.
On the positive side, impermeability of the capillary endothelial
lining may be a useful property under certain conditions: (a) confine-
ment of drug within a physiological compartment, (b) use of particles
whose direction or release characteristics are under external control,
and (c) drug delivery to the lung, liver and spleen.
Two forms of external control have been explored. Liposomes
can be made from lipids with release characteristics which are a func-
tion of a temperature gradient [479] due to either local inflammation
or localized heating via collimated radiation. Drug is released from
circulating liposomes as they pass through the target region [480].
Another approach involves the use of microspheres of denatured al-
bumin [457] and, more recently, Sephadex R [481] containing ferro-
magnetic particles. The microspheres are restricted at the micro-
vascular level under the influence of a directed external field. En-
hanced drug delivery to the target, in theory, can be achieved by
this approach.
58 / Li et al.

PASSIVE TARGETING

-PMS uptake 8 lysosomotropism

H | capillary
tsieve plate blockage
passage

normal
ACTIVE TARGETING capillary
diameter
I—antibody-antigen events H
h-extracorporeal guidance H
OOI I lymphotropism 1 4 7 10 100

01 I 4

MICROSPHERE DIAMETERS (MICRONS)

Fig. 5 Strategies i n achieving d r u g t a r g e t i n g . (From Ref. 483.)

Microspheres have also been used for passive targeting to organs

such as the liver, spleen, lung and kidney (Fig. 5) [482,483]. In-
travenous injection of particles between 7 and 12 ym leads to mechan-
ical filtration by the lungs, whereas particles between 2 and 12 ym
leads to their blockage in the first capillary bed encountered. Such
blockage can lead to first-order targeting of, for example, the liver
and kidney, and second-order targeting to tumor-bearing organs [484]

MICROSPHERE

TARGET

Fig. 6 Method of chemoembolism to achieve drug targeting.

 Influence of Drug Properties on Design J 59

This latter effect is probably due to a qualitative and quantitative

difference in the capillary networks of the tumor compared to those
of the host organ [485],
Recently, intraarterial injection of biodegradable microspheres
was used to produce a tumor chemoembolism in cancer chemotherapy
[486-488]. Figure 6 gives the rationale behind this use. A mixture
of drug and starch microspheres (about 40 ym) were injected together.
The large size of microspheres caused temporary blockage of the tumor-
bearing organ's arteriole, thereby increasing absorption time of the
drug by the tumor organ. However, obstruction of the feeder vessels
of a tumor using microsphres by themselves could also bring about
tumor regression [489] .
In addition to the difficulties encountered by carriers to extrav-
asate, drug targeting by carriers also suffers from such problems as
stability of the carrier on storage and in vivo, drug loading, immuno-
genicity, and degradability. Consequently, except for passive target-
ing to the reticuloendothelial system of the liver and spleen, the con-
cept of systemic drug targeting via carriers and biological recogniza-
tion has met with little success. It is clear that, for successful tar-
geting, a better understanding of diseases and the biology of the
body at a cellular and molecular level is needed.

IX. CONCLUSIONS

In the past decade, the number of new drug entities appearing on the
market yearly has declined and pharmaceutical manufacturers for a
variety of reasons have a renewed interest in improving existing
dosage forms and developing more sophisticated drug delivery systems,
including those employing the principles of sustained/controlled drug
release. The need for a sustained/controlled release preparation often
arises: (a) as a result of undesirable drug properties, such as short
biological half-life, local irritation, extensive metabolism, and narrow
therapeutic index, (b) perhaps through the nature of the disease
state, or (c) for patient compliance reasons. Most important of all
is the need to improve the efficacy and safety of drug through proper
temporal and/or spatial control of drug release.
In considering a drug for this mode of drug delivery, certain
criteria have to be examined and evaluated. These are the physico-
chemical, pharmacokinetic and pharmacodynamic characteristics of the
drug. With each drug property there is a range of values that lends
itself to the design of sustained/controlled release products, and
outside this range the design becomes more difficult or, in the extreme,
prohibitive. Extremes of aqueous solubility, oil /water partition coef-
ficients, binding, extensive metabolism/degradation of the drug dur-
ing transit from the point of drug delivery to the target area, and
60 I Li et ol,

narrow therapeutic index are some of the limiting factors in formulating

an effective sustained release product. Paradoxically, all these limi-
tations are precisely the reasons why controlled release drug delivery
is desirable. Furthermore, advances in biotechnology have brought
about peptides and proteins which, by virture of their chemical and
biological properties, demand special systems for their delivery.
Theoretically, each of these limitations can be overcome and success-
ful controlled drug delivery can be accomplished by using physical,
chemical, biological, and biomedical engineering approaches, alone or
in combination, as described in subsequent chapters.
Throughout this chapter, an attempt has been made to delineate
the influence of drug properties on the design of sustained/controlled
release drug delivery system. Information on the physicochemical
properties of a new or existing drug is usually relatively abundant.
In addition, with the increase in application of pharmacokinetic analy-
sis, there is a steady growth in the volume of information on the
biological parameters of drug action, such as absorption rate constant,
biological half-life and volume of distribution, which may also be avail-
able to the formulator. When examining animal and clinical data in the
literature, th formulator must take into consideration conflicting in-
formation which is not uncommon due to differences in experimental
design and compartmental analysis of the data. Obviously, many of
these uncertainties have to be resolved in the course of evaluating a
drug for sustained/controlled drug delivery. Moreover, for some
drugs, the various biological parameters behave differently in a single
dose vs. a multiple dose situation or in a single dose v s . a continuous
infusion situation [490] . Consequently, multiple dose and perhaps
continuous infusion studies are a necessary prerequisite in terms of
evaluation. Thus, each drug must be evaluated for its potential as
a sustained/controlled release product by examining the complete pro-
file for that drug, being cognizant of the limiting and restraining
aspects of drug properties.
In this chapter, we have also tried to emphasize the importance
of routes other than oral for systemic drug administration. Although
the oral route is preferred for the majority of drugs, it is beset with
numerous potential problems such as possible degradation, first-pass
metabolism, and variable and limited residence time. The transdermal
route has proved to be effective for controlled delivery of certain
drugs. The nasal route is potentially useful to deliver drugs include
peptides and proteins which undergo extensive first-pass metabolism.
The rectal route offers a longer residence time than the nasal and
buccal routes and may allow controlled release of drugs for a day or
two. Replacement of the defecated unit with a new unit may permit
controlled release for extended periods of time. The parenteral route
is currently the preferred route to achieve drug targeting since other
routes are commonly impermeable to drug carrier complexes. Even
 Influence of Drug Properties on Design I 61

this route is beset with the problem of inability of the drug-carrier

complex to traverse the capillary endothelium before reaching its tar-
get in extravascular tissues. Thus, drug targeting has met with
little success except in the case of direct injection into the target
tissues. As a result, placement of the controlled release system in
the vicinity of the target tissue becomes the alternative. This modal-
ity does improve therapeutic drug efficacy allowing the use of a lower
initial dose and less frequent dosing. Ideally, in order to avoid un-
desirable side effects, drug candidates for local treatment should
possess limited permeability or are prone to immediate inactivation
after exerting their local actions.
In the final analysis, a complete knowledge and understanding
of the behavior of a drug and the limitation of a particular route of
administration, as well as judicious selection of the approach, is in-
dispensable to the process of designing a useful controlled release
product. It is the usual case that the desired temporal pattern of
release, i . e . , a constant tissue drug level, is not achieved. In ad-
dition, it has to be realized that, without exception, sustained and/
or controlled drug release products on the market today do not maxi-
mize drug utilization. These products commonly do not take into ac-
count changes in drug need during the course of treatment due to
circadian rhythm, changes in the pathological state, patient variation,
etc. Thus, the term, controlled drug delivery, is used in a rather
loose sense. Nevertheless, these types of products are a significant
improvement over their nonsustained counterparts in terms of temporal
drug level control and patient compliance. The challenge of drug
delivery is the recognition of how far away we usually are from maxi-
mization of drug therapy and the substantial changes that are yet to
be made in the area of controlled drug delivery.

REFERENCES

1. V. F. Smolen and L. A. Ball ( e d s . ) , Controlled Drug Bioavail-

ability, Vols. 1 and 2, John Wiley, New York, 1984.
2. R. I. Langer and D. L. Wise ( e d s . ) , Medical Applications of
Controlled Release, Vols. 1 and 2, CRC Press, Florida, 1984.
3. S. D. Bruck ( e d . ) , Controlled Drug Delivery, Vols. 1 and 2,
CRC Press, Florida, 1984.
4. R. L. Juliano, ( e d . ) , Drug Delivery Systems, Oxford, New York,
1980.
5. J. M. Anderson and S. W. Kim ( e d . ) , Recent Advances in Drug
Delivery Systems, Plenum, New York, 1984.
6. Y. W. Chien, Novel Drug Delivery Systems: Fundamentals,
Developmental Concepts and Biomedical Assessments, Marcel
Dekker, New York, 1982.
62 / Li et al.

7. T . J . Roseman and S. Z. Mansdorf ( e d . ) , Controlled Release

Delivery Systems, Marcel D e k k e r , New Y o r k , 1983.
8. A. F . Kydonienus ( e d . ) , Controlled Release Technologies:
Methods, Theory and Applications, Vols. 1 and 2, CRC P r e s s ,
Florida, 1980.
9. P . Goldman, Rate-controlled d r u g d e l i v e r y , N. Engl. J. Med.
307, 286 (1982).
10. W. A. C h e c k , New d r u g s and d r u g - d e l i v e r y s y s t e m s in t h e y e a r
2000, Am J. Hosp. Pharm. 41, 1536 (1984).
11. N . L. H e n d e r s o n , Recent a d v a n c e s in d r u g delivery system
t e c h n o l o g y , I n , Annual Reports in Medicinal Chemistry, Vol. 18
(H. J . H e s s , e d . ) , Academic P r e s s , New Y o r k , 1983.
12. A. Zaffaroni, Systems for controlled d r u g d e l i v e r y , Med. Res.
Rev. 1, 373 (1981).
13. H. A. S t r u y k e r B o u d i e r , Rate-controlled d r u g d e l i v e r y : Pharma-
cological, t h e r a p e u t i c and i n d u s t r i a l p e r s p e c t i v e s , Trends Pharma-
col. Sci. 3, 162 (1982).
14. S. K. C h a n d r a s e k a r a n , F . T h e e u w e s , a n d S . I. Yum, The d e -
sign of controlled d r u g delivery s y s t e m s . I n , Drug Design
(E. J . A r i e n s , e d . ) , Vol. 8, Academic P r e s s , New York, 1979,
p p . 133-167.
15. O. Vaizoglu and P . S p e i s e r , Intelligent d r u g delivery s y s t e m s ,
Trends Pharmacol. Sci. 3, 28 (1982).
16. J . U r q u h a r t , Rate-controlled d r u g d o s a g e , Drugs 23, 207 (1982).
17. L. R. Beck and V. Z . P o p e , C o n t r o l l e d - r e l e a s e delivery systems
for hormones: a review of t h e i r p r o p e r t i e s and c u r r e n t t h e r a -
p e u t i c u s e , Drugs 27, 528 (1984).
18. R. A . Siegel and R. L a n g e r , Controlled release of p o l y p e p t i d e s
and o t h e r macromolecules, Pharm. Res. 1, 2 (1984).
19. Y . W. Chien and J . R. Robinson, "Smart" d r u g - d e l i v e r y s y s t e m s ,
J. Parenter. Sci. Technol. 36, 231 (1982).
20. E. P . Goldberg ( e d . ) , Targeted Drugs, Wiley, New Y o r k , 1983.
21. K. Heilman, Therapeutic Systems, 2nd e d . , George Thieme Ver-
l a g , S t u t t g u r s t , 1984.
22. G. S . B a n k e r , Pharmaceutical applications of controlled r e l e a s e :
on overview of t h e p a s t , p r e s e n t , and f u t u r e . I n , Medical
Applications of Controlled Release (R. S. Langer and D . L.
Wise, e d . ) , CRC P r e s s , Florida, 1984, p p . 1-34.
23. M. V. Sefton, D . G. Allen, V . H o r v a t h , and W. Zingg, Insulin
delivery at variable r a t e s . I n , Recent Advances in Drug De-
livery ( J . M. A n d e r s o n and S. W. Kim, e d s . ) , Plenum P r e s s ,
New Y o r k , 1984, p p . 349-365.
24. T . A. H o r b e t t , B . D . R a t n e r , J . Kost, and M. S i n g h , A bio-
r e s p o n s i v e membrane for insulin d e l i v e r y . I n , Recent Advances
in Drug Delivery ( J . M. A n d e r s o n and S . W. Kim, e d s . ) , Plen-
um P r e s s , New York, 1984, p p . 209-220.
 Influence of Drug Properties on Design I 63

25. F . Theeuwes a n d W. B a y n e , Dosage form i n d e x an objective

c r i t e r i o n for evaluation of c o n t r o l l e d - r e l e a s e d r u g delivery s y s -
tems, J. Pharm. Sci. 66, 1388 (1977).
26. J . Koch-Weser, Serum d r u g c o n c e n t r a t i o n s as t h e r a p e u t i c g u i d e s ,
N. Engl. J. Med. 287, 227 (1972).
27. L . A . Pagliaro a n d L. Z. B e n e t , Critical compilation of terminal
h a l f - l i v e s , p e r c e n t e x c r e t e d u n c h a n g e d , and c h a n g e s of half-life
in r e n a l a n d hepatic d y s f u n c t i o n s for s t u d i e s in humans with
r e f e r e n c e s , J. Pharmacokin. Biopharm. 3, 333 (1975).
28. M. Gibaldi a n d P . J . McNamara, S t e a d y - s t a t e c o n c e n t r a t i o n s of
d r u g s with s h o r t half-lives when a d m i n i s t e r e d in oral s u s t a i n e d
release formulations, Int. J. Pharm. 2, 167 (1979).
29. J . F a r a and J . U r q u h a r t , The value of infusion a n d injection
regimens in a s s e s s i n g efficacy and toxicity of d r u g s , Trends
Pharmacol. Sci., 5, 21 (1984).
30. P . L . C a r l , P . K. C h a k r a v a r t y , J . A. Katzenellenbogen, and
M. J . Weber, P r o t e a s e - a c t i v a t e d " p r o d u r g " for c a n c e r chemo-
t h e r a p y , Proc. Natl, Acad. Sci. USA 77, 2224 (1980).
31. P . K. C h a k r a v a r t y , P . L . C a r l , M. J . Weber, and J . A . Kat-
z e n e l l e n b o g e n , Plasmin-activated p r o d r u g s for c a n c e r chemo-
t h e r a p y . 1. S y n t h e s i s a n d biological activity of peptidylacivicin
and peptidylphenylenediamine m u s t a r d , J. Med. Chem. 26, 633
(1983).
32. P . K. C h a k r a v a r t y , P . L. C a r l , M. J . Weber, a n d J . A . Kat-
zenellenbogen, Plasmin-activated p r o d r u g s for c a n c e r chemo-
t h e r a p y . 2. S y n t h e s i s a n d biological activity of p e p t i d y l de-
r i v a t i v e s of doxorubicin, J. Med. Chem., 26, 638 (1983).
33. M. E. Morrison, M . J . Yagi, and G. Cohen, In v i t r o s t u d i e s of
2 , 4 - d i h y d r o x y p h e n y l a l a n i n e , a p r o d r u g t a r g e t e d against maligant
melanoma cells, Proc. Natl. Acad. Sci. USA 82, 6020 (1985).
34. S . S. D a v i s , J . G. H a r d y , M. J . Taylor, D . R. Whaley, a n d
C . J . Wilson, The effect of food on t h e g a s t r o i n t e s t i n a l t r a n s i t
of pellets and osmotic device ( O s m e t ) , Int. J. Pharm. 21, 331
(1984).
35. W. H. B a r r , J . A d i r , and L. G a r r e t t s o n , D e c r e a s e of t e t r a c y c l i n e
a b s o r p t i o n in man b y sodium b i c a r b o n a t e , Clin. Pharmacol. Ther.
12, 799 (1971).
36. V. Manninen, K. Ojala, a n d P . Reisell, New formulation of di-
goxin, Lancet 2, 922 (1972).
37. J . G. Wagner, P . G. Welling, K. O. L e e , and J . E. Walker,
In vivo a n d in v i t r o availability of commercial warfarin t a b l e t s ,
J. Pharm. Sci. 60, 666 (1971).
38. B . Katchen and S . Symchowicz, Correlation of dissolution r a t e
and griseofulvin absorption in man, J. Pharm. Sci. 56, 1108
(1967).
64 I Li et al.

39. T . R. B a t e s , D. A. L a m b e r t , a n d W. H. J o n e s , Correlation
between t h e r a t e of dissolution a n d a b s o r p t i o n of salicylamide
from tablet and s u s p e n s i o n dosage forms, J. Pharm. Sci. 58,
1468 (1969).
40. C. Hansen a n d W. J . D u n n , I I , Linear r e l a t i o n s h i p s between
lipophilic c h a r a c t e r and biological activity of d r u g s , J. Pharm.
Sci. 61, 1 (1972).
41. T . Fujita, J . Iwasa, and A. H a n s c h , A s u b s t i t u e n t c o n s t a n t , IT,
d e r i v e d from p a r t i t i o n coefficients, J. Am Chem. Soc. 86, 5175
(1964).
42. B . Keerman, K. Hellstrom, a n d A. Rosen, Metabolism of p r o -
p a n t h e l i n e in m a n , Clin. Pharm. Ther. 13, 212 (1972).
43. W. H. B a c h r a c h , Anticholinergic d r u g s , Am. J. Digest. Dis. 3,
743 (1958).
44. B . K. Martin, Potential effects of t h e plasma p r o t e i n s on d r u g
d i s t r i b u t i o n , Nature 207, 274 (1965).
45. J - P . Tillement, G. Houin, R. Zini, S. Urien, B . A l b e n g r e s ,
The b i n d i n g of d r u g s to blood plasma macromolecules, Recent
Adv. Drug Res. 13, 59 (1984).
46. L. D . De Leve a n d K. M. P i a s k y , Clinical significance of plasma
b i n d i n g of basic d r u g s , Trends Pharmacol Sci. 3, 283 (1981).
47. M. Rowland, Protein b i n d i n g a n d d r u g c l e a r a n c e , Clin. Pharma-
cokin. 9, ( S u p p l . 1 ) , 10 (1984).
48. J . J . Mackichan, Pharmacokinetic c o n s e q u e n c e s of d r u g displace-
ment from blood a n d t i s s u e p r o t e i n s , Clin. Pharmacokin. 9,
( S l i p p l . ) , 32 (1984).
49. B . K. Martin, Kinetics of elimination of d r u g s p o s s e s s i n g high
affinity for t h e plasma p r o t e i n s , Nature 207, 959 (1965).
50. R. R. L e v i n e , The influence of t h e intraluminal intestinal milieu
on a b s o r p t i o n of an o r g a n i c cationic a n d anionic a g e n t , J. Phar-
macol. Exp. Ther. 131, 328 (1961).
51. K. P a r k , S. L. Cooper, and J . R. Robinson, Bioadhesive h y -
d r o g e l s . I n , Hydrogels in Medicine and Pharmacy (N. P e p p a s ,
e d . ) , Vol. 2, CRC P r e s s , Boca Raton (in p r e s s ) .
52. S. S. C h r a i , T* F . P a t t o n , A . Mehta, a n d J . R . Robinson,
Lacrimal and instilled fluid dynamics in r a b b i t e y e s , J. Pharm.
Sci., 62, 1112 (1973).
53. V. H. L. Lee and J . R. Robinson, Mechanistic a n d q u a n t i t a t i v e
evaluation of p r e c o r n e a l pilocarpine disposition in albino r a b b i t s ,
J. Pharm. Sci. 68, 673 (1979).
54. H. A, Quigley, I. P . Pollack, a n d T . S . Harbin, J r . , Pilocar-
pine O c u s e r t s : l o n g - t e r m clinical trials and selected p h a r m a -
codynamics, Arch. Ophthalmol. 93, 771 (1975).
55. E. R. G a r r e t t , D r u g systems affecting availability a n d reliability
of r e s p o n s e , J. Am. Pharm. Assoc. NS9, 110 (1969).
56. R. R. Sheline, Metabolism of foreign compounds b y g a s t r o i n t e s -
tinal microorganisms, Pharmacol. Rev. 25, 451 (1973).
 Influence of Drug Properties on Design I 65

57. W. H. B a r r a n d S . Riegelman, Intestinal d r u g a b s o r p t i o n a n d

metabolism. I . Comparison of methods a n d models to s t u d y
physiological factors of in v i t r o a n d in vivo intestinal a b s o r p t i o n ,
J. Pharm. Sci. 59, 154 (1970).
58. C. C. B o o t h , Sites of absorption in t h e small i n t e s t i n e . Fed.
Proc, 26, 1583 (1967).
59. M. Weiner, S . S h a p i r o , J . A x e l r o d , J . Cooper, a n d B . B r o d i e ,
The physiological disposition of dicumarol in man, J. Pharmacol.
Exp. Ther. 99, 409 (1950).
60. R. M. L e v i n e , M. R. Blair, a n d B . B . C l a r k , F a c t o r s influencing
t h e i n t e s t i n a l a b s o r p t i o n of c e r t a i n m o n o - q u a r t e r n a r y anticho-
linergic compounds with special r e f e r e n c e to benzomethamine,
J. Pharmacol. Exp. Ther. 114, 78 (1955).
61. L. Weinstein, A n t i b i o t i c s . IV. Miscellaneous antimicrobial, a n t i -
fungal, and antiviral a g e n t s . I n , The Pharmacological Basis of
Therapeutics (L. S. Goodman and A . Gilman, e d s . ) , 4th E d . ,
Macmilan, New York, 1970, p . 1269.
62. G. Levy and W. J . J u s k o , Factors affecting t h e a b s o r p t i o n of
riboflavin in man, J. Pharm. Sci. 55, 285 (1966).
63. A. B . Morrison, C . B . P e r u s s e , and J . A. Campbell, P h y s i o -
logic availability and in v i t r o release of riboflavin in s u s t a i n e d -
release vitamin p r e p a r a t i o n s , N. Engl. J. Med. 263, 115 (1960).
64. E. B . B r o w n , J r . a n d B . W. J u s t u s , In v i t r o a b s o r p t i o n of
radioiron b y e v e r t e d p o u c h e s of r a t i n t e s t i n e , Am. J. Physiol.
194, 319 (1958).
65. R. E. R e e d , Iron deficiency anemia " r e f r a c t o r y " to oral i r o n ,
Missouri Med. 66, 120 (1969).
66. C. E. Blezek, J . L . Lach, a n d J . K. Guillory, Some dissolution
a s p e c t s of f e r r o u s sulfate t a b l e t s , Am. J. Hosp. Pharm. 27,
533 (1970).
67. E. J . Middleton, E. N a g y , and A . B . Morrison, Studies on t h e
a b s o r p t i o n of orally administered iron from s u s t a i n e d - r e l e a s e
p r e p a r a t i o n s , N. Engl. J. Med. 274, 136 (1966).
68. P . C r o s l a n d - T a y l o r , D . H. Keeling, and B . W. Cromie, Trial of
slow-release t a b l e t s of f e r r o u s sulfate, Curr. Ther. Res. 7,
244 (1965).
69. T . H. Bothwell, G. Pirzio-Biroli, and C . A. F i n c h , Iron a b s o r p -
t i o n . I . F a c t o r s influencing a b s o r p t i o n , J. Lab. Clin. Med.
51, 24 (1958).
70. I. M. B a i r d , R. L . Walters, and D. R. S u t t o n , Absorption of
slow-release iron and effects of ascorbic acid in normal subjects
and after partial g a s t r e c t o m y , Br. Med. J. 4, 505 (1974).
71. J . J . Webster, T r e a t m e n t of iron deficiency anemia in p a t i e n t s
with iron i n t o l e r a n c e : clinical evaluation of c o n t r o l l e d - r e l e a s e
form of f e r r o u s s u l f a t e , Curr. Ther. Res. 4, 130 (1962).
72. S . T . C a l l e n d e r , Quick a n d slow-release i r o n : a d o u b l e - b l i n d
trial with a single daily dose regimen, Br. Med. J. 4, 531 (1969).
66 / Li et al.

73. D . P . Bentley and A . J a c o b s , Accumulation of s t o r a g e iron in

p a t i e n t s t r e a t e d for iron-deficiency anemia, Br. Med. J. 2, 64
(1975).
74. G. J . Mouratoff and R. C . B a t t e r m a n , Serum i r o n a b s o r p t i o n
t e s t s of s u s t a i n e d - r e l e a s e form of oral i r o n , J. New Drugs 1,
157 (1961).
75. T. P . S t e v e n s o n , T h e r a p e u t i c a s s a y of s u s t a i n e d - r e l e a s e form of
oral i r o n , Curr. Ther. Res. 4, 107 (1962).
76. L. B . P o s n e r and F . Wilson, Evaluation of s u s t a i n e d - r e l e a s e
molyb denized f e r r o u s sulfate in iron-deficiency anemia of p r e g -
n a n c y , J. New Drugs 3, 155 (1963).
77. E. K r u g e r - T h i e m e r , W. Diller, L. Dettli, P . B u n g e r , a n d J .
Seydel, Demonstration des Einflusses d e r Eiweissbindung u n d
d e r Ionisation duf die Pharm ackokinetick am kombinierten g a s k i -
n e t i s c h e n Modell nach v a n ' t Hoff and Langmuir, Antibiot. Chemo-
ther. 12, 111 (1964).
78. E. K r u g e r - T h i e m e r and P . B u n g e r , The role of t h e r a p e u t i c
regimen in dosage d e s i g n . P a r t I, Chemotherapia 10, 61 ( 1 9 6 5 -
1966).
79. E. K r u g e r - T h i e m e r and P . B u n g e r , The role of t h e r a p e u t i c r e g i -
men in dosage d e s i g n . Part I I , Chemotherapia 10, 129 ( 1 9 6 5 -
1966).
80. E. K r u g e r - T h i e m e r , P . B u n g e r , L. Kettli, P . S p r i n g , and E.
Wempe, Dosage regimen calculation of chemotherapeutic a g e n t s .
P a r t I I I . Sulfasymazine, Chemotherapia 10, 325 (1965-1966).
81. E. K r u g e r - T h i e m e r , W. Diller, and P . B u n g e r , Pharmacokinetic
models r e g a r d i n g p r o t e i n b i n d i n g of d r u g s . I n , Antimicrobial
Agents and Chemotherapy—1965 (G. L. Hobby, e d . ) , American
Society of Microbiology, Ann A r b o r , Mi., 1966, p p . 1 8 3 - 1 9 1 .
82. S . Riegelman, J . C. K. Loo, and M. Rowland, Shortcomings in
pharmacokinetic analysis by conceiving t h e b o d y to exhibit p r o p -
e r t i e s of a single compartment, J. Pharm. Sci. 57, 117 (1968).
83. M. Gibaldi, R. Nagashima a n d G. L e v y , Relationship between
d r u g concentration in plasma or serum and amount of d r u g in
t h e b o d y , J. Pharm. Sci. 58, 193 (1969).
84. A. R. DiSanto a n d J . G. Wagner, Potential e r r o n e o u s assignment
of nonlinear d a t a to t h e classical linear two-compartment open
model, J. Pharm. Sci. 61, 552 (1972).
85. T . T a y l o r , L . F . C h a s s e a u d , R. Major, E. Doyle, and A. D a r -
r a g h , Isosorbide 5-mononitrate pharmacokinetics in h u m a n s ,
Biopharm. Drug Disp. 2, 2 5 5 ( 1 9 8 1 ) .
86. M. M. R e i d e n b e r g , D . D r a y e r , A . L. DeMarco, and C . T . Bello,
Hydralazine elimination in man, Clin. Pharmacol, Ther. 14, 970
(1973).
87. H. F . S c h r a n , F . L. S. T s e a n d S . I . B h u t a , Pharmacokinetics
and pharmacodynamics of bromocriptine in t h e r a t , Biopharm.
Drug Disp. 6, 301 (1985).
 Influence of Drug Properties on Design I 67

88. C . B . Coutinho, H. E. Spiegel, S . A. Kaplan, M. Yu, R. P .

C h r o i s t i a n , J . J . C a r b o n e , J . Symington, J . A . C h e r i p k o , M.
Lewis, A . T o n c h e n , a n d T . C r e w s , Kinetics of a b s o r p t i o n and
excretion of levodopa in d o g s , J. Pharm. Sci. 60, 1014 (1971).
89. W. B . A b r a m s , C . B . Coutinho, A. S. Leon, and H. E. Spiegel,
Absorption and metabolism of levodopa, JAMA 218, 1912 (1971).
90. M. S a n d l e r , F . Karoum, a n d C . R. J . R u t h v e n , M - h y d r o x y -
p h e n y l a c e t i c acid formation from L-dopa in man: Suppression
b y neomycin, Science 166, 1417 (1969).
91. M. S a n d l e r , C . R. J . R u t h v e n , B . L. Goodwin, K. R. H u n t e r ,
and G. M. S t e r n , Variation of levodopa metabolism with g a s t r o i n -
t e s t i n a l absorption s i t e , Lancet 1, 238 (1974).
92. A. C . Woods, G. A . Glaubiger, and T . N . C h a s e , S u s t a i n e d -
release levodopa, Lancet 1, 1391 (1973).
93. G. C u r z o n , J . F r i e d e l , L. G r i e r , C D . M a r s d e n , J . D . P a r k e s ,
M. Shipley, and K. J . Zilkha, S u s t a i n e d - r e l e a s e l e v o d o p a , Lan-
cet 1, 781 (1973).
94. D . P e r r i e r a n d M. Gibaldi, Influence of f i r s t - p a s s effect on t h e
systemic availability of p r o p o x y p h e n e , J. Clin. Pharmacol. 12,
449 (1972).
95. W. H. B a r r and S . Riegelman, Intestinal d r u g absorption a n d
metabolism. I I . Kinetic a s p e c t s of intestinal g l u c u r o n i d e con-
jugation, J. Pharm. Sci. 59, 164 (1970).
96. G. Levy and J . J . Matsuzawa, Pharmacokinetics of salicylamide
in man, J. Pharmacol. Exp. Ther. 156, 285 (1967).
97. R . J o h a n s s o n , C . G. R e g a r d h , and J . Sjogren, Absorption of
alprenolol in man from t a b l e t s with different r a t e s of r e l e a s e ,
Acta. Pharm. Suec. 8, 59 (1971).
98. J . G. Wagner, E. J . A n t a l , A. T . Elvin, W. R. Gillespie,
E. A. P r a t t , a n d K. S. A l b e r t , Theoretical d e c r e a s e in s y s -
temic availability with d e c r e a s e in i n p u t r a t e at s t e a d y - s t a t e for
f i r s t - p a s s d r u g s , Biopharm. Drug Disp. 6, 341 (1985).
99. E. M. J o h n s o n , J r . , A. B . H r k e y , D. J . Blehm, a n d P . Needle-
man, Clearance and metabolism of organic n i t r a t e s , J. Pharmacol.
Exp. Ther. 182, 56 (1972).
100. P . Needleman, S . L a n g , and E. M. J o h n s o n , J r . , Organic n i -
t r a t e s : Relationship between biotransformation and rational
angina p e c t o r i s t h e r a p y , J. Pharmacol. Exp. Ther. 181, 489
(1972).
101. D . G. F r i e n d , J . P . O'Hare, a n d H. D . Levine, Action of t r i -
ethanolamine t r i n i t r a t e in angina p e c t o r i s , Am. Heart J. 48,
775 (1954).
102. M. G. B o g a e r t , M. T . Rosseel, a n d A . F . d e S c h a e p d r y v e r ,
The metabolic fate of n i t r o g l y c e r i n ( T r i n i t r i n ) in relation t o i t s
v a s c u l a r effects, Eur. J. Pharmacol. 12, 224 (1970).
103. R. A . T u r n e r , Absorption of n i t r o g l y c e r i n from t h e alimentary
t r a c t of t h e r a b b i t , J. Pharm. Sci. 54, 464 (1965).
68 I Li et al.

104. I . R. E. Pilkington and J . J . P u r v e s , Long acting glyceryl

t r i n i t r a t e in angina p e c t o r i s of o u t - p a t i e n t s , Br. Med. J. 1,
38 (1960).
105. T . Winsor, H. K a y e , and B . Mills, Hemodynamic r e s p o n s e of
oral l o n g - a c t i n g n i t r a t e s : evidence of g a s t r o i n t e s t i n a l a b s o r p -
t i o n , Chest 62, 407 (1972).
106. I. Hirshleifer, P e r i p h e r a l hemodynamic effects of oral controlled-
release n i t r o g l y c e r i n (Nitrong) in man, Curr. Ther. Res. 15,
158 (1973).
107. H. I. R u s s e k , B . L. Zohman, A . E. Drumm, W. Weingarten,
and V. J . D o r s e t , Long a c t i n g c o r o n a r y vasodilator d r u g s :
Metamine, P a v e r i l , N i t r o g l y n , and P e r i t r a t e , Circulation 12,
169 (1955).
108. W. Modell, Clinical pharmacology of antianginal d r u g s , Clin.
Pharmacol. Ther. 3, 97 (1962).
109. S. H. C u r r y and S . M. A b u r a w i , A n a l y s i s , disposition and
pharmacokinetics of n i t r o g l y c e r i n , Biopharm. Drug Disp. 6,
235 (1985).
110. M. H. Wendkos and N . Meshulam, Comparative effects of place-
bo a n d s u s t a i n e d - r e l e a s e n i t r o g l y c e r i n in angina s u b j e c t s , J.
Clin. Pharmacol. 13, 160 (1973).
111. M. P r e t i , G. A b b o n d a t i , a n d C . C a r p i , Protective action of a
s u s t a i n e d release form of n i t r o g l y c e r i n in an infarct e x p e r i m e n -
tally i n d u c e d b y isoproterenol in the r a t , Boll. Chim. Farm.
108, 576 (1969).
112. L. W. D i t t e r t , Pharmacokinetic c o n s i d e r a t i o n s in clinical d r u g
t r i a l s , Drug IntelL Clin. Pharm. 8, 222 (1974).
113. P . J . N i e b e r t g a l l , E. T . S u g i t a , and R. L. S c h n a a r e , Potential
d a n g e r s of common d r u g dosing regimen, Am. J. Hosp. Pharm.
31, 53 (1974).
114. K. R. Heimlich, D . R. MacDonnell, T . L. F l a n a g a n , P . D .
O'Brien, Evaluation of a s u s t a i n e d - r e l e a s e form of p h e n y l p r o -
panolamine hydrochloride b y u r i n a r y excretion s t u d i e s , J. Pharm.
Sci. 50, 232 (1961).
115. F . O'Grady, W. R. L. B r o w n , H. Gaya, and I . P . MacKintosh,
Antibiotic levels on continuous i n t r a v e n o u s infusion, Lancet 2,
209 (1971).
116. H. S. B r o w n , S . M. Caiola, F . M. Eckel, D . C. McCleod,
C. C. Pulliam, a n d H. B . Woodhall, Cephalexin, Drug I nt ell.
Clin. Pharm. 5, 134 (1971).
117. R. E. C u t l e r , Pharmacokinetics of furosemide in normal s u b -
jects a n d functionally a n e p h r i c p a t i e n t s , Clin. Pharmacol. Ther.
16, 588 (1974).
118. J . Kampmann, J . M. Hansen, K. S i e r s b a e k - N i e l s e n , and H.
L a u r s e n , Effects of some d r u g s on penicillin half-life in blood,
Clin. Pharmacol. Ther. 13, 516 (1972).
 Influence of Drug Properties on Design I 69

119. D. S c h u p p a n y , S . Riegelman, B . von Lehmann, A . P i l b r a n d t ,

a n d C . B e c k e r , Preliminary pharmacokinetics s t u d i e s of p r o p y l -
thiouracil in h u m a n s , J. Pharmacokinet. Biopharm. 1, 307 (1973).
120. D . G. Shand a n d R. E . R a n g n o , The disposition of p r o p r a n o l o l .
I . Elimination d u r i n g oral a b s o r p t i o n in man, Pharmacology 7,
159 (1972).
121. G. H. E v a n s , A. S. Nies, and D . G. S h a n d , The disposition
of p r o p r a n o l o l . I I I . Decreased half-life a n d volume of d i s t r i -
b u t i o n as a r e s u l t of plasma b i n d i n g in man, monkey, dog and
r a t , J. Pharmacol. Exp. Ther. 186, 114 (1973).
122. K. Verebely and C. E. I n t u r r i s i , Disposition of p r o p o x y p h e n e
in man after a single oral d o s e , Clin. Pharmacol. Ther. 15,
302 (1974).
123. L. Graffner, G. J o h a n s s o n , and J . S j o g r e n , Pharmacokinetics
of procainamide i n t r a v e n o u s l y and orally as conventional a n d
slow-release t a b l e t s , Clin. Pharmacol. Ther. 17, 414 (1975).
124. J . Koch-Weser, S. W. Klein, L . L. F o o - C a n t o , J . A. K a s t e r ,
and R. W. D e S a n t i s , A n t i a r r h y t h m i c p r o p h y l a x i s with p r o c a i n -
amide in a c u t e myocardial i n f a r c t i o n , N. Engl. J. Med. 281,
1253 (1969).
125. J . Koch-Wester and S . W. Klein, Procainamide dosage s c h e d u l e s ,
plasma c o n c e n t r a t i o n s a n d clinical effects, JAMA 215, 1454 (1971).
126. R. Ruosteenoja, P . T o r s t i , and A. Sothmann, E x p e r i e n c e s on
a s u s t a i n e d - r e l e a s e procainamide p r e p a r a t i o n , Curr. Ther. Res.
15, 707 (1973).
127. E. K a r l s s o n , Plasma levels of procainamide after administration
of conventional a n d s u s t a i n e d - r e l e a s e t a b l e t s , Eur. J. Clin.
Pharmacol. 6, 245 (1973).
128. R. J . Levine and A . Sjoerdsma, Estimation of monoamine oxi-
dase activity in man: t e c h n i q u e s and a p p l i c a t i o n s , Ann. NY
Acad. Sci. 107, 966 (1963).
129. J . C . H a r t e r , W. J . R e d d y , and G. W. T h o r n , S t u d i e s on an
i n t e r m i t t e n t corticosteroid dosage regimen, N. Engl. J. Med.
269, 591 (1963).
130. C . J . F a l l i e r s , H. Chai, L. Molk, H. B a n e , and R. R. de A.
C a r d o s o , Pulmonary a n d adrenal effects of a l t e r n a t e - d a y c o r t i -
costeroid t h e r a p y , J. Allergy Clin. Immunol. 49, 156 (1972).
131. M. E. J a c o b s o n , The rationale of a l t e r n a t e - d a y c o r t i c o s t e r o i d
t h e r a p y , Postgrad Med. 49, 181 (1971).
132. J. G. Wagner, O. W. C a r p e n t e r , and E . J . Collins, S u s t a i n e d
action oral medication. I . A q u a n t i t a t i v e s t u d y of prednisolone
in m a n , in t h e d o g , a n d in v i t r o , J. Pharmacol. Exp. Ther.
129, 101 (1960).
133. C. J . Migeon, F . K. T y l e r , J . P . Mahoney, A. A. F l o r e n t i n ,
H. C a s t l e , E. L. B l i s s , a n d L . T . Samuels, The d i u r n a l variation
70 I Li et al.

of plasma levels a n d u r i n a r y e x c r e t i o n of 1 7 - h y d r o x y corticos-

t e r o i d s in normal s u b j e c t s , night w o r k e r s and blind s u b j e c t s ,
J. Clin. Endocrinol. Metab. 16, 622 (1956).
134. R. E. P e t e r s o n , Metabolism of a d r e n o c o r t i c o s t e r o i d s in man,
Ann. NY Acad. Sci. 82, 846 (1959).
135. P . F . D ' A r c y , J . P . Griffin, J . S. J e n k i n s , W. F . K i r k , a n d
A. W. C. Peacock, S u s t a i n e d - r e l e a s e formulation of prednisolone
administered orally to man, J. Pharm. Sci. 60, 1028 (1971).
136. I. I . Lubowe, S u s t a i n e d - r e l e a s e oral methylprednisolone in d e r -
matology: a clinical evaluation, Curr. Ther. Res. 4, 111 (1962).
137. E. Nelson, Pharmaceuticals for p r o l o n g e d action, Clin. Pharmacol.
Ther. 4, 283 (1963).
138. G. W. T h o r n , R. E. F u i s z , and R. C . F u i s z , Steroid Therapy:
A Clinical Update for the 1970s, Medcom, New Y o r k , 1971.
139. J . J . B u r n s , R. K. Rose, T . C h e n k i n , A . Goldman, A. S c h u l -
e r t , and B . B . Rodie, The physiological disposition of p h e n y l -
b u t a z o n e (Butazolidin) in man a n d a method for i t s elimination
in biological material, J. Pharmacol. Exp. Ther. 109, 346 (1953).
140. D . T . C a r r a n d A. G. Karlson, Optimal dosage regimens of
a n t i t u b e r c u l o s i s d r u g s , Am. Rev. Respir. Dis. 84, 90 (1961).
141. F . J . R o b e r t s , Single daily dose t r e a t m e n t of p s y c h i a t r i c p a -
t i e n t s with phenothiazine d e r i v a t i v e s , J. Ment. Sci. 107, 104
(1961).
142. L. E. Hollister, S t u d i e s of delayed-action medication. I. Me-
probamate administered as conventional t a b l e t s and as two de-
layed action c a p s u l e s , N. Engl. J. Med. 266, 281 (1962).
143. I . Haides, Single daily dose of a new form of amitriptyline in
d e p r e s s i v e i l l n e s s , Br. J. Psychiatry 120, 521 (1972).
144. A n o n . , Two new a n t i d e p r e s s i v e p r e p a r a t i o n , Drug Ther. Bull.
9, 99 (1971).
145. J . R. Gomez and G. Gomez, D e p r e s s i o n in general p r a c t i c e :
comparison between t h r i c e daily amitriptyline t a b l e t s and a
single s u s t a i n e d - r e l e a s e capsule at n i g h t , Br. J. Clin. Pract.
26, 33 (1972).
146. L. E. Hollister, S . H. C u r r y , J . E. D o e r r , and S. L. K a n t e r ,
S t u d i e s of delayed-action medication. V. Plasma levels a n d
u r i n a r y e x c r e t i o n of four different dosage form of chlorproma-
zine, Clin. Pharmacol. Ther. 11, 49 (1970).
147. T . J . Mellinger, Serum c o n c e n t r a t i o n s of thioridazine after
different oral medication form, Am. J. Psychiatry 121, 1119
(1965).
148. L. E. Hollister, Studies of p r o l o n g e d - a c t ion medication.
I I . Two phenothiazine t r a n q u i l i z e r s (thiroidazine and c h l o r -
promazine) administered as coated t a b l e t s a n d p r o l o n g e d - a c t i o n
p r e p a r a t i o n s , Curr. Ther. Res. 4, 471 (1962).
 Influence of Drug Properties on Design I 71

149. M. H r u s k a , B . Morris, and J . J . Hsu, T h e r a p e u t i c effects of

different modes of chlorpromazine administration, Dis. New,
Syst. 27, 522 (1966).
150. C. B a r t l e t t , Comparison of thioridazine t a b l e t s to chlorproma-
zine s p a n s u l e s in t h e maintenance c a r e of chronic s c h i z o p h r e n i c s ,
Curr. Ther. Res. 13, 100 (1971).
151. H. M. Solomon and J . J . S c h r o g i e , The anticoagulant r e s p o n s e
to b i s h y d r o x y c o u m a r i n . I . The role of individual v a r i a t i o n ,
Clin. Pharmacol. Ther. 8, 66 (1967).
152. M. A . S c h w a r t z , E. Postma, a n d Z. Gaunt, Biological half-life
of chlordiazepoxide and its metabolite, demoxepam, in man,
J. Pharm. Sci. 60, 1500 (1971).
153. H. W. J u n and E . J . T r i g g s , Blood levels of c h l o r p h e n t e r m i n e
in man, J. Pharm. Sci. 59, 206 (1970).
154. J . A. T a y l o r , Pharmacokinetics a n d biotransformation of c h l o r -
propamide in man, Clin. Pharmacol. Ther. 13, 710 (1972).
155. B . P e p i t p i e r r e , L. P e r r i n , M. R u d h a r d t , A . H e r r e r u , and
J . F a b r e , Behavior of chlorpropamide in renal insufficiency and
u n d e r t h e effect of associated d r u g t h e r a p y , Int. J. Clin. Phar-
macol. Ther. Toxicol. 6, 120 (1972).
156. L. Hillestad, T . H a n s e n , a n d M. Melsom, Diazepam metabolism
in normal man. 2. Serum concentration and clinical effect
after oral administration a n d cumulation, Clin. Pharmacol. Ther.
16, 485 (1974).
157. U. Klotz, G. R. A v a n t , A. Hoyumpa, S. S c h a n k e r , and G. R.
Wilkinson, Effects of age and liver disease in t h e disposition
and elimination of diazepam in adult man, J. Clin. Invest. 55,
247 (1975).
158. L. M. Cummins, Y. C . Martin, and E. E. S c h e r f l i n g , Serum
a n d u r i n e levels of ethchlorvynol in man, J. Pharm. Sci. 60,
261 (1971).
159. J . E. D o h e r t y , Digitalis glycosides pharmacokinetics a n d t h e i r
clinical implications, Ann. Intern. Med. 79, 299 (1973).
160. L. S t o r s t e i n , Studies on digitalis. 1. Renal e x c r e t i o n of digi-
toxin a n d i t s cardioactive metabolites, Clin. Pharmacol. Ther.
16, 14 (1974).
161. J . E. D o h e r t y , W. H. P e r k i n s , a n d G. K. Mitchell, T r i t i a t e d
digoxin s t u d i e s in human s u b j e c t s , Arch. Intern. Med. 108,
531 (1961).
162. C. McMartin, R . K. Rondel, J . Vinter, B . R. Allan, P . M.
H u m b e r s t o n e , A. W. D . Leisman, G. S a n d l e r , a n d J . L. T h i r -
k e t t l e , The fate of g u a n e t h i d i n e in two h y p e r t e n s i v e p a t i e n t s ,
Clin. Pharmacol. Ther. 11, 423 (1970).
163. L. E. Hollister and G. L e v y , Kinetics of meprobamate elimina-
tion in h u m a n s , Chemotherapia 9, 20 (1964).
164. K. A r n o l d , Rate of decline of d i p h e y l h y d a n t o i n in human p l a s -
ma, Clin. Pharmacol. Ther. 11, 121 (1970).
72 / Li et al.

165. M. C. MacDonald, D . S. Robinson, D. S y l v e s t e r , and J . J .

Jeffe, The effects of chloral b e t a i n e and glutethimide adminis-
t r a t i o n on warfarin plasma levels a n d hypoprothrombinemic
r e s p o n s e in man, Clin. Pharmacol. Ther. 10, 80 (1969).
166. J . G. Wagner, A s p e c t s of pharmacokinetics and biopharmaceu-
tics in relation to d r u g a c t i v i t y , Am. J. Pharm. 141, 5 (1969).
167. H. Nau, R. Zierer, H. Spielmann, D. N e u b e r t , and C. G a n s a u ,
A new model for embryotoxicity t e s t i n g : t e t r a t o g e n i c i t y a n d
pharmacokinetics of valproic acid following c o n s t a n t - r a t e admin-
i s t r a t i o n in t h e mouse u s i n g human t h e r a p e u t i c d r u g and meta-
bolite c o n c e n t r a t i o n s , Life Sci. 29, 2803 (1981).
168. B . I. S i k i c , J . M. Colins, E. G. Mimnaugh, a n d T . E. Gram,
Improved t h e r a p e u t i c i n d e x of bleomycin when adminsitered b y
continuous infusion in mice, Cancer Treat. Rep. 62, 2011 (1978).
169. B . E c k s t e i n , K. Shaw, a n d G. S t e r n , S u s t a i n e d - r e l e a s e levodopa
in Parkinsonism, Lancet 1, 431 (1973).
170. B . W. McGuiness a n d J . B . P a r k i n , New l o n g - a c t i n g formula-
tion of chlorpheniramine maleate in hay f e v e r , Br. J. Clin.
Pract. 25, 139 (1971).
171. G. Levy and B . A . H a y e s , Physicochemical b a s i s of t h e buf-
fered acetylsalicylie acid c o n t r o v e r s y , N. Engl. J. Med. 262,
1053 (1960).
172. V. H e r b e r t , D r u g s effective in iron-deficiency and o t h e r h y -
p o c h r o n i c anemias. I n , The Pharmacological Basis of Thera-
peutics (L. S . Goodman and A . Gilman, e d s . ) , 4th e d . , Mac-
millan, New Y o r k , 1970, p . 1045.
173. AMA Department of D r u g s , AMA Drug Evaluations, 2nd e d . ,
American Medical Association, Chicago, 1973, p . 183.
174. C. B o r o d a , R. B . Miller, S . T . Leslie, E. G. Nicol, and I .
Thomson, Comparison of t h e bioavailability of aminophylline in
a conventional base and in a c o n t i n u o u s release b a s e , J. Clin.
Pharmacol. 13, 383 (1973).
175. J . R. Hoon, Bleeding g a s t r i t i s i n d u c e d b y long-term release
a s p i r i n , JAMA 229, 841 (1974).
176. E. J a c o b s and J . P r i n g o t , Gastric u l c e r s due to t h e intake of
potassium chloride, Am. J. Digest. Dis. 18, 289 (1973).
177. D. R. B a k e r , W. H. S c h r a d e r , and C . R. Hitchcock, Small-
bowel ulceration a p p a r e n t l y associated with thiazide a n d p o t a s -
sium t h e r a p y , JAMA 190, 586 (1964).
178. L. Gee, B . B e r g , T . G. T o n g , a n d C . B e c k e r , E n t e r i c - c o a t e d
potassium s u p p l e m e n t s , JAMA 228, 975 (1974).
179. J . M. Jefferson and P . A u k l a n d , E n t e r i c - c o a t e d potassium
chloride: A continuous h a z a r d , Br. Med. J. 1, 456 (1974).
180. W. Hasker and J . McCaffrey, Ulceration of a Meckel's d i v e r -
ticulum due to a potassium chloride t a b l e t , Med. J. Aust. 2,
261 (1972).
 Influence of Drug Properties on Design I 73

181. B . L. Phillips, Potassium-induced bowel u l c e r a t i o n , Br. J. Clin.

Pract. 28, 143 (1974).
182. W. H. Thomas, Measurement of dissolution r a t e s of potassium
chloride from v a r i o u s slow release potassium chloride tablets
u s i n g a specific ion e l e c t r o d e , J. Pharm. Pharmacol. 25, 27
(1973).
183. E. L. T a r p l e y , C o n t r o l l e d - r e l e a s e potassium supplementation,
Curr. Ther. Res. 16, 734 (1974).
184. C . Graffner and J . S j o g r e n , Potassium absorption from s u s t a i n e d -
release t a b l e t s , Acta Pharm. Suec. 8, 13 (1971).
185. T . J . McKenna, J . F . Donohoe, J . J . Healy, B . C a n n i n g , and
F . P . Muldowney, P o t a s s i u m - s p a r i n g a g e n t s d u r i n g d i u r e t i c
t h e r a p y in h y p e r t e n s i o n , Br. Med. J. 2, 739 (1971).
186. E. M. C l a r k s o n , Slow sodium: an oral slowly released sodium
chloride p r e p a r a t i o n , Br. Med. J. 3, 604 (1971).
187. A n o n . , Slow Na, Drug Ther. Bull, 9, 98 (1971).
188. M. A . S c h n e i d e r m a n , M. H. Myers, Y. S. S a t h e , and P . Kof-
f s k y , Toxicity, t h e t h e r a p e u t i c i n d e x and t h e r a n k i n g of d r u g s ,
Science 144, 1212 (1964).
189. O. J a r d e t z k y , On t h e q u a n t i t a t i v e evaluation of pharmacologic
a g e n t s , J. New Drugs 6, 203 (1966).
190. T . R u d y , p e r s o n a l communication, 1976.
191. J . H. Gaddum, Pharmacology, Oxford University P r e s s , New
Y o r k , 1953.
192. C . A. Winter, A s t u d y of comparative antihistaminic activity of
six compounds, J. Pharmacol. Exp. Ther. 90, 224 (1947).
193. J . C. K r a n t z , J r . , C . J . C a r r , a n d B . N . La D u , J r . , The
Medical Principles of Medical Practice, 7th e d . , William & Wilkins,
Baltimore, 1969, p . 28.
194. B . S . K a t c h e r , Rheumatoid a r t h r i t i s , J. Am. Pharm. Assoc.
NS12, 383 (1972).
195. E. H. Wiseman, Plasma salicylate c o n c e n t r a t i o n s following chronic
administration of aspirin as conventional a n d s u s t a i n e d - r e l e a s e
t a b l e t s , Curr. Ther. Res. 11, 681 (1969).
196. J . B . Dick-Smith, Pilot trial of s u s t a i n e d - r e l e a s e a s p i r i n (Bi-
P r i n ) , Med. J. Aust. 1, 18 (1970).
197. E. H. Wiseman and N . J . F e d e r i c i , Development of a s u s t a i n e d -
release aspirin t a b l e t , J. Pharm. Sci. 57, 1535 (1968).
198. M. S . Vora, Z. J . Zimmer, and P . V. Maney, S u s t a i n e d -
release a s p i r i n tablet u s i n g an insoluble m a t r i x , J. Pharm. Sci.
53, 487 (1964).
199. S. C . H a r v e y , Gastric a n t a c i d s and d i g e s t a n t s . I n , The Phar-
macological Basis of Therapuetics ( L . S. Goodman and A. Gil-
man, e d s . ) , 4th e d . , Macmillan, New York, 1965, p . 1013.
200. W. A. Sodeman, J r . , N . A. A u g u r , and H. M. Pollard, P h y s i o -
logy a n d pharmacology of belladonna t h e r a p y in antipeptic di-
s e a s e , Med. Clin. North Am. 53, 1379 (1969).
74 I Li et al.

201. D . R . R e e s e , S. M. F r e e , J . V. Swintosky, a n d M. I . G r o s s -
m a n , The effect of dosage forms on t h e d u r a t i o n and continuity
of belladonna alkaloids, Am. J. Dig. Dis. 4, 220 (1958).
202. H. B u r n e s s , Clinical evaluation of a s u s t a i n e d - r e l e a s e belladon-
na p r e p a r a t i o n , Am. J. Dig. Dis. 22, 111 (1955).
203. A . M . K a s i c h , Relief of n o c t u r n a l pain in duodenal u l c e r , Am.
J. Gastroenterol. 33, 66 (1960).
204. M. H. Alp and A . K. G r a n t , Effect of s u s t a i n e d - r e l e a s e h e x o -
cyclium t a b l e t s on g a s t r i c acid s e c r e t i o n , Med. J. Aust. 1, 337
(1969).
205. R . A . K e r r , Angina p e c t o r i s , J. Am. Pharm. Assoc. NS12, 178
(1972).
206. M. Kamil and I . K l i n g e r , Timed disintegration c a p s u l e s of p e n -
t a e r y t h r i t o l t e t r a n i t r a t e in a selected angina g r o u p , NY State
J. Med. 59, 3398 (1959).
207. T . M. Feinblatt and E . A . F e r g u s o n , Timed-disintegration c a p -
s u l e s : a f u r t h e r s t u d y . An in vivo r o e n t g e n o g r a p h i c s t u d y ,
blood level s t u d y and relief of angina pain with p e n t a e r y t h r i t o l
t e t r a n i t r a t e , N. Engl. J. Med. 256, 331 (1957).
208. J . L. Schelling and L. L a s a g n a , A s t u d y of c r o s s - t o l e r a n c e to
c i r c u l a t o r y effects of o r g a n i c n i t r a t e s , Clin. Pharmacol. Ther.
8, 256 (1967).
209. A . Wilson, The modification of t h e duration of d r u g action,
J. Pharm. Pharmacol. 11, 446 (1959).
210. J . S . T a k a h a s h i and M. Zatz, Regulation of circadian r h y t h m i -
c i t y , Science 217 1104 (1982).
211. J . A. Martinex-O'Gerrall, Circadian r h y t h m s , J. Occup. Med.
10, 305 (1968).
212. G. G. L u c e , Biological Rhythms in Psychiatry and Medicine,
National I n s t i t u t e of Mental Health, B e t h e s d a , Md, 1970.
213. C. E. B r u s h and R. F a y e r w e a t h e r , O b s e r v a t i o n s on the c h a n g e s
in blood p r e s s u r e d u r i n g normal s l e e p , Am. J. Physiol. 5,
199 (1901).
214. H. Brooks and J . H. C a r r o l l , Clinical s t u d y of t h e effects of
sleep and r e s t blood p r e s s u r e , Arch Intern. Med. 10, 97 (1912).
215. T . Aimoto, B . H. R o h d e , G. C. Y. Chiou, and J . K. L a u b e r ,
N - A c e t y l t r a n s f e r a s e activity a n d melatonin level in t h e e y e s of
glaucomtous c h i c k e n s , J. Ocular Pharmacol. 1, 149 (1985).
216. E. Marte and F . H a l b e r g , Circadian susceptibility in relation
to administration of pharmacologic a g e n t s , Fed. Proc. 20, 305
(1961).
217. E. Haus and F . H a l b e r g , 24-hour r h y t h m in susceptibility of
C Mice to a toxic dose of e t h a n o l , J. Appl. Physiol. 14, 878
(1959).
218. P . J . Wedlund and R. H . L e v y , T i m e - d e p e n d e n t kinetics VII:
Effect of diurnal oscillations on the time c o u r s e of carbamazepine
 Influence of Drug Properties on Design I 75

autoinduction in t h e r h e s u s monkey, J. Pharm. Sci. 72, 905

(1983).
219. E. L. Dubois and D . C . A d l e r , Single daily dose oral adminis-
t r a t i o n of corticosteroids in rheumatic d i s o r d e r s : An analysis
of i t s a d v a n t a g e s , efficacy a n d side effects, Curr. Ther. Res.
5, 43 (1963).
220. R. J . J a r r e t t a n d H. Keen, Diurnal variation of oral glucose
t o l e r a n c e : a possible p o i n t e r to t h e evolution of diabetes mel-
l i t u s , Br. Med. J. 2, 341 (1969).
221. N . S . H a y n e r , M. D . Kjelsberg, F . H. E p s t e i n , and T . F r a n c i s ,
C a r b o h y d r a t e tolerance and diabetes in a total community,
T e c u m s e h , Michigan. I . Effects of a g e , s e x and t e s t condi-
tions on o n e - h o u r glucose t o l e r a n c e in a d u l t s , Diabetes 14, 413
(1965).
222. N. F r e i n k e l , M. Mager, and L. Vinnick, Cyclicity in t h e i n t e r -
r e l a t i o n s h i p s between plasma insulin and glucose d u r i n g s t a r v a -
tion in normal y o u n g m e n , J. Lab. Clin. Med. 17, 171 (1968).
223. C. Faiman and J . A. Morrhouse, Diurnal variation in the levels
of glucose and r e l a t e d s u b s t a n c e s in h e a l t h y and diabetic s u b -
jects d u r i n g s t a r v a t i o n , Clin. Sci. 32, 111 (1967).
224. A. N . R i g a s , A. H. B i t t l e s , D . R. H a d d e n , and D . A. D . Mont-
gomery, Circadian variation of glucose, insulin and free fatty
acids d u r i n g long-term u s e of oral hypoglycemic a g e n t s in dia-
b e t e s mellitus, Br. Med. J. 4, 25 (1968).
225. M. A. Kimble, D i a b e t e s , J. Am. Pharm. Assoc. NS14, 80 (1974).
226. W. J . M. H r u s c h e s k y , Circadian timing of c a n c e r c h e m o t h e r a p y ,
Science 228, 73 (1985).
227. S. A. Nicholson, T . E. A d r i a n , A. J . Bacarese-Hamilton,
B . Gillham, M. T . J o n e s , a n d S. R. Bloom, 24-Hour variation
in content and release of hypothalamic n e u r o p e p t i d e s in t h e
r a t , Reg. Peptides 7, 385 (1983).
228. G. L e y e n d e c k e r , T . S t r u v e , and E . J . Plotz, Induction of
ovulation with chronic i n t e r m i t t e n t (pulsatile) administration
of LH-RH in women with hypothalamic a n d hyperprolactinemic
a m e n o r r h e a , Arch. Gynecol. 229, 117 (1980).
229. W. F . Crowley J r . and J . W. M c A r t h u r , Stimulation of t h e
normal m e n s t r u a l cycle in Kallman's syndrome b y pulsatile a d -
ministration of luteinizing h o r m o n e - r e l e a s i n g hormone (LHRH),
J. Clin. Endocrinol. Metab. 51, 173 (1980).
230. G. L e y e n d e c k e r , L. Wildt a n d M. Hansmann, P r e g n a c i e s follow-
ing chronic i n t e r m i t t e n t (pulsatile) administration of Gn-RH b y
means of a p o r t a b l e pump ("Zyklomat")—A new approach to
t h e t r e a t m e n t of infertility in hypothalamic a m e n o r r h e a , J. Clin.
Endocrinol. Metab. 51, 1214 (1980).
231. C . S . Tarn, J . N . M. H e e r s c h e , T . M. M u r r a y , and J . A. P a r -
sons , P a r a t h y r o i d hormone stimulates t h e b o n e apposition r a t e
76 I Li et at.

i n d e p e n d e n t l y of its r e s o r p t i v e action: Differential effects of

i n t e r m i t t e n t and continuous administration, Endocrinology 110,
506 (1982).
232. A. Soil, C. R. Kahn, D . M. Neville, J r . and J . Roth, Insulin
r e c e p t o r deficiency in genetic and a c q u i r e d o b e s i t y , J. Clin.
Invest. 56, 779 (1975).
233. J . R. Gavin, J . R o t h , D . M. Neville, P . deMeyts, and D . N .
B u e l l , Insulin d e p e n d e n t regulation of insulin r e c e p t o r concen-
t r a t i o n s : a d i r e c t demonstration in cell c u l t u r e , Proc. Natl.
Acad. Sci. USA 71, 84 (1974).
234. A. J . W. H s u e n , H. L. Dufau, and K. J . C a t t , Regulation of
lutein zing hormone r e c e p t o r s in t e s t i c u l a r cells b y g o n a d o t r o p i n ,
Biochem. Biophys. Res. Commun. 72, 1145, 1976.
235. M. A . Lesniak and J . Roth, Regulation of r e c e p t o r c o n c e n t r a -
tion b y homologous hormone. Effect of human growth hormone
on its r e c e p t o r in IM-9 l y m p h o c y t e s , J. Biol. Chem. 251, 3720
(1976).
236. P . M. Hinkle and A . H. Tashjian, J r . , T h y r o t r o p i n - r e l e a s i n g
hormone r e g u l a t e s t h e n u m b e r of i t s own r e c e p t o r s in t h e GH3
s t r a i n of p i t u i t a r y cells in c u l t u r e , Biochemistry 14, 3845 (1975).
237. P . E. Belchetz, T . M. Plant, Y. Nakai, E. J . Keogh, a n d
E. Knobil, Hypophyseal r e s p o n s e s to continuous a n d i n t e r m i t -
t e n t delivery of hypothalamic g o n a d o t r o p i n - r e l e a s i n g hormone,
Science 202, 631 (1978).
238. H. J . L y n c h , R. W. R i v e s t , and R. J . Wurtman, Artificial
induction of melatonin r h y t h m s b y programmed microinfusion,
Neuroendocrinology 31, 106 (1980).
239. J . V. Moore, D o s e - r e s p o n s e c u r v e s after in vivo experimental
c h e m o t h e r a p y : influence of r o u t e of administration on biological
outcomes, Cancer Chemother. Pharmacol. 15, 91 (1985).
240. L. Z. B e n e t , Effect of r o u t e of administration and distribution
on d r u g action, J. Pharmacok. Biopharm. 6, 559 (1978).
241. Y. W. C h i e n , L o n g - a c t i n g p a r e n t e r a l d r u g formulations, J.
Parenteral Sci. Technol. 35, 106 (1981).
242. G. F . J . R u s s e l l , S t a r c h m i c r o s p h e r e s d r u g delivery s y s t e m s ,
Pharm., Int. 3, 260 (1983).
243. S . S. D a v i s , Colloids as d r u g delivery s y s t e m s , Pharm. Tech-
nol. 5, 71 (1981).
244. T. R. Tice and D . R. Cowar, Biodegradable c o n t r o l l e d - r e l e a s e
p a r e n t e r a l s y s t e m s , Pharm. Technol. 8, 25 (1984).
245. Y. Morimoto, K. S u g i b a y a s h i and M. Akimoto, Magnetic g u i d -
ance of f e r r o c o l l o i d - e n t r a p p e d emulsion for site-specific d r u g
d e l i v e r y , Chem. Pharm. Bull. 31, 279 (1983).
246. M. A . Davis and T . A. T a u b e , Pulmonary perfusion imaging:
acute toxicity and safety factors as a function of particle size,
J. Nucl. Med. 19, 1209 (1978).
 Influence of Drug Properties on Design I 77

247. E. F . E v a n s , J . D . P r o c t o r , M. F r a t k i n , J . Velandia, a n d
A. J . Wasserman, Blood flow in muscle g r o u p s and d r u g s a b -
s o r p t i o n , Clin. Pharmacol. Ther. 17, 44 (1975).
248. A . T . Florence and W. R . Vezin, Prolongation of t h e action
of i n t r a m u s c u l a r formulations of p h e n o t h i a z i n e s . I n , Optimiza-
tion of Drug Delivery, Alfred Benzon Symposium 17 (H. B u n d -
g u a a r d , A. B . H a n s e n , and H. Kofod, e d s . ) , M u n k s g a a r d
C o p e n h a g e n , 1982, p p . 9 3 - 1 1 3 .
249. M. Ermini, F . C a r p i n o , M. Russo a n d G. Benagiano, S t u d i e s
on s u s t a i n e d c o n t r a c e p t i v e effects with s u b c u t a n e o u s poly-
dim ethylsiloxane i m p l a n t s , Acta Endocrinol. 73, 360 (1973).
250. S . L . Sendelbeck and C . L. G i r d i s , Disposition of a 14c-labeled
bioerodible p o l y o r t h o e s t e r and i t s h y d r o l y s i s p r o d u c t s ,
4-hydroxybutyrate and cis,trans-l,4-bis(hydroxymethyl)cyclo-
h e x a n e , in r a t s , Drug Metab. Disp. 13, 291 (1985).
251. K. Hirano, T . Ichihashi and H. Yamada, S t u d i e s on t h e a b s o r p -
tion of practically water-insoluble d r u g s following injection.
V. S u b c u t a n e o u s absorption in r a t s from solutions in water
immiscible oils, J. Pharm. Sci. 71, 495 (1982).
252. M. Pfeffer, R . D . Smyth, K. A. Pittman, and P . A. Nardella,
Pharmacokinetics of s u b c u t a n e o u s a n d i n t r a m u s c u l a r b u t o r p h e n o l
in d o g s , J. Pharm. Sci. 69, 801 (1980).
253. D . I . Abramson, Blood Vessels and Lymphatics, Academic P r e s s ,
New Y o r k , 1962, p . 520.
254. J . Schou, S u b c u t a n e o u s and i n t r a m u s c u l a r injection of d r u g s .
I n , Concepts in Biochemical Pharmacology, Part 1 (B . B . Brodie
and J . R. Gillette, e d s . ) , S p r i n g e r - V e r l a g , Heidelberg, 1971,
p p . 47-66.
255. B . E. B a l l a r d , Biopharmaceutical considerations in s u b c u t a n e o u s
and i n t r a m u s c u l a r d r u g administration, J. Pharm. Sci. 57, 357
(1967).
256. A. E. J o r g e n s e n and J . Schou, The local effect of cholinergic
a g e n t s and cholinesterase inhibition on t h e clearance of s u r c o s e
from muscles, Acta. Pharmacol. (Kbh) 23, 205 (1965).
257. G. F . Warner, E. L. Dobson, N. Pace, M. E. J o h n s o n , a n d
C . R. F i n n e y , Studies of human p e r i p h e r a l blood flow: t h e
effect of injection volume on t h e i n t r a m u s c u l a r radiosodium
clearance r a t e , Circulation 8, 732 (1953).
258. R. B . S u n d and J . Schou, The determination of absorption
r a t e s from rat muscles: an experimental a p p r o a c h to k i n e t i c
d e s c r i p t i o n s , Acta Pharmacol. Toxicol. 21, 313 (1964).
259. K. Kakemi, H. S e z a k i , K. Okumura and S. Ashida, Absorption
and e x c r e t i o n of d r u g s XXXIX. The absorption of isonicotinic
acid d e r i v a t i v e s from t h e skeletal muscle of t h e r a t s , Chem.
Pharm. Bull. 17, 1332 (1969).
78 I Li et at.

260. K. Kakemi, H. S e z a k i , K. Okumura, C . Takada and S. F u r u -

sawa, Absorption of d r u g s from t h e skeletal muscle of t h e r a t s
( 2 ) , Chem. Pharm. Bull. 19, 2058 (1971).
261. K. Kakemi, H. Sezaki, K. Okumura, H. Kobayashi a n d S . F u r u -
sawa, Absorption of d r u g s from t h e skeletal muscle of t h e r a t s
( 3 ) . Effect of w a t e r - s o l u b l e a d j u v a n t s a n d vehicles on t h e
i n t r a m u s c u l a r a b s o r p t i o n , Chem. Pharm. Bull. 20, 443 (1972).
262. K. O k u m u r a , H. Sezaki, and K. Kakemi, Absorption of d r u g s
from t h e skeletal muscle of t h e r a t s ( 4 ) . Absorption of cationic
d r u g s from t h e muscle, Chem. Pharm. Bull. 20, 1607 (1972).
263. H. Kobayashi, T . Nishimura, K. Okumura, S. Muranishi, a n d
H. Sezaki, Effect of p o l y s o r b a t e s on absorption r a t e s of w a t e r -
soluble, micelle-free d r u g s administered i n t r a m u s c u l a r l y in t h e
r a t , J. Pharm. Sci. 63, 580 (1974).
264. R. H. Levy and M. Rowland, Absorption kinetics of a s e r i e s
of local a n e s t h e t i c s from r a t s u b c u t a n e o u s t i s s u e . I, J. Pharm-
acokin. Biopharm. 2, 313 (1974).
265. R. H. Levy and M. Rowland, Absorption k i n e t i c s of a series
of local a n e s t h e t i c s from r a t s u b c u t a n e o u s t i s s u e . I I . Effects
of v a s o d i l a t o r s , J. Pharmacokin. Biopharm. 2, 337 (1974).
266. K. Hirano, T . Ichihashi a n d H. Yamada, Studies on t h e a b s o r p -
tion of practically water-insoluble d r u g s following injection.
I. I n t r a m u s c u l a r a b s o r p t i o n from water-immiscible oil solutions
in r a t s , Chem. Pharm. Bull. 29, 519 (1981).
267. K. Hirano, T . Ichihashi a n d H. Yamada, S t u d i e s on t h e a b s o r p -
tion of practically water-insoluble d r u g s following injection.
II. I n t r a m u s c u l a r a b s o r p t i o n from aqueous s u s p e n s i o n s in r a t s ,
Chem. Pharm. Bull. 29, 817 (1981).
268. K. Hirano, T . Ichihashi and H. Yamada, Studies on t h e a b s o r p -
tion of practically water-insoluble d r u g s following injection.
V I . Subcutaneous absorption from aqueous s u s p e n s i o n s in r a t s ,
J. Pharm. Sci. 71, 500 (1982).
269. V. Bocci, Evaluation of r o u t e s of administration of i n t e r f e r o n
in c a n c e r : A review and a p r o p o s a l , Cancer Drug Delivery 1,
337 (1984).
270. J . R. Howard and J . H a d g r a f t , The clearance of oily vehicles
following i n t r a m u s c u l a r injections in r a b b i t s , Int. J. Pharm.
16, 31 (1983).
271. W. S . Nimmo, D r u g s , d i s e a s e s and a l t e r e d g a s t r i c e m p y t i n g ,
Clin. Pharmacokin. 1, 189 (1976).
272. A. F . Hoffman, J . H. D r e s s m a n , C . F . Code, K. F . Witztum,
Controlled e n t r y of orally administered d r u g s : physiological
c o n s i d e r a t i o n s , Drug Dev. Ind. Pharm. 9, 1077 (1983).
273. I . L . MacGregor, P . Martin, a n d J . H. Meyer, Gastric empty-
ing of solid food in normal man and after subtotal gastrectomy
and t r u n c a l vagotomy with p y l o r o p l a s t y , Gastroenterology 72,
206 (1977).
 Influence of Drug Properties on Design I 79

274. H. S. C h ' n g , H. P a r k , P . Kelly a n d J . R. Robinson, Bioad-

h e s i v e polymers as platforms for oral controlled d r u g delivery
II: S y n t h e s i s and evaluation of swelling, water-insoluble bio-
a d h e s i v e p o l y m e r s , J. Pharm. Sci. 73, 399 (1985).
275. M. A. L o n g e r , H. S. C h f n g , and J . R. Robinson, Bioadhesive
polymers as platforms for oral controlled d r u g delivery III:
Oral delivery of chlorothiazide u s i n g a bioadhesive polymer,
J. Pharm. Sci. 74, 406 (1985).
276. R. Groning and G. Heun, Oral dosage forms with controlled
g a s t r o i n t e s t i n a l t r a n s i t , Drug Dev. Ind. Pharm. 10, 527 (1984).
277. M. J . Dew, P . J . H u g h e s , M. G. Lee, B . K. Evans a n d J .
R h o d e s , An oral p r e p a r a t i o n to release d r u g s in t h e human
colon, Br. J. Clin. Pharmacol. 14, 405 (1982).
278. C. Bogentoft, C . Eskilsson, U. E. J o n s s o n , P . O. L a g e r s t r o m ,
K. Lovgren and L. Rosen, Delivery of d r u g s to t h e colon b y
means of a new e n c a p s u l a t e d oral dosage form, Acta Pharm.
Seu 20, 311 (1983).
279. D . R. F r i e n d and G. W. C h a n g , A colon specific d r u g - d e l i v e r y
system b a s e d on d r u g glycides a n d t h e glycosidases of colon
b a c t e r i a , J. Med. Chem. 27, 261 (1984).
280. M. Gibaldi and J . L. K a n i g , Absorption of d r u g s t h r o u g h t h e
oral mucosa, J. Oral Ther. Pharmac. 1, 440 (1965).
281. N. F . H. Ho and W . I . Higuchi, Quantitative i n t e r p r e t a t i o n of
in vivo buccal a b s o r p t i o n of alkonoic acids b y t h e physical
model a p p r o a c h , J. Pharm. Sci. 60, 537 (1971).
282. I. A. Siegel, Effect of chemical s t r u c t u r e on nonelectrolyte
p e n e t r a t i o n of oral mucosa, J. Invest. Dermatol. 76, 137 (1981).
283. I. A. Siegel, Permeability of t h e oral mucosa. I n , The Struc-
ture and Function of Oral Mucosa ( J . Meyer, C . A. S q u i e r ,
and S . J . Gerson, e d s . ) , Pergamon P r e s s , Oxford, 1984, p p .
95-108.
284. R. P . Walton, Absorption of d r u g s t h r o u g h t h e oral mucosa.
I I I . F a t - w a t e r solubility coefficient of alkaloids, Proc. Soc.
Exp. Biol. Med. 32, 1488 (1935).
285. I . A . Segel, K. T . I z u t s u and E. Watson, Mechanisms of n o n -
electrolyte p e n e t r a t i o n across dog a n d r a b b i t oral mucosa,
Arch. Oral Biol. 26, 357 (1981).
286. A. C . Moffat, Absorption of d r u g s t h r o u g h t h e oral mucosa.
I n , Topics in Medicinal Chemistry, Vol. 4, J o h n Wiley & S o n s ,
New Y o r k , 1971, p p . 1-26.
287. A. H. Beckett and R. D . Hossie, Buccal a b s o r p t i o n of d r u g s .
I n , Handbook of Experimental Pharmacology, Vol. 28, P a r t I
( B . B . Brodie and J . R. Gillete, e d s . ) , S p r i n g e r - V e r l a g ,
H e i d e l b e r g , 1971, p p . 2 5 - 4 6 .
288. S. S. D a v i s , P . B . Daly, J . W. K e n n e r l e y , M. F r i e r , J . G.
Hardy and C. G. Wilson, Design and evaluation of s u s t a i n e d
80 I Li et al.

release formulations for oral and buccal administration, Adv.

Pharmacother. 1, 17 (1982).
289. J . A b r a m s , Nitrate delivery systems in p e r s p e c t i v e s , a decade
of p r o g r e s s , Am. J. Med. 75, 38 (1984).
290. A. B . de B o e r , L. G. J . Leede and D . D . B r e i m e r , Rectal
d r u g administration: partial avoidance of hepatic f i r s t - p a s s
elimination, Pharm. Int. 3, 267 (1982).
291. W. A . Ritschel, H. Elconin, G. J . Alcorn, and D . D . D e n s o n ,
F i r s t - p a s s elimination of lidocaine in t h e r a b b i t after p e r o r a l
a n d rectal r o u t e of administration, Biopharm. Drug Disp. 6,
281 (1985).
292. L . G. J . Leede, A. G. de Boer, C D . Feijen and D . D . B r e i -
m e r , Site specific rectal d r u g administration in man with an
osmotic s y s t e m : influence on " f i r s t - p a s s " elimination of lido-
caine, Pharm. Res. 1, 129 (1984).
293. J . J . T u k k e r , D . J . de Blaey a n d G. A. C h a r b o n , Rectal
motility and bioavailability, Pharm. Res. 1, 173 (1984).
294. F . Moolenaar and A . J . M. Schoonen, Biop harm ace u t i c s of t h e
rectal administration of d r u g s , Pharm. Int. 1, 144 (1980).
295. N. S e n o i r , Rectal administration of d r u g s . I n , Advances in
Pharmaceutical Sciences, Vol. 4, Academic P r e s s , London,
1974, p p . 363-435.
296. C J . de Blaey and J . Polderman, Rationales in t h e d e s i g n of
rectal a n d vaginal delivery forms of d r u g s . I n , Drug Design,
Vol. 9 ( E . J . A r i e n s , e d . ) , Academic P r e s s , New Y o r k , 1980,
p p . 237-266.
297. K. Morimoto, Y. Iwamoto, T . Katashima, T . T a k e e d a , Y. Naka-
moto, and K. Morisaka, Absorption and bioavailability of diclo-
fenac after rectal administration of diclofenac-Na gel p r e p a r a t i o n
in r a t and man, Pharm. Res., 2, 166 (1985).
298. T. Nishihata, J . R y t t i n g a n d T . Higuchi, Enhanced r e c t a l a b -
sorption of t h e o p h y l l i n e , lidocaine, cefnetazole and levodopa b y
s e v e r a l a d j u v a n t s , J. Pharm. Sci. 71, 865 (1982).
299. T. Nishihata, J . R y t t i n g a n d T . Higuchi, Effect of salicylate
on rectal absorption of lidocaine, levodopa a n d cefmetazole in
r a t s , J. Pharm. Sci. 71, 869 (1982).
300. T . Nishihata, J . R y t t i n g , T . Higuchi, L. Caldwell and S . J .
Selk, Enhancement of rectal absorption of w a t e r - s o l u b l e anti-
biotics in d o g s , Int. J. Pharm. 21, 239 (1984).
301. T . N i s h i h a t a , K. Yasiu, M. Yamazaki a n d A . Kamada, Effect
of a d j u v a n t s on t h e rectal u p t a k e of bleomycin in r a t s , J.
Pharm. Dyn. 7, 278 (1984).
302. T . Nishihata, J . R y t t i n g , T . Higuchi and L. Caldwell, En-
hanced rectal absorption of insulin a n d h e p a r i n in r a t s in t h e
p r e s e n c e of n o n - s u r f a c t a n t a d j u v a n t s , J. Pharm. Pharmacol.
33, 334 (1981).
 Influence of Drug Properties on Design I 81

303. T . Nishihata, G. Liversidge and T . Higuchi, Effect of aprotinin

on rectal delivery of i n s u l i n , J. Pharm. Pharmacol. 35, 616
(1983).
304. T . Nishihata, J . R y t t i n g , L. Caldwell, S . Yoshioka and T . Hig-
u c h i , Adjuvant effect on rectal a b s o r p t i o n . I n , Optimization
of Drug Delivery, Alfred Benzon Symposium 17 (H. B u n d g a a r d ,
A. B . H a n s e n , a n d H. Kofod, e d s . ) , M u n k s g a a r d , C o p e n h a g e n ,
1982, p p . 1 7 - 3 4 .
305. N . Yata, W. M. Wu, R. Yamajo, T . Murkami, Y. Higashi, and
T . Higuchi, Enhanced rectal a b s o r p t i o n of sodium ampicillin b y
N-acyl d e r i v a t i v e s of collagen p e p t i d e in r a b b i t s and r a t s ,
J. Pharm. Sci. 74, 1058 (1985).
306. T . Nishihata, C. S. Lee, M. Yamamoto, J . R y t t i n g , and T .
Higuchi, The effects of salicylate on t h e rectal absorption of
phenylalanine and some p e p t i d e s , and t h e effects of t h e s e p e p -
t i d e s on t h e rectal absorption of cefoxitin and cefmetazole,
J. Pharm. Sci. 73, 1326 (1984).
307. K. N a k a n i s h i , A . Ogata, M. Masada and T . Nadai, Effect of
n o n - s t e r o i d a l anti-inflammatory d r u g s on t h e rectal mucosa,
Chem. Pharm. Bull. 32, 1956 (1983).
308. K. Nakanishi, M. Masada and T . Nadai, Effect of pharmaceutical
a d j u v a n t s on t h e rectal permeability of d r u g s I I I . Effect of
r e p e a t e d administration a n d r e c o v e r y of t h e permeability, Chem.
Pharm. Bull. 31, 4161 (1983).
309. A. G. de Boer, F . Moolenenaar, L. G. J . de Leede a n d D . D .
Breimer, Rectal d r u g administration: clinical pharmacokinetic
c o n s i d e r a t i o n , Clin. Pharmacokin. 7, 285 (1982).
310. A. H u s s a i n , S . Hirai, R. B a w a r s h i , Nasal absorption of p r o p a -
nolol in r a t s , J. Pharm. Sci. 73, 1300 (1984).
311. A . Hussain, S . Hirai, and C . H. H u a n g , Nasal a b s o r p t i o n of
t e s t o s t e r o n e in r a t s , J. Pharm. Sci. 73, 1300 (1984).
312. A. H u s s a i n , R. Kimura, C . H. Huang and T . K a s h i h a r a , Nasal
a b s o r p t i o n of naloxone a n d b u p r e n o r p h i n e in r a t s , Int. J. Pharm.
21, 233 (1984).
313. A. Hussain, R. Kimura, C . H. Huang and R. Mustafa, Nasal
absorption of ergotamine t a r t r a t e in r a t s , Int. J. Pharm. 21,
289 (1984).
314. K. S. E. S u , K. M. Campanale and C. L. G r i e s , Nasal d r u g
delivery system of a q u a r t e r n a r y ammonium compound: clofiliu-
um t o s y l a t e , J. Pharm. Sci. 73, 1251 (1984).
315. A. N . F i s h e r , K. Brown, S . S . D a v i s , G. D . P a r r , and D. A .
Smith, The nasal a b s o r p t i o n of sodium cromoglycate in t h e
albino r a b b i t , J. Pharm. Pharmacol. 37, 38 (1985).
316. R. L. B r o n a u g h and R. F . S t e w a r t , Methods for in v i t r o p e r -
c u t a n e o u s absorption s t u d i e s V: Permeation t h r o u g h damaged
s k i n , J. Pharm. Sci. 74, 1062 (1985).
82 / Li et at.

317. D . L. London, W. R. B u t t , S . S. L y n c h , J . C. Marshall,

S. Owusu, W. R. Robinson and J . M. S t e p h e n s o n , Hormal r e -
s p o n s e to i n t r a n a s a l l u t e i n i z i n g hormone, J. Clin. Endocrinol.
37, 829 (1973).
318. J . Keenan and M. A . Chamberlain, Nasal mucosal a b s o r p t i o n of
t e t r a c o s a c t r i n as indicated b y a r i s e in plasma fluorogenic c o r t i -
c o s t e r o i d s , Br. Med. J. 4, 407 (1969).
319. K. Muller and M. Osier, Induction of l a b o r , a comparison of
i n t r a v e n o u s , i n t r a n a s a l and t r a n s b u c c a l oxytocin, Acta Obstet.
Gynecol Scand. 46, 59 (1967).
320. G. Bauman, A . Walser, P . A. Desaulles, F . J . A. Paesi and
L. Geller, Corticotropic action of an i n t r a n a s a l l y applied s y n t h e t i c
ACTH d e r i v a t i v e , J. Clin. Endocrinol. 42, 60 (1976).
321. S . Hirai, T . Ikenaga a n d T . Matsuzawa, Nasal absorption of
insulin in d o g s , Diabetes 27, 296 (1978).
322. S. Hirai, T . Yashiki and H. Mima, Effect of s u r f a c t a n t s on t h e
nasal a b s o r p t i o n of insulin in r a t s , Int. J. Pharm. 9, 165 (1981).
323. T . Nagai, Y . Nishimoto, N . Nambu, Y. Suzuki and K. S e k i n e ,
Powder dosage form of insulin for nasal administration, J. Con-
trolled Release 1, 15 (1984).
324. K. Morimoto, K. Morisaka a n d A . Kamada, Enhancement of nasal
a b s o r p t i o n of insulin and calcitonin u s i n g polyacrylic acid gel,
J. Pharm. Pharmacol. 37, 134 (1985).
325. K. S. E. S u , K. M. Campanale, L. G. Mendelsohn and C . L.
Gries, Nasal delivery of p o l y p e p t i d e s I : Nasal absorption of
e n k e p h a l i n s in r a t s , J. Pharm. Sci. 74, 394 (1985).
326. D . F . P r o c t o r and G. K. Adams I I I , Physiology a n d pharmacol-
ogy of nasal function a n d mucus s e c r e t i o n , Pharmacol. Ther.,
P a r t B , 2, 493 (1976).
327. G. D . P a r r , Nasal delivery of d r u g s , Pharm. Int. 4, 202 (1983).
328. S. Hirai, T. Yashiki, T . Matsuzawa and H. Mima, Absorption
of d r u g s from t h e nasal mucosa of r a t , Int. J. Pharm. 7, 317
(1981).
329. O. G. R a b b e , H. C . Yeh, G . J . Newton, R. F . Phalen and
D . J . Velasquez, I n , Inhaled Particles IV, P a r t 1, B r i t i s h Oc-
cupational Hygiene Society, E d i n b u r g h , 1977, p . 13.
330. J . W. P a t e r s o n , A. J . Woolcock and G. M. Shenfield, S t a t e of
a r t : bronchodilator d r u g s , Am. Rev. Respir. Dis. 120, 1149
(1979).
331. K. Horsfield, S t r u c t u r e of t h e t r a c h e o b r o n c h i a l t r e e . I n , Sci-
entific Foundations of Respiratory Medicine ( J . G. S c a d d i n g
a n d G. Cummings, e d s . ) , W. B . S a u n d e r s , Philadelphia, 1981,
p p . 54-70.
332. W. D. F e n n and H. R a h n , Handbook of Physiology: Respira-
tion, American Physiology Society, Washington, DC, 1973.
333. H. Von Hayek, The Human Lung, Hafer, New York, 1960.
 Influence of Drug Properties on Design I 83

334. P . E . Morrow, Task g r o u p of l u n g dynamics: Disposition and

r e t e n t i o n models for i n t e r n a l dosimetry of t h e human r e s p i r a t o r y
t r a c t , Health Phys. 12, 173 (1966).
335. M. B . Dolovich, J . S a n c h i s , C . Rossman a n d M. T . Newhouse,
Aerosol p e n e t r a n c e : a s e n s i t i v e index of p e r i p h e r a l airway o b -
s t r u c t i o n , J. Appl. Physiol. 40, 468 (1976).
336. S. P . Newman, F . Moren, D . Pavia, F . Little and S . W. C l a r k e ,
Deposition of p r e s s u r i z e d s u s p e n s i o n aerosols inhaled t h r o u g h
e x t e n s i o n d e v i c e s , Am. Rev. Respir. Dis. 124, 317 (1981).
337. K. F . Lampe, Influence of disease on pharmacokinetic p a r a m e t e r s
of inhaled s u b s t a n c e s . I n , Modeling of Inhalation Exposure to
Vapors: Uptake, Distribution, and Elimination, Vol. II (V.
F i s e r o v a - B e r g e r o v a , e d . ) , CRC P r e s s , Florida, 1983, p p . 157-
164.
338. J . D . Brain and P . A . V a l b e r g , Deposition of aerosols in t h e
r e s p i r a t o r y t r a c t , Am. Rev. Respir. Dis. 120, 1325 (1979).
339. J . H e y d e r , Mechanism of aerosol particle deposition, Chest 80,
820 (1981).
340. R. H i c k s , Pulmonary fibrosis: a l l e r g i e s , d u s t diseases and
d r u g s , Pharm. Int. 5, 304 (1984).
341. D . F . P r o c t o r , I . A n d e r s e n a n d G. L i n q u i s t , Clearance of
inhaled p a r t i c l e s from t h e human n o s e , Arch. Intern. Med. 131,
132 (1973).
342. R. E. A l b e r t , M. Lippmann, J . Spiegelman, C . Strehlow, W.
B r i s c o e , P . Wolfson, a n d N . Nelson, The clearance of r a d i o -
active p a r t i c l e s from t h e human l u n g s . I n , Inhaled Particles
and Vapors II ( C . N . Davies, e d . ) , Pergamon P r e s s , Oxford,
1967, p p . 361.
343. C . W. LaBelle and H. B r i e g e r , P a t t e r n s and mechanisms in t h e
elimination of d u s t from t h e l u n g . I n , Inhaled Particles and
Vapors ( C . N. D a v i e s , e d . ) , Pergamon P r e s s , Oxford, 1961,
p p . 356.
344. F . F . H a h n , G. J . Newton, and PI L . B r y a n t , In v i t r o p h a g o -
cytosis of r e s p i r a b l e - s i z e d monodisperse p a r t i c l e s by alveolar
m a c r o p h a g e s . In, Pulmonary Macrophage and Epithelial Cells,
CONF-760927, U . S . Department of Commerce, Springfield, VA,
1977, p p . 424.
345. F . J . S t r e c k e r , T i s s u e r e a c t i o n s in r a t l u n g s after d u s t inhala-
ation with special r e g a r d to bronchial d u s t elimination and to
t h e p e n e t r a t i o n of d u s t into t h e l u n g i n t e r s t i c e s a n d lymphatic
n o d e s . I n , Inhaled Particles and Vapors II ( C . N . D a v i e s ,
e d . ) , Pergamon P r e s s , Oxford, 1967, p p . 141.
346. J . M. L a u w e r y n s and J . H. B a e r t , Alveolar clearance a n d t h e
role of t h e pulmonary l y m p h a t i c s , Am. Rev. Respir. Dis. 115,
627 (1977).
84 I Li et at.

347. E. A. B . Brown, T h e localization, metabolism, a n d t h e effects

of d r u g s a n d t o x i c a n t s in l u n g , Drug Metab. Rev. 3, 33 (1974).
348. M. Simonescu, U l t r a s t r u c t u r a l organization of t h e alveolar-
capillary u n i t , I n , Metabolic Activities and the Lung, Ciba
Foundation Symposium No. 78 ( J . Vane, e d . ) , Amsterdam,
1980, p p . 1 1 - 2 6 .
349. E. E. S c h n e e b e r g e r , S t r u c t u r a l b a s i s for some permeability
p r o p e r t i e s of t h e air-blood b a r r i e r , Fed. Proc. Fed. Am. Soc.
Exp. Biol. 37, 2471 (1978).
350. O. D . Wangensteen, L. E. Wittmers, J r . , and J . A. J o h n s o n ,
Permeability of t h e mammalian blood-gas b a r r i e r and its com-
p o n e n t s , Am. J. Physiol. 216, 719 (1969).
351. E. Taylor and K. A. Gaar, J r . , Estimation of equivalent p o r e
radii of pulmonary capillary and alveolar membranes, Am. J.
Physiol. 218, 1133 (1970).
352. J . Gil, Organization of microcirculation in t h e l u n g , Ann. Rev.
Physiol. 42, 177 (1980).
353. S . L. S c h w a r t z , I n t e r a c t i o n of nicotine and o t h e r amines with
t h e endocytic and exocytic functions and m a c r o p h a g e s , Fed.
Proc. 35, 85 (1976).
354. U. Smith and J . W. R y a n , An electron microscopic s t u d y of
t h e v a s c u l a r endothelium as a site for b r a d y k i n i n and ATP a c t i -
vation in r a t l u n g , I n , Advances in Experimental Medical Bio-
logy, Vol. 8 ( N . B a c k , F . S i c u t e r i , and M. R. Silva, e d s . ) ,
1970, p p . 249-262.
355. R. Effros, Small solutes and w a t e r . In, Lung Biology in Health
and Disease, Vol. 7 ( N . C . S t a u b , e d . ) , Marcel D e k k e r , New
Y o r k , 1978, p p . 183-222.
356. S . J . Eunaad, L . S . S c h a n k e r , Absorption of d r u g s from t h e
rat l u n g , Am. J. Physiol. 223, 1227 (1972).
357. L. S . S c h a n k e r and M. J . L e s s , L u n g pH and pulmonary a b -
s o r p t i o n of nonvolatile d r u g s in t h e r a t , Drug. Metab. Dispos.
5, 174 (1977).
358. S . J . Enna and L. S. S c h a n k e r , Phenol r e d a b s o r p t i o n from
t h e rat lum: evidence of c a r r i e r t r a n s p o r t , Life Sci. 12, 231
(1973).
359. T . H. G a r d i n e r and L. S. S c h a n k e r , Absorption of disodium
cromoglycate from t h e r a t l u n g : Evidence of c a r r i e r t r a n s p o r t ,
Xenobiotica 4, 725 (1974).
360. K. R. Chapman, A. C . B r a u d e and A. S . R e b u c k , Anticho-
linergic t h e r a p y in asthma and chronic b r o n c h i t i s , Hosp. Formu-
lary 17, 686 (1982).
361. J . Hartiala, P . Uotila and W. N i e n s t e d t , Absorption and metab-
olism of i n t r a t r a c h e a l l y instilled Cortisol and beclamethasone
dipropionate in t h e isolated p e r f u s e d rat l u n g , Med. Biol. 57,
294 (1979).
 Influence of Drug Properties on Design I 85

362. P . A . Routledge and D . G. S h a n d , Presystemic d r u g elimina-

t i o n , Ann. Rev. Pharmacol. 19, 447 (1979).
363. R . H. B r i a n t , E . W. Black well, F . M. Williams, D . S. Davies
and C . T . Dollery, T h e metabolism of sympathomimetic b r o n c h o -
dilator d r u g s by t h e isolated p e r f u s e d dog l u n g , Xenobiotica
3, 787 (1973).
364. Y. S . B a k h l e , F i r s t - p a s s metabolism of e n d o g e n o u s and e x o -
genous s u b s t r a t e s b y l u n g . I n , Presystemic Drug Elimination
( C . F . George and D . G. S h a n d , e d . ) , B u t t e r w o r t h Scientific,
London, 1982, p p . 147-172.
365. T . E. P i c k e t t , T . C. Orton and M. W. A n d e r s o n , A s t u d y of
t h e dynamics of imipramine accumulation in t h e isolated p e r -
fused r a b b i t l u n g , Drug Metab. Dispos. 3, 389 (1975).
366. D . P . B e n z i g e r and J . Edelson, Absorption from t h e v a g i n a ,
Drug Metab. Rev. 14, 137 (1983).
367. D . J . Black and M. E. Orme, Interindividual variability in oral
c o n t r a c e p t i v e disposition, TIPS 5, 480 (1984).
368. H. Okada, I . Yamazaki, Y . Ogawa, S. Hirai, T . Yashiki, and
H. Mima, Vaginal a b s o r p t i o n of a potent luteinizing hormone-
r e l e a s i n g hormone analog (leuprolide) in r a t s I: Absorption b y
various r o u t e s and a b s o r p t i o n e n h a n c e m e n t , J. Pharm. Sci. 71,
1367 (1982).
369. H. O k a d a , I . Yamazaki, T . Yashiki, and H. Mima, Vaginal
a b s o r p t i o n of a potent luteinizing hormone-releasing hormone
analogue (leuprolide) in r a t s I I : Mechanism of a b s o r p t i o n e n -
hancement with o r g a n i c a c i d s , J. Pharm. Sci. 72, 75 (1983).
370. M. H. B u r g o s and C . E. Roig de V a r g a s - l i n a r e s . I n , The
Human Vagina (E. S . E. Hafez and T . N . E v a n s , e d . ) , Elsevier/
North Holland Biomedical P r e s s , Amsterdam, 1978, p p . 6 3 - 6 9 .
371. C. E. F l o w e r s , J r . , L . R. B e c k , and W. H. Wilborn, T h e con-
t r a c e p t i v e a s p e c t s of t h e anatomy, morphology, and physiology
of t h e v a g i n a . I n , Vaginal Contraception (G. I . Zatuchni,
A. J . S o b r e e r o , J . J . Speidel and J . J . S c i a r r a , e d s . ) , H a r p e r
and Row, H a g e r s t o w n , 1979, p p . 1 3 - 2 2 .
3 72. R. E . T r u s s e l l a n d R. F . MacDougal, Vaginal acidity (in vivo
glass electrode measurement) in late p r e g n a n c y and its relation
to t h e vaginal flora, Am. J. Obstet. Gynecol. 39, 77 (1940).
373. T . Y o t s u y a n a g i , A. Molokhia, S . Hwang, N . F . H. Ho, G. L.
Flynn and W . I . Higuchi, System approach to vaginal delivery
of d r u g s I : Development of in situ vaginal d r u g a b s o r p t i o n
p r o c e d u r e , J. Pharm. Sci. 64, 71 (1975).
374. E. Owada, C . R. B e h l , S . S . Hwang, L. S u h a r d j a , G. L.
F l y n n , and W. I . Higuchi, Vaginal d r u g a b s o r p t i o n in r h e s u s
monkeys I : Development of methodology, J. Pharm. Sci. 66,
216 (1977).
86 I Li et al.

375. S . Hwang, E. Owada, T . Y o t s u y a n a g i , L. S u h a r d j a , G. L.

F l y n n , and W. I . Higuchi, Systems a p p r o a c h to vaginal delivery
of d r u g s I I : I n situ vaginal a b s o r p t i o n of u n b r a n c h e d aliphatic
alcohols, J. Pharm. Sci. 65, 1574 (1976).
376. S . Hwang, E. Owada, L . S u h a r d j a , N. F . H. Ho, G. L. F l y n n ,
and W. I . Higuchi, Systems a p p r o a c h t o vaginal delivery of
d r u g s V: In s i t u vaginal a b s o r p t i o n of 1-alkanoic a c i d s , J.
Pharm. Sci. 66, 781 (1977).
377. C. R . B e h l , System a p p r o a c h to t h e s t u d y of vaginal d r u g
a b s o r p t i o n in r h e s u s monkey, P h . D . T h e s i s , University of
Michigan, Ann A r b o r , 1979.
378. G. L. F l y n n , N . F . H. Ho, S . Hwang, E . Owada, A. Molokhla,
C. R. B e h l , W. I . Higuchi, T . Y o t s u y a n a g i , Y . S h a h , and
J . P a r k , I n t e r f a c i n g matrix release and membrane absorption—
analysis of s t e r o i d a b s o r p t i o n from a vaginal device in t h e
r a b b i t d o e . I n , Controlled Release Polymeric formulations
( D . R. Paul and F . W. H a r r i s , e d s . ) , Am. Chem. Soc, Wash-
i n g t o n , D . C . , 1976, p . 87.
379. D . R. Mishell, J r . , M. T a l a s , A. F . Parlow and D . L. Moyer,
Contraception b y means of a Silastic vaginal r i n g i m p r e g n a t e d
with m e d r o x y p r o g e s t e r o n e a c e t a t e , Am. J. Obstet. Gynecol.
107, 100 (1970).
380. D. R . Mishell, J r . , M. Lumkin, S . S t o n e , Inhibition of ovulation
with cyclic u s e of p r o g e s t r o n e - i m p r e g n a t e d i n t r a v a g i n a l d e v i c e s ,
Am. J. Obstet. Gynecol. 113, 927 (1972).
381. M. R. Henzl, D. R. Mishell, J r . , J . G. Velazquez, and W. E.
Leitch, Basic s t u d i e s for prolonged p r o g e s t o g e n administration
b y vaginal d e v i c e s , Am. J. Obstet. Gynecol. 117, 101 (1973).
382. N . H. L a u e r s e n and K. H. Wilson, T h e abortifacient effects of
a newly developed vaginal silastic device impregnated with an
0.5% concentration of 1 5 ( 5 ) - 1 5 - m e t h y l - p r o s t a g l a n d i n - F 2 ( a l p h a ) -
methyl e s t e r in t h e first t r i m e s t e r , Contraception 13, 697 (1976).
383. A. Victor and D. B . J o h n s o n , C o n t r a c e p t i v e r i n g s : self-
administered t r e a t m e n t g o v e r n e d b l e e d i n g , Contraception 16,
137 (1977).
384. D . R. Mishell, J r . , D . E. Moore, I. Roy, P . F . B r e n n e r , and
M. A. P a g e , Clinical performance and endocrine profiles with
c o n t r a c e p t i v e vaginal r i n g s containing a combination of estradiol
and d - n o r g e s t r e l , Am. J. Obstet. Gynecol. 130, 55 (1978).
385. T . M. J a c k a n i c z , Levonorgestrel and estradiol release from an
improved c o n t r a c e p t i v e vaginal r i n g , Contraception 24, 323
(1981).
386. E. Diczfalusy and B-M. L a n d g r e n , Some pharmacokinetic and
pharmacodynamic p r o p e r t i e s of vaginal delivery systems t h a t
release small amounts of p r o g e s t o g e n s at a n e a r z e r o - o r d e r
r a t e . I n , Long-Acting Contraceptive Delivery Systems (G. I.
 Influence of Drug Properties on Design I 87

Z a t u c h n i , A. J . S o b r e r o , J . J . Speidel a n d J . J . S c i a r r a ,
e d s . ) , H a r p e r and Row, H a g e r s t o w n , 1984, p p . 213-227.
387. E. S . N u w a y s e r , D . L. Williams, P . M. Meier, T . C . Wu, S. F .
Merchant, and J . H. K e r r i g a n , A microcapsule system for d r u g
d e l i v e r y . I n , Proceedings of Drug Delivery Systems (H. L.
Gabelnick, e d . ) , U . S . Department of Health, Education, and
Welfare, B e t h e s d a , Maryland, 1976, p p . 1 9 3 - 2 5 1 .
388. D . L. G a r d n e r , A. J . P a t n a u s and D . L . F i n k , Steroid release
from microcapsules. I n , Proceedings of Drug Delivery Systems
(H. L . Gabelnick, e d . ) , U . S . Department of Health, Education,
and Welfare, B e t h e s d a , Maryland, 1976, p p . 1 9 3 - 2 5 1 .
389. D . L. G a r d n e r , D . J . F i n k , and C . R. H a s s l e r , Potential d e -
livery of c o n t r a c e p t i v e a g e n t s to t h e female r e p r o d u c t i v e t r a c t .
I n , Controlled Release of Pesticides and Pharmaceuticals ( D . H.
Lewis, e d . ) , Plenum P r e s s , New York, 1981, p p . 99-109.
390. G. A. D i g e n i s , M. J a y , R. M. B e i h n , T . R. Tice, and L. R.
B e c k , External s c i n t i g r a p h y in t h e s t u d y of l o n g - a c t i n g con-
t r a c e p t i v e delivery s y s t e m s . I n , Long-Acting Contraceptive
Delivery Systems (G. I . Zatuchni, A. J . S o b r e r o , J . J . Speidel,
and J . J . S c i a r r a , e d s . ) , H a r p e r and Row, H a g e r s t o w n , 1984,
p p . 241-245.
391. A. Victor, Vaginal absorption of c o n t r a c e p t i v e s t e r o i d s . I n ,
Long-Acting Contraceptive Delivery Systems (G. I. Z a t u c h n i ,
A. J . S o b r e r o , J . J . Speidel and J . J . S c i a r r a , e d s . ) , H a r p e r
and Row, H a g e r s t o w n , 1984, p p . 241-245.
392. Y . W. Chien, S. Y. Mares, J . B e r g , S . H u b e r , H. J . L a m b e r t ,
and K. F . K i n g , Controlled d r u g release from polymeric delivery
devices I I I : In v i t r o - i n vivo correlation for i n t r a v a g i n a l release
of ethynodiol diacetate from silicone devices in r a b b i t s , J.
Pharm. Sci. 64, 1776 (1975).
393. I . Sivin, D . R. Mishell, J r . , A . Victor, S. Diaz, F . A. S a n -
c h e z , N . C . Nielsen, O. Akinla, T . Pyorala, E. C o u t i n h o ,
A . F a u n d e s , S. Roy, P . B r e n n e r , T . A h r e n , M. P a v e z , V.
B r a c h e , O. F . Giwa-Osagie, M. O. F a s o n , B . Zausner-Guelman,
E. D a r z e , J . C. Silva, J . Diaz, T . M. J a c k a n i c z , J . S t e r n ,
and H. Nash, A multicenter s t u d y of l e v o n o r g e s t r e l - e s t r a d i o l
c o n t r a c e p t i v e vaginal r i n g s . I I . Subjective and objective mea-
s u r e of effects, Contraception 24, 359 (1981).
394. G. E. Egli, and M. Newton, The t r a n s p o r t of c a r b o n p a r t i c l e s
in t h e human female r e p r o d u c t i v e t r a c t , Fertil. Steril. 12, 151
(1961).
395. D . H. de B o e r , T r a n s p o r t of p a r t i c u l a t e matter t h r o u g h t h e
human female genital t r a c t , J. Reprod. Fertil. 28, 295 (1972).
396. N . S. Mason, D . V. S . G u p t a , D . W. Keller, R. S . Young-
q u i s t , and R . S. S p a r k s , Microencapsulation of p r o g e s t r o n e
for contraception b y i n t r a c e r v i c a l injection. I n , Biomedical
88 / L i et at.

Applications of Microencapsulation ( F . Lim, e d . ) , CRC P r e s s ,

Florida, 1984, p p . 7 6 - 8 4 .
397. P . Lahteenmaki, H. K u r u n m a k i , T . L u u k k a i n e n , P . O. A. Lah-
teenmaki, K. Ratsula, J . Toivonen, Development of i n t r a c e r v i -
cal s t e r o i d - r e l e a s i n g s y s t e m . I n , Long-Acting Contraceptive
Delivery Systems (G. I . Zatuchni, A. J . S o b r e r o , J . J . Speidel,
a n d J . J . S c i a r r a , e d s . ) , H a r p e r and Row, H a g e r s t o w n , MD,
1984, p p . 595-600.
398. H. M. Hasson, Morphologic f e a t u r e s affecting IUD p e r f o r m a n c e .
I n , IUD Technology (E. S. E. Hafez and W. A. A . Van O s ,
e d s . ) , G. K. Hall Medical P u b l i s h e r s , Boston, 1980, p p . 1 3 - 1 9 .
399. O. Puroinen a n d H. L. Kaihola, Uterine size measured b y u l t r a -
sound d u r i n g t h e menstrual c y c l e , Acta Obstet. Gynecol. Scand.
54, 247 (1975).
400. H. T a t u m , Clinical a s p e c t s of i n t r a u t e r i n e c o n t r a c e p t i o n : Cir-
cumspection 1976. I n , Modern Trends in Infertility and Con-
ception Control (E. Wallach and R. Kempers, e d s . ) , Williams
and Wilkins, Baltimore, 1979, p . 333.
401. H. J . T a t u m , I n t r a u t e r i n e c o n t r a c e p t i o n , Am. J. Obstet. Gyne-
col. 112, 1000 (1972).
402. C . C. C h a n g and H. J . T a t u m , Effects of i n t r a u t e r i n e c o p p e r
wire on r e s o r p t i o n of f e t u s e s in r a t s , Contraception 11, 79
(1975).
403. F . Hefnawi, O. Kandil, G. A s k a l a n i , I . S e r o u r , K. Zaki, F .
N a s r , M. Mousa, Mode of action of t h e c o p p e r IUD: effect on
endometrium c o p p e r and cervical mucus sperm migration. I n ,
Analysis of Intrauterine Contraception ( F . Hefnawi and S. Segal,
e d s . ) , North-Holland Publishing C o . , Amsterdam, 1975, p . 459.
404. T . Tamaya, Y. Nakata, Y. Ohno, S . Nioka, N. F u r u t a , and
H. Okada, T h e mechanism of action of t h e c o p p e r i n t r a u t e r i n e
d e v i c e , Fertil. Steril. 27, 767 (1976).
405. B . P h a r r i s s and C. Mitchell, Values of steroidal i n t r a u t e r i n e
contraception for developing c o u n t r i e s , J. Steroid Biochem. 11,
469 (1979).
406. J . J . S c i a r r a , A. Scommengna and G. I . Zatuchi, Research
and new developments in i n t e r u t e r i n e c o n t r a c e p t i o n . I n , IUD
Technology (E. S . E. Hafez and A. J . M. A u d e b e r t , e d s . ) ,
MTP P r e s s , L a n c a s t e r , 1982, p p . 165-174.
407. G. F . Odland, S t r u c t u r e of t h e s k i n . I n , Biochemistry and
Physiology of the Skin (L. A. Goldsmith, e d . ) , Oxford Univer-
sity P r e s s , New York, 1983, p p . 3 - 6 3 .
408. R. Scheuplein, Mechanisms of p e r c u t a n e o u s absorption I I :
T r a n s i e n t diffusion a n d t h e relative importance of various
r o u t e s of skin p e n e t r a t i o n , J. Invest. Dermatol. 45, 334 (1967).
409. R . J . Scheuplein, Mechanism of p e r c u t a n e o u s a b s o r p t i o n ,
J. Invest. Dermatol. 48, 79 (1967).
 Influence of Drug Properties on Design I 89

410. W. J . Albery and J . Had g r a f t , P e r c u t a n e o u s a b s o r p t i o n : In

vivo e x p e r i m e n t s , J. Pharm. Pharmacol. 31, 140 (1979).
411. T . Higuchi, Physical chemical analysis of t h e p e r c u t a n e o u s a b -
sorption p r o c e s s from creams and o i n t m e n t s , J. Soc. Cosmet.
Chem. 11, 85 (1960).
412. A. M. Kligman, A biological brief on p e r c u t a n e o u s a b s o r p t i o n ,
Drug Develop. Ind. Pharm. 9, 521 (1983).
413. J . H a d g r a f t , P e r c u t a n e o u s a b s o r p t i o n : possibilities and p r o b -
lems, Int. J. Pharm. 16, 255 (1983).
414. R. J . Scheuplein and I. H. Blank, Permeability of t h e s k i n ,
Physiol. Rev. 51, 702 (1971).
415. R. H. Guy and H. I . Maibach, D r u g delivery to local s u b c u -
t a n e o u s s t r u c t u r e s following topical administration, J. Pharm.
Sci. 72, 1375 (1983).
416. J . Wepierre and J - P . Marty, P e r c u t a n e o u s absorption of d r u g s ,
Trends Pharmacol. Sci. 1, 23 (1979).
417. J . Wepierre, F a c t e u r s p h y s i q u e s et physiologiques i n t e r v e n a n t
d a n s l'absorption p e r c u t a n e e d e s medicaments. I n , Actualites
Pharmacologiques, 31e s e r i e , Masson, P a r i s , 1979, p p . 170-202.
418. J . E. Shaw, Development of t r a n s d e r m a l t h e r a p e u t i c s y s t e m s ,
Drug Dev. Ind. Pharm. 9, 579 (1983).
419. S. K. C h a n d r a s e d a r a n , Controlled release of scopolamine for
p r o p h y l a x i s of motion s i c k e n e s s , Drug Dev. Ind. Pharm. 9,
627 (1983).
420. W. R. Good, T r a n s d e r m ^ - N i t r o controlled delivery of n i t r o -
glycerin via t h e t r a n s d e r m a l r o u t e , Drug Dev. Ind. Pharm. 9,
647 (1983).
421. A. Karim, T r a n s d e r m a l a b s o r p t i o n : a u n i q u e o p p o r t u n i t y for
a constant delivery of n i t r o g l y c e r i n , Drug Dev. Ind. Pharm.
9, 671 (1983).
422. J . E. Shaw, Pharmacokinetics of n i t r o g l y c e r i n a n d clonidine
delivered b y t h e t r a n s d e r m a l r o u t e , Am. Heart J. 108, 217
(1984).
423. D . L. S e k u r a and J . Scala, The p e r c u t a n e o u s a b s o r p t i o n of
alkylmethyl sulfoxide, Adv. Biol. Skin 12, 257 (1972).
424. R. J . Folkman and H. I . Maibach, P e r c u t a n e o u s p e n e t r a t i o n of
h y d r o c o r t i s o n e with u r e a , Arch. Dermatol. 109, 58 (1974).
425. R. E. S t o u g h t o n , Enhanced p e r c u t a n e o u s p e n e t r a t i o n with
l - d o d e c y l a z a c y c l o h e p t a n - 2 - o n e ( A z o n e ) , Arch. Dermatol. 118,
474 (1982).
426. R. E. S t o u g h t o n and W. O. McClure, A z o n e R : A new n o n -
toxic e n h a n c e r of c u t a n e o u s p e n e t r a t i o n , Drug Dev. Ind. Pharm.
9, 725 (1983).
427. N. B a k e r and J . H a d g r a f t , Faciliated p e r c u t a n e o u s a b s o r p t i o n :
a model s y s t e m , Int. J. Pharm. 8, 193 (1981).
90 I Li et a/.

428. N . B o d o r , J . Zupan, and S . Selk, Improved delivery t h r o u g h

biological membranes VII. Dermal delivery of cromoglycic acid
(cromolyn) via i t s p r o d r u g s , Int. J. Pharm. 7, 63 (1980).
429. C . D . Yu, J . L. F o x , N. F . H. Ho, and W. I . Higuchi, P h y s i -
cal model of evaluation of topical p r o d r u g delivery-simultaneous
t r a n s p o r t a n d bioconversion of v i d a r a b i n e - 5 f - v a l e r a t e I I : Param-
e t e r d e t e r m i n a t i o n s , J. Pharm. Sci. 68, 1341 (1979).
430. C . D . Yu, J . L. F o x , N. F . H. Ho, and W. I . Higuchi, P h y s i -
cal model evaluation of topical p r o d r u g d e l i v e r y - s i m u l t a n e o u s
t r a n s p o r t and bioconversion of v i d a r a b i n e - 5 T - v a l e r a t e I I : p a r a m -
e t e r d e t e r m i n a t i o n s , J. Pharm. Sci. 86, 1347 (1979).
431. J . H a d g r a f t , Theoretical a s p e c t s of metabolism in t h e e p i d e r m i s ,
Int. J. Pharm. 4, 229 (1980).
432. R. H. Guy and J . H a d g r a f t , P e r c u t a n e o u s metabolism with
s a t u r a b l e enzyme k i n e t i c s , Int. J. Pharm. 11, 187 (1982).
433. R. C. Scott and P . H. D u g a r d , A potential model for s t u d y i n g
a b s o r p t i o n t h r o u g h abnormal s t r a t u m corneum, J. Pharm. Phar-
macol. 34, 35 (1982).
434. C . R . B e h l , E. E. Linn, G. L . F l y n n , N. F . H. Ho, W. I .
Higuchi, and C. L. P i e r s o n , Permeation of skin and e s c h a r
b y a n t i s e p t i c s I I : influence of controlled b u r n s on t h e permea-
tion of p h e n o l , J. Pharm. Sci. 72, 397 (1983).
435. J . H. T r u e b l o o d , R. M. Rossomondo, W. H. Carlton and L . A.
Wilson, Corneal contact times of ophthalmic v e h i c l e s . Evaluation
b y m i c r o s c i n t i g r a p h y , Arch. Ophthalmol. 93, 127 (1975).
436. H. B e n s o n , Permeability of t h e cornea to topically applied d r u g s ,
Arch. Ophthalmol. 91, 313 (1974).
437. J . W. Shell, Ophthalmic d r u g delivery s y s t e m s , Surv. Ophthal-
mol. 29, 117 (1984).
438. A. Mitra, Passive and facilitated t r a n s p o r t of pilocarpine a c r o s s
t h e corneal membrane of t h e r a b b i t , P h . D . T h e s i s , University
of K a n s a s , 1983.
439. E. Tomlinson, S . S. D a v i s , O. Olejnik, and C. G. Wilson,
Altered ocular disposition of sodium cromoglycate upon i o n - p a i r
and complex coacervate formation with dodecylbenzyldimethyl-
ammonium c h l o r i d e , J. Pharm. Pharmacol. 31, 749 (1981).
440. V. H. L . Lee, P . T . U r r e a , R. E. Smith and D . J . Schanzlin,
Ocular d r u g bioavailability from topically applied liposomes,
Surv. Ophthalmol. 29, 335 (1985).
441. C. P . Wei, J . A. A n d e r s o n , and I . Leopold, Ocular a b s o r p t i o n
and metabolism of topically applied e p i n e p h r i n e and a dipivalyl
e s t e r of e p i n e p h r i n e . Invest. Ophthalmol. Vis. Sci. 17, 315
(1978).
442. S. S. Chrai and J . R. Robinson, Ocular evaluation of methyl-
cellulose vehicle in albino r a b b i t s , J. Pharm. Sci. 63, 1218
(1974).
 influence of Drug Properties on Design I 91

443. T . F . P a t t o n and J . R. Robinson, Ocular evaluation of poly-

vinyl alcohol, J. Pharm. Sci. 64, 1312 (1975).
444. C. A . A l d e r , D . M. Maurice and M, E. P a t t e r s o n , The effect
of viscosity of t h e vehicle on t h e p e n e t r a t i o n of fluorescein
into t h e human e y e , Exp. Eye. Res. 11, 34 (1971).
445. H. W. Hui and J . R . R o b i n s o n , Effect of particle dissolution r a t e
on ocular d r u g bioavailability, J. Pharm. Sci. 75, 280 (1986).
446. R. E . S t r a t f o r d , D . C . Yang, M. A. Redell and V. H. L . Lee,
Effects of topically applied liposomes on disposition of epine-
p h r i n e a n d insulin in t h e albino r a b b i t e y e , Int. J. Pharm. 13,
263 (1983).
447. R. E. S t r a t f o r d , D . C . Y a n g , M. A . Redell a n d V. H. L . Lee,
Ocular d i s t r i b u t i o n of liposome-encapsulated e p i n e p h r i n e and
inulin in t h e albino r a b b i t , Curr. Eye. Res. 2, 377 (1983).
448. G. Smolin, M. Okumoto, S . Feiler, D . Condon, I d o x u r i d i n e -
liposome t h e r a p y for h e r p e s simplex k e r a t i t i s , Am. J. Ophthal-
mol. 91, 220 (1981).
449. H. E. Schaeffer and D . L. K r o h n , Liposomes in topical d r u g
d e l i v e r y , Invest. Ophthalmol Vis. Sci. 22, 220 (1982).
450. M. B a r z a , J . Baum, F . Szoka, Pharmacokinetics of s u b c o n j u n c -
tival liposome-encapsulated gentamicin in normal r a b b i t e y e s ,
Invest. Ophthalmol. Vis. Sci. 25, 486 (1984).
451. J . W. Shell and R. W. B a k e r , Diffusion systems for controlled
release of d r u g s to t h e e y e , Ann. Ophthalmol. 6, 1037 (1974).
452. R. C. Capozza, L. S e n d e l b e c k , W. J . Balkenhol, P r e p a r a t i o n
a n d evaluation of a bioerodible n a l t r e x o n e delivery s y s t e m .
I n , Polymeric Delivery Systems: Midland Macromolecular Mono-
g r a p h s , Vol. 5, Gordon and B r e a c h , New Y o r k , 1978, p p .
59-73.
453. H. B u n d g a a r d , D r u g t a r g e t i n g : P r o d r u g s . I n , Topics in
Pharmaceutical Sciences 1983 (D. D. Breimer and P . S p e i s e r ,
e d s . ) , Elsevier Science P u b l i s h e r s , 1983, p p . 3 2 9 - 3 4 3 .
454. N . Bodor, Novel a p p r o a c h e s to t h e d e s i g n of safer d r u g s : soft
d r u g s and site-specific chemical delivery s y s t e m s , Adv. Drug
Res. 13, 255 (1984).
455. C. R . Alving, Delivery of liposome-encapsulated d r u g s to
m a c r o p h a g e s , Pharmac. Ther. 22, 407 (1983).
456. C. A. H u n t , H. Kinada, M. R a e d e r - S h i k o r r , K. Hirano, J .
Nakamura, R. A b r a , and H. S c r e i e r , Liposomes, Are t h e y ef-
fective d r u g c a r r i e r s ? I n , Topics in Pharmaceutical Sciences
1983 (D. D . Breimer and P . S p e i s e r , e d s . ) , Elsevier Science
P u b l i s h e r s , 1983, p p . 2 5 7 - 2 6 3 .
457. K . J . Widder and A. E. S e n y e i , Magnetic m i c r o s p h e r e s : A
vehicle for selective t a r g e t i n g of d r u g s , Pharmac. Ther. 20,
377 (1983).
92 / Li et ol.

458. P . C o u v r e u r , B . Kante, L. Grislain, M. Roland, and P . S p e i s e r ,

Toxicity of polyalkylcyanoacrylate nanoparticles I I : Doxorubicin-
loaded n a n o p a r t i c l e s . J. Pharm. Sci. 71, 790 (1982).
459. D . C. E d w a r d s , T a r g e t i n g potential and antibody c o n j u g a t e s ,
Pharmac. Ther. 23, 147 (1983).
460. R. B . B a n k e r t , Development and u s e of monoclonal antibodies
in t h e t r e a t m e n t of c a n c e r , Cancer Drug Delivery, 1, 251
(1984).
461. R. O b r i s t , Monoclonal antibodies as d r u g c a r r i e r s in oncology,
Trends Pharmacol. Sci., 4, 375 (1983).
462. U. Zimmermann, Cellular d r u g - c a r r i e r systems and t h e i r p o s -
sible t a r g e t i n g . I n , Targeting of Drugs (E. P . G o l d b e r g ,
e d . ) , John Wiley & S o n s , 1983, p p . 153-200.
463. D . A. Lewis and H. O. Alpar, T h e r a p e u t i c possibilities of
d r u g s e n c a p s u l a t e d in e r y t h r o c y t e s , Int. J. Pharm. 22, 137
(1984).
464. M. J . P o z n a n s k y , Enzyme-protein c o n j u g a t e s : new possibilities
for enzyme t h e r a p y , Pharmac. Ther. 21, 53 (1983).
465. L. G r o s , H. Ringsdorf, and H. S c h u p p , Polymeric antitumor
a g e n t s on a molecular and on a cellular l e v e l , Agnew. Chem.
Int. Engl. 20, 305 (1981).
466. D . P . Worth, J . N. H a r v e y , J . Brown, and M. R. Lee, C-L-
glutamyl-L-dopa is a dopamine p r o - d r u g , relatively specific for
t h e k i d n e y in normal s u b j e c t s , Clin. Sci. 69, 207 (1985).
467. V. J . Stella and K . J . Himmelstein, P r o d r u g a n d site-specific
d r u g d e l i v e r y , J. Med. Chem. 23, 1275 (1984).
468. J . W. S i m p k i n s , N. Bodor, and A. E n z , Direct evidence for
b r a i n - s p e c i f i c release of dopamine from a r e d o x delivery s y s -
tem, J. Pharm. Sci. 74, 1033 (1985).
469. A. W. Segeal, E. J . Willis, G. Slvain, C . D . V. Black, and
G. G r e g o r i a d i s , Morphological o b s e r v a t i o n s on the cellular and
subcellular destination of i n t r a v a s c u l a r l y administered lipo-
somes, Br. Exp. Pathol. 55, 320 (1974).
470. L. R. McDougall, J . K. D u n i c k , M. S. McNamee, and J . P .
K r i s s , Distribution and fate of s y n t h e t i c lipid vesicles in t h e
mouse: a combined radiounclide and spin label s t u d y , Proc.
Natl. Acad. Sci. USA 71, 3487 (1974).
471. G. Gregoriadis and E. D . N e e r u n j u n , Control of t h e r a t e h e p a -
tic u p t a k e and catabolism of l i p o s o m e - e n t r a p p e d p r o t e i n s i n -
jected into t h e r a t s . Possible t h e r a p e u t i c applications, Eur.
J. Biochem. 47, 179 (1974).
472. G. Gregoriadis and E. D . N e e r u n j u n , Homing of liposomes to
t a r g e t cells, Biochem. Biophys. Res. Comm. 65, 537 (1975).
473. V. T . Marchesi, T . W. Tillack, R. L. J a c k s o n , J . P . S e g r e s t ,
and R. E. S c o t t , Chemical characterization and surface o r i e n t a -
tion of t h e major glycoprotein of t h e human e r y t h r o c y t e mem-
b r a n e , Proc. Natl. Acad. Sci. USA 69, 1445 (1972).
 Influence of Drug Properties on Design I 93

474. R. L . Juliano and D . J . Stamp, Lectin-mediated attachment of

g l y c o p r o t e i n - b e a r i n g liposomes to cells, Nature 261, 235 (1976).
475. G. Weissman, D . Bloomgarden, R. Kaplan, C . Cohen, S. Hoff-
s t e i n e , T . Collins, A. Gotlier and D . Nagle, A general method
for t h e i n t r o d u c t i o n of enzymes b y means of immunoglobulin-
coated liposomes of deficient cells, Proc. Natl. Acad. Sci. USA
72, 88 (1975).
476. G. G r e g o r i a d i s , A. Meehan and M. M. Mah, I n t e r a c t i o n s of
a n t i b o d y - b e a r i n g small unilamellar liposomes with t a r g e t free
a n t i g e n in vitro and in vivo, Biochem. J. 200, 203 (1981).
477. G. P o s t e , R. K i r s c h , and T . Koestler, T h e challenge of lipo-
some t a r g e t i n g in v i v o . I n , Liposome Technology, Vol. I I I .
Targeted Drug Delivery and Biological Interaction (G. G r e g o r i -
a d i s , e d . ) , CRC P r e s s , Boca R a t o n , 1984, p p . 1-28.
478. M. J . P o z n a n s k y and R. L. Juliano, Biological a p p r o a c h e s to
t h e controlled d r u g delivery of d r u g s : A critical r e v i e w , Phar-
macol. Rev. 36, 277 (1985).
479. R. L. Magin and M. R. Niesman, T e m p e r a t u r e - d e p e n d e n t d r u g
release from l a r g e unilammellar liposomes, Cancer Drug Delivery
1, 109 (1984).
480. J . N. Weinstein, R. D . K l a u s n e r , T . I n n e r a r i t y , E. Ralston, and
R. Blumental, Phase t r a n s i t i o n r e l e a s e , a new a p p r o a c h to the
i n t e r a c t i o n of p r o t e i n s with lipid v e s i c l e s : Application to lipo-
p r o t e i n s , Biochim. Biophys. Acta 647, 270 (1981).
481. V. P . T o r c h i l i n , M. I . T a t i s o v , and V. N. Smirnov, Magnetic
S e p h a d e x as a c a r r i e r for enzyme immobilization and d r u g t a r -
g e t i n g , J. Biomed. Mater. Res. 19, 461 (1985).
482. M. K a n k e , G. H. Simmons, D . L. Weiss, B . A. B i v i n s , and
P . P . Deluca, Clearance of 1 4 l C r - l a b e l e d m i c r o s p h e r e s from blood
and d i s t r i b u t i o n in specific o r g a n s following i n t r a v e n u o u s and
i n t r a a r t e r i a l administration in beagle d o g s , J. Pharm. Sci. 69.
755 (1980).
483. J . J . B u r g e r , E. Tomlinson, E. M. A. Mulder and J . G. McVie,
Albumin microspheres for i n t r a a r t e r i a l tumor t a r g e t i n g . I . P h a r -
maceutical a s p e c t s , Int. J. Pharm. 23, 3 3 3 ( 1 9 8 5 ) .
484. R. J . W. B l a n c h a r d , I . G r o t e n h u i s , J . W. L a F a r e , and J . F .
P e r r y , Blood s u p p l y to hepatic V2 carcinoma implants as mea-
s u r e d b y radioactive m i c r o s p h e r e s , Proc. Soc. Exp. Biol. Med.
118, 465 (1965).
485. B . Lindell, K. F . A r o n s e h , U. Rothman, and H. O. S j o g r e n ,
T h e circulation in liver t i s s u e and experimental liver metastases
before a n d after embolization of t h e liver a r t e r y , Res. Exp.
Med. 171, 63-70 (1977).
486. S. Dakhil, W. Ensminger, K. C h o , N i e d e r h u b e r , K. Doan, and
R. Wheller, Improved regional selectivity of hepatic arterial
BCNU with d e g r a d a b l e m i c r o s p h e r s , Cancer 50, 631 (1982).
94 / Li et al.

487. R. F . T u m a , J . O. F o r s b e r g , and B . A g e r u p , Enhanced u p -

t a k e of actinomycin D in t h e dog k i d n e y b y simultaneous injec-
tion of d e g r a d a b l e s t a r c h m i c r o s p h e r e s into t h e renal a r t e r y ,
Cancer 50, 1 (1982).
488. T . Kato, R. Nemoto, H. Mori, M. T a k a h a s h i , Y. Tamakawa,
and M. Harada, Arterial chemoembolization with microencapsu-
lated a n t i - c a n c e r d r u g , JAMA 245, 1123 (1981).
489. S . B e n i t a , Microcapsules: New applications and c h a r a c t e r i z a -
t i o n , Labo-Pharma. Probl. Tech. 32, 694 (1984).
490. J . T . Doluisio and L. W. D i t t e r t , Influence of r e p e t i t i v e dosing
of t e t r a c y c l i n e s on biological half-life in s e r u m , Clin. Pharma-
col. Ther. 8, 222 (1974).
References

1 Chapter 1 Influence of Drug Properties

and Routes of Drug Administration on the
Design of Sustained and Controlled
Release Systems

I . INTRODUCTION

In recent years, considerable attention has been focused on

the

development of new drug delivery systems. This is evidenced

by

the spate of books [1-8] and review articles [9-18]

published on

this subject. There are a number of reasons for the intense

interest

in new systems. First, recognition of the possibility of

repatenting

successful drugs by applying the concepts and techniques of

con

trolled release drug delivery systems, coupled with the

increasing

expense in bringing new drug entities to market, has

encouraged

the development of new drug delivery systems. Second, new

systems

are needed to deliver the novel, genetically engineered

pharmaceuti

cals, i . e . , peptides and proteins, to their sites of

action without in

curring significant immunogenicity or biological

inactivation. Third,

treating enzyme deficient diseases and cancer therapies can

be im

proved by better targeting. Finally, therapeutic efficacy

and safety
of drugs, administered by conventional methods, can be
improved by

more precise spatial and temporal placement within the

body, thereby

reducing both the size and number of doses. If one were to

conceptualize the ideal drug delivery system, two

prerequisites would come to mind. First, it should deliver

drug at

a rate dictated by the needs of the body over the period of

treat

ment. This may necessitate delivery at a constant rate for

drugs

that have a clear relationship between steady state plasma

levels and

the resultant therapeutic response, or at a variable rate

for drugs

which need either a series of peaks and valleys or act on a

rhythmn.

Second, it should channel the active entity solely to the

site of action.

This may necessitate delivery to specific receptors, as in

the case of

Hi and H2 antagonists, localization to tumor cells, as

required by

most cancer treatments, or to specific areas of the body as

for ar

thritis or gout. At present, no available drug delivery

systems can

achieve all these lofty goals. Conventional dosage forms,

including

prolonged-release dosage forms, are unable to control

either the rate

or site of action. While rate-controlled release drug

delivery systems

are capable of delivering a drug at some predetermined rate

either

systemically or locally for a specific period of time, they

do so with

virtually no control over the fate of the drug once it

enters the body.

Targeted drug delivery systems, on the other hand, while

capable

of achieving site specific delivery, are usually unable to

control the

release kinetics of drug in a predictable manner. To date,

their

usefulness is limited to systemic administration. This

chapter will describe those factors influencing the design

of sustained/controlled drug delivery systems with

particular empha

sis on limitations imposed by the intrinsic physicochemical

and biologi

cal properties of a drug candidate and by the route of

administration.

I I . TERMINOLOGY

Before initiating a discussion of sustained and controlled

release

dosage forms, it is necessary to provide a short

explanation of termi

nology used because there is considerable confusion in this

area.

The general consensus is that controlled release denotes

systems

which can provide some control, whether this be of a

temporal or

spatial nature, or both, of drug release in the body. In

other words,

the system attempts to control drug concentrations in the

target t is

sue or cells. Thus, prolonged release or sustained release

systems,

which only prolong therapeutic blood or tissue levels of

the drug for

an extended period of time, cannot be considered as

controlled re

lease systems by this definition. They are distinguished

from rate

controlled drug delivery systems, which are able to specify

the re

lease rate and duration in vivo precisely, on the basis of

simple in

vitro tests [15]. Drug targeting, on the other hand, can be

con

sidered as a form of controlled release in that it

exercises spatial

control of drug release within the body. Since

rate-controlled re

lease and drug targeting represent totally separate

delivery ap

proaches, they will be discussed separately in this

chapter. In general, controlled delivery attempts to: 1.
Sustain drug action at a predetermined rate by maintaining
a relatively constant, effective drug level in the body
with concomitant minimization of undesirable side effects
associated with a sawtooth kinetic pattern 2. Localize
drug action by spatial placement of a controlled release
system (usually rate-controlled) adjacent to or in the
diseased tissue or organ 3. Target drug action by using
carriers or chemical derivatization to deliver drugs to a
particular "target" cell type In practice, very few of the
applied systems embrace all of these

actions. In most cases, the release system creates constant

concen
tration of drug within the body over an extended period of
time.

The assumption is that there is a steady state drug levels

in plasma

and in target tissues or cells are correlated. Ideally, it

is desirable

to place the drug at the target, be it a tissue, a

population of cells,

or receptors, leaving the rest of the body drug free.

Obviously,

this would be quite difficult, especially if the target is

sheltered

from systemic circulation by various barr iers . For

example, drug

targeting to the brain via systemic administration is

severely limited

by selectivity of the blood-brain barrier. In order to

maintain a constant drug level in either plasma or

target tissue, release rate from the controlled release

system should

be equal to the elimination rate from plasma or target t

issue. The

most conventional method to achieve a constant plasma level

is the

use of intravenuous infusion. However, this would be

inconvenient

for most therapeutic situations so that other noninvasive

routes, such

as the oral or transdermal route, are preferred. Various

designations such as "smart" [19], "targeted" [20],

"intelligent" [15], "novel" [6], and "therapeutic" [21],

have been

given to controlled release systems. Therapeutic systems

have also

been used interchangeably with rate-controlled release

systems.

These usually operate on an advanced engineering

system-control

approach, consisting of a logic element with or without a

sensor.

Three types of therapeutic systems are available, namely,

passive

preprogrammed, active preprogrammed, and active

self-programmed

[22] . Most rate-controlled release systems fall in the

category of

passive preprogrammed, in which the release rate is

predetermined

and is irresponsive to the external biological environment.

Examples

of active preprogrammed are few and include most metered

insulin

pumps, whose release rate can be altered by a source

external to

the body [23]. The active, self-programmed therapeutic

systems

modulate release rate of the drug in response to

information, regis

tered by a sensor, on the changing biological environment

such as

blood sugar level in diabetes [24] . In our view, the term

therapeutic

system, while helpful for marketing purposes, is

inappropriate as a

substitute for controlled release systems since

non-controlled release
systems are therapeutic systems also. ZERO-ORDER
CONTROLLED RELEASE .SUSTAINED RELEASE TIME

Fig. 1 Plasma drug concentration-profiles for conventional

tablet

or capsule formulation, a sustained release formulation,

and a zero

order controlled release formulation. Figure 1 shows

comparative blood drug level profiles obtained

from administration of conventional, controlled as well as

prolonged

release dosage forms. Thus, the conventional tablet or

capsule pro

vides only a single and transient burst of drug. As long as

the

amount of drug is above the minimum effective

concentration, a phar

macological response is observed. Problems occur when the

therapeu

tic range is very narrow or when the peak is greater than

the upper

limit of this range. Indeed, one of the main purposes of

controlled

release is to improve safety and minimize side effects of

the drug by

reducing fluctuations in drug level. Prolonged-release

dosage forms

also reduce fluctuations in plasma drug levels by slowing

down the

absorption rate due to slower drug release rate. In many

cases,

this is achieved by intermittently releasing a small burst

of drug

over a prolonged period of time as in the case of

repeat-action dos
age forms.

I I I . RATIONALE OF SUSTAINED/CONTROLLED DRUG DELIVERY

The basic rationale for controlled drug delivery is to

alter the phar

macokinetics and pharmacodynamics of pharmacologically

active moieties

by using novel drug delivery systems or by modifying the

molecular

structure and/or physiological parameters inherent in a

selected route

of administration. It is desirable that the duration of

drug action

become more a design property of a rate-controlled dosage

form, and

less, or not at all, a property of the drug molecule's

inherent kinetic

properties. Thus, optimal design of controlled release

systems

necessitates a thorough understanding of the

pharmacokinetics and

pharmacodynamics of the drug. As mentioned earlier, the

primary objectives of controlled drug

delivery are to ensure safety and to improve efficacy of

drugs as well

as patient compliance. This is achieved by better control

of plasma

drug levels and less frequent dosing. For conventional

dosage forms,

only the dose (D) and dosing interval (T ) can vary and,
for each

drug, there exists a therapeutic window of plasma

concentration, be
low which, therapeutic effect is insufficient, and above
which unde

sirable or toxic side effects are elicited. As an index of

this window,

the therapeutic index TI can be used. This is often defined

as the

ratio of median lethal dose (LD50) to median effective dose

(ED50).

Alternatively, it can be defined as the ratio of maximum

drug concen

tration (C* m a x ) in blood that can be tolerated to the

minimum concen

tration (C* m i n ) needed to produce an acceptable

therapeutic response.

Table 1 lists the therapeutic indices of a variety of drugs

in plasma

in humans. For drugs whose disposition show pronounced

linear, one-compart

ment characteristics, Theeuwes and Bayne [25] have

demonstrated the

following relationship between dosing interval (x) and

therapeutic

index (TI) . Thus, T < t 1 / 2 ( l n TI)/ln 2 (1)

where t^/2 is the half-life. Since the therapeutic index

for most

drugs is around 2, it will be necessary to dose the

patients at inter

vals shorter than the half-life. Such inconvenient regimens

often

result in reduced compliance and inadequate treatment. For

drugs

with pronounced multicomp art mental characteristics, a

better estimate
of the dosing interval may be obtained by replacing t i /2
with 0.693*

(MRT), where MRT is the mean residence time. In such cases,

the

drug must be given even more frequently than suggested by

Eq. (1). In general, the dosing interval may be increased
either by modi

fying the drug molecule to decrease the rate of elimination

(k e j) or

by modifying the release rate of a dosage form to decrease

the rate

of absorption ( k a ) . Both approaches seek to decrease

fluctuations

in plasma levels during multiple dosing, allowing the

dosing interval

to increase without either overdosing or underdosing. When

attempt

ing to extend the dosing interval by decreasing the rate of

absorp

tion, the formulator will be confronted with the

physiological con

straint of a finite residence time at the absorption site.

For example,

an effective absorption time for orally administered drugs

is about

9-12 hr . If the rate of absorption decreases too much,

some of the

unabsorbed drug will pass into the large intestine, where

absorption

is slower and more variable and where bacterial degradation

of the

drug may occur. Thus, drugs with half-lives of 6 hr or less

and

Table 1. Usual Ranges of Therapeutic Serum Concentrations

and

Terminal Half-Lives in Humans

Drug

substance

Digit oxin

Digoxin

Lidocaine

Lithium

Nortriptyline

Phenytoin

Procainamide

Propranolol

Quinidine

Salicylates

Theophylline Therapeutic serum concentrations a (C* . to

C* ) min max 14-30 yg/liter 0.9-2 yg/liter 1.5-5
mg/liter 0.5-1.3 mEq 50-140 yg/liter 10-20 mg/liter 4-8
mg/liter 20-50 yg/liter 2-5 mg/liter 150-300 mg/liter
10-20 mg/liter Terminal half-lives 0 6.3-11.3 days
1.4-2.2 days 1.2-1.7 hr 14.2-24.1 hr 18.2-35.0 hr
18.7-27.6 hr 2.5-4.7 hr 1.1-9.9 hr 3.0-16.0 hr 2.9-22
hr 5.3-8.3 hr

"Data were obtained from

Data were obtained from Koch-Weser [26] . Pagliaro and

Benet [27] ,

possessing therapeutic indices less than 3 must be given no

less

frequently than every 12 hr [28]. Unless gastrointestinal

transit

time can be lengthened, once-daily oral dosing may prove to

be dif
ficult to achieve for drugs with such extremely short
half-lives [28] .

For other routes of administration, where residence time is

less of a

problem, dosing intervals can be lengthened to months or

even years .

For example, implants containing contraceptives may be

effective for

a year or two. In summary, only when the rate-limiting

step resides in the drug

delivery system, and not in physiological constraints, can

control

over drug administration be achieved.

IV . FACTORS INFLUENCING THE DESIGN AND PERFORMANCE OF

SUSTAINED/CONTROLLED RELEASE PRODUCTS

To establish criteria for the design of controlled release

products,

a number of variables must be considered. 1. Drug

properties: The physiochemical properties of a drug,
including stability, solubility, partitioning
characteristics, charge, and protein binding propensity,
play a dominant role in the design and performance of
controlled release systems. 2. Route of drug delivery:
The area of the body in which drugs will be applied or
administered can be restrictive on the basis of
technological achievement of a suitable controlled release
mechanism or device. At times, the drug delivery system, in
certain routes of administration, can exert a negative
influence on drug efficacy, particularly during chronic
administration, and hence other routes of administration
should be considered. Performance of the controlled
release systems may also be influenced by physiological
constraints imposed by the particular route, such as
first-pass metabolism, GI motility, blood supply, and
sequestration of small foreign particles by the liver and
spleen. 3. Target sites: In order to minimize unwanted
side effects, it is desirable to maximize the fraction of
applied dose reaching the target organ or tissue. This can
be partially achieved by local administration or by the
use of carriers. However, the absorptive surfaces of most
routes are impermeable to macromolecules or other targeted
delivery systems, thereby necessitating either
intravascular or intraarterial administration. 4. Acute or
chronic therapy: Consideration of whether one expects to
achieve cure or control of a condition and the expected
length of drug therapy are important factors in designing
controlled release systems. Attempts to generate a one
year contraceptive implant presents significantly different
problems in design than does an antibiotic for acute
infection. Moreover, long term toxicity of rate-controlled
drug delivery systems is usually different from that of
conventional dosage forms [29]. 5. The disease:
Pathological changes during the course of a disease can
play a significant role in the design of a suitable drug
delivery system. For example, in attempting to design an
ocular controlled-release product for an external
inflammation, the time course of changes in protein content
in ocular fluids and in the integrity of the ocular
barriers would have to taken into consideration.
Sometimes, one can take advantage of the unique
manifestations of the disease state. For example, the
higher plasminogen activator levels in some tumor cells
can lead to preferential bioconversion of peptidyl prodrugs
in these cells [30-32]. Similarly, the higher tyrosinase
level in melanoma cells has been demonstrated to allow
targeting to and preferential bioconversion of 2,
4-dihydroxphenylalanine in them [33]. 6. The patient:
Whether the patient is ambulatory or bedridden, young or
old, obese or gaunt, e tc . , can influence the design of
a controlled release product. An implant or intramuscular
injection of a drug to a bedridden patient with little
muscle movement may perform in a manner significantly
different from that of an ambulatory patient. Some of
these factors represent individual patient variation and
cannot be controlled by the research scientist while
others must be considered. For example, single unit
controlled release products are particularly prone to
intra- and inter-subject variation because of
variabilities in individual GI motility [34] . While all
of these variables are important in the design of con

trolled and targeted release delivery systems, our

discussion will

center on drug properties and routes of administration as

they relate

to controlled release drug delivery in general. In

particular, this
chapter is concerned with increasing the visibility of some
of the

detrimental or prohibitive factors in the design of

controlled release

system. The release mechanism and the applicability of the

various

approaches (physical, chemical, and biological) used in the

design of

individual controlled release system will be discussed in

Chapters

8-15. To establish a basis for discussion of the influence

of drug prop

erties and the route of administration on

sustained/controlled release

product design, it is worthwhile focusing on: 1. Behavior

of the drug in its delivery system 2. Behavior of the drug
and its delivery system in the body The first of these two
elements is concerned with the ways in

which drug properties can influence release characteristics

from its

delivery system. For conventional drug delivery systems,

the rate

limiting step in drug availability is usually absorption of

drug across

a biological membrane such as the gastrointestinal wall

(Scheme 1). In

a sustained/controlled release product, one aims for

release of drug Drug release Absorption

( D r u ^ D o s a f f e form ~ ~ ( D r u g ) Solu t ion at

~ * ( D r V g ) absorption site Target area
Elimination Scheme 1

from the dosage form as the rate-limiting step instead.

Thus, drug

availability is controlled by the kinetics of drug release

rather than
absorption. Consequently, the associated rate constant(s)
for drug

release from the dosage form are smaller than the

absorption rate

constant and kinetically the process appears as shown in

Scheme 2. Drug release (Drug)^ „ • (Drug)™ . *-
Elimination to Dosage form & Target area Scheme 2

To control drug release one can employ a variety of

approaches, such

as dissolution, diffusion, swelling, osmotic pressure,

complexation,

ion-exchange, and magnetic field, each of these will be

amplified on

in subsequent chapters. The interplay between

physiochemical prop

erties of a drug and characteristics of its delivery system

determines

the temporal release pattern that is observed. The second

element, behavior of the drug and its delivery system

in the body, is extremely complex, involving the fate of

drug during

transit to the target area as well as its fate while in the

biophase.

Availability of drug to its target will depend on its

pharmacokinetics

as well as that of its carrier. In the case of drug

targeting, the

carrier is used to alter the pharmacokinetics of drug in

the body.

The influence of physiological constraints on the fate of

the delivery

system in the body is usually negative, for example, oral

absorption
is usually limited by GI transit time of the delivery
system. From the previous discussion, it is clear that the
formulation and

performance of sustained/controlled release dosage forms

have roots

in the physicochemical properties of the drug and its

carrier. The

pharmacokinetics and pharmacodynamics, to a large extent,

are de

rived functions of the intrinsic properties of the drug.

Thus, devel

opment and assessment of a sustained/controlled drug

delivery system

requires a rather complete knowledge of the intrinsic

properties of a

drug and the ways in which it can influence the design of

sustained/

controlled release systems. Oftentimes, undesirable

physiochemical

and biological properties can be altered by suitable

chemical modifica

tion, by use of a carrier, or perhaps can be altered by

suitable

chemical modification, by use of a carrier, or perhaps by

administra

tion via another route. The first approach will be

discussed in Chan

ter 9, while the other two approaches will be briefly

discussed in this

chapter and further amplified upon in subsequent chapters.

V. PHYSICOCHEMICAL PROPERTIES OF A DRUG INFLUENCING DRUG

PRODUCT DESIGN AND PERFORMANCE

The performance of a drug in its release pattern from the

dosage
form as well as in the body proper is a function of its
properties. Influence of Drug Properties on Design I 13

These properties can at times prohibit/restrict placement

of the drug

in a sustained/controlled release form, restrict the route

of drug ad

ministration, and significantly modify performance for one

reason or

another. Most of the time these properties are restrictive

rather than

prohibitive, making sustained/controlled release product

design more

difficult. For the purpose of this discussion, it is

convenient to de

scribe the properties of a drug as being either

physiochemical or bio

logical. Obviously, there is no clear distinction between

these two

since the biological properties of a drug are a function of

its physi

cochemical properties. By our definition, physiochemical

properties

are those that can be determined from in vitro experiments.

Biologi

cal properties will be those that result from typical

pharmacokinetic

studies on the absorption, distribution, metabolism, and

excretion

(ADME) characteristics of a drug as well as those resulting

from

pharmacological studies.

A. Aqueous Solubility
Since drugs must be in solution before they can be
absorbed, com

pounds with very low aqueous solubility usually suffer oral

bioavail

ability problems because of limited gastrointestinal

transit time of the

undissolved drug particles and limited solubility at the

absorption

site. Unfortunately, for many compounds, the site of

maximum ab

sorption will also be the area in which the drug is least

soluble. For

example, tetracycline dissolves to a greater extent in the

stomach

than in the intestine, although it is best absorbed in the

intestine

[35]. Such drugs may be poor candidates for

sustained/controlled

release systems, unless the system is capable of retaining

the drug

in the stomach and gradually releasing it to the small

intestine or

unless the solubility is made higher and independent of the

external

environment by encapsulating the drug with an acid (if the

drug is

a weak base) or a base (if the drug is a weak acid) in a

membrane

system. Examples of other drugs which are limited in

absorption by

their dissolution rate are digoxin [36], warfarin [37],

griseofulvin

[38] , and salicylamide [39] . Although the action of a

drug can be
prolonged by making it less soluble, this may occur at the
expense

of inconsistent and incomplete bioavailability. The choice

of mechanism for oral sustained/controlled release sys

tems is limited by aqueous solubility of the drug.

Diffusional systems

will be poor choices for slightly soluble drugs since the

driving force

for diffusion, the concentration in aqueous solution, will

be low. In

contrast, such drugs may be effectively incorporated in

matrix systems. In selecting polymer coatings for
sustained/controlled systems,

the dissolution rate of a drug must be considered. Some

antiobiotics

and high molecular weight drugs may have reasonably good to

excel

lent aqueous solubility, but very slow dissolution rates.

On the

positive side, the slow dissolution rate of such compounds

can be

utilized to achieve sustained/controlled drug release by

incorporation

in a matrix system. On the negative side,

dissolution-limited bio

availability may occur. Aqueous solubility also limits the

loading efficiency of drugs into

a variety of carriers such as liposomes, erythrocytes, and

other mi

croparticles. Most water-soluble drugs tend to leak out

from such

carriers readily.

B. Partition Coefficient and Molecular Size

Partition coefficient and molecular size influence not only
the permea

tion of a drug across biological membranes, but also

diffusion across

or through a rate-controlling membrane or matrix. Following

admin

istration, the drug must traverse a variety of membranes to

gain

access to the target area. Drugs with extremely high

partition coef

ficient ( i . e . , very oil-soluble) readily penetrate the

membranes but

are unable to proceed further, while drugs with excessive

aqueous

solubility, i . e . , low oil/water partition coefficients

cannot penetrate

the membranes. A balance in the partition coefficient is

needed to

give an optimum flux for permeation through the biological

and rate

controlling membranes. Hansen and Dunn [40] as well as

Fujita et

al. [41] have shown that, for many body tissues, such as
the gas

trointestinal tract, skin, and blood-aqueous barrier of the

eye, the

optimum n-octanol/water partition coefficient at which

maximum flux

occurs is approximately 1000. The ability of a drug to

diffuse through membranes, its so called

diffusivity, is related to its molecular size by the

following equation: Log D = -S v log V + k v = -s M log M
+ 1^
where D is diffusivity, M is molecular weight, V is
molecular volume,

and s v , SJVI, k v , and k]yj are constants in a

particular medium. In

general, the denser the medium, the smaller the

diffusivity. For

drugs of intermediate molecular weight (150-400),

diffusivities through

flexible polymers are typically of the order of 10"^ cm 2

s e c 1 .

C. Drug Stability

The stability of a drug in the environment to which it is

exposed is

another physicochemical factor to be considered in the

design of sus

tained/controlled release systems. Drugs that are unstable

in the

stomach can be placed in a slowly soluble form or have

their release

delayed until they reach the small intestine. However, such

a strate

gy would be detrimental for drugs that either are unstable

in the

small intestine or undergo extensive gut-wall metabolism,

as evidenced

by decreased bioavailability when these drugs are

administered from

a sustained release dosage form [42,43]. To achieve better

bioavail

ability and controlled release of drugs that are unstable

in the small

intestine, a different route of administration should be

chosen. Con
trolled release of nitroglycerin is a good example. On the
positive

side, the presence of metabolizing enzymes at the site of

administra

tion or along the pathway to the target area can sometimes

be utilized

in controlled drug delivery. Chapter 8 will describe some

of these

approaches.

D. Protein Binding

It is well known that many drugs bind to plasma proteins

with a con

comitant influence on the duration of drug action [44-48].

Since

blood proteins are for the most part recirculated and not
eliminated,

drug protein binding can serve as a depot for drug

producing a pro

longed release profile, especially if a high degree of

drug-binding

occurs. This aspect of prolonged drug activity has been

described

in the literature [49]. There are, however, other

drug-protein in

teractions that have a bearing on drug performance. Levine

[50] has

shown that quaternary ammonium compounds bind to mucin in

the GI

t ract . Drugs bound to mucin may increase absorption, if

the bound

drug act as a depot. However, if degradation and/or washing

of the

drug further down the GI tract occurs, binding of drug to

mucin may

result in a reduction of free drug available for

absorption. The issue

of drug and vehicle interaction with the mucin layer and

its influence

on extent and duration of drug absorption has been reviewed

[51] .

V I . BIOLOGICAL FACTORS INFLUENCING DESIGN AND

PERFORMANCE OF SUSTAINED/CONTROLLED RELEASE PRODUCTS

The design of a sustained/controlled release product should

be based

on a comprehensive picture of drug disposition. This would

entail

a complete examination of the ADME characteristics of a

drug follow

ing multiple dosing. Unfortunately, an imcomplete picture

of a drug's

disposition is usually the case and decisions are generally

made on

this basis. The biological parameters that form the basis

of controlled

release product design will be described in Chapters 5 and

6. Every pharmacokinetic property and biological response
parameter

has a useful range for the design of sustained/controlled

release

products, outside of which sustained/controlled release

product de

sign becomes difficult or impossible. Presumably, with

unlimited

technological capability and strategic placement of a drug

in the

body, all of these limitations could be circumvented but

this capability
is usually not available and thus constraints are generally
imposed.

In the following discussion, it is assumed that the level

of drug in

blood or body tissue parallels biological activity of the

drug.

A . Absorption

To maintain constant blood or tissue level of drug, it must

be uni

formly released from the controlled release system and then

uniformly

absorbed. It would be desirable to have the released dose

completely

absorbed as well but this is not a prohibitive

consideration. Usually,

the rate-limiting step in drug delivery from a controlled

release pro

duct is release from the dosage form rather than

absorption. Thus,

rapid drug absorption, relative to drug release from a

dosage form,

is expected but this is not always the case. In addition,

variation

in both the extent and rate of drug absorption can occur,

particularly

with orally administered drugs. The fraction of drug

absorbed from a single noncontrolled dose

of drug can sometimes be quite low for a variety of

reasons, such as

drug degradation due to solvolysis or metabolism, binding

of drugs

to proteins, physical loss, or perhaps site- or

dose-dependent absorp
tion. Nevertheless, as long as the drug is uniformly
absorbed, albeit

incomplete, a successful controlled release product can be

generated.

As stated earlier it is preferable, but not essential, to

have the drug

completely absorbed. The development of the controlled

release ocu

lar system, Ocusert^, is an excellent illustration of

dealing with this

problem. Pilocarpine is usually absorbed across the cornea

to the

extent of about 1% from an applied dose, the extensive loss

due to

drainage and absorption into nontarget tissues [52,53].

However,

despite the low fraction of dose absorbed, a controlled

release product

was prepared that in fact significantly improved the low

bioavailability

problem and was able to maintain a constant level of drug

in the tar

get tissues for extended periods of time [54]. When

considering orally administered drugs, significant loss
prior

to appearance in the systemic circulation can occur through

hydroly

tic degradation in the contents of the GI tract [55],

metabolism by

the intestinal flora [56] , and metabolism during its

transit across the

GI wall [57] . Metabolism at the site of administration is

a potential
problem for all routes of administration, as is hydrolytic
degradation.

However, some routes, such as the GI tract , possess a

relatively

rich supply of metabolizing enzymes whereas other, such as

the pre

corneal portion of the eye, have few. Hydrolytic and

metabolic reac

tions are usually first order in drug concentrations, but

fortunately

degradation is primarily restricted to drugs in solution,

and thus

drugs in the solid state or in solid dosage forms are

protected from

degradation. Indeed, placement of a labile drug in a

sustained or

controlled release drug delivery system can sometimes

improve the

fraction of dose absorbed. The extent of this protection,

hence im

proved bioavailability, is at times difficult to predict a

priori and

thus it is sometimes necessary to rely on empirical

manipulations of

the release rate after obtaining blood or tissue drug

levels with a

prototype controlled release system. If the drug were

erratically absorbed, as might occur in a route

of administration with variable absorptive surface, such as

the GI

tract , design of a controlled release product would be

more difficult

or prohibitive. With respect to the oral route, it is well

known that
the absorptive character of the different segments of the
GI tract

varies [58], which in turn can influence the amount and

rate of ab

sorption for certain drugs. The oral anticoagulant

dicumarol [59],

the quaternary ammonium compounds hexamethonium and

decamethonium

[60] , and the aminoglycosides such as gentamicin and

kanamycin [61]

are examples of such drugs. Similarly, drugs absorbed by

specialized

transport processes and drugs at special sites of the GI

tract are

also poor candidates for controlled release products.

Riboflavin is

absorbed by an active transport process, a process which is

satur

able [62] , and is preferentially absorbed in the upper

part of the

GI tract [63]. Consequently, unless this drug can be

localized at

the absorptive site one expects a gradation in absorption

for this drug

but this is not necessarily prohibitive. Indeed, riboflavin

has been

formulated in various sustained release multivitamin

preparations.

However, Morrison et al. [63] found that such preparations

provided

no demonstrable advantages over conventional preparations.

Iron is another drug which is not uniformly well absorbed
along
the length of the GI tract . The greatest uptake of drug
occurs at

the upper part of the duodenum with significantly reduced

absorptive

capacity in the lower segment of the intestine [64-66] .

Middleton

et al. [67] found that iron given in divided doses, a

situation analo

gous to a sustained release product, was only 68% as

available as the

same amount of drug taken as a single dose. Sustained

release iron

products have been evaluated by several investigators and

the results

are equivocal. Crosland-Taylor et al. [68] found that

absorption of

iron from sustained release tablets was extremely variable.

Bothwell

et al. [69] reported that the amount of iron absorbed from

Spansules 1 *

was a function of the rate at which drug was released;

significant

reduction in the amount of iron absorbed occurred in the

Spansules R

with slow release rates . On the other hand, Baird et al.

[70] found

that iron formulated in a wax matrix sustained release

product was as

well absorbed as conventional ferrous sulfate tablets.

Indeed, Web

ster [71], Callender [72], and Bent ley and Jacobs [73]
detected no

significant differences in the elevation of hemoglobin

levels in iron
deficient anemic patients taking the sustained release
Gradumet R and

nonsustained release ferrous sulfate products. These

studies, to

gether with others [74-76], leave in doubt the

appropriateness of

some commercially available sustained release iron

preparations. Never

theless, they indicate that the selection of sustaining

mechanisms has

an important bearing on ultimate biological response. When

considering the problem of variable absorption rates, it is

necessary to cite intramuscular injections as a route of

administration

with significant difficulties in this regard. Aside from

the large in

dividual variation with this route of administration, due

to muscle

mobility, water content, tissue integrity, e tc . , there

is the additional

problem of tissue insult upon initial injection and further

changes in

the tissue from repeated injection, all of which can change

the release

and absorption pattern of a drug. A more prohibitive

aspect of the absorption process via the oral

route is the magnitude of the absorption rate constant. For

single

nonsustained doses, a minimum absorption rate constant of

0.25 h r" l

to 0.35 hr" 1 is necessary for 95% of the administered

dose to be ab

sorbed, assuming that the GI transit time is between 10 and

12 hr .

To formulate drugs at the lower limit of absorption rate

constants

into controlled or sustained release systems, the desired

rate constant

of release from the dosage form would have to be even

lower, result

ing in decreased bioavailability. As the GI transit time is

finite, a

suitable controlled release system, giving a high fraction

of dose ab

sorbed, can be difficult to design. In addition, the rate

constant

of release based on absorption considerations may be very

different

from that based on biological half-life considerations so

that a com

promise is achieved generating less than ideal release

rates . In es

sence, oral drugs which are slowly absorbed are poor

candidates for

sustained dosage forms primarily because drug availability

is limited

by GI transit time. An example of a slowly absorbed drug is

iron.

Other problems relative to the design of a sustained

release iron

dosage form have already been described.

B. Distribution

The distribution of drugs into tissues can be an important

factor in

the overall drug elimination kinetics since it not only

lowers the con
centration of circulating drug but it also can be rate
limiting in its

equilibration with blood and extracellular fluid. One

aspect of this

distribution is binding of drug to tissues and proteins in

blood. An

extensive discussion of this phenomenon can be found in a

series of

papers by Kruger-Thiemer et al. [77-81]. In general, the

bound

portion of a drug can be considered inactive and unable to

cross

membranes. At high binding one sees prolonged drug action.

The apparent volume of distribution of a drug is frequently
used

to describe the magnitude of distribution, including

binding, within

the body. Conceptually, this pharmacokinetic parameter can

be

viewed as a proportionality constant relating plasma or

serum concen

tration of drug to total amount of drug in the body. Since

rate

processes are driven by concentration and not amount, it is

this

quantity in which we are interested. Physiological

interpretation of

the apparent volume of distribution is difficult in the

one-compartment

kinetic system and even more difficult in cases where

multicompart

ment kinetics are operative. Indeed, in the absence of

definitive
studies, it should probably be treated as a proportionality
constant

or "fudge factor" rather than a specific physiological

parameter. Un

like drugs that follow one-compartment kinetics, those with

multicom

partment kinetics usually do not equilibrate with various

tissues in

stantaneously. Consequently, the apparent volume of

distribution

assumes different values depending on the time course of

drug dis

position. Thus, one has to be cautious in interpreting the

numerical

values of apparent volumes of distribution in the

literature. For design of sustained/controlled release
products one would like

to have as much information on drug disposition as possible

but, in re

ality, decisions are usually based on only a few

pharmacokinetic param

eters, one of which is the apparent volume of distribution.

The appar

ent volume of distribution influences the concentration and

amount of

drug either circulating in the blood or in target tissues.

It can also in

fluence the elimination kinetics of a drug. Unfortunately,

the influ

ence is frequently not a predictable one because of

difficulties in in

terpreting apparent volume of distribution. Nevertheless,

the mag

nitude of apparent volume of distribution can be used as a

guide for

additional studies and for some a priori comments

concerning drug

dosing and hence the need for a prolonged release system.

These

a priori comments are made in conjunction with

consideration of other

pharmacokinetic parameters, such as amount of drug in the

various

compartments and elimination constants for removal of drug

from these

compartments. The total apparent volume of distribution

for a drug at steady

state can be calculated from Eqs. (2-4): V S = [ ( k 1 2 +

k 2 1 ) / k 2 1 ] V p ( 2 ) V d extrap = [(a - 3)/k 21 -
3)]V (3) V d area = V d ss + [(k el - 3)/k 21 ]V (4)

where V^ss, Vdextrap., and Vdarea are apparent volumes of

distri

bution at steady state—Vdextrap, is that obtained by the

extrapola

tion method, Vdarea is that obtained by the area method, V

p is the

volume of the central compartment, a is the fast

disposition constant,

3 is the slow disposition constant, k e i is the constant

for elimination

of drug from the central compartment, ki2 is the constant

for dis

tribution of drug from the central to peripheral

compartment, and

k2i is that from the peripheral to central compartment.

Riegelman

et al. [82] demonstrated that the best estimate of total

drug volume
at steady state is V^ss, while V^extrap. and V^area tend to
over

estimate this parameter. While V^ss can be used to

correctly estimate amount of drug in

the body when amount of drug in the peripheral compartment

is at a

maximum, it tends to underestimate or overestimate amount

of drug

in the body at other times during the time course of drug

disposition.

This observation has been elaborated upon by Gibaldi et al.

[83],

who proposed the use of V^area instead of V^ss to estimate

amount

of drug in the body. To avoid ambiguity inherent in

apparent volume of distribution as

an estimator of amount of drug in the body, and noting that

the same

parameter does not differentiate relative distribution of

drug in two

or more compartments, one can use the T/P ratio as defined

in Eq.

(5) to describe relative amount of drug in the central and

peripheral

compartments at steady state. Provided amount of drug in

the cen

tral compartment (P) is known, the amount of drug in the

peripheral

compartment (T) and hence total amount of drug in the body

can be

calculated: T/P = k 1 2 / ( k 2 1 - 3) (5)

where ki2> k2i , and 3 are as defined previously. Note that

one
cannot infer from the T/P ratio the physical state of the
drug, such

as the extent of binding, in the two compartments. The

model merely

assumes that distribution between the two compartments is

controlled

by two first-order constants, k^2 and k21- Moreover, it

implies that

the amount of drug transferred to the tissues increases

proportionally

with dose without limit. In view of this shortcoming of the

model,

DiSanto and Wagner [84] proposed a nonlinear model to

describe dis

position kinetics of drugs in tissues. From the preceding

discussion it can be seen that the distribution

characteristics of a drug can be described by the volume of

distri

bution at steady state and the T/P ratio. However, one

should be

aware of the fundamental difference between the two

parameters;

namely, Vdss estimates the extent of distribution in the

body, while

the T/P ratio estimates the relative distribution of drug

between com

partments. One cannot predict a priori the magnitude of

volume of

distribution at steady state from the T/P ratio, and vice

versa. In

deed, Table 2 shows that the two parameters behave

independently

of each other. As examples, the T/P ratio for procainamide

is about

10 times that for pentobarbital although the Vdss for both

drugs is

about the same. Similarly, while the T/P ratio for

procainamide is

larger than that for digoxin, the volume of distribution at

steady

state of procainamide is less than that of digoxin.

Table 2 Relationship Between Apparent Volume

of Distribution at Steady State (V^ss) and T/P

Ratio

Drug

Amoxicillin

Cefazolin

Diazepam

Digoxin

Furosemide

Meperidine

Metolazone

Pentobarbital

Pivampicillin

Procainamide

Sulfisoxazole

Theophylline

Tobramycin

Tolbutamide

Trimethoprim T/P 1.04 2.20 2.85 4.31 0.96 2.04 2.71

1.30 1.16 14.35 0.60 0.97 1.78 0.27 1.24 Vdss
(liters) 22 9 130 500 5 289 113 63 13 62 11 40
34 24 12 Ref. 91 92 93 94 95 96 97 98 99 100
101 102 103,104 105 106 Presently, there are
insufficient data to allow one to gauge the

relative importance of the two parameters in terms of

contribution to

approximating drug distribution characteristics. Presumably

one can

use volume of distribution at steady state as a starting

point. Noting

that the 95% confidence interval on the average value for

volume of

distribution of drugs at steady state is about 35 ± 1

liters, volumes

of distribution exceeding total body water volume (about 50

liters in

a 70-kg man) would suggest extensive tissue accumulation

and/or

binding of drugs. Table 3 lists some examples of such

drugs. Pro

vided that drug elimination is rate-limited by the release

of drug from

tissue binding sites and that drug is released from the

tissues to

give concentrations exceeding the threshold level or within

the thera

peutic range, one can probably assume that such drugs are
inherently

sustained. Naturally, in the absence of information on

binding con

stants and extent of binding, one should be cautious in

asserting

Table 3 Examples of Drugs with Apparent Volumes of Distr

ibut ion
Larger Than Total Body Water Volume (52 l i t e r s ) V s
' 1 / 2 , 6 TBCb

D r u g ( l i ters) ( h r ) (ml/min) Ref.

Chlorphentermine

Clindamycin

Diazepam

Digoxin

Lidocain

Meperidine

Metolazone

Ouabain

Pentobarbi ta l

Phenytoin

Practolol

Procainamide

Propranolol

Quinidine

Tetracycl ine 213 83 130 500 1430 62 100 40 2.8

30.8 34 120 289 113 24-74 63 54 151 2.7 182 146
9.6 62 342 49 170 1.8 3.2 19.8 230-690 22 21.3
265 3.3 7.2 120 107 108,109 93 94 110 96 66,97
111 98 112,113 114 100 115,116 117,118 119,120

Terminal longl inear halfl ife.

b Tota l body clearance = V d s s (0 .693/ t ) .

t he above assumption. As shown in Table 3, t he 3 half-l

ives ( t i / 2 , ^ )

of lidocaine and metolazone differ by a factor of 10 al

though they have
similar volumes of dis t r ibut ion at s teady s t a t e .
A similar pa t t e rn is

obse rved in the pa i r s quinidine-diazepam, pentobarbi ta

l -procainamide ,

and chlorphentermine-propranolol . It follows tha t Vdss

and t i / 2 , 3 are

not re la ted l inear ly . A possible solution to th is

dilemma is to use total

body clearance at s teady s ta te as defined in Eq . (6) to

gauge the im

por tance of t i s sue b inding in d r u g elimination k

ine t ics . Total body clearance at s teady s ta te = V d
s s (0 .693/ t / 2 ) (6)

Consider the lidocaine-metolazone example in th is l igh t

. Lidocaine

with a clearance of 820 ml/min probably exper iences less t

i ssue

binding than metolazone with a clearance of 66 ml/min and

hence

would be cleared from the body at a faster rate.

Furthermore, from

the standpoint of need for sustained drug delivery,

lidocaine would

be a more likely candidate than metolazone. Presently,

while it is recognized that the disposition of many

drugs follows multicompartment kinetics, dose calculations

for sus

tained release products are based primarily on

one-compartment ki

netic considerations. Whether such an approach represents a

good

approximation to the more complex multicompartment kinetics

situation

has yet to be proven. Nevertheless, it should be pointed

out that

implicit in such an approach is the assumption that tissue

distribution

in the additional compartments has minimal influence on

dose consid

erations. According to this approach, for a given

therapeutic con

centration of drug, the dose would be similar for drugs

with similar

volumes of distribution. This assumption hold only when the

rela

tive distribution of the two drugs between compartments is

similar.

The error introduced would be especially pronounced in the

extreme

case where the active sites of the two drugs reside in

different com

partments. In order to minimize this error, one may have to

incor

porate the T/P ratio into sustaining dose considerations

for drugs

exhibiting multicompartment kinetics. In summary, no

conclusion can be made on the relative impor

tance of volume of distribution at steady state and the T/P

ratio in

estimating the distribution characteristics of a drug.

Undoubtedly,

both parameters contribute to this aspect of drug

disposition. Per

haps mention should be made of the use of T/P ratio in

conjunction

with total body clearance at steady state to gain further

insight into
drug disposition. Table 4 gives an example of how this can
be done.

C. Metabolism

Metabolism of a drug can either inactivate an active drug

or convert

an inactive drug to an active metabolite. Metabolic

alteration of a

drug can occur in a variety of tissues, some of which are

richer in

enzymes than others. For example, the organ most

responsible for

metabolism is the liver and thus the greatest metabolic

conversion

occurs after a drug has been absorbed into the general

circulation.

Clearly, for optimal bioavailability, the route of drug

administration

may be dictated by the drug's metabolic pattern.

Metabolism of a drug will be reflected in the elimination
constant

of a drug or by the appearance of metabolite. It is

possible to in

corporate this pharmacokinetic property into the design of

a con

trolled release product, provided that the rate and extent

of meta

bolism are predictable and that the rate constant(s) for

the process

are not too large. Undoubtedly, complex metabolic patterns

would

make the design much more difficult, particularly when

biological

activity is wholely or partly due to a metabolite, as is

the case in
Table 4 Use of T/P Ratio and Total Body Clearance at Steady
State

to Estimate D r u g Disposition Charac ter i s t ics

T/P Total body

r a t i o 8 c l ea rance 0 Disposition cha rac t e r i s

t i c s 0

High High Little a n d / o r weak t i s sue b inding

High Low Extensive a n d / o r s t rong t i s sue b ind ing

; possible extens ive a n d / o r s t r o n g plasma
prote in b inding

Low Low S t rong t i s sue b ind ing ; extens ive a n d / o

r s t r o n g plasma prote in b inding

Low High Little or weak plasma protein b inding

Average T/P ratio i s 1.

^Average total body clearance at s teady s ta te is about

80 ml/min.

c Assume tha t elimination of d r u g occurs primarily in

the central com

pa r tmen t .

isosorbide 2 ,5-d in i t ra te [85 ] . There a r e ,

however , two areas of con

cern relat ive to metabolism that significantly r e s t r i

c t sus ta ined release

p roduc t des ign . F i r s t , if a d r u g , upon chronic

administrat ion, i s

capable of e i ther inducing or inhibi t ing enzyme syn

thes i s , it will be

a poor candidate for a sus ta ined release produc t because

of the dif

ficulty of maintaining uniform blood levels of d r u g .

Second, if t he r e
is a variable blood level of d r u g t h rough ei ther
intest inal (or o ther

t i s sue) metabolism or t h r o u g h a f i r s t -pass

effect, th is also will make

p repara t ion of a sus ta ined release p roduc t

difficult. Since most of

these p rocesses a re sa tu rab le , the fraction of d r u

g lost would be

dose-dependent and one would anticipate a significant

reduct ion in

bioavailability if a d r u g is slowly re leased over a

period of time. There are some excellent examples of these
metabolic d r u g p r o b

lems in the l i t e r a t u r e . Hydralazine is

metabolized by the intest inal

wall and /o r the l iver du r ing absorpt ion , al though

it is well absorbed

[86 ] . In con t ra s t , bromocript ine is incompletely

absorbed , the poor

bioavailability of which is fu r the r r educed b y first

pass metabolism

in the l iver r e su l t ing in an absolute bioavailability

of only 6% [87] .

Likewise, only 23-30% of an orally administered dose of

levopoda

reaches the systemic circulation as intact d r u g [88] and

the plasma

level after an oral dose is about 20% of tha t after an in

t ravenous

dose [89 ] . Abrams [89] s t a t ed tha t the orally

adminis tered dose of

the d r u g was completely absorbed and a t t r i bu t ed

the reduct ion in

bioavailability to metabolism of the d r u g d u r i n g

its first p a s s t h r o u g h

the l iver . In addi t ion, Sandler et a l . [90,91] r epo

r t ed tha t levodopa

was metabolized by gut microbial flora, thus constituting

an additional

route of loss of drug prior to absorption. The metabolism

of levo

dopa by the gut flora was shown to occur mostly in the

portion of

the GI tract distal to the duodenum [91]. This would

significantly

reduce the amount of drug available for absorption from

oral sustained

release products, since a substantial portion of the dose

released past

the duodenum would be lost. This may be one of the reasons

for the

findings of Woods et al. [92] and Curzon et al. [93] that

as far as

duration of action was concerned, Brocadopa Temtabs (a

sustained

release levodopa product) provided no advantage over the

standard

form of levodopa. Perrier and Gibaldi [94] predicted that

due to a first-pass effect,

a maximum of about 41% of an oral dose of propoxyphene

would reach

the systemic circulation, provided the entire dose was

released, ab

sorbed, and not metabolized during its transit through the

intestinal

wall. Their experimental results indicated that only 18% of

a 65-mg
dose, 28% of a 130-mg dose, and 33% of a 195-mg dose
reached the

systemic circulation, implying that bioavailability was

dose dependent.

Provided that this dose-dependent bioavailability could be

predicted,

a sustained release delivery system could be generated

although it

makes the sustained dosage form candidacy of propoxyphene

less

desirable. Dose-dependent bioavailability behavior has

also been demonstrated

for salicylamide [57,95,96], which is metabolized during

its passage

through the intestinal wall. Barr and Riegelman [57,95]

showed that

as much as 60% of the drug administered in a small dose

that appeared

in blood was in the glucuronide form. Johansson et al. [97]

obtained

similar results with alprenolol. They showed that the

metabolism of

drug during its passage through the intestinal wall was

more complete

when it was administered in a sustained release form than

in conven

tional tablets. However, these investigators claimed that

this increase

in drug loss was not enough to render sustained release

tablets un

suitable. This would be in accord with our expectation that

as long

as the extent of metabolism is constant, albeit extensive,

a suitable
sustained release product can be generated. It does,
however, sug

gest that some manipulation of the dosage form release rate

may be

needed to accommodate this metabolism. Wagner et al. have

derived

an equation to calculate variation of systemic availability

with input

rate [98]. One final example centers on nitroglycerin. The

effectiveness

of the oral route of administering nitroglycerin as opposed

to the sub

lingual route was the focus of several studies and reviews

[99-109]

and a conflicting picture emerged. Historically, the

argument against

the oral route of administration is that nitroglycerin is

extensively

metabolized during its first pass through the liver

[99,100], but

recently this has been challenged [109]. Nonetheless,

Friend et al.

[101] found that nitroglycerin in doses of 2 mg orally four

times

daily exerted no observable effect in angina pectoris, an

effect that

was indistinguishable from that of a placebo. Similarly,

Bogaert et al.

[102] detected no significant fall in blood pressure after

oral admin

istration of nitroglycerin despite high plasma levels of

the drug. No

explanation was offered for this observation. Other studies

[103-107],

in contrast, indicated that nitroglycerin was absorbed from

the GI

tract in sufficient quantities to bring about peripheral

vasodilation.

Since sustained release nitroglycerin products are

available on the

market, one can assume improved performance against angina

attacks

for these systems. Indeed, Turner [103] and others

[104-106,110,

111] found that sustained release products gave a duration

of action

longer than oral nonsustained tablets. This observation is

not incom

patible with the view that nitroglycerin is extensively

metabolized

during first pass through the liver, as long as metabolism

is constant.

However, it is incompatible with reports on lack of

biological activity

via the oral route. The role of prolonged act on

nitroglycerin pro

ducts in angina pectoris therapy will be evaluated

subsequently from

the standpoint of therapeutic need. Based on the few

examples just cited, controlled release systems

for drugs which are extensively metabolized is possible as

long as

the rate of metabolism is not too great nor metabolism

variable with

the oral and other routes. It is reasonable to assume that

a con
trolled release product can be made as long as the
metabolism remains

predictable.

D. Duration of Action

The biological half-life and hence duration of action of a

drug obvi

ously play a major role in the process of considering a

drug for con

trolled release. Factors influencing the biological

half-life of a drug

include its elimination, metabolism, and distribution pat

terns. Dittert

[112] has stated that most drugs have half-lives of

elimination in the

range of 1-20 hr . Drugs with short half-lives require

frequent dos

ing on order to minimize fluctuations in blood levels

accompanying

conventional oral dosage regimens [113]. Therefore,

controlled re

lease dosage forms would appear very desirable for such

drugs. At

present, the lower limit of the biological half-life needed

for controlled

release products has not been defined. Basic

pharmacokinetic prin

ciples (Chapter 5) suggest that for a given steady-state

drug con

centration, the zero-order rate of release of a drug from

its dosage

form is directly proportional to its rate of elimination.

Thus, for a

drug with a very short half-life, the desired rate of

release will be

quite large. For a modest duration of time over which the

drug is

to be released, this large rate of release in turn will

lead to a pro

hibitively large dose, so that the upper limit imposed on

the size of

the tablet, capsule, or other dosage form may be exceeded.

Table 5

Table 5 Ratio of Susta ining Dose to Immediate

Release Dose, $m/$i> a s a Function of t i / 2 and

In tended Durat ion of Release 8

h/2

(h r )

10 Td = 6 h r 4.6 2.08 1.39 1.04 0.83 0.69 0.59

0.52 0.46 0.42 Td = 8 hr 5.54 2.77 1.85 1.39 1.11
0.92 0.79 0.69 0.62 0.55 Td = 12 h r 8.32 4.16 2.77
2.08 1.66 1.39 1.19 1.04 0.92 0.83

HBased on a one-compartment open model.

shows the rat io of sus ta in ing dose <2> m to immediate

release dose $i

as a function of the biological half-life of d r u g and in

t ended dura t ion

of release T ^ . Table 6 l is ts t he maximum size D of t h

e controlled r e

lease dosage un i t . Table 7 l is ts some examples of d r

u g s with extreme

ly shor t half l ives . To d a t e , t he numerical value

of biological half-life which makes

a d r u g a good candidate for controlled release has not

been e s t ab

l i shed. Heimlich et a l . [114] quoted a value of about 4

h r . For a

d r u g with such a half-life, the rat io of sus ta in ing

dose to immediate

release dose is approximately 2 if the durat ion of in

tended release is

12 hr (Table 5) . Moreover, for this durat ion of in tended

re lease ,

it would be possible to formulate a controlled release dose

unit of 1

g even if t he immediate release dose (minimum effective

dose) is 325

mg (Table 6 ) . Consider ing th i s cr i ter ion alone,

propranolol ( t i / 2 =

4 h r ) [120,121], p ropoxyphene ( t i / 2 = 3 h r ) [122],

and procainamide

( t i / 2 = 3 h r ) [123] would be border l ine candidates

for prolonged r e

lease p r o d u c t s . As an i l lus t ra t ion ,

Koch-Weser et a l . [124,125] sug

ges ted tha t dose of procainamide must be administered

every 3 h r
to p r e v e n t f luctuations of plasma level by more than
50%. Susta ined

release formulations of procainamide are available and have

been shown

Table 6 Maximum Value of the Ratio of Sus ta in ing to

Immediate Release Dose, $ m / $ i , as a Function of Initial

Dose Dj and Size of the Sus ta ined Release Unit D a ($ /$

. )max m 1

Di (mg) 5

10

25

50

75

100

125

250

325

500

1000 D = 1000 199 99 99 19 12.3 9 7 3 2 1 mg D

= 500 99 49 19 9 5.7 4 3 1 0.5 mg D = 250 49 24
9 4 2.3 1.5 1 0

Based on a one-compartment open model.

b C*m/* i )max = ° / D i " *•

Table 7 Examples of Drugs with

Extremely Short Half-Lives Half-life

D r u g

Ampicillin

Cephalexin
Cloxacillin

Furosemide

Levodopa

Penicillin G

Propylthiouraci l (min) 100 54 90 29.5 45 45 63

Ref. 115 116 115 117 89 118 119

to be capable of e i ther maintaining the rapeu t i c

plasma level or mini

mizing the f luctuations in plasma level over an 8-hr per

iod [123,126,

127] . In e s sence , assuming a durat ion of release of 6,

8, or 12 h r ,

d r u g s with halfl ives between 4 and 6 h r and whose

minimum effective

doses are in the r ange of 125-325 mg will impose lit t le

problem insofar

as dose size is concerned . It should be pointed out tha t

the durat ion of action of many d r u g s ,

such as monoamine oxidase inhib i tors [128] and cor t

icosteroids [129,

130] , i s longer than that sugges t ed by the i r

biological ha l f l ives . As

a case in po in t , it i s the pe r s i s t ence of

antiinflammatory effects of

cor t icos tero ids tha t forms the bas i s for a l t e rna
te -day dosing schedule

and this is unre la ted to the biological half-life as

shown in Table 8.

This dosage regimen has the additional advantage of

minimizing ad re

nal suppress ion side effects f requent ly associated with

chronic cor t i
costeroid t he rapy [131] . T h u s , it is p robably
justified to assume

that sus ta ined release cor t icosteroids are unnecessa ry

from the s t and

point of t h e r a p y , undes i rable from the point of

view of side effects

[132] , and unphysiological from that of the diurnal var ia

t ions in Cor

tisol secret ions [133,134] . In fact, sus ta ined release

formulations of

prednisolone sodium phospha te and methylprednisolone have

been

shown to be equally effective as conventional t ab le t s ,

offering no

advan tages over the la t te r [135,136] , Similarly, the

re is little reason to p r e p a r e sus ta ined release
formu

lat ions for d r u g s with long biological ha l f l ives .

Nelson [137] has

indicated tha t if t he r e are no appreciable differences

in effect iveness

when a d r u g is given as a single la rge dose pe r day or

in severa l

smaller doses th roughout the day , the the rapeu t i c

need for a p r o

longed action dosage form would be doubtful .

Phenylbutazone is

such a d r u g . Due to extens ive prote in b ind ing , i

ts r a t e of metabo

lism is relat ively slow, resu l t ing in a biological

half-life of about 72

h r [139] . Para-aminosalicylic acid [140] and the

phenothiazines [141]
belong to the same category as pheny lbu tazone . Examples
of other

d r u g s with long biological halfl ives are shown in

Table 9. S u r p r i s

ing ly , sus ta ined release p roduc t s for d r u g s with

int r ins ical ly long

biological half-l ives are available. As expec ted , l i t

t le or not t h e r a

peut ic advan tages have been demonstra ted in these p r o

d u c t s over

Table 8 Biological Half-Life and Durat ion of Antiinflam

matory Effects of Selected Cort icosteroids Half-life

Durat ion

Drug (h r ) (h r ) Ref.

Methylprednisolone 3.3 24-36 138

Prednisone 1.0 36 131

Table 9 Examples of D r u g s with Long Biological

Half-Lives

D r u g

Bishydroxycoumarin

Chlordiazepoxide

Chlorphentermine

Chlorpropamide

Diazepam

Ethchlorvynol

Digitoxin

Digoxin

Guanethidine
Meprobamate

Phenytoin

Warfarin Half-life 27 h r 15 h r 41 h r 36 h r 54 h r
20 h r 24 h r 5-7 days 28 days 34 h r 9-10 days 11.3
h r 22 h r 52 h r Ref. 151 152 153 154,155 156 157
158 159 160 159,161 162 163 164 165

conventional table ts or capsu les . Notable examples a re

meprobamate

[142] , amitripyline [143-145] , and phenothiazines

[146-150] .

E. Side Effects

It is believed that for some d r u g s , the incidence of

side effects is

a function of plasma concentra t ions [166] . Theoret ical

ly , the inci

dence of side effects can be minimized by controll ing the

concent ra

tion at which the d r u g exis t s in plasma at any given

time, and hence

controlled release formulations appear to offer a solution

to this p r o b

lem. Nau et a l . [167] and Sikic et a l . [168] demonstra

ted tha t the

toxic effects of valproic acid and bleomycin, respec t ive

ly , were ame

l iorated upon adminis ter ing these d r u g s as a

constant infusion than

as a bo lu s . Eckstein et a l . [169] r epo r t ed tha t

Brocadopa Temtabs ,

a controlled release form of levodopa, lowered the

incidence of d r u g

induced dysk ines i s , and the pa t ien ts in the s tudy

seemed to be able
to tolerate a l a rge r daily dose of the d r u g . On the
other hand , a

sus ta ined release p roduc t of prednisolone p roduced

adrenocort ical

suppress ion to a degree indis t inguishable from tha t p

roduced by the

same dose given in conventional tab le ts [135] . Moreover,

an at tempt

to reduce the incidence of drowsiness due to

chlorpheniramine maleate

by dispensing the drug in a porous matrix was unsuccessful

[1701.

Thus, the success or failure of these specific products to

minimize

side effects would appear to be related to the type and

success of

preparing a controlled release product. The technique of

controlled release has been more widely used to

lower the incidence of GI side effects than that of

systemic side ef

fects and appears to produce more satisfactory results.

Drugs that

are prone to cause gastric irritation include aspirin

[171], ferrous

sulfate [172], potassium chloride [173], nitrofurantoin,

and several

others. It is postulated that by slowing the rate at which

these

drugs are released, the likelihood of GI irritation would

be reduced

due to a smaller amount of drug exposed to the GI mucosa at

any

given time [174]. Such is the case with sustained release

ferrous
sulfate products [71,74,76] and an aminophylline sustained
release

preparation [175]. In contrast, two cases of gastric

bleeding follow

ing the ingestion of Bayer's Timed-Release Aspirin were

reported

[176] . The extent of gastric bleeding relative to that due

to conven

tional aspirin tablets was not quantitated, however.

Nevertheless,

this observation suggests that controlled release

preparations are

not foolproof against GI side effects. One of the common

complaints of oral potassium therapy is gastric

irritation associated with its use [176]. To circumvent

this problem,

enteric coated tablets are usually prepared, but this has

led to another

problem, namely, intestinal erosion and stenosis due to a

high local

concentration of potassium ions released in the intestine

[177-181] .

Placement of potassium chloride in a controlled release

system, such

as a wax matrix (Slow-K), programmed to release its

contents over

4-6 hr appears to be a satisfactory solution [182-185].

Moreover,

it has been shown that such tablets are as bioavailable as

their non

sustained counterparts [184], Utilizing the same principles

as Slow

K, a sustained release form of sodium chloride (Slow-Na)

has been

formulated. The incidence of side effects such as nausea

and vomit

ing is claimed to be less than that in a tablet or capsule

[186,187],

and the formulation has been used to treat and to prevent

acute

and chronic deficiency in athletes and in patients on

maintenance

sodium therapy. In summary, it would appear that drug

properties

can induce local and systemic side effects which can often
be circum

vented by placement in a suitable controlled release

system. The

specific controlled release mechanism employed depends on

the drug

property inducing side effects.

F. Margin of Safety

Among the indices used to describe the margin of safety of

a drug

[188-190], the therapeutic index as defined in Eq. (7) is

the most

widely used: Therapeut ic index = Median toxic dose/median

effective dose = T D 5 0 / E D 5 Q (7)

However, th is ratio p rov ides no information on (a) t he

n a t u r e of t h e

d is t r ibut ion of toxicity and effect iveness , (b) the

size of doses p r o

ducing the rapeu t i c and toxic effects , and (c) plasma

or serum d r u g

concentra t ions cor responding to toxic and therapeut ic l

eve l s . Con
sequen t ly , i t can only be used as a c rude estimate of
the re la t ive

safety of a d r u g . As might be expected and as i l lus t

ra ted in Table

10, t he r e is wide variat ion in the the rapeu t ic index

for various d r u g s .

In genera l , the l a rge r t he ra t io , the safer is the

d r u g ; in pa r t i cu la r ,

a d r u g i s cons idered to be relat ively safe if i ts

the rapeu t ic index

exceeds 10 [190] . However, since the definition of the

rapeu t ic index

is relat ive r a t h e r than absolute , the toxic and

therapeut ic effects have

to be clearly defined. Decisions on margin of safety of a d

r u g p e r

haps can be be t t e r made on the basis of i ts the rapeu

t i c index in com

bination with the r ange of plasma concentrat ion within

which the d r u g

is considered to be therapeut ical ly safe and effective.

This approach

has been ve ry valuable as a the rapeu t i c guide in

monitoring d r u g

t h e r a p y , especially for d rugs with nar row the

rapeu t i c indices and a

nar row range of the rapeu t ic concentra t ion , such as

the cardiac gly

cosides and ant iar rhythmic (Table 11) [26 ,113] . In des
igning controlled or sus ta ined release systems for d rugs

with narrow the rapeu t i c ind ices , it is imperat ive

tha t the d r u g release

p a t t e r n be prec ise so tha t t he plasma concentrat

ion achieved is within

the therapeut ical ly safe and effective r a n g e .

However, a prec ise r e

lease p a t t e r n by itself is not sufficient to ensu re

attainment of such

Table 10 Therapeut ic Indices of Selected

Drugs

D r u g

Aprobarbi ta l

C hlorp henir amine

Digitoxin

Diphenhydramine

Penicillin

Phenobarbi tal

Tripelennamine Therapeut ic index 5.3 1400 1 .5-2 .0

2300 MOO 2.6 19,000 Ref. 191 192 193 192 193 191
192

Table 11 Examples of Drugs with

Narrow Ranges of Therapeutic Plasma

Concentration at Steady State Range of therapeutic

Drug concentration

Digoxin 0.02-2 yg/liter

Digitoxin 14-30 yg/liter

Lidocaine 1.5-4 mg/liter

Lithium 0.5-1.3 mEq/liter

Phenytoin 10-20 yg/liter

Procainamide 4-8 mg/liter

Propranolol 20-50 yg/ml

Quinidine 2-5 mg/liter

Theophylline 10-16 yg/ml

Source: Refs. 26,113.

plasma levels. There are other factors, such as patient

variability

and the very important drug accumulation upon multiple

dosing fac

tors (Chapter 6), that can potentially alter plasma drug

level. Con

sidering all these factors it is obvious that the design of

sustained

release system for drugs with narrow therapeutic indices

can be dif

ficult. Nevertheless, it is conceivable that an unfavorable

therapeutic

index can be overcome by suitable manipulation of

prolongation mech

amisms. Indeed, it is the same narrow therapeutic index

that makes

it desirable to precisely control drug concentration.

G. Role of Disease State

Strictly speaking, disease state and circadian rhythm are

not drug

properties. However, in a few instances they are equally

important

as drug properties in considering a drug for controlled

release. In

deed, it is not unusual for a disease state to act as a

stimulus for

development of a controlled release drug delivery system. A

case in
point is rheumatoid arthritis, for which aspirin is still
the drug of

choice [194] . Normally, aspirin would not be considered to

be a

likely candidate for sustained release because its

biological half-life

is 6 hr [195]. However, a sustained release product would

be ad

vantageous to maintain therapeutic concentrations,

particularly

throughout the night, thus alleviating morning stiffness

[196]. Note

that a limitation to formulating a sustained release

aspirin preparation

is the size of a dose, which necessitates the taking of two

sustained

release tablets to obtain the desired degree and duration

of relief.

The results of several studies indicated that sustained

release aspirin

tablets in the proper dosage provided and maintained blood

levels at

therapeutic concentration over 8-10 hr, a duration that was

about

twice as long as that provided by nonsustained release

tablets [196

198]. Among the therapeutic armamentarium in peptic ulcer

management

are belladonna alkaloids and synthetic anticholinergics.

Although the

usefulness of this class of drugs in this disease state is

controversial

[199] , they are sometimes prescribed as adjuncts to

therapy by virtue

of their ability to decrease gastric secretion of acid and

pepsin induced

by vagal stimulation [200]. Since belladonna alkaloids are

relatively

short-acting [201], a sustained release dosage form may be

helpful

to exercise continuous control on gastric acid and pepsin

secretion.

Burness [202] and Resse et al. [201 found that sustained

release

belladonna preparations employing the Spansule^ principle

appeared

to maintain therapeutic plasma concentrations of alkaloids

from 8 to

12 hr , but they did not measure gastric acid and pepsin

output.

Kasich [203] as well as Alp and Grant [204] reported

similar findings

with hexocyclium. In contrast, Bachrach [43] found that the

prolonged

acting forms Antrenyl Prolonged 1 *, Prantal Repetabs R ,

Banthine Pro

longed^, and Probanthine Prolonged** did not sufficiently

extend the

duration of action of drug and he attributed this

observation to the

design of the products concerned. Angina pectoris is

another disease state that probably would be

benefited by sustained release medications. In spite of the

dispute

over the efficacy of nitroglycerin when administered by the

oral route,
sustained release nitroglycerin preparations are available.
Similar to

the situation with the orally administered nonsustained

products, there

are conflicting reports on the value of sustained release

nitroglycerin

products in controlling the symptoms of angina pectoris.

One reason

that may account for this confusion is the high incidence

of placebo

response to prophylaxis of angina pain [205] . The findings

of Russek

et al. [107] and Pilkington and Purves [104] supported the

argument

that a sustained release ntiroglycerin preparation was of

questionable

value in conferring propylaxis to those patients suffering

from the

typical short attacks of angina pectoris. They based their

conclusions

on the findings of studies employing sustained release

ntiroglycerin

preparations containing from 6 to 10 times the dose

normally used sub

lingually. However, Winsor et al. [105], Hirshleifer [106],

Turner

[103], Wendkos and Meshulam [110], and Preti et al. [ I l l

] obtained

results contrary to those of Russek and Pilkington. They

found

that the sustained release nitroglycerin preparations used

in their

studies not only reduced the incidence and severity of

angina attacks
but also lowered the nitroglycerin requirements. Kamil and
Klinger

[206] as well as Feinblatt and Ferguson [207] reported

similar find

ings with pentaerythritol tetranitrate, another drug used

in angina

pectoris. The conflicting nature of the above reports

suggests that

additional studies are warranted to establish the role of

sustained

release preparations as a prophylactic aid in angina

pectoris. Per

haps the acute and fleeting nature of angina attacks [205]

, the large

placebo effect [205], and the development of tolerance with

chronic

administration of long-acting oral nitrate preparations

[208] should

be major consideration in the design and interpretation of

such stud

ies. An interesting statement on the need for prolonged

action forms

of nitrates in the prophylactic treatment of angina

pectoris was made

by Wilson [209]. He noted that prophylaxis carries with it

the dan

ger of obscuring the warning symptoms of pain, eventually

leading

to over-exertion with potentially harmful results.

H. Role of Circadian Rhythm

Several biological processes and disease states have been

shown to
be influenced by circadian rhythm [210]. As examples, acute
myo

cardial insufficiency occurs most commonly around 4:00 a.m.

[211]

and epileptic seizures have the highest incidence in the

morning

[212]. Liver enzyme activity [248], blood pressure

[213,214], and

intraocular pressure [215] also follow a circadian rhythm.

As a re

sult, the response to certain drugs also follows a

circadian rhythm.

These include digitalis glycosides, diuretics, and

psychoactive drugs

such as the amphetamines, barbiturates, carbamazepine,

ethyl alcohol,

and chlordiazepoxide [211,212,216-218]. The disease of

asthma follows a circadian rhythm, with most of

the attacks occuring before bedtime [219]. This observation

is postu

lated to be related to a low Cortisol level at that time

[211] . It was

found that the highest Cortisol level occurred between 12

midnight

and 4:00 a.m. [211], Like many other diurnal variations,

this vari

ation in Cortisol levels makes the design of a controlled

release dos

age form much more difficult. Foremost among the

limitations is

GI transit time. Methylprednisolone has been made available

in a

prolonged action product (Medrol MeduleR). In one study

[219],
such a product was shown to produce the same duration of
relief of

rheumatoid arthritis as the same dose administered as a

conventional

tablet. Although circadian variations of corticosteroid

levels is well

known, there is some uncertainty as to whether diurnal

variations

in glucose and insulin levels exist. Jarrett and Keen [220]

reported

that in diabetics, the diurnal variation in glucose

appeared not to

exist, or when it did, it was to a lesser extent. Prior to

the reports

of Jarrett and Keen [220], Hayner et al. [221], Freinkel et

al. [222],

and Faiman and Morrhouse [223] obtained results opposite to

those of

the former investigators, that is, a diurnal variation in

blood glucose

existed in the diabetic but not in the normal subject, with

blood glu

cose levels significantly higher in the morning than in the

afternoon.

Freinkel et al. [222] also found that, in normal subjects,

insulin level

was higher in the morning than in the afternoon. Rigas et

al. [224]

postulated that insulin synthesis and storage proceeded to

a greater

extent during the night than during the day, thus

accounting for

Freinkel's observations on diurnal variation in insulin

levels. Theo

retically, once diurnal variations in blood glucose and/or

insulin are

established, controlled release oral hypoglycemic products

could be

designed to release their contents in accordance with

circadian rhythm.

However, the fluctuation in blood glucose levels in

diabetics is not

controlled solely by diurnal variations but also by such

variables as

diet and exercise [225], Conceivably, the net result of

interaction

of these two influences is to diminish the importance of

circadian

rhythm in dosage form design. Perhaps the classes of drugs

that would benefit the most from in

corporation of circadian rhythm into their dosing regimen

are the

chemotherapeutic agents and peptide hormones. That the

timing of

chemotherapy is possible in conferring greater specificity

is based on

the assumption that , unlike malignant tissues, normal

tissues are un

der more stringent circadian control. Hrushesky [226]

demonstrated

that during the course of treatment of ovarian cancer

patients with

a combination of adriamycin and cisplatin, administration

of adriamycin

in the morning and cisplatin in the evening caused fewer

complications
than a regimen in which the order of dosing of these drugs
was re

versed. The secretion of neuropeptides and peptide hormones

like

LHRH, parathyroid hormone, and growth hormone is also under

cir

cadian control [227]. Thus, the treatment of conditions by

a number

of these substances, notably LHRH [228-230], parathyroid

hormone

[231], and triiodothyronine [232] has been found to benefit

more

from intermittent, periodic administration than from

constant infusion,

in part because a constant tissue level of these substances

may lead

to down regulation of their receptors [233-237] . The net

effect of

circadian regulation of these substances is to make the

design of a

controlled release system for such substances more

challenging, as

exemplified by a prototype delivery device programmed to

release

melatonin, a pineal gland hormone, in a periodic fashion

[238].

V I I . SELECTED ROUTES OF DRUG ADMINISTRATION

The route of administration has a significant impact on the

therapeu

tic outcomes of a drug [239,240] . In controlled and

sustained drug

delivery system design, the parenteral and oral routes have

received
by far the most attention, although transdermal route is
gaining at

tention recently. At the same time, advances in

biotechnology have

made possible an increasing number of peptides and proteins

which,

by virtue of the biophysical and biochemical properties,

have made

specific demands on the route of delivery as well as on the

design of

delivery systems. Thus, routes which were of minor

importance as

ports of drug delivery in the past have assumed added

importance in

peptide and protein delivery. These include the buccal,

rectal, nasal,

pulmonary, vaginal, intrauterinal, and ocular routes. The

purpose

of this section is to present an overview of the

physiological con

straints inherent in each of the routes mentioned above.

A. Parenteral

Strictly speaking, parenteral products are all systems

administered

outside of the GI t ract . However, parenteral routes are

more common

ly restricted to injectables such as subcutaneous,

intramuscular, intra

peritoneal, intrathecal, and intraventricular sites.

1. Intravenous /Intraarterial

The intravenous route is attractive because drugs are

placed directly
into the blood with the associated potential to give an
immediate bio

logical response. However, sustaining blood concentrations

of drugs

given by intravenous injection poses a considerably

challenge. Al

though continuous intravenous infusion can be tailored to

maintain

a constant and sustained drug level within a therapeutic

concentration

range during the entire treatment period, such a mode of

drug ad

ministration necessitates continuous hospitalization during

treatment

and requires frequent drug level monitoring. There are

several reasons for the lack of commercial sustained

release intravenous products. Aside from the irretrievable

nature of

such injected drugs, there are the issues of

biocompatibility and

limitations on the size of injected drugs. Thus, wishing to

avoid

blockage of small capillaries requires that only very small

particles

be employed as physical systems for intravenous injections.

However,

the reticuloendothelial system, consisting primarily of

liver, spleen,

lung, and bone marrow, sequesters "foreign" substances out

of the

blood stream rapidly, thus making it difficult to sustain

drugs via

this route. Numerous attempts to provide either

prolongation of drug release
or spatial placement of drug, a very desirable attribute
for cancer

chemotherapy, have been made. Each appears to suffer from

one or

more deficiencies. Thus, loaded red blood cells, where a

drug is

placed within a red blood cell, offers a number of

attractive features,

the most notable being biocompatability and a duration akin

to the

half-life of a red blood cell, i . e . , 30 days. However,

such factors

as loading capacity of red blood cells for drug, damage to

the cell

during drug loading resulting in sequestration by the

reticuloendo

thelial system, and lack of control of drug release from

the red blood

cell have reduced the therapeutic utility of such systems

for controlled

drug delivery. Liposomes and other particulate systems

suffer from

similar shortcomings, which will be discussed in Chapter

13. In general, depot-type parenteral controlled drug
release formula

tions duplicate the benefits of continuous intravenous

infusion without

its potential discomfort. Various techniques have been used

[241-245],

including viscous vehicles, suspension, sparingly soluble

derivatives

and biodegradable microspheres. Biodegradable microspheres

are par
ticularly attractive because labile drugs such as peptides
and proteins

are protected by and released at a controlled, efficacous

rate for de

sired periods of time from this delivery system. These

microspheres

can also be utilized to direct drugs to certain organs

through capil

lary blockade [243,246]. Its success depends on the size of

the

microspheres used and on the mode of administration

(intravenous or

intraarterial). Microspheres with a diameter exceeding 25

ym upon

intraarterial administration can be entrapped temporarily

in the first

capillary bed encountered. In contrast, microspheres

greater than

7 ym in diameter when given intravenously will be trapped

in the

lungs by mechanical filtration, while smaller ones will be

cleared by

the reticuloendothelial system [247] . The key to a

reproducible de

gree of occlusion for a given dose appears to be due to

lack of a

tendency of microspheres to aggregate. However, the use of

blockage

incurs the risk of irreversible cellular damage. The brain

can only

tolerate a few minutes of anoxia, in comparison to the

majority of

organs which can tolerate a 20-40-min "shutdown."

2. Intramuscular /Subcutaneous

Next to oral administration, injection into subcutaneous or

muscular

tissues is the most commonly used and acceptable route of

drug ad

ministration. These routes of administration are most

useful either

when the disease state or the pharmacokinetic properties of

a drug

preclude oral dosing, or prolonged drug action is desired.

The

latter can be achieved in a number of ways [241,248],

including re

duction of aqueous solubility, gelling of the oily vehicle,

use of bio

degradable systems, implants, or a combination of these.

All of these

approaches aim to decrease the release rate of a drug from

its dosage

form and will be discussed further in Chapter 10. A major

factor

that needs to be considered during development of

biodegradable sys

tems and implants is biocompatibility of the polymers.

Release rate

from implants may decrease with time when a fibrous

envelope is

formed around the system as a result of bioincompatibility

[249] . In

addition, for biodegradable systems as exemplified by

poly(ortho

esters) , it is imperative that breakdown products of the

polymer be
nontoxic [250] . In general, drugs are assumed to be
absorbed at the same rate

when given intramuscularly and subcutaneously and the sites

are

often considered bioequivalent [251,252]. However, subtle

differences

between these two modalities of drug administration do

exist. The

vascularity in the subcutaneous tissue is poorer than that

of muscle

tissue [253] and thus may lead to slower absorption unless

there is

compensation with an increase in surface area. Moreover,

lymphatic

vessels of subcutaneous tissue are mainly found in the

connective

tissue, whereas those of the muscular tissue usually exist

where

facial planes enter muscles [253]. Unlike intravenous

injections, subcutaneous and intramuscular

injections require an absorption step before a drug reaches

the sys

temic circulation. However, since absorption from

subcutaneous and

muscle tissue does not involve passage through an

epithelial layer

and the tissues are well supplied with capillary and

lymphatic vessels,

absorption from these routes is usually faster relative to

the oral

route. Depending on its physicochemical properties, the

rate-limiting

step in drug absorption from aqueous solution may be either

drug
diffusion in the connective tissue [254,255] or blood flow
through

and around the injection site [247,256-260]. Therefore, any

factor

that influences the above two parameters should influence

the absorp

tion rate. For example, vasoconstrictors such as

epinephrine reduce

the subcutaneous absorption of a number of drugs, whereas

hyaluroni

dase which digests connective tissues markedly increases

drug absorp

tion from both muscle and subcutaneous tissues [254] .

Probably due

to differences in blood flow, absorption is most rapid

following injec

tions into the deltoid muscle and least so when injected

into the glu

teal muscle [247]. In contrast, the absorption rate of

drugs adminis

tered intramuscularly does not seem to be affected by the

water con

tent of connective tissues [254] . Recently, intramuscular

and subcutaneous absorption from aqueous

solutions [259-265], oil solutions [251,266], and aqueous

suspensions

[267,268] has been examined. Absorption from aqueous and

oil solu

tions follows first-order kinetics. Absorption rate

decreases with

increasing volume, probably because of mechanical

compression of the

adjacent capillary bed and because of a smaller

area-to-volume ratio

[257] . Moreover, absorption rate was found to be inversely

related

to molecular size for water soluble compounds and directly

proportion

al to partition coefficient for lipophilic compounds [258].

Low molecu

lar weight compounds are readily absorbed via the

capillaries, while

high molecular weight compounds appear to be absorbed

primarily

via lymphatic vessels [255] . Inclusion of adjuvants such

as serum

albumin was found to increase subcutaneous absorption of

high molec

ular weight compounds, but the mechanism is unknown [269].

For oil solutions, absorption rate depends on partitioning
between

the oil and the aqueous medium in the connective tissue,

with little

dependence on viscosity. Clearance of oily vehicles

following intra

muscular and subcutaneous injections has been studied in

albino rab

bits [270]. It was found to be independent of the injection

site.

However, clearance was mainly via capillary vessels whereas

clearance

via lymphatic uptake or phagocytosis by cells was found to

be insig

nificant. In the case of suspensions, the absorption rate

increases

with decreasing particle size, probably due to an increase

in lateral
spread of the particles in the connective tissue [267,268].
Phagocy

tosis appears unimportant except for exceedingly fine drug

particles.

B. Oral

The oral route is by far the most popular route of drug

administra

tion. Nevertheless, current knowledge on mechanisms of drug

ab

sorption, GI transit and the microenvironment of the GI

tract is still

incomplete. In addition, oral administration is also beset

with inher

ent physiological constraints such as chemical degradation

in the

stomach, gastric empyting, intestinal motility, mucosal

surface area,

specific absorption sites, and metabolic degradation during

passage

through the mucosa and subsequently the liver. Adding to

these

constraints is the commonly substantial intra- and

intersubject vari

ability associated with some of these factors. Generally,

these factors

cannot be controlled and hence severely limit the design of

oral drug

delivery systems. The duration of a drug after oral

administration is mainly a func

tion of drug-releated properties such as rate of absorption

and clear

ance as well as residence time of the delivery system at

the absorp
tion site. Most sustained release drug delivery systems
developed

thus far are aimed at slowing the apparent absorption rate

by reduc

ing drug release rate from the dosage form. However, these
systems

will have only limited utility in oral controlled

administration of drugs

unless they can remain in the vicinity of the absorption

site for the

life time of drug delivery. The residence time of most

sustained/controlled release dosage

forms is primarily determined by gastric emptying and

intestinal

motility. Gastric emptying is influenced by factors such as

auto

nomic and hormonal activity, and volume, composition,

viscosity,

osmolality, pH, caloric value, temperature of stomach

contents as

well as by many drugs [271]. The human/canine stomach

behaves

differently in the fed and fasted states [272]. During the

fed state,

fluids and solid particles smaller than 2 mm are discharged

together

whereas solid particles larger than 2 mm, including pellets

and tablets

are retained until arrival of the next phase III of the

migrating motor

complex (MMC) [273], In the fasted state, gastric emptying

patterns

of fluids depend on the volume administered. A lag phase is

com

monly observed for volumes of fluid less than 100 ml. The
onset of

discharge depends on the phase activity of the stomach, and

fluid

is discharged before the suspended particles. In contrast,

large

volumes of fluids (>200 ml) are discharged immediately, as

in the

fed state, and the square root of volume vs . times or an

exponential

relationship is usually observed. Motility of the small

intestine during digestion consists mainly of

segmental contractions, whose purpose is to mix its

contents. Distal

propulsion also occurs, but its mechanism is unknown [272],

Distal

propulsion in fasted state occurs mainly in phase III of

the MMC. Liquids are spread out over the entire small
intestine quite

quickly following ingestion. It has been found that the

transit of

liquids and solids are similar in the small intestine, so

that differ

ences in their GI transit time are primarily due to

differences in

gastric emptying time. Studies in humans have shown a

surprising

consistency of small intestinal motility in that ,

irrespective of dosage

form, it takes approximately three hours for substances to

traverse

the small intestine. The methodology of studying GI transit

has
been summarized by Hoffman et al. [272]. It is generally
assumed that the desirable site of absorption is

the proximal and mid small intestine, the transit time of

most delivery

systems in which is only 2-3 hr long [272]. Consequently, a

sus

tained release formulation of about 12-hr duration or

longer can only

be achieved by slowing gastric emptying. Several approaches

have

been proposed for prolongation of GI transit time. These

include

flotation tablets and capsules (U.S. patent #4,140,755),

unfolding of

stratified medicated sheet (BE patent #867,692),

bioadhesive polymers

[274,275], certain fatty acids [276], and certain drugs

such as pro

pantheline. However, the use of drugs is generally

considered un

desirable because of potential side effects. An important

issue relative to oral controlled release products is

the animal species that is used during the design phase of

these

systems. Although our understanding of the anatomical and

physio

logical aspects of all animals is rudimentary, there are

certain species

which seem to be preferred. The beagle dog is a frequently

utilized

animal for this purpose, in spite of marked differences in

its transit

time and GI pH relative to human subjects. Transit time of

dosage

forms in the dog is only two-thirds of that in humans,

analogous to

that in a young child, aged 1-3. This can be an important

consid

eration for those systems that require drug absorption for

an extended

time. Thus, for such systems, dogs will show incomplete

absorption.

The second issue is GI pH. Some workers have found (a) a

higher

pH in the stomach as compared to humans and (b) an acid pH

ex

tending over a larger segment of the small intestine of the

beagle

dog. As an alternative animal species to obviate this pH

problem

some pharmaceutical firms routinely employ the cynomolgus

monkey as

well as rodents. Here, a word of caution regarding the use

of ro

dents as test animals is in order. The rat has a portion of

its stom

ach in keratinized form with unknown stomach emptying of

oral con

trolled release dosage forms. Moreover, both the rat and

the rabbit

eat their own feces, thereby rendering the composition of

stomach

contents and the associated influence of this composition

on drug re

lease and stomach emptying somewhat uncertain. In summary,

because of limited residence time and possible exis
tence of an absorption window for some drug, control of GI
transit

time and site-specific release through specific binding of

the drug

delivery system to the absorption site are attractive

approaches to

controlled oral administration. With some exceptions,

targeting of

drugs is not the primary concern for most orally

administered drugs.

Rather, the aim is to increase the amount of drug delivered

to, with

concommitant prolongation in, the general circulation. For

this rea

son, most systems employed are of the sustained release

type. In

cases where systems are used to target a drug, the site of

absorption

rather than the site of action is targetted. The assumption

is that

by increasing drug concentration at the absorption site,

the amount

of drug reaching the site of action will increase

correspondingly.

This is exemplified by colon drug delivery [277-279].

C . Buccal /Sublingual

Drugs can be absorbed from the oral cavity through the oral
mucosa

either sublingually (under the tongue) or buccally (between

the cheek

and gingiva). In general, rapid absorption from these

routes is ob

served because of the thin mucous membrane and rich blood

supply.

For highly hydrophilic drugs (log P < 2), which also suffer
from ex

tensive presystemic elimination and require a rapid onset

of action,

sublingual or buccal administration may offer advantages

over oral

administration. After absorption, drug is transported

through the

deep lingual vein or facial vein which then drains into the
general

circulation via the jugular vein. Thus, the buccal and

sublingual

routes can be used to bypass hepatic T, first-pass TT

elimination. Lym

phatic uptake of drug also occurs, but is less common

[280]. Drug absorption into the oral mucosa is mainly via
passive dif

fusion into the lipoidal membrane [281-283]. Compounds with

favorable

oil-to-water partition coefficients are readily absorbed

through the

oral mucosa. Since the mean pH of saliva is 6.0, adequate

absorp

tion through the oral mucosa occurs if the pK a is greater

than 2 for

an acid or less than 10 for a base. An oil-water partition

coefficient

range of 40-2000 is considered optimal for drugs to be

absorbed

sublingually [284,285]. Compounds administered by either

the buccal

or sublingual routes include steroids, barbiturates,

papain, trypsin,
and streptokinase-streptodornase [282]. Besides
transcellular diffu

sion, there is evidence that water-soluble molecules with a

molecular

volume of less than 80 cm 3 /mole cross primarily through

membrane

pores and large water-soluble molecules pass paracellularly

[285].

Regardless of polarity, large molecules are poorly absorbed

[286, 287]. Conventional buccal and sublingual dosage
forms are typically

short acting because of limited contact time between the

dosage form

and the oral mucosa. Since sublingual administration of

drugs inter

feres with eating, drinking, and talking, this route is

generally con

sidered unsuitable for prolonged administration. On the

other hand,

the duration of buccal drug administration can be prolonged

with

saliva-activated adhesive troches without the problems of

sublingual

administration [288]. Unfortunately, the buccal

nitroglycerin adhesive

troche has yet to be met with commercial success [289] .

D. Rectal

The rectal route is commonly used as an alternative when

oral admin

istration is inconvenient because of inability to swallow

or because of

gastrointestinal side effects such as nausea, vomiting and

irritation.
More important, rectal drug administration has the
advantage of mini

mizing or avoiding hepatic first pass metabolism [290,291].

For in

stance, the rectal bioavailability of lidocaine in man is

65%, as com

pared to an oral bioavailability of 30% [291]. The human

rectum is about 15-20 cm long. In the resting state

the rectum does not have any active motility. Normally the
rectum

is empty and contains only 2-3 ml of inert mucous fluid (pH

7-8)

which has no enzymatic activity or buffering capacity.

There are

no villi or micrivilli on the rectal mucosa and thus, a

very limited

surface area (200-400 cm^) is available for absorption. The

internal

volume of the rectum depends on the pressure exerted on the

rectum

by the surrounding organs. This pressure, together with

motility,

affects spreading of a dosage form. Both blood and

lymphatic vessels are abundant in the submucosal

region of the rectal wall. The upper veins drain into the
portal cir

culation, while the lower and middle veins drain directly

into the

inferior vena cava. However, there are extensive

anastomoses among

these veins, so that a clear-cut anatomical differentiation

cannot be

made. Nevertheless, systemic bioavailability seems to

depend on the

site of absorption in the rectum [292], rectal motility

[293], as well

as animal species [291]. In general, absorption occurs at

a slower rate and to a lesser

extent than after oral drug administration with a

particular dose

[294] . Drug absorption from the rectum is assumed to occur

by

mechanisms similar to those operating in other parts of the

GI tract ,

i . e . , passive diffusion [295,296]. For poorly

water-soluble drugs,

the rectal absorption rate is determined by the release

surface area

rather than by drug concentration in the dosage form.

Absorption

from aqueous and alcoholic solutions is in general much

faster than

that from suppository, which is often very much dependent

on the

particle size of the active ingredient as well as on the

nature of the

suppository base, surfactants and other addditives

[294-298]. Recently, some non-surfactant adjuvants, such
as the salicylates,

have been found to enhance rectal absorption of

water-soluble drugs

[298-301] and high molecular weight drugs like insulin,

heparin, and

gastrin [302-304]. Some peptides, such as N-acyl

derivatives of col

lagen peptide [305], have also been found to exert a

self-enhancing
effect [306]. Apparently, a high local concentration and/or
simul

taneous absorption of the adjuvants are required to alter

membrane

permeability, thereby assuring rapid drug absorption in the

rectum

[300,304], Membrane permeability enhancement by

non-steroidal anti

inflammatory drugs is reversible [307] whereas that by

surfactant

adjuvants and chelating agents is not [308] . Design of

rectal controlled release drug delivery systems is likely

to be limited by some inherent problems of the rectal area,

including

interruption of absorption by defecation and, in certain

parts of the

world, lack of patient acceptance of this route. Only a

limited num

ber of compounds given rectally have been shown as

effective as when

given orally [309]. Thus, this route may serve as an

alternative

pathway to oral administration for compounds that undergo

extensive

first-pass metabolism or for high molecular

weight/enzymatically sen

sitive compounds such as insulin and heparin.

E. Nasal

For many years, the nasal route was used primarily for
local action

on the nasal mucosa. Despite its use in systemic delivery

of desmo
pressin and vasopressin, its use as an alternate route for
poorly ab

sorbed oral drugs seems to have been ignored until

recently. A

variety of drugs including propranolol [310] , testosterone

[311] ,

naloxone [312], buprenorphrine [312], ergotamine tartrate

[313],

clofilium tosylate [314], cromolyn sodium [315], meclizine

[316], as

well as endogenous hormones such as

luteinizing-hormone-releasing

hormone [317], tetracosactrin [318], oxytocin [319], ACTH

[320],

insulin [321-324], and enkephalins [325], have been shown

to be

absorbed nasally in animals and humans. By virtue of

relatively

rapid drug absorption, possible bypassing of presystemic

clearance,

and relative ease of administration, delivery of drugs by

the nasal

route offers an attractive alternative for administering

systemically

active drugs. The anatomy of the nasal cavity is described

in detail elsewhere

[326,327]. The thickness and vascularity of the mucous

membrane

lining the nasal cavity depends on location. The mucous

membrane

is thickest and most vascular in the upper regions and over

the sep

tum, whereas it is very thin on the floor of the nasal

cavity and in
the sinuses. The surface area of the nasal cavity is
increased by

the sinuses, where most drug absorption occurs [328]. The

absorp

tive surface area is further increased by the microvilli in

the mucous

membrane. The vascular bed of the nasal mucosa provides

rapid ab

sorption with little metabolizing capacity. The pH of nasal

mucosal

surface is reported to be around 7.4 [328]. Dosage forms

must deposit and remain in the nasal cavity suffici

ently long for effective absorption to occur. Aerosol and

particulate

dosage forms should contain particles greater than 4 ym to

minimize

their passage into the lung [329] , where mucociliary

clearance will

remove most particulate materials. However, before nasal

delivery

can be a viable alternative route for systemic drug

absorption, it

will be necessary to have a better understanding of how to

control

particle deposition within the nasal cavity reproducibly,

how drug

and particle interact with mucus, and how certain disease

states of

the nasal mucosa may affect the rate and extent of drug
absorption.

F. Pulmonary

Delivery of medication to the respiratory tract for

localized therapy
of respiratory diseases is commonly accomplished via the
airways be

cause of their enormous surface area and accessibility

[330] . The

respiratory tract consists of a nasopharyngeal region, a

tracheo

bronchial region, and lungs (bronchioles and alveoli). The

diameter

of the dichotomous branchings of the bronchial tree

decreases in the

distal parts of the respiratory tract , with a simultaneous

increase in

total cross-sectional area and the total surface area

[331]. Thus,

the flow in the central airway is rapid and turbulent,

whereas flow

in the peripheral airways is smooth and laminar [332] . The

total sur

face area of alveoli in an adult is about 35 m 2 during

expiration and

about 100 m 2 during deep inspiration [333] . Thus, most

solute ex

change takes place at the alveolar level. For purposes of

discussion of the deposition and clearance of

inhaled aerosols, the airways can be divided into three

functional

regions [334] (Fig. 2): 1. Nasopharyngeal region—cavity to

entrance of trachea 2. Tracheobronchial region—trachea to
terminal bronchioles 3. Pulmonary region—bronchioles to
alveoli, no ciliated cells In general, prediction of the
site of deposition of an aerosolized

drug is difficult because airway sizes and anatomy differ

from person

to person and appear to be influenced by pathological

changes.

Naso pharyngeal:

particles greater

than 5^im deposited

Tracheo bronchial 1

particles between

2 and 5 ^m deposited

in this region

Pulmonary:

particles less than

2>um deposited by

diffusion and random

capture.

Fig. 2 Disposition of particles in various regions of the

respiratory

t ree .

Moreover, alterations in regional ventilation that result

from lung

disease can influence the site at which a drug is deposited

[335-337].

Deposition of aerosolized particles is mediated by a

variety of mechan

isms, depending on particle size, shape, density, charge

and hygro

scopicity [338,339]. The geometry of the airways and

physiological

factors such as breathing patterns, air flow dynamics in

the respira

tory t ract , and variations of the relative humidity and

temperature

inside the airways also influence deposition. The influence

of particle

size on aerosol deposition is depicted in Figure 3 [340] .

Therapeutic aerosols are typically polydispersed with sizes
ranging

from 1 to 10 ym (341). These particles are small enough to

be carried

down the respiratory tract with inspired air [342] . Large

particles

(>5 ym) are usually deposited via inertial impaction on the

upper

airways, where air velocity is high [341]. Pathological

changes usu

ally increase the inertial impact by narrowing the airways

[339,341].

Moderate size particles (1-5 ym) can sediment out of the

air stream

under the force of gravity. Deposition by sedimentation

occurs pre

dominantly in the lower levels of the airways, where air

velocity is

low [341]. Thus, peripheral deposition of aerosols is

maximized by

inhaling slowly, followed by a period of breath holding

[339]. For

submicron particles, diffusion becomes important. All

particles smal

ler than about 10 ym in diameter are deposited to some

extent in the

pulmonary region of the lung upon inhalation, while

deposition of

particles smaller than 0.01 ym is usually negligible

because of diffu
sional deposition in the nasopharyneal and tracheobronchial
regions.

Thus, the efficiency of deposition of intermediate size

particles

[0.02-1.0 ym] is less compared to larger and smaller sizes.

Particulate material deposited in the respiratory tract may
eventu

ally be cleared by mucociliary action and/or the lymphatic

system Pharynx Larynx Trachea Primary bronchi
Secondary bronchi Terminal bronchioles Respiratory
bronchioles Alveolar duct Alveoli

and/or may be transferred to the blood [340,343] (Fig. 4).

The

physiocochemical characteristics of aerosols, site of

deposition, and

respiratory physiology are important determinants of

clearance.

Soluble deposited particles, on the other hand, are cleared

via ab

sorption into the blood stream. Clearance of insoluble

particles de

posited on the ciliated regions of the respiratory tract is

mainly

via mucociliary transport [335,342,343], whereas those

deposited on

the non-ciliated surfaces of the pulmonary region may be

phagocy

tized by macrophages [344,345] or may leak into the

interstitium [346],

which may then be translocated to a lymph node [347] . The

mechan

isms of deposition and clearance are summarized in Table

12. Once the aerosolized drug particles deposit on the
alveolar sur
face, they must cross the alveolar-capillary barrier before
reaching

the systemic circulation. Both alveolar epithelium and

pulmonary

capillary endothelium are continuous, but the former has

more tight

junctions than the latter [348-350]. Physiological

measurements give

an equivalent pore radius of 8-10 A for alveolar epithelium

and 20

200 A for capillary endothelium [351,352]. Thus, the

alveolar epithe

lium has a much lower permeability to liquids and solutes

than the

pulmonary endothelium. Of special interest is the large

number of

pinocytotic, lamellar vesicles, many of which discharge

their content

Q. 100 rAlveolar and terminal airway

^ 801— deposition

iZ 60

Q 4 0

2 2 0 / Mouth breathing ' • / . ••" / 8 0 1 2 4 6 %

Submicron range PARTICLE DIAMETER (/xm) 10

Fig. 3 Effect of particle size on deposition of particles

in various

regions of the respiratory t ree . The curves indicate the

proportion

of total material of any particle size likely to deposit

upon an internal

surface: __•_•_> nasal compartment; , tracheobronchial com

partment; , pulmonary compartment. (From Ref. 340.) l .
Mouth breathing Nasal Oral — / a s t r o i n t e s t i
n a l t r a c t M u c o c i l i a r y e s c a l a t o r

1 ^ L^— L Urn—

T \ Pharyngeal 7 0 % deposition (10-30/ im)

Tracheobronchial 6 % deposition (10/im) Lower airways 8
lungs 2 4 % deposition (5/ im -lower airways) (< 1 /Am
-alveolar parenchyma) Macrophages f ^"v H Blood
(depending on solubility) J Lymph nodes

EXCRETION •-Interstitial space Residue Peribronchial

and subpleural lymphatic channels

Fig. 4 The ultimate distribution of particulate material

inhaled and de

posited in airways and lungs, as affected by lung clearance

mechanisms.

The figures in individual compartments represent the

proportions that

are typically likely to be deposited of an inhalable dust

of uniform par

ticle size distribution. Solid arrows indicate major

routes, and dotted

arrows indicate minor routes of particle distribution.

(From Ref. 340.)

Table 12 Deposition and Clearance of Inhaled Aerosols

Region Deposition Clearance

Nasopharyngeal Impaction Diffusion Interception

Attraction Mucociliary Sneezing Blowing Dissolution

Tracheobronchial Impaction Diffusion Settling

Interception Attraction Mucociliary Coughing
Dissolution

Pulmonary Diffusion Settling Attraction Interception

Dissolution Phagocytes Lymph flow

into the capillary lumen [353,354]. These vesicles contain

enzymes
for metabolism of adenine nucleotide and angiotensin I
[354]. The

basal lamina subtending the cellular layers offer a

substantial barrier

to the penetration of large molecules [355] . In general,

drug absorption from the lung is considerably faster

than from the intestine [356] . However, the nature of drug

transport

from the pulmonary epithelium to blood is poorly

understood. Results

to date reveal that , the absorption rate of small

lipophilic molecules

is related to the oil/water partition coefficient [357],

whereas the ab

sorption rate of some organic cations and anions as well as

neutral,

hydrophilic saccharide molecules appears to be related to

molecular

size, suggesting diffusion through aqueous membrane pores

[357].

While large hydrophilic molecules such as aminoglycoside

antibiotics

are poorly absorbed [357] , others such as phenol red [358]

and crom

olyn sodium [359] appear to be better absorbed when

compared to

oral absorption. However, this is primarily the result of a

saturable

carrier-type transport process in the pulmonary epithelium

[358,359]. For drugs used for local treatment of pulmonary
disorders, it is

desirable that the drug exert a local effect with minimal

systemic ab
sorption [360,361]. Successful use of inhaled
corticosteroids in the

treatment of asthma with minimal systemic side effects was

due to

metabolism of the drug prior to entry into the circulation

[362] . It

appears that presystemic metabolism of drugs delivered by

the intra

bronchial route may differ quantitatively from their

metabolism follow

ing systemic administration [363,364]. Besides metabolism,

the lung

can also bind and accumulate drugs, especially basic drugs

. This

binding is mostly reversible [365] and can prolong duration

of the

drug in the body. In summary, the efficiency of delivery

of drugs via the airways

is relatively poor in man. As much as 90% of the instilled

dose may

impact in the mouth and pharynx or be swallowed without

ever reach

ing the lung. Thus, success of pulmonary delivery will

depend on a

number of factors. First, drugs used in aerosols must be

quite po

ent but with negligible systemic side-effects. Second, the

drug must

be able to gain access to its target site. Third, drug must

bind to

tissue components thereby providing a high local

concentration for

prolonged periods. Finally, better aerosol delivery from

nebulizers
is needed to enhance the amount of drug reaching the lung.
Never

theless, controlled delivery of drugs to the respiratory

area is useful

mainly for localized treatment of inflammation or cancer.

It is unlikely

that this route will supplant the oral or intravenous

routes to achieve

systemic effects.

G. Vaginal

Intravaginal controlled release drug administration of

steroidal com

pounds or spermicidal agents is aimed at obtaining

contraception for

prolonged periods with minimal systemic side effects. In

general,

most steroids are readily absorbed so that their

bioavailability after

intravaginal administration is higher than from oral

administration be

cause of a reduced first-pass metabolism [366,367].

Recently, the

vaginal route has also been investigated for peptide and

protein drug

delivery [368,369]. The human vagina is a fibromuscular

tube 4 to 6 in. long, directed

upward and backward, extending from the vulva to the lower

part of

the uterine cervix. It is in the form of a collapsed tube

under nor

mal conditions. The vagina is drained by a rich plexus,

which em
pties into internal iliac veins [370]. Blood supply to the
vagina is

via uterine and pedendal arteries, which arise from the

iliac ar tery. The vagina consists of three principal
layers: an outer fibrous

layer, a middle muscular layer, and the epithelial layer.

The epitheli

al layer consists of lamina propria and a surface

epithelium [370] ,

which is composed of noncornified, stratifeid squamous

cells. The

vaginal epithelium is essentially devoid of glands, but its

surface is

kept moist by a cervical secretion, whose composition and

volume

varies with age, stage of menstrual cycle, and degree of

sexual ex

citement [371] . After puberty, the pH of vaginal fluid

varies between

4 and 5 depending on the stage of the cycle and location

[372] . Cells

of the superficial mucosal layer contain a high level of

glycogen,

which is metabolized to lactic acid (pK a = 3.79) in the

vaginal canal

to maintain the vaginal pH on the acidic side. The pH is

lowest

around the anterior fornix and highest around the cervix.

Higuchi et al. have developed an in situ method to study
vaginal

abosrption in the rabbit [373] and monkey [374]. The

absorption

rates of a series of unbranched aliphatic alcohols from

methanol to
octanol in the rabbit vagina were found to be first-order
and increased

with increasing chain length [375]. The barrier of

absorption appears

to consist of an aqueous diffusion layer in contact with

the membrane,

which in turn is composed of parallel lipoidal and aqueous

pore path

ways [376]. For drugs with high membrane permeability,

vaginal

absorption is determined by permeability of the aqueous

diffusion

layer; whereas for drugs with low membrane permeability,

such as

testosterone and hydrocortisone, vaginal absorption is

determined by

membrane permeability. Similar results were obtained with

alcohols

in the monkey [374] and 1-alkanoic acids in the rabbit

[376]. No

correlation between vaginal membrane permeability and

menstrual cycle

was found in the monkey [377]. However, at ovulation, the

monkey's

vaginal permeability is several-fold lower than that of the

noncyclic

rabbit [378]. Two major types of intravaginal controlled

release systems are

available: vaginal rings [379-386] and microcapsules

[387-390]. The

rationale for vaginal ring steroid-releasing systems is

based on the

observation that steroids readily penetrate the vaginal

mucosa [391]
and that the vagina can accomodate foreign bodies of
reasonable size

with minimal discofort for an extended period of time.

There are

two common types of vaginal rings: homogeneous [380] and

shell [385].

Burst effect of drug release on insertion and a declining

release rate

after extended wear are commonly observed with homogenous r

ings.

Shell rings apparently minimize the burst effect and are

able to main

tain a steady drug release rate . For most vaginal rings,

the rate of

vaginal drug absorption shortly after insertion is

controlled by either

an aqueous hydrodynamic diffusion layer or by the vaginal

wall. At

later times, the rate of vaginal absorption is determined

by the drug

release rate from the ring [392]. Reported problems

associated with the use of vaginal rings are:

erosion of the vaginal wall, ring expulsion, interference

with coitus,

unpleasant ring odor, and difficulty with storage and

sanitation [393],

These problems are usually the major causes for

discontinued use of

vaginal rings and, because of these problems, vaginal rings

have re

ceived only moderate acceptance. A potential intravaginal

contraceptive system free of most of the

aforementioned problems is the biodegradable microsphere.

The ratio

nale for its development is that inert particles have been

demonstrated

to be able to migrate from the vagina across the cervix

into the fallopi

an tube or the perimetrial lining of the uterus without

causing erosion

of the vaginal wall by virtue of its small size [294,295] .

Microspheres for intracervical administration have also
received

attention. Small doses of progesterone can be released

locally to alter

the structure of the cervical mucus so as to interfere with

sperm

migration [396] . In addition, a medicated intracervical

system has

been tested [397] . The rationale for its development is

that contrac

tility is less severe in the lower segment of the uterus,

especially the

cervix. This system still incurs the problems of expulsion

and pos

sibility of infection and does not offer enough advantages

over exist

ing intravaginal or intrauterinal systems to be worth

pursuing.

H. Intrauterine

The effectiveness of nonmedicated intrauterine devices

(IUDs) is pri

marily dependent on the relationship of the device

morphology (size,

shape, and area) to uterine geometry [398]. The human

uterus is a
pear-shaped, muscular s tructure, about 3 in. in length and
about 2

in. wide, consisting of a body, fundus, isthmus, and

cervix. Its

wall has three layers: an external peritoneal layer

(perimetrium) , a

middle muscular layer (myometrium), and an inner mucous

membrane

(endometrium). This organ undergoes dynamic changes in the

size

and shape of its various segments during different phases

of the

menstrual cycle [399]. Lack of structural adaptability and

unfavor

able geometry of the device may lead to clinical

complications such

52 / Li et ah

as expulsion, bleeding, infection, perforation, and pain.

It appears

that the mode of action of nonmedicated systems originates

promptly

in the uterus, disappears rapidly, is not affected by

menstruation

and does not interfere with the normal

estrogen-progesterone balance

[400], The objectives in the development of medicated IUDs

are to enhance

their contraceptive effectiveness with concomitant

reduction in pain

and bleeding. These objectives are achieved by using small

devices

and the incorporation of antifertility agents such as

steroids and/or
antifibrinolytic agents-proteinase inhibitors such as
aminocaproic acid,

tranexamic acid and aprotonin, and/or antiprostaglandins.

Since the contraceptive action of the medicated device lies
mainly

with the antifertility agent itself but not with the

structural features

of the device, the geometry and size should be designed for

minimal

clinical complications. The T or 7 configurations came

closest to the

ideals set forth above [ 401] . The major contraceptive

agents employed

in medicated IUD T s include copper, progresterone and

levonorgestrel.

The most extensively studied IIJD's have been Progestasert

R and

Cu-7^. The concept of continuous intrauterine

administration of proges

terone is based on these observations: (a) local effect of

progester

one on the uterus might reduce the incidence of expulsion

and bleed

ing provoked by the inert device, (b) the estrogenic

component of

oral contraceptives is not essential for contraception, and

(c) progestin

only mini-pills provide adequate contraception, possibly by

preventing

blastocyte implantation without inhibiting ovulation. The

ProgestasertR

system is a T-shaped progesterone-containing drug delivery

system

enclosed by a rate-limiting membrane. It releases 65 yg/day

for a

period of 1 year. Cu-7R is a polypropylene 7-shaped device

with 89 mg of copper

wire surrounding the vertical arm, giving a surface area of

200 mm^

of copper, which is released at 9.87 yg/day for up to 40

months.

The exact mechanism by which copper works as a

contraceptive agent

is unclear. Copper is known to be cytotoxic if present in

sufficiently

high concentrations [402]. It interferes with implantation

of the fetus

in rats [403], enhances the spermatocidal and

spermatodepressive

action of the IUD [404] , and inhibits the binding of

estrogen and

progesterone to their receptors [404] .

Levonorgestrel-releasing IUDs have also been studied
clinically.

Since levonorgestrel is effective at concentrations lower

than those

required with progesterone, the system can have a life time

of about

7 years . Furthermore, it is believed that levonorgestrel

offers a

balance of estrogenic and progestational activity, which

may lessen

intermenstrual bleeding [405]. Future research in

intrauterine controlled drug administration

will depend on increased understanding of reproductive

physiology

so that contraception can be achieved by interference with

pertinent
reproductive processes at the right time with minimal side
effects.

Future research will most likely focus on minimizing

intermenstrual

bleeding and pain, searching for longer duration systems as

well as

self-regulating drug delivery systems. An example of a self

regulating system may be one that utilizes human chorionic

antibodies

as a sensor, so that drug delivery will occur only when an

egg has

undergone fertilization, but not at other times [406].

I. Transdermal

The skin is one of the most extensive and readily

accessible organs

of the human body. It covers an area of about 2 m2 and at

any

point in time is in contact with about one-third of all

blood circulating

through the body [407]. Skin consists of three tissue

layers: epi

dermis, dermis, and hypodermis (subcutaneous t issue). The

rate

limiting step in percutaneous absorption of most drugs

appears to be

passage through the stratum corneum [408-414] . The pathway

of

drug movement through this layer is believed to be mainly

transcellu

lar, although the paracellular pathway may become important

for small

molecular weight compounds [408] . In addition to being a

diffusion

barrier , the stratum corneum also serves as a reservoir

for compounds

such as corticosteroids, griseofulvin and many other drugs.

While

drugs are carried away by the capillary network upon

reaching the

subcutaneous tissue, there is evidence that certain drugs

such as

thyroxin, 3-methoxypsoralen, estradiol and corticosteroids,

remain

in this layer for an extended period of time [415-417].

Such locali

zation of drugs may prove desirable for exerting local

effects in deep

er tissues of the skin or for prolonged release of drugs.

In the past, topically applied dermatological drugs were
used for

localized treatment of skin diseases only. Recently, due to

a better

understanding of the anatomy and physiology of the skin as

well as

a more thorough understanding of percutaneous absorption,

the limited

permeability of human skin has also been utilized for

systemic drug

administration. There are several advantages to the

transdermal route provided

the drug is absorbed in sufficient quantity to exert a

systemic effect.

Thus, it is possible to: 1. Avoid hepatic "first-pass"

metabolism and gastrointestinal incompatibility of drugs
2. Provide controlled administration for drugs with narrow
therapeutic indices, thereby reducing side effects or
inadequate dosing 3. Allow utilization of drugs with
short biological half-lives 4. Enhance therapeutic
efficacy 5. Reduce frequency of dosing 6. Improve patient
compliance 7. Permit relatively abrupt termination of drug
effect by removal of the patch from the skin surface
These advantages aside, systemic drug absorption from
ointments

or creams is commonly unpredictable, partly because of

variability in

skin permeation and partly because of the difficulty in

delivering a

dose reliably. The use of rate-controlled tranddermal drug

delivery

systems appears to minimize these two problems. However,

because

of the relatively low permeability of skin by most drugs,

these systems

are only applicable for highly potent drugs which permeate

the skin

rapidly, which cause no irritation to the skin, and which

are relative

ly stable to enzymes present in the epidermis. The

additional require

ment is that the drug delivery system rather than the skin
acts as

the rate-limiting step in the overall transport process

[418]. Drugs

such as scopolamine [419], nitroglycerin [420,421], and

clonidine [422]

have been administered in this fashion. The low skin

permeability of most drugs necessitates the use of

penetration enhancers such as dimethyl sulfoxide [423],

urea [424],

and, more recently, Azone R [425,526]. One of the major

difficulties

associated with penetration enhancers is lack of

specificity. This,

coupled with a lack of understanding of their mechanism of

action,

limits the rational design and use of penetration

enhancers. Occlusion has been shown to enhance drug
absorption across the

skin. It appears to do so partly by increasing hydration of

the

stratum corneum and partly by raising the temperature of

the skin

surface. However, the contribution of changes in blood flow

due to

this treatment is still unclear [412]. Ion-pair formation

between a carrier molecule and an anionic drug

has been proposed to enhance penetration [427] . This

approach takes

advantage of the pH gradient that exists across the stratum

corneum

and the hydrophilic nature of the viable epidermis. Another

approach

to improve penetration of poorly absorbed molecules is the

use of

prodrugs [428-430]. In this case, the metabolic activity of

the skin

is used to transform prodrugs to active drugs. With a

better under

standing of metabolizing enzymes in the skin, the use of

prodrugs

can be an attractive approach. Theoretical considerations

suggest

that this is a useful approach in enhancing drug permeation

[431,432]. One factor that has not been extensively
studied is the influence

of pathological states in skin permeability. Bronaugh and

Stewart

[316], Scott et al. [433], as well as Flynn et al. [434],

have con

ducted studies on drug absorption through abnormal and

damaged

skin. A better understanding of percutaneous absorption

through

diseased skin is needed for effective treatment of

cutaneous diseases.

J . Ocular

For treatment of many disease affecting the external eye

and anterior

segment of the eye, topical instillation is preferred over

systemic ad

ministration because a high drug concentration at the

absorbing mem

brane can be obtained, thereby maximizing drug delivery to

the af

fected tissues while minimizing systemic side effects.

However, topi

cal application of drugs to the eye is impeded

significantly by effici

ent ocular physiological protective mechanisms, such as

drainage, tear

turnover, limited permeability of corneal membranes to most

drugs,

and aqueous humor turnover. Typically, drug from an

instilled aque

ous solution is essentially eliminated from the precorneal

area within

1-2 min of application [435] , so that less than 3% of an

applied dose

penetrates into the aqueous humor following topical

instillation of an

aqueous solution [436]. The duration of drug action is ,

therefore,

brief, and frequent dosing is needed. The duration of drug

action in the eye can be extended by two

approaches: (a) reducing drainage through the use of

viscosity

enhancing agents, suspensions, emulsions, ointments,

erodible and

nonerodible matrices [437] and (b) improving corneal drug

penetration

through the use of ionophores [438], ion-pairs [439],

liposomes [440],

and prodrugs [441]. For low viscosity solutions, the

improvement

in ocular bioavailability is usually modest [442-444].

Suspensions

and emulsions suffer from the same problem as low viscosity

solutions

in that the contact time, though lengthened, is still

relatively brief.

Moreover, in the case of suspensions, the solid particles

must dissolve

slow enough to offer an advantage over a saturated solution

[455].

The release rate of drug is usually rapid from swollen

hydrophilic

matrices such as soft contact lenses. Release rate from

lipophilic

ointments can be slower, but these systems suffer from the

problem

of blurring vision thus reducing their use to night time

medication.
The use of ion-pair and ionophores is limited to a small
group of drugs

and their improvement is still considered moderate

[438,439]. Lipo

somes appear to be able to enhance the absorption of large,

hydro

philic molecules [446-450] and may prove to be useful in

delivering

macromolecules such as peptides and proteins. Their

usefulness in

delivering lipophilic molecules seems to depend on the way

the drugs

are incorporated into the liposomes [446,447,450] . The use

of lipo

somes in ocular drug delivery has been reviewed [440].

Prodrugs can be used to improve ocular bioavailability by
enhanc

ing corneal penetration, protecting the parent compound

from meta

bolism, or decreasing its elimination. Recently, the first

ophthalmic

prodrug, dipivalyl epinephrine, was marketed under the

trade name

Propine-^. With improved corneal penetration

characteristics, a much

lower dose of epinephrine is needed, thereby reducing

side-effects.

Via a different mechanism to affect ocular drug absorption,

systems

such as OcusertR [451] and erodible matrices [452], which

provide

controlled drug delivery to the conjunctival sac, are able

to reduce

fluctuations commonly observed with pulse-entry systems,

thereby

allowing the use of drugs with very short biological

half-lives. More

over, systems such as Ocusert R do optimize precorneal

delivery of

drug. Unfortunately, patient acceptance of these systems is

unsatis

factory partly because they are easily expelled during

sleep. In summary, the currently available ocular drug
delivery systems

are far from ideal. Future research should be directed

toward con

trolled delivery to the absorbing surface with minimization

of non

productive loss. Since eye-drops are the most acceptable

dosage form,

it appears that the ideal dosage form should be of low

viscosity but

reside near the absorbing surface for an extended period of

time and

release its drug in a controlled manner.

V I I I . DRUG TARGETING

The objective of drug targeting is to achieve a desired

pharmacological

response at a selected site without undesirable

interactions at other

sites. This is especially important in cancer chemotherapy

and en

zyme replacement treatment. At present, drug targeting is

achieved

by one of two approaches. The first approach involves

chemical modi

fication of the parent compound to a derivative which is

activated only

at the target site [453,454]. The second approach utilizes

carriers

such as liposomes [455,456], microspheres [457],

nanoparticles [458],

antibodies [459-461], cellular carriers (erythrocytes and

lymphocytes)

[462,463] , and macro molecules [464,465] to direct the

drug to its site

of action. There are a variety of strategies to modify the

chemical structure

of drug molecules, the most common being the prodrug

approach and

the most sophisticated being the chemical delivery system

approach

(Chapter 8). A prodrug is an inactive chemical derivative

of a par

ent compound that is activated predictably in vivo to the

active drug

species, but, with few exceptions [466], it cannot achieve

site-specific

delivery [467], In contrast, a chemical delivery system

involves

transformation of the active drug by synthetic means into

an inactive

derivative which, when placed in the body, will undergo

several pre

dictable enzymatic transformations principally at its site

of action.

This approach has proven to be successful in local delivery

of drugs

to the eye, brain and testes [454,468]. Because of

impermeability of the GI tract to most macromolecules
and instability of the drug-carrier complex in the hostile
environment

of the GI tract, administration of large drug-carrier

complexes is

restricted to intravenous or intraarterial injections or to

direct in

jection into the target tissue such as a tumor. At present,

the major

obstacle of drug targeting using macromolecular and

particulate car

riers is rapid sequestration of intravascularly

administered drug car

riers by mononuclear phagocytes of the reticuloendothelial

system

(RES) [469-470] . Because of rapid clearance, only a small

fraction of

the injected carrier untimately reaches the target, if at

all. The ap

proaches have been attempted to alleviate this problem. The

first

involves blocking the RES prior to administering the drug

carrier

[471,472]. However, paralysis of the RES is undesirable

especially

in cancer patients. Without the first-line defense

mechanism of the

RES against infectious agents, these cancer patients will

be at risk

to infections. A second approach is to impart specificity

to the drug carrier

by coupling specific ligands onto its external surface.

These include

desialylated fetulin [427], erthyrocyte membrane

glycoproteins [473,
474], heat aggregated immunoglobulins [475], monoclonal
antibodies

[460], and native immunoglobulins [476]. So far, none of

these

strategies has proven to be successful due to difficulties

in preserv

ing the recognition ability in vivo and avoiding triggering

any im

munological response. Another obstacle in targeting

particulate drug carriers is the

vascular system itself. This subject has been carefully

reviewed by

Poste [477] as well as by Poznansky and Juliano [478]. In

order

for a drug carrier to be able to recognize the target , it

must first

extravasate. The vascular endothelium of most tissues and

organs,

being continuous with an effective pore diameter of 2 nm,

is essenti

ally impermeable to molecular assemblages such as liposomes

(0.025

5.0 pm) and nanoparticles (<1 urn). Significant

extravasation of the

structures in this size range is only possible at those

sites with a

discontinuous endothelium, notably in the sinusoids of the

liver and

spleen, where the effective pore diameter is approximately

100 nm,

Thus, most particulate matter is confined to the general

circulation. On the positive side, impermeability of the
capillary endothelial
lining may be a useful property under certain conditions:
(a) confine

ment of drug within a physiological compartment, (b) use of

particles

whose direction or release characteristics are under

external control,

and (c) drug delivery to the lung, liver and spleen. Two
forms of external control have been explored. Liposomes

can be made from lipids with release characteristics which

are a func

tion of a temperature gradient [479] due to either local

inflammation

or localized heating via collimated radiation. Drug is

released from

circulating liposomes as they pass through the target

region [480].

Another approach involves the use of microspheres of

denatured al

bumin [457] and, more recently, Sephadex R [481]

containing ferro

magnetic particles. The microspheres are restricted at the

micro

vascular level under the influence of a directed external

field. En

hanced drug delivery to the target, in theory, can be

achieved by

this approach. PASSIVE T A R G E T I N G -PMS uptake 8

lysosomotropism H tsieve plate passage

OOI A C T I V E T A R G E T I N G I—antibody-antigen
events H h-extracorporeal guidance H I lymphotropism 1 |
capillary blockage normal capillary diameter 4 7 10
100 01 I 4 MICROSPHERE DIAMETERS (MICRONS)

Fig. 5 Strategies in achieving drug ta rget ing . (From

Ref. 483.) Microspheres have also been used for passive
targeting to organs
such as the liver, spleen, lung and kidney (Fig. 5)
[482,483]. In

travenous injection of particles between 7 and 12 ym leads

to mechan

ical filtration by the lungs, whereas particles between 2

and 12 ym

leads to their blockage in the first capillary bed

encountered. Such

blockage can lead to first-order targeting of, for example,

the liver

and kidney, and second-order targeting to tumor-bearing

organs [484] MICROSPHERE TARGET

Fig. 6 Method of chemoembolism to achieve drug targeting.

This latter effect is probably due to a qualitative and

quantitative

difference in the capillary networks of the tumor compared

to those

of the host organ [485], Recently, intraarterial injection

of biodegradable microspheres

was used to produce a tumor chemoembolism in cancer

chemotherapy

[486-488]. Figure 6 gives the rationale behind this use. A

mixture

of drug and starch microspheres (about 40 ym) were injected

together.

The large size of microspheres caused temporary blockage of

the tumor

bearing organ's arteriole, thereby increasing absorption

time of the

drug by the tumor organ. However, obstruction of the feeder

vessels

of a tumor using microsphres by themselves could also bring

about
tumor regression [489] . In addition to the difficulties
encountered by carriers to extrav

asate, drug targeting by carriers also suffers from such

problems as

stability of the carrier on storage and in vivo, drug

loading, immuno

genicity, and degradability. Consequently, except for

passive target

ing to the reticuloendothelial system of the liver and

spleen, the con

cept of systemic drug targeting via carriers and biological

recogniza

tion has met with little success. It is clear that, for

successful tar

geting, a better understanding of diseases and the biology

of the

body at a cellular and molecular level is needed.

IX. CONCLUSIONS

In the past decade, the number of new drug entities

appearing on the

market yearly has declined and pharmaceutical manufacturers

for a

variety of reasons have a renewed interest in improving

existing

dosage forms and developing more sophisticated drug

delivery systems,

including those employing the principles of

sustained/controlled drug

release. The need for a sustained/controlled release

preparation often

arises: (a) as a result of undesirable drug properties,

such as short
biological half-life, local irritation, extensive
metabolism, and narrow

therapeutic index, (b) perhaps through the nature of the

disease

state, or (c) for patient compliance reasons. Most

important of all

is the need to improve the efficacy and safety of drug

through proper

temporal and/or spatial control of drug release. In

considering a drug for this mode of drug delivery, certain

criteria have to be examined and evaluated. These are the

physico

chemical, pharmacokinetic and pharmacodynamic

characteristics of the

drug. With each drug property there is a range of values

that lends

itself to the design of sustained/controlled release

products, and

outside this range the design becomes more difficult or, in

the extreme,

prohibitive. Extremes of aqueous solubility, oil /water

partition coef

ficients, binding, extensive metabolism/degradation of the

drug dur

ing transit from the point of drug delivery to the target

area, and

narrow therapeutic index are some of the limiting factors

in formulating

an effective sustained release product. Paradoxically, all

these limi

tations are precisely the reasons why controlled release

drug delivery

is desirable. Furthermore, advances in biotechnology have

brought
about peptides and proteins which, by virture of their
chemical and

biological properties, demand special systems for their

delivery.

Theoretically, each of these limitations can be overcome

and success

ful controlled drug delivery can be accomplished by using

physical,

chemical, biological, and biomedical engineering

approaches, alone or

in combination, as described in subsequent chapters.

Throughout this chapter, an attempt has been made to
delineate

the influence of drug properties on the design of

sustained/controlled

release drug delivery system. Information on the

physicochemical

properties of a new or existing drug is usually relatively

abundant.

In addition, with the increase in application of

pharmacokinetic analy

sis, there is a steady growth in the volume of information

on the

biological parameters of drug action, such as absorption

rate constant,

biological half-life and volume of distribution, which may

also be avail

able to the formulator. When examining animal and clinical

data in the

literature, th formulator must take into consideration

conflicting in

formation which is not uncommon due to differences in

experimental
design and compartmental analysis of the data. Obviously,
many of

these uncertainties have to be resolved in the course of

evaluating a

drug for sustained/controlled drug delivery. Moreover, for

some

drugs, the various biological parameters behave differently

in a single

dose vs. a multiple dose situation or in a single dose vs .

a continuous

infusion situation [490] . Consequently, multiple dose and

perhaps

continuous infusion studies are a necessary prerequisite in

terms of

evaluation. Thus, each drug must be evaluated for its

potential as

a sustained/controlled release product by examining the

complete pro

file for that drug, being cognizant of the limiting and

restraining

aspects of drug properties. In this chapter, we have also

tried to emphasize the importance

of routes other than oral for systemic drug administration.

Although

the oral route is preferred for the majority of drugs, it

is beset with

numerous potential problems such as possible degradation,

first-pass

metabolism, and variable and limited residence time. The

transdermal

route has proved to be effective for controlled delivery of

certain

drugs. The nasal route is potentially useful to deliver

drugs include
peptides and proteins which undergo extensive first-pass
metabolism.

The rectal route offers a longer residence time than the

nasal and

buccal routes and may allow controlled release of drugs for

a day or

two. Replacement of the defecated unit with a new unit may

permit

controlled release for extended periods of time. The

parenteral route

is currently the preferred route to achieve drug targeting

since other

routes are commonly impermeable to drug carrier complexes.

Even

this route is beset with the problem of inability of the

drug-carrier

complex to traverse the capillary endothelium before

reaching its tar

get in extravascular t issues. Thus, drug targeting has met

with

little success except in the case of direct injection into

the target

tissues. As a result, placement of the controlled release

system in

the vicinity of the target tissue becomes the alternative.

This modal

ity does improve therapeutic drug efficacy allowing the use

of a lower

initial dose and less frequent dosing. Ideally, in order to

avoid un

desirable side effects, drug candidates for local treatment

should

possess limited permeability or are prone to immediate

inactivation

after exerting their local actions. In the final analysis,

a complete knowledge and understanding

of the behavior of a drug and the limitation of a

particular route of

administration, as well as judicious selection of the

approach, is in

dispensable to the process of designing a useful controlled

release

product. It is the usual case that the desired temporal

pattern of

release, i . e . , a constant tissue drug level, is not

achieved. In ad

dition, it has to be realized that , without exception,

sustained and/

or controlled drug release products on the market today do

not maxi

mize drug utilization. These products commonly do not take

into ac

count changes in drug need during the course of treatment

due to

circadian rhythm, changes in the pathological state,

patient variation,

etc. Thus, the term, controlled drug delivery, is used in a

rather

loose sense. Nevertheless, these types of products are a

significant

improvement over their nonsustained counterparts in terms

of temporal

drug level control and patient compliance. The challenge of

drug

delivery is the recognition of how far away we usually are

from maxi
mization of drug therapy and the substantial changes that
are yet to

be made in the area of controlled drug delivery.

1. V. F. Smolen and L. A. Ball (eds . ) , Controlled Drug

Bioavailability, Vols. 1 and 2, John Wiley, New York, 1984.

2. R. I. Langer and D. L. Wise (eds . ) , Medical

Applications of Controlled Release, Vols. 1 and 2, CRC
Press, Florida, 1984.

3. S. D. Bruck (ed . ) , Controlled Drug Delivery, Vols. 1

and 2, CRC Press, Florida, 1984.

4. R. L. Juliano, (ed . ) , Drug Delivery Systems, Oxford,

New York, 1980.

5. J . M. Anderson and S. W. Kim (ed . ) , Recent Advances

in Drug Delivery Systems, Plenum, New York, 1984.

6. Y. W. Chien, Novel Drug Delivery Systems: Fundamentals,

Developmental Concepts and Biomedical Assessments, Marcel
Dekker, New York, 1982.

7. T . J . Roseman and S. Z. Mansdorf ( e d . ) ,

Controlled Release Delivery Systems, Marcel D e k k e r ,
New York, 1983.

8. A. F . Kydonienus ( e d . ) , Controlled Release

Technologies: Methods, Theory and Applications, Vols. 1
and 2, CRC P r e s s , Florida, 1980.

9. P . Goldman, Rate-control led d r u g de l ivery , N.

Engl. J. Med. 307, 286 (1982).

10. W. A. Check , New d r u g s and d rug -de l ive ry sys

tems in t he yea r 2000, Am J. Hosp. Pharm. 41, 1536
(1984).

11 . N. L. Henderson , Recent advances in d r u g del ivery

system technology, I n , Annual Reports in Medicinal
Chemistry, Vol. 18 (H. J . Hess , e d . ) , Academic P r e
s s , New York, 1983.

12. A. Zaffaroni, Systems for controlled d r u g de l ivery

, Med. Res. Rev. 1, 373 (1981).

13. H. A. S t r u y k e r Boudier , Rate-control led d r u

g del ivery: Pharmacological, the rapeu t i c and indus t r
ia l pe r spec t ive s , Trends Pharmacol. Sci. 3, 162
(1982).

14. S. K. C h a n d r a s e k a r a n , F . Theeuwes, and S

. I. Yum, The design of controlled d r u g del ivery sys
tems . In , Drug Design (E. J . Ar iens , e d . ) , Vol.
8, Academic P r e s s , New York, 1979, p p . 133-167.

15. O. Vaizoglu and P . Speiser , Intelligent d r u g del

ivery sys t ems , Trends Pharmacol. Sci. 3, 28 (1982).

16. J . U r q u h a r t , Rate-control led d r u g dosage ,

Drugs 23, 207 (1982).

17. L. R. Beck and V. Z. Pope, Control led-re lease del

ivery systems for hormones: a review of the i r p rope r t
i e s and c u r r e n t t h e r a peut ic u s e , Drugs 27,
528 (1984).

18. R. A. Siegel and R. Langer , Controlled release of

polypept ides and o ther macromolecules, Pharm. Res. 1, 2
(1984).

19. Y. W. Chien and J . R. Robinson, "Smart" d rug-de l ive

ry sys tems , J. Parenter. Sci. Technol. 36, 231 (1982).

20. E. P . Goldberg ( e d . ) , Targeted Drugs, Wiley, New

York , 1983.

21 . K. Heilman, Therapeutic Systems, 2nd e d . , George

Thieme Verl ag , S t u t t g u r s t , 1984.

22. G. S . B a n k e r , Pharmaceutical applications of

controlled re lease : on overview of the p a s t , p r e s
e n t , and f u t u r e . In , Medical Applications of
Controlled Release (R. S. Langer and D . L. Wise, e d . )
, CRC P r e s s , Florida, 1984, p p . 1-34.

23. M. V. Sefton, D . G. Allen, V. Horva th , and W. Zingg,

Insulin delivery at var iable r a t e s . In , Recent
Advances in Drug Delivery ( J . M. Anderson and S. W. Kim,
e d s . ) , Plenum P r e s s , New York, 1984, p p .
349-365.

24. T . A. Horbet t , B . D. Ra tne r , J . Kost , and M. S

ingh , A biorespons ive membrane for insulin de l ivery .
In , Recent Advances in Drug Delivery ( J . M. Anderson
and S . W. Kim, e d s . ) , Plenum P r e s s , New York,
1984, p p . 209-220.
25. F . Theeuwes and W. Bayne , Dosage form index an
objective cr i ter ion for evaluation of control led-re
lease d r u g del ivery s y s tems, J. Pharm. Sci. 66, 1388
(1977).

26. J . Koch-Weser, Serum d r u g concentra t ions as the

rapeu t i c gu ides , N. Engl. J. Med. 287, 227 (1972).

27. L . A. Pagliaro and L. Z. Bene t , Critical compilation

of terminal hal f l ives , pe rcen t exc re ted unchanged
, and changes of half-life in renal and hepat ic dysfunct
ions for s tudies in humans with r e f e r ences , J.
Pharmacokin. Biopharm. 3, 333 (1975).

28. M. Gibaldi and P . J . McNamara, S t eady s t a t e

concent ra t ions of d r u g s with shor t halfl ives when
adminis tered in oral sus ta ined release formulations,
Int. J. Pharm. 2, 167 (1979).

29. J . Fara and J . U r q u h a r t , The value of

infusion and injection regimens in assess ing efficacy and
toxicity of d r u g s , Trends Pharmacol. Sci., 5, 21
(1984).

30. P . L . Car l , P . K. C h a k r a v a r t y , J . A.
Katzenel lenbogen, and M. J . Weber, Pro tease-ac t iva
ted "p rodu rg" for cancer chemot h e r a p y , Proc. Natl,
Acad. Sci. USA 77, 2224 (1980).

31. P . K. C h a k r a v a r t y , P . L . Car l , M. J .
Weber, and J . A. Katzenel lenbogen, Plasmin-act ivated p r
o d r u g s for cancer chemot h e r a p y . 1. Synthes i s
and biological act ivi ty of peptidylacivicin and pept
idylphenylenediamine m u s t a r d , J. Med. Chem. 26, 633
(1983).

32. P . K. C h a k r a v a r t y , P . L. Ca r l , M. J .
Weber, and J . A. Katzenellenbogen, Plasmin-act ivated p r
o d r u g s for cancer chemot h e r a p y . 2. Synthes i s
and biological activity of pept idyl der iva t ives of
doxorubicin, J. Med. Chem., 26, 638 (1983).

33. M. E. Morrison, M . J . Yagi , and G. Cohen, In v i t

ro s tud ies of 2 ,4 -d ihydroxyphenyla lan ine , a p r o
d r u g t a rge t ed against maligant melanoma cells ,
Proc. Natl. Acad. Sci. USA 82, 6020 (1985).

34. S . S. Davis , J . G. Hardy , M. J . Taylor , D . R.

Whaley, and C . J . Wilson, The effect of food on the gas
t ro in tes t ina l t r ans i t of pel lets and osmotic
device (Osmet) , Int. J. Pharm. 21, 331 (1984).

35. W. H. B a r r , J . Adir , and L. Gar re t t son ,

Decrease of te t racycl ine absorpt ion in man by sodium b
ica rbona te , Clin. Pharmacol. Ther. 12, 799 (1971).

36. V. Manninen, K. Ojala, and P . Reisell, New formulation

of digoxin, Lancet 2, 922 (1972).

37. J . G. Wagner, P . G. Welling, K. O. Lee, and J . E.

Walker, In vivo and in v i t ro availability of commercial
warfarin t a b l e t s , J. Pharm. Sci. 60, 666 (1971).

38. B . Katchen and S . Symchowicz, Correlat ion of

dissolution ra te and griseofulvin absorption in man, J.
Pharm. Sci. 56, 1108 (1967).

39. T . R. B a t e s , D. A. Lambert , and W. H. J o n e s

, Correlation between t h e r a t e of dissolution and
absorpt ion of salicylamide from tablet and suspension
dosage forms, J. Pharm. Sci. 58, 1468 (1969).

40. C. Hansen and W. J . Dunn , I I , Linear re la t

ionships between lipophilic cha rac te r and biological
activity of d r u g s , J. Pharm. Sci. 61, 1 (1972).

41. T . Fuji ta , J . Iwasa, and A. Hansch, A subs t i tuen

t cons t an t , IT, der ived from par t i t ion
coefficients, J. Am Chem. Soc. 86, 5175 (1964).

42. B . Keerman, K. Hellstrom, and A. Rosen, Metabolism of

p r o panthel ine in man, Clin. Pharm. Ther. 13, 212
(1972).

43. W. H. Bach rach , Anticholinergic d r u g s , Am. J.

Digest. Dis. 3, 743 (1958).

44. B . K. Martin, Potential effects of the plasma pro te

ins on d r u g d i s t r ibu t ion , Nature 207, 274
(1965).

45. J P . Tillement, G. Houin, R. Zini, S. Urien, B . A

lbengres , The b ind ing of d r u g s to blood plasma
macromolecules, Recent Adv. Drug Res. 13, 59 (1984).

46. L. D. De Leve and K. M. P iasky , Clinical significance

of plasma b inding of basic d r u g s , Trends Pharmacol
Sci. 3, 283 (1981).

47. M. Rowland, Protein b inding and d r u g c learance ,

Clin. Pharmacokin. 9, (Suppl . 1 ) , 10 (1984).

48. J . J . Mackichan, Pharmacokinetic consequences of d r

u g displacement from blood and t i s sue p ro t e in s ,
Clin. Pharmacokin. 9, ( S l i p p l . ) , 32 (1984).

49. B . K. Martin, Kinetics of elimination of d r u g s

possess ing high affinity for t he plasma p r o t e i n s
, Nature 207, 959 (1965).

50. R. R. Levine, The influence of the intraluminal intest

inal milieu on absorpt ion of an organic cationic and
anionic agen t , J. Pharmacol. Exp. Ther. 131, 328 (1961).

51. K. P a r k , S. L. Cooper, and J . R. Robinson,

Bioadhesive hyd roge l s . In , Hydrogels in Medicine and
Pharmacy (N. Peppas , e d . ) , Vol. 2, CRC P r e s s ,
Boca Raton (in p r e s s ) .

52. S. S. Chra i , T* F . Pa t ton , A. Mehta, and J . R.

Robinson, Lacrimal and insti l led fluid dynamics in rabbi
t eyes , J. Pharm. Sci., 62, 1112 (1973).

53. V. H. L. Lee and J . R. Robinson, Mechanistic and quant

i ta t ive evaluation of precorneal pilocarpine
disposition in albino r a b b i t s , J. Pharm. Sci. 68,
673 (1979).

54. H. A, Quigley, I . P . Pollack, and T . S . Harbin, J r

. , Pilocarpine O c u s e r t s : long-term clinical t r ia
ls and selected pharmacodynamics, Arch. Ophthalmol. 93, 771
(1975).

55. E. R. Ga r r e t t , D r u g systems affecting

availability and reliability of r e s p o n s e , J. Am.
Pharm. Assoc. NS9, 110 (1969).

56. R. R. Sheline, Metabolism of foreign compounds by gas t

ro in tes tinal microorganisms, Pharmacol. Rev. 25, 451
(1973).

57. W. H. B a r r and S . Riegelman, Intest inal d r u g

absorpt ion and metabolism. I . Comparison of methods and
models to s tudy physiological factors of in v i t ro and
in vivo intes t inal absorp t ion , J. Pharm. Sci. 59, 154
(1970).

58. C. C. Booth , Sites of absorpt ion in the small in tes

t ine . Fed. Proc, 26, 1583 (1967).
59. M. Weiner, S . Shapiro , J . Axelrod, J . Cooper, and B
. Brodie , The physiological disposition of dicumarol in
man, J. Pharmacol. Exp. Ther. 99, 409 (1950).

60. R. M. Levine , M. R. Blair , and B . B . Clark ,

Factors inf luencing the in tes t ina l absorpt ion of cer
ta in mono-quar te rna ry antichol inergic compounds with
special reference to benzomethamine, J. Pharmacol. Exp.
Ther. 114, 78 (1955).

61. L. Weinstein, Ant ibiot ics . IV. Miscellaneous

antimicrobial , ant i fungal , and ant iviral a g e n t s .
In , The Pharmacological Basis of Therapeutics (L. S.
Goodman and A. Gilman, e d s . ) , 4th E d . , Macmilan,
New York, 1970, p . 1269.

62. G. Levy and W. J . J u s k o , Factors affecting the

absorpt ion of riboflavin in man, J. Pharm. Sci. 55, 285
(1966).

63. A. B . Morrison, C. B . P e r u s s e , and J . A.

Campbell, Physiologic availability and in v i t ro release
of riboflavin in sus ta inedrelease vitamin p r epa ra t i
ons , N. Engl. J. Med. 263, 115 (1960).

64. E. B . Brown, J r . and B . W. J u s t u s , In v i t

ro absorpt ion of radioiron by eve r t ed pouches of ra t
in t e s t ine , Am. J. Physiol. 194, 319 (1958).

65. R. E. Reed, I ron deficiency anemia " re f rac tory" to

oral i ron , Missouri Med. 66, 120 (1969).

66. C. E. Blezek, J . L . Lach, and J . K. Guillory, Some

dissolution aspects of fer rous sulfate t ab l e t s , Am.
J. Hosp. Pharm. 27, 533 (1970).

67. E. J . Middleton, E. Nagy , and A. B . Morrison,

Studies on the absorpt ion of orally adminis tered iron
from sus ta inedre lease p r e p a r a t i o n s , N.
Engl. J. Med. 274, 136 (1966).

68. P . Cros land-Taylor , D . H. Keeling, and B . W.

Cromie, Trial of s low-release tab le ts of fe r rous
sulfate , Curr. Ther. Res. 7, 244 (1965).

69. T . H. Bothwell, G. Pirzio-Biroli , and C . A. F inch ,

Iron a b s o r p t ion. I . Factors inf luencing absorp t
ion , J. Lab. Clin. Med. 51, 24 (1958).

70. I . M. Ba i rd , R. L . Walters , and D. R. Su t ton ,

Absorpt ion of slow-release iron and effects of ascorbic
acid in normal subjects and after par t ia l gas t rec
tomy, Br. Med. J. 4, 505 (1974).

71. J . J . Webster, Treatment of iron deficiency anemia in

pa t ien t s with i ron in to lerance: clinical evaluation
of control led-re lease form of fer rous sul fa te , Curr.
Ther. Res. 4, 130 (1962).

72. S . T . Cal lender , Quick and slow-release i r o n : a

double-bl ind tr ial with a single daily dose regimen, Br.
Med. J. 4, 531 (1969).

73. D. P . Bentley and A. J acobs , Accumulation of s to

rage iron in pa t ien ts t r e a t e d for i
ron-deficiency anemia, Br. Med. J. 2, 64 (1975).

74. G. J . Mouratoff and R. C . Bat te rman, Serum i ron

absorpt ion t e s t s of sus ta inedre lease form of oral
i ron , J. New Drugs 1, 157 (1961).

75. T. P . S tevenson , Therapeut ic assay of sus ta inedre

lease form of oral i ron , Curr. Ther. Res. 4, 107 (1962).

76. L. B . Posner and F . Wilson, Evaluation of sus ta

inedre lease molyb denized ferrous sulfate in i
ron-deficiency anemia of p r e g nancy , J. New Drugs 3,
155 (1963).

77. E. Kruger -Th iemer , W. Diller, L. Dettl i , P . B u n

g e r , and J . Seydel , Demonstrat ion des Einflusses der
Eiweissbindung u n d der Ionisation duf die Pharm
ackokinetick am kombinierten gask i net i schen Modell nach
van ' t Hoff and Langmuir , Antibiot. Chemother. 12, 111
(1964).

78. E. Kruger -Thiemer and P . B u n g e r , The role of

therapeut ic regimen in dosage des ign . Par t I ,
Chemotherapia 10, 61 (19651966).

79. E. Kruger -Thiemer and P . B u n g e r , The role of

the rapeu t i c r eg i men in dosage de s ign . Par t I I ,
Chemotherapia 10, 129 (19651966).

80. E. Kruger -Th iemer , P . B u n g e r , L. Kett l i , P

. S p r i n g , and E. Wempe, Dosage regimen calculation
of chemotherapeut ic a g e n t s . Par t I I I .
Sulfasymazine, Chemotherapia 10, 325 (1965-1966) .

81. E. Kruge r -Th iemer , W. Diller, and P . B u n g e r ,

Pharmacokinetic models r e g a r d i n g pro te in b
inding of d r u g s . In , Antimicrobial Agents and
Chemotherapy—1965 (G. L. Hobby, e d . ) , American Society
of Microbiology, Ann Arbo r , Mi., 1966, p p . 183-191 .

82. S . Riegelman, J . C. K. Loo, and M. Rowland,

Shortcomings in pharmacokinetic analysis by conceiving the
body to exhibit p r o p er t ies of a single compartment ,
J. Pharm. Sci. 57, 117 (1968).

83. M. Gibaldi, R. Nagashima and G. Levy, Relationship

between d r u g concentrat ion in plasma or serum and
amount of d r u g in the body , J. Pharm. Sci. 58, 193
(1969).

84. A. R. DiSanto and J . G. Wagner, Potential e r roneous

assignment of nonlinear data to t he classical l inear
two-compartment open model, J. Pharm. Sci. 61, 552 (1972).

85. T . Taylor , L . F . Chasseaud , R. Major, E. Doyle,

and A. Dar r a g h , Isosorbide 5-mononitrate pharmacokinet
ics in humans , Biopharm. Drug Disp. 2, 2 5 5 ( 1 9 8 1 )
.

86. M. M. Re idenberg , D. D r a y e r , A. L. DeMarco, and

C . T . Bello, Hydralazine elimination in man, Clin.
Pharmacol, Ther. 14, 970 (1973).

87. H. F . Sch ran , F . L. S. Tse and S . I . Bhu ta ,

Pharmacokinetics and pharmacodynamics of bromocript ine in
the r a t , Biopharm. Drug Disp. 6, 301 (1985).

88. C. B . Coutinho, H. E. Spiegel , S . A. Kaplan, M. Yu,

R. P . Chrois t ian , J . J . Carbone , J . Symington, J .
A. Cher ipko , M. Lewis, A. Tonchen, and T . Crews ,
Kinetics of absorpt ion and excret ion of levodopa in dogs
, J. Pharm. Sci. 60, 1014 (1971).

89. W. B . Abrams, C. B . Coutinho, A. S. Leon, and H. E.

Spiegel , Absorpt ion and metabolism of levodopa, JAMA
218, 1912 (1971).

90. M. Sandler , F . Karoum, and C. R. J . Ru thven ,

M-hydroxyphenylacet ic acid formation from L-dopa in man:
Suppress ion by neomycin, Science 166, 1417 (1969).

91. M. Sandler , C . R. J . R u t h v e n , B . L. Goodwin,

K. R. Hun te r , and G. M. S t e rn , Variation of
levodopa metabolism with gas t ro intes t inal absorpt ion
s i t e , Lancet 1, 238 (1974).
92. A. C . Woods, G. A. Glaubiger , and T. N. Chase , Susta
inedrelease levodopa, Lancet 1, 1391 (1973).

93. G. Curzon , J . Fr iede l , L. Gr ier , C D . Marsden,

J . D . P a r k e s , M. Shipley, and K. J . Zilkha, Sus
ta inedre lease levodopa, Lancet 1, 781 (1973).

94. D . Pe r r i e r and M. Gibaldi, Influence of f i r s t

p a s s effect on the systemic availability of p
ropoxyphene , J. Clin. Pharmacol. 12, 449 (1972).

95. W. H. B a r r and S. Riegelman, Intest inal d r u g

absorpt ion and metabolism. I I . Kinetic aspec t s of
intest inal glucuronide conjugat ion, J. Pharm. Sci. 59,
164 (1970).

96. G. Levy and J . J . Matsuzawa, Pharmacokinetics of

salicylamide in man, J. Pharmacol. Exp. Ther. 156, 285
(1967).

97. R. Johansson , C . G. Rega rdh , and J . Sjogren,

Absorpt ion of alprenolol in man from tab le t s with
different r a t e s of re lease , Acta. Pharm. Suec. 8, 59
(1971).

98. J . G. Wagner, E. J . Anta l , A. T . Elvin, W. R.

Gillespie, E. A. P r a t t , and K. S. Alber t ,
Theoretical decrease in s y s temic availability with
decrease in inpu t ra te at s t e ady s t a t e for f i r
s t -pa s s d r u g s , Biopharm. Drug Disp. 6, 341 (1985).

99. E. M. Johnson , J r . , A. B . Hrkey , D. J . Blehm,

and P . Needleman, Clearance and metabolism of organic n i
t r a t e s , J. Pharmacol. Exp. Ther. 182, 56 (1972).

100. P . Needleman, S . Lang , and E. M. Johnson , J r . ,

Organic n i t r a t e s : Relationship between
biotransformation and rat ional angina pector is t h e r a
p y , J. Pharmacol. Exp. Ther. 181, 489 (1972).

101. D . G. F r i end , J . P . O'Hare, and H. D . Levine,

Action of t r i ethanolamine t r in i t r a t e in angina
pec to r i s , Am. Heart J. 48, 775 (1954).

102. M. G. Bogaer t , M. T . Rosseel , and A. F . deSchaepd

ryve r , The metabolic fate of n i t roglycer in (Tr in i
t r in ) in relation to i t s vascular effects , Eur. J.
Pharmacol. 12, 224 (1970).
103. R. A. T u r n e r , Absorpt ion of n i t roglycer in
from the alimentary t r ac t of the r abb i t , J. Pharm.
Sci. 54, 464 (1965).

104. I . R. E. Pilkington and J . J . P u r v e s , Long

act ing glyceryl t r i n i t r a t e in angina pector is
of o u t p a t i e n t s , Br. Med. J. 1 , 38 (1960).

105. T . Winsor, H. Kaye, and B . Mills, Hemodynamic r e

sponse of oral long-act ing n i t r a t e s : evidence of
gas t rointes t inal abso rp t ion , Chest 62, 407 (1972).

106. I . Hirshleifer , Per ipheral hemodynamic effects of

oral control ledrelease n i t roglycer in (Nitrong) in man,
Curr. Ther. Res. 15, 158 (1973).

107. H. I . Russek , B . L. Zohman, A. E. Drumm, W.

Weingarten, and V. J . Dorse t , Long ac t ing coronary
vasodilator d r u g s : Metamine, Paver i l , Ni t roglyn,
and Pe r i t r a t e , Circulation 12, 169 (1955).

108. W. Modell, Clinical pharmacology of antianginal d r u

g s , Clin. Pharmacol. Ther. 3, 97 (1962).

109. S. H. C u r r y and S . M. Aburawi , Analysis ,

disposition and pharmacokinet ics of n i t rog lycer in ,
Biopharm. Drug Disp. 6, 235 (1985).

110. M. H. Wendkos and N. Meshulam, Comparative effects of

placebo and sus ta inedre lease n i t roglycer in in angina
sub jec t s , J. Clin. Pharmacol. 13, 160 (1973).

111. M. P re t i , G. Abbondat i , and C. Carp i , Protect

ive action of a sus ta ined release form of n i t roglycer
in in an infarct exper imentally induced by isoproterenol
in the r a t , Boll. Chim. Farm. 108, 576 (1969).

112. L. W. D i t t e r t , Pharmacokinetic considerat ions

in clinical d r u g t r i a l s , Drug IntelL Clin. Pharm.
8, 222 (1974).

113. P . J . Nieber tgal l , E. T . Sugi ta , and R. L.

Schnaa re , Potential d a n g e r s of common d r u g
dosing regimen, Am. J. Hosp. Pharm. 31, 53 (1974).

114. K. R. Heimlich, D . R. MacDonnell, T . L. F lanagan, P

. D . O'Brien, Evaluation of a sus ta inedre lease form of
pheny lp ro panolamine hydrochlor ide by u r ina ry excret
ion s tud ie s , J. Pharm. Sci. 50, 232 (1961).
115. F . O'Grady, W. R. L. Brown, H. Gaya, and I . P .
MacKintosh, Antibiotic levels on cont inuous in t r
avenous infusion, Lancet 2, 209 (1971).

116. H. S. Brown, S . M. Caiola, F . M. Eckel, D. C.

McCleod, C. C. Pulliam, and H. B . Woodhall, Cephalexin,
Drug I nt ell. Clin. Pharm. 5, 134 (1971).

117. R. E. Cu t le r , Pharmacokinetics of furosemide in

normal s u b jects and functionally anephr ic pa t i en t s
, Clin. Pharmacol. Ther. 16, 588 (1974).

118. J . Kampmann, J . M. Hansen, K. Siersbaek-Nielsen, and

H. Laur sen , Effects of some d r u g s on penicillin
half-life in blood, Clin. Pharmacol. Ther. 13, 516 (1972).

119. D. S c h u p p a n y , S . Riegelman, B . von Lehmann,

A. P i lb rand t , and C . Becker , Preliminary
pharmacokinet ics s tud ies of p ropy l thiouracil in
humans , J. Pharmacokinet. Biopharm. 1, 307 (1973).

120. D . G. Shand and R. E . Rangno, The disposition of

propranolo l . I . Elimination du r ing oral absorpt ion
in man, Pharmacology 7, 159 (1972).

121. G. H. E v a n s , A. S. Nies, and D . G. Shand , The

disposition of propranolol . I I I . Decreased half-life
and volume of d i s t r i but ion as a resu l t of plasma b
inding in man, monkey, dog and r a t , J. Pharmacol. Exp.
Ther. 186, 114 (1973).

122. K. Verebely and C. E. I n t u r r i s i , Disposition

of p ropoxyphene in man after a single oral dose , Clin.
Pharmacol. Ther. 15, 302 (1974).

123. L. Graffner , G. Johansson , and J . S jogren,

Pharmacokinetics of procainamide in t ravenous ly and
orally as conventional and slow-release t ab l e t s ,
Clin. Pharmacol. Ther. 17, 414 (1975).

124. J . Koch-Weser, S. W. Klein, L . L. Foo-Canto, J . A.

Kas te r , and R. W. DeSant i s , Ant ia r rhythmic
prophylax is with procainamide in acute myocardial infarct
ion, N. Engl. J. Med. 281, 1253 (1969).

125. J . Koch-Wester and S . W. Klein, Procainamide dosage

schedu les , plasma concentra t ions and clinical effects
, JAMA 215, 1454 (1971).

126. R. Ruosteenoja, P . Tor s t i , and A. Sothmann, Exper

iences on a sus ta inedre lease procainamide p repa ra t
ion , Curr. Ther. Res. 15, 707 (1973).

127. E. Kar lsson, Plasma levels of procainamide after

administrat ion of conventional and sus ta inedre lease t
ab le t s , Eur. J. Clin. Pharmacol. 6, 245 (1973).

128. R. J . Levine and A. Sjoerdsma, Estimation of

monoamine oxidase act ivi ty in man: t echn iques and appl
icat ions , Ann. NY Acad. Sci. 107, 966 (1963).

129. J . C . Ha r t e r , W. J . Reddy , and G. W. Tho rn ,

Studies on an in termit tent cort icosteroid dosage
regimen, N. Engl. J. Med. 269, 591 (1963).

130. C. J . Fal l ie rs , H. Chai , L. Molk, H. Bane , and

R. R. de A. Cardoso, Pulmonary and adrenal effects of a l
t e rna te -day cor t i costeroid t h e r a p y , J.
Allergy Clin. Immunol. 49, 156 (1972).

131. M. E. Jacobson, The rat ionale of a l t e rna te -day

cor t icosteroid t h e r a p y , Postgrad Med. 49, 181
(1971).

132. J . G. Wagner, O. W. C a r p e n t e r , and E . J .

Collins, Sus ta ined action oral medication. I . A quant i
ta t ive s tudy of prednisolone in man, in the dog, and in
v i t r o , J. Pharmacol. Exp. Ther. 129, 101 (1960).

133. C. J . Migeon, F . K. Ty le r , J . P . Mahoney, A. A.

F lorent in , H. Cast le , E. L. Bl i ss , a n d L . T .
Samuels, The d iurnal var iat ion of plasma levels and u r
ina ry excret ion of 17-hydroxy cor t icostero ids in
normal subjec ts , night workers and bl ind sub jec t s ,
J. Clin. Endocrinol. Metab. 16, 622 (1956).

134. R. E. Pe te r son , Metabolism of adrenocor t icos

tero ids in man, Ann. NY Acad. Sci. 82, 846 (1959).

135. P . F . D 'Arcy, J . P . Griffin, J . S. J e n k i n s

, W. F . Kirk , and A. W. C. Peacock, Sus ta inedre lease
formulation of prednisolone administered orally to man, J.
Pharm. Sci. 60, 1028 (1971).

136. I . I . Lubowe, Sus ta inedre lease oral

methylprednisolone in der matology: a clinical evaluat ion,
Curr. Ther. Res. 4, 111 (1962).

137. E. Nelson, Pharmaceuticals for prolonged act ion,

Clin. Pharmacol. Ther. 4, 283 (1963).
138. G. W. T h o r n , R. E. Fu i sz , and R. C. Fu isz ,
Steroid Therapy: A Clinical Update for the 1970s, Medcom,
New York, 1971.

139. J . J . B u r n s , R. K. Rose, T . Chenkin , A.

Goldman, A. Schule r t , and B . B . Rodie, The
physiological disposition of pheny l butazone (Butazolidin)
in man and a method for i t s elimination in biological
material , J. Pharmacol. Exp. Ther. 109, 346 (1953).

140. D . T . Ca r r and A. G. Karlson, Optimal dosage

regimens of an t i tuberculos is d r u g s , Am. Rev.
Respir. Dis. 84, 90 (1961).

141. F . J . R o b e r t s , Single daily dose t rea tment

of psych ia t r i c pa t i en t s with phenothiazine de r
iva t ives , J. Ment. Sci. 107, 104 (1961).

142. L. E. Hollister, S tudies of delayed-act ion

medication. I . Meprobamate administered as conventional
table ts and as two delayed action capsu les , N. Engl. J.
Med. 266, 281 (1962).

143. I . Haides, Single daily dose of a new form of

amitriptyline in depress ive i l lness , Br. J. Psychiatry
120, 521 (1972).

144. A n o n . , Two new an t idepress ive p repa ra t ion

, Drug Ther. Bull. 9, 99 (1971).

145. J . R. Gomez and G. Gomez, Depress ion in general p

rac t i ce : comparison between thr ice daily
amitriptyline tab le t s and a single sus ta inedre lease
capsule at n igh t , Br. J. Clin. Pract. 26, 33 (1972).

146. L. E. Hollister, S . H. C u r r y , J . E. Doerr , and

S. L. Kante r , S tudies of delayed-act ion medication. V.
Plasma levels and u r ina ry excret ion of four different
dosage form of chlorpromazine, Clin. Pharmacol. Ther. 11,
49 (1970).

147. T . J . Mellinger, Serum concent ra t ions of

thioridazine af ter different oral medication form, Am. J.
Psychiatry 121, 1119 (1965).

148. L. E. Hollister, Studies of prolonged-act ion

medication. I I . Two phenothiazine t ranqui l i ze rs (
thiroidazine and chlorpromazine) adminis tered as coated
tab le ts and prolonged-act ion p r e p a r a t i o n s ,
Curr. Ther. Res. 4, 471 (1962).

149. M. H r u s k a , B . Morris , and J . J . Hsu,

Therapeut ic effects of different modes of chlorpromazine
administrat ion, Dis. New, Syst. 27, 522 (1966).

150. C. Ba r t l e t t , Comparison of thioridazine tab le

ts to chlorpromazine spansu les in the maintenance care of
chronic sch izophrenics , Curr. Ther. Res. 13, 100 (1971).

151. H. M. Solomon and J . J . Schrogie , The anticoagulant

r e sponse to b i shydroxycoumar in . I . The role of
individual var ia t ion , Clin. Pharmacol. Ther. 8, 66
(1967).

152. M. A. Schwar tz , E. Postma, and Z. Gaunt , Biological

half-life of chlordiazepoxide and i ts metabolite,
demoxepam, in man, J. Pharm. Sci. 60, 1500 (1971).

153. H. W. J u n and E . J . T r i g g s , Blood levels of

chlorphentermine in man, J. Pharm. Sci. 59, 206 (1970).

154. J . A. Taylor , Pharmacokinetics and biotransformation

of chlorpropamide in man, Clin. Pharmacol. Ther. 13, 710
(1972).

155. B . Pep i tp ie r re , L. P e r r i n , M. R u d h a r
d t , A. He r r e ru , and J . F a b r e , Behavior of
chlorpropamide in renal insufficiency and u n d e r t he
effect of associated d r u g t h e r a p y , Int. J. Clin.
Pharmacol. Ther. Toxicol. 6, 120 (1972).

156. L. Hillestad, T . Hansen, and M. Melsom, Diazepam

metabolism in normal man. 2. Serum concentrat ion and
clinical effect after oral administration and cumulation,
Clin. Pharmacol. Ther. 16, 485 (1974).

157. U. Klotz, G. R. Avant , A. Hoyumpa, S. Schanker , and

G. R. Wilkinson, Effects of age and l iver disease in the
disposition and elimination of diazepam in adult man, J.
Clin. Invest. 55, 247 (1975).

158. L. M. Cummins, Y. C. Martin, and E. E. Scherf l ing ,

Serum and ur ine levels of e thchlorvynol in man, J.
Pharm. Sci. 60, 261 (1971).

159. J . E. Dohe r ty , Digitalis glycosides pharmacokinet

ics and the i r clinical implications, Ann. Intern. Med.
79, 299 (1973).
160. L. S to r s t e in , Studies on digi tal is . 1. Renal
excret ion of digitoxin and i t s cardioact ive metaboli
tes , Clin. Pharmacol. Ther. 16, 14 (1974).

161. J . E. Dohe r ty , W. H. Pe rk in s , and G. K.

Mitchell, Tr i t ia ted digoxin s tudies in human sub jec
t s , Arch. Intern. Med. 108, 531 (1961).

162. C. McMartin, R. K. Rondel, J . Vinter , B . R. Allan,

P . M. Humberstone, A. W. D . Leisman, G. Sandler , and J
. L. Th i r ke t t l e , The fate of guanethidine in two
hype r t ens ive pa t i en t s , Clin. Pharmacol. Ther.
11, 423 (1970).

163. L. E. Hollister and G. Levy, Kinetics of meprobamate

elimination in humans , Chemotherapia 9, 20 (1964).

164. K. Arnold , Rate of decline of d ipheylhydantoin in

human p las ma, Clin. Pharmacol. Ther. 11, 121 (1970).

165. M. C. MacDonald, D . S. Robinson, D. S y l v e s t e r

, and J . J . Jeffe , The effects of chloral beta ine and
glutethimide administ ra t ion on warfarin plasma levels
and hypoprothrombinemic response in man, Clin. Pharmacol.
Ther. 10, 80 (1969).

166. J . G. Wagner, Aspects of pharmacokinetics and

biopharmaceut ics in relation to d r u g act ivi ty , Am.
J. Pharm. 141, 5 (1969).

167. H. Nau, R. Zierer , H. Spielmann, D. Neuber t , and C.

Gansau, A new model for embryotoxicity t e s t i ng : te t
ra togenic i ty and pharmacokinet ics of valproic acid
following cons t an t r a t e admini s t ra t ion in the
mouse us ing human therapeut ic d r u g and metabolite
concent ra t ions , Life Sci. 29, 2803 (1981).

168. B . I . Sikic , J . M. Colins, E. G. Mimnaugh, and T.

E. Gram, Improved the rapeu t i c index of bleomycin when
adminsi tered by continuous infusion in mice, Cancer
Treat. Rep. 62, 2011 (1978).

169. B . Eckste in , K. Shaw, and G. S t e rn , Sus ta

inedre lease levodopa in Parkinsonism, Lancet 1, 431
(1973).

170. B . W. McGuiness and J . B . Pa rk in , New long-ac t

ing formulation of chlorpheniramine maleate in hay fever ,
Br. J. Clin. Pract. 25, 139 (1971).
171. G. Levy and B . A. Hayes , Physicochemical bas is of
the buffered acetylsalicylie acid con t rove r sy , N.
Engl. J. Med. 262, 1053 (1960).

172. V. Herbe r t , D r u g s effective in iron-deficiency

and other h y pochronic anemias. I n , The Pharmacological
Basis of Therapeutics (L. S . Goodman and A. Gilman, e d s
. ) , 4th e d . , Macmillan, New York, 1970, p . 1045.

173. AMA Department of D r u g s , AMA Drug Evaluations,

2nd e d . , American Medical Association, Chicago, 1973, p
. 183.

174. C. Boroda, R. B . Miller, S . T . Leslie, E. G. Nicol,

and I . Thomson, Comparison of the bioavailability of
aminophylline in a conventional base and in a cont inuous
release b a s e , J. Clin. Pharmacol. 13, 383 (1973).

175. J . R. Hoon, Bleeding gas t r i t i s induced by

long-term release asp i r in , JAMA 229, 841 (1974).

176. E. Jacobs and J . Pr ingot , Gastr ic u lcers due to

the intake of potassium chlor ide, Am. J. Digest. Dis. 18,
289 (1973).

177. D. R. Baker , W. H. S c h r a d e r , and C. R.

Hitchcock, Smallbowel ulceration apparent ly associated
with thiazide and po tas sium t h e r a p y , JAMA 190, 586
(1964).

178. L. Gee, B . B e r g , T . G. Tong, and C. Becker ,

Enter ic-coated potassium supplements , JAMA 228, 975
(1974).

179. J . M. Jefferson and P . Aukland, Enter ic-coated

potassium chloride: A continuous h a z a r d , Br. Med. J.
1, 456 (1974).

180. W. Hasker and J . McCaffrey, Ulceration of a Meckel's

d iver ticulum due to a potassium chloride table t , Med.
J. Aust. 2, 261 (1972).

181. B . L. Phil l ips , Potassium-induced bowel u lcera t

ion, Br. J. Clin. Pract. 28, 143 (1974).

182. W. H. Thomas, Measurement of dissolution r a t e s of

potassium chloride from var ious slow release potassium
chloride tablets us ing a specific ion e lect rode, J.
Pharm. Pharmacol. 25, 27 (1973).
183. E. L. Tarp ley , Control led-release potassium
supplementat ion, Curr. Ther. Res. 16, 734 (1974).

184. C . Graffner and J . S jogren , Potassium absorpt ion

from sus ta inedrelease t ab l e t s , Acta Pharm. Suec. 8,
13 (1971).

185. T . J . McKenna, J . F . Donohoe, J . J . Healy, B .

Canning , and F . P . Muldowney, Potass ium-spar ing agen
ts du r ing diure t ic t he r apy in h y p e r t e n s i o
n , Br. Med. J. 2, 739 (1971).

186. E. M. Cla rkson , Slow sodium: an oral slowly released

sodium chloride p repa ra t ion , Br. Med. J. 3, 604
(1971).

187. A n o n . , Slow Na, Drug Ther. Bull, 9, 98 (1971).

188. M. A. Schneiderman, M. H. Myers, Y. S. Sa the , and P

. Koffsky , Toxici ty , t he the rapeu t i c index and the
r ank ing of d r u g s , Science 144, 1212 (1964).

189. O. J a r d e t z k y , On the quant i ta t ive

evaluation of pharmacologic a g e n t s , J. New Drugs 6,
203 (1966).

190. T . R u d y , personal communication, 1976.

191. J . H. Gaddum, Pharmacology, Oxford Universi ty P r e

s s , New York , 1953.

192. C. A. Winter, A s tudy of comparative antihistaminic

act ivi ty of six compounds, J. Pharmacol. Exp. Ther. 90,
224 (1947).

193. J . C. Kran tz , J r . , C . J . C a r r , and B . N.

La Du, J r . , The Medical Principles of Medical Practice,
7th e d . , William & Wilkins, Baltimore, 1969, p . 28.

194. B . S . Ka tcher , Rheumatoid a r t h r i t i s , J.

Am. Pharm. Assoc. NS12, 383 (1972).

195. E. H. Wiseman, Plasma salicylate concentra t ions

following chronic administration of aspir in as
conventional and sus ta inedre lease t ab l e t s , Curr.
Ther. Res. 11, 681 (1969).

196. J . B . Dick-Smith, Pilot tr ial of sus ta inedre

lease aspir in (BiP r i n ) , Med. J. Aust. 1, 18 (1970).
197. E. H. Wiseman and N . J . Feder ic i , Development of
a sus ta inedrelease aspir in tab le t , J. Pharm. Sci. 57,
1535 (1968).

198. M. S . Vora, Z. J . Zimmer, and P . V. Maney, Sus ta

inedrelease aspir in tablet us ing an insoluble matr ix ,
J. Pharm. Sci. 53, 487 (1964).

199. S. C . Harvey , Gastric antacids and d iges t an t s .

In , The Pharmacological Basis of Therapuetics (L . S.
Goodman and A. Gilman, e d s . ) , 4th ed . , Macmillan,
New York, 1965, p . 1013.

200. W. A. Sodeman, J r . , N . A. Augur , and H. M.

Pollard, Physiology and pharmacology of belladonna t h e r
a p y in ant ipept ic disease , Med. Clin. North Am. 53,
1379 (1969).

201. D . R. Reese , S. M. F r e e , J . V. Swintosky, and

M. I . Grossman, The effect of dosage forms on the durat
ion and continui ty of belladonna alkaloids, Am. J. Dig.
Dis. 4, 220 (1958).

202. H. B u r n e s s , Clinical evaluation of a sus ta

inedre lease belladonna p repa ra t ion , Am. J. Dig. Dis.
22, 111 (1955).

203. A . M . Kasich, Relief of nocturna l pain in duodenal

u lcer , Am. J. Gastroenterol. 33, 66 (1960).

204. M. H. Alp and A. K. Gran t , Effect of sus ta inedre

lease hexocyclium table ts on gas t r ic acid secre t ion,
Med. J. Aust. 1, 337 (1969).

205. R. A. Ke r r , Angina pec to r i s , J. Am. Pharm.

Assoc. NS12, 178 (1972).

206. M. Kamil and I . Kl inger , Timed dis integrat ion

capsules of pen tae ry th r i to l t e t r an i t r a t e
in a selected angina g r o u p , NY State J. Med. 59, 3398
(1959).

207. T . M. Feinblat t and E. A. Fe rguson , Timed-dis

integrat ion capsu les : a fu r the r s t u d y . An in
vivo roen tgenographic s t u d y , blood level s t udy and
relief of angina pain with pen tae ry th r i to l t e t r
a n i t r a t e , N. Engl. J. Med. 256, 331 (1957).

208. J . L. Schell ing and L. Lasagna, A s tudy of c ross

to le rance to c i rcula tory effects of organic n i t r a
t e s , Clin. Pharmacol. Ther. 8, 256 (1967).

209. A. Wilson, The modification of the durat ion of d r u

g action, J. Pharm. Pharmacol. 11, 446 (1959).

210. J . S . Takahashi and M. Zatz, Regulation of circadian

rhy thmic i ty , Science 217 1104 (1982).

211. J . A. Mart inex-O'Gerral l , Circadian r h y t h m s

, J. Occup. Med. 10, 305 (1968).

212. G. G. Luce , Biological Rhythms in Psychiatry and

Medicine, National Ins t i tu te of Mental Health, Be
thesda , Md, 1970.

213. C. E. Brush and R. Fayerwea the r , Observat ions on

the changes in blood p r e s s u r e dur ing normal s leep
, Am. J. Physiol. 5, 199 (1901).

214. H. Brooks and J . H. Carrol l , Clinical s tudy of t h

e effects of sleep and r e s t blood p r e s s u r e ,
Arch Intern. Med. 10, 97 (1912).

215. T . Aimoto, B . H. Rohde , G. C. Y. Chiou, and J . K.

Lauber , N-Acety l t ransferase act ivi ty and melatonin
level in the eyes of glaucomtous ch ickens , J. Ocular
Pharmacol. 1, 149 (1985).

216. E. Marte and F . Halberg , Circadian suscept ibi l i

ty in relation to administration of pharmacologic agen t s
, Fed. Proc. 20, 305 (1961).

217. E. Haus and F . Halberg , 24-hour rhythm in suscept

ibi l i ty of C Mice to a toxic dose of e thanol , J.
Appl. Physiol. 14, 878 (1959).

218. P . J . Wedlund and R. H. Levy, Time-dependent kinet

ics VII: Effect of diurnal oscillations on the time course
of carbamazepine autoinduction in the r h e s u s monkey,
J. Pharm. Sci. 72, 905 (1983).

219. E. L. Dubois and D . C . Adler , Single daily dose

oral administ ra t ion of cort icosteroids in rheumatic d i
so rde r s : An analysis of i t s advan t ages , efficacy
and side effects , Curr. Ther. Res. 5, 43 (1963).

220. R. J . J a r r e t t and H. Keen, Diurnal var iat ion

of oral glucose to le rance : a possible poin ter to the
evolution of diabetes mell i tus , Br. Med. J. 2, 341
(1969).
221. N . S . Hayner , M. D . Kjelsberg, F . H. Epste in ,
and T . F ranc i s , Carbohydra te tolerance and diabetes
in a total community, Tecumseh, Michigan. I . Effects of
age , sex and tes t condit ions on one-hour glucose
tolerance in adu l t s , Diabetes 14, 413 (1965).

222. N. Fre inke l , M. Mager , and L. Vinnick, Cyclicity

in the i n t e r re la t ionships between plasma insulin
and glucose dur ing s t a rva tion in normal young men, J.
Lab. Clin. Med. 17, 171 (1968).

223. C. Faiman and J . A. Morrhouse, Diurnal variat ion in

the levels of glucose and re la ted subs tances in heal
thy and diabetic s u b jects du r ing s t a rva t ion ,
Clin. Sci. 32, 111 (1967).

224. A. N. Rigas , A. H. Bi t t les , D . R. Hadden, and D

. A. D . Montgomery, Circadian variat ion of glucose,
insulin and free fat ty acids du r ing long-term use of
oral hypoglycemic agents in diabe tes mellitus, Br. Med. J.
4, 25 (1968).

225. M. A. Kimble, Diabetes , J. Am. Pharm. Assoc. NS14, 80

(1974).

226. W. J . M. Hruschesky , Circadian timing of cancer

chemotherapy, Science 228, 73 (1985).

227. S. A. Nicholson, T . E. Adr ian , A. J .

Bacarese-Hamilton, B . Gillham, M. T . Jones , and S. R.
Bloom, 24-Hour variat ion in content and release of
hypothalamic neuropep t ides in the r a t , Reg. Peptides
7, 385 (1983).

228. G. Leyendecker , T . S t r u v e , and E . J . Plotz,

Induction of ovulation with chronic in termit tent
(pulsati le) administration of LH-RH in women with
hypothalamic and hyperprolact inemic amenorrhea, Arch.
Gynecol. 229, 117 (1980).

229. W. F . Crowley J r . and J . W. McArthur , Stimulation

of the normal menstrual cycle in Kallman's syndrome by
pulsati le administration of luteinizing hormone-releas ing
hormone (LHRH), J. Clin. Endocrinol. Metab. 51, 173
(1980).

230. G. Leyendecker , L. Wildt and M. Hansmann, Pregnacies

following chronic in termi t tent (pulsat i le)
administration of Gn-RH by means of a por table pump
("Zyklomat")—A new approach to the t reatment of infert i
l i ty in hypothalamic amenorrhea , J. Clin. Endocrinol.
Metab. 51, 1214 (1980).

231. C. S . Tarn, J . N. M. Heersche , T . M. Murray , and

J . A. Par sons , Para thyro id hormone stimulates the bone
apposition ra te independent ly of i ts r e sorp t ive act
ion: Differential effects of in termit tent and continuous
adminis t ra t ion, Endocrinology 110, 506 (1982).

232. A. Soil, C. R. Kahn, D . M. Neville, J r . and J .

Roth, Insulin recep tor deficiency in genetic and acquired
obes i ty , J. Clin. Invest. 56, 779 (1975).

233. J . R. Gavin, J . Roth , D . M. Neville, P . deMeyts ,

and D . N . Buel l , Insulin dependent regulat ion of
insulin receptor concent r a t i ons : a di rect demonstrat
ion in cell cu l t u r e , Proc. Natl. Acad. Sci. USA 71,
84 (1974).

234. A. J . W. Hsuen , H. L. Dufau, and K. J . Ca t t ,

Regulation of lutein zing hormone recep to r s in tes t
icular cells by gonadotropin , Biochem. Biophys. Res.
Commun. 72, 1145, 1976.

235. M. A. Lesniak and J . Roth, Regulation of recep tor

concent ration by homologous hormone. Effect of human
growth hormone on i ts recep tor in IM-9 lymphocytes , J.
Biol. Chem. 251, 3720 (1976).

236. P . M. Hinkle and A. H. Tashjian, J r . , Thyro t rop

inre leas ing hormone regula tes the number of i t s own
recep to r s in the GH3 s t ra in of p i tu i ta ry cells
in c u l t u r e , Biochemistry 14, 3845 (1975).

237. P . E. Belchetz , T . M. Plant , Y. Nakai, E. J .

Keogh, and E. Knobil, Hypophyseal r e sponses to
continuous and intermitten t del ivery of hypothalamic
gonadotropin-re leas ing hormone, Science 202, 631 (1978).

238. H. J . Lynch, R. W. Rives t , and R. J . Wurtman,

Artificial induct ion of melatonin rhy thms by programmed
microinfusion, Neuroendocrinology 31, 106 (1980).

239. J . V. Moore, Doseresponse c u r v e s after in vivo

experimental chemotherapy: influence of route of
administration on biological outcomes, Cancer Chemother.
Pharmacol. 15, 91 (1985).

240. L. Z. Bene t , Effect of route of administration and

dis t r ibut ion on d r u g action, J. Pharmacok.
Biopharm. 6, 559 (1978).

241. Y. W. Chien, Long-act ing pa ren te ra l d r u g

formulations, J. Parenteral Sci. Technol. 35, 106 (1981).

242. G. F . J . Russel l , S tarch microspheres d r u g

delivery sys tems , Pharm., Int. 3, 260 (1983).

243. S . S. Davis , Colloids as d r u g del ivery sys tems

, Pharm. Technol. 5, 71 (1981).

244. T. R. Tice and D . R. Cowar, Biodegradable control

led-re lease pa ren te ra l sys tems , Pharm. Technol. 8,
25 (1984).

245. Y. Morimoto, K. Sugibayashi and M. Akimoto, Magnetic

guidance of ferrocol loid-entrapped emulsion for si
te-specific d r u g de l ivery , Chem. Pharm. Bull. 31,
279 (1983).

246. M. A. Davis and T. A. Taube , Pulmonary perfusion

imaging: acute toxicity and safety factors as a function
of par t ic le size, J. Nucl. Med. 19, 1209 (1978).

247. E. F . E v a n s , J . D . Proc tor , M. F ra tk in ,

J . Velandia, and A. J . Wasserman, Blood flow in muscle g
roups and d r u g s ab sorpt ion , Clin. Pharmacol. Ther.
17, 44 (1975).

248. A. T . Florence and W. R. Vezin, Prolongation of the

action of in t ramuscular formulations of phenoth iaz ines
. In , Optimization of Drug Delivery, Alfred Benzon
Symposium 17 (H. Bundguaa rd , A. B . Hansen, and H. Kofod,
e d s . ) , Munksgaard Copenhagen, 1982, p p . 93-113.

249. M. Ermini, F . Carpino , M. Russo and G. Benagiano,

Studies on sus ta ined cont racept ive effects with
subcutaneous polydim ethylsi loxane implants , Acta
Endocrinol. 73, 360 (1973).

250. S . L . Sendelbeck and C. L. Girdis , Disposition of a

14c-labeled bioerodible polyor thoes te r and i t s
hydrolys is p r o d u c t s , 4 -hyd roxybu ty ra t e and
c i s , t r a n s l , 4 b i s ( h y d r o x y m e t h y l )
c y c l o hexane , in r a t s , Drug Metab. Disp. 13, 291
(1985).

251. K. Hirano, T . Ichihashi and H. Yamada, Studies on the

abso rp tion of pract ical ly waterinsoluble d r u g s
following injection. V. Subcutaneous absorpt ion in r a t
s from solutions in water immiscible oils, J. Pharm. Sci.
71, 495 (1982).

252. M. Pfeffer, R. D . Smyth, K. A. Pi t tman, and P . A.

Nardella, Pharmacokinetics of subcutaneous and in t
ramuscular butorphenol in dogs , J. Pharm. Sci. 69, 801
(1980).

253. D . I . Abramson, Blood Vessels and Lymphatics,

Academic P r e s s , New York, 1962, p . 520.

254. J . Schou, Subcutaneous and in t ramuscular injection

of d r u g s . In , Concepts in Biochemical Pharmacology,
Par t 1 (B . B . Brodie and J . R. Gillette, e d s . ) ,
Sp r inge r -Ver l ag , Heidelberg, 1971, p p . 47-66 .

255. B . E. Bal lard, Biopharmaceutical considerat ions in

subcutaneous and in t ramuscular d rug administrat ion, J.
Pharm. Sci. 57, 357 (1967).

256. A. E. Jo rgensen and J . Schou, The local effect of

cholinergic agents and chol inesterase inhibition on the
clearance of surcose from muscles , Acta. Pharmacol. (Kbh)
23, 205 (1965).

257. G. F . Warner, E. L. Dobson, N. Pace, M. E. Johnson ,

and C. R. F inney , Studies of human per iphera l blood
flow: the effect of injection volume on the in t
ramuscular radiosodium clearance r a t e , Circulation 8,
732 (1953).

258. R. B . Sund and J . Schou, The determination of

absorpt ion r a t e s from rat muscles: an experimental
approach to kinet ic desc r ip t ions , Acta Pharmacol.
Toxicol. 21, 313 (1964).

259. K. Kakemi, H. Sezaki , K. Okumura and S. Ashida,

Absorption and excret ion of d r u g s XXXIX. The absorpt
ion of isonicotinic acid der ivat ives from the skeletal
muscle of the r a t s , Chem. Pharm. Bull. 17, 1332
(1969).

260. K. Kakemi, H. Sezaki , K. Okumura, C. Takada and S. F

u r u sawa, Absorpt ion of d r u g s from the skeletal
muscle of the r a t s ( 2 ) , Chem. Pharm. Bull. 19, 2058
(1971).

261. K. Kakemi, H. Sezaki , K. Okumura, H. Kobayashi and S

. Fu ru sawa, Absorpt ion of d r u g s from the skeletal
muscle of the r a t s ( 3 ) . Effect of water-soluble
adjuvants and vehicles on the in t ramuscular absorp t ion
, Chem. Pharm. Bull. 20, 443 (1972).

262. K. Okumura, H. Sezaki , and K. Kakemi, Absorpt ion of

d r u g s from the skeletal muscle of the r a t s ( 4 ) .
Absorpt ion of cationic d r u g s from the muscle, Chem.
Pharm. Bull. 20, 1607 (1972).

263. H. Kobayashi , T . Nishimura, K. Okumura, S. Muranishi

, and H. Sezaki , Effect of polysorbates on absorpt ion r
a t e s of watersoluble, micelle-free d r u g s
administered in t ramuscular ly in the r a t , J. Pharm.
Sci. 63, 580 (1974).

264. R. H. Levy and M. Rowland, Absorpt ion kinet ics of a

ser ies of local anes the t ics from ra t subcutaneous t i
s s u e . I, J. Pharmacokin. Biopharm. 2, 313 (1974).

265. R. H. Levy and M. Rowland, Absorpt ion kinet ics of a

ser ies of local anes the t ics from ra t subcutaneous t i
s s u e . I I . Effects of vasodi la tors , J.
Pharmacokin. Biopharm. 2, 337 (1974).

266. K. Hirano, T . Ichihashi and H. Yamada, Studies on the

abso rp tion of pract ical ly waterinsoluble d r u g s
following injection. I . In t ramuscular absorpt ion from
water-immiscible oil solutions in r a t s , Chem. Pharm.
Bull. 29, 519 (1981).

267. K. Hirano, T . Ichihashi and H. Yamada, Studies on the

abso rp tion of pract ical ly waterinsoluble d r u g s
following injection. II . In t ramuscular absorpt ion from
aqueous suspens ions in r a t s , Chem. Pharm. Bull. 29,
817 (1981).

268. K. Hirano, T . Ichihashi and H. Yamada, Studies on t

he abso rp tion of practical ly waterinsoluble d r u g s
following injection. VI . Subcutaneous absorpt ion from
aqueous suspens ions in r a t s , J. Pharm. Sci. 71, 500
(1982).

269. V. Bocci, Evaluation of rou tes of administration of

in ter feron in cance r : A review and a proposa l ,
Cancer Drug Delivery 1, 337 (1984).

270. J . R. Howard and J . Hadgraf t , The clearance of

oily vehicles following in t ramuscular injections in r a
b b i t s , Int. J. Pharm. 16, 31 (1983).
271. W. S. Nimmo, D r u g s , d iseases and a l tered gas t
r ic empyt ing, Clin. Pharmacokin. 1, 189 (1976).

272. A. F . Hoffman, J . H. Dressman, C. F . Code, K. F .

Witztum, Controlled e n t r y of orally adminis tered d r
u g s : physiological considera t ions , Drug Dev. Ind.
Pharm. 9, 1077 (1983).

273. I . L . MacGregor, P . Martin, and J . H. Meyer, Gastr

ic emptying of solid food in normal man and after subtotal
gastrectomy and t runca l vagotomy with pyloroplas ty ,
Gastroenterology 72, 206 (1977).

274. H. S. C h ' n g , H. Pa rk , P . Kelly and J . R.

Robinson, Bioadhesive polymers as platforms for oral
controlled d r u g delivery II : Syn thes i s and
evaluation of swelling, waterinsoluble bioadhesive polymers
, J. Pharm. Sci. 73, 399 (1985).

275. M. A. Longer , H. S. Ch f ng, and J . R. Robinson,

Bioadhesive polymers as platforms for oral controlled d r
u g del ivery III : Oral del ivery of chlorothiazide us
ing a bioadhesive polymer, J. Pharm. Sci. 74, 406 (1985).

276. R. Groning and G. Heun, Oral dosage forms with

controlled gas t ro intes t inal t r a n s i t , Drug Dev.
Ind. Pharm. 10, 527 (1984).

277. M. J . Dew, P . J . Hughes , M. G. Lee, B . K. Evans

and J . Rhodes , An oral p repara t ion to release d r u g
s in the human colon, Br. J. Clin. Pharmacol. 14, 405
(1982).

278. C. Bogentoft , C . Eskilsson, U. E. Jonsson , P . O.

Lagers t rom, K. Lovgren and L. Rosen, Delivery of d r u g
s to the colon by means of a new encapsula ted oral dosage
form, Acta Pharm. Seu 20, 311 (1983).

279. D . R. Fr iend and G. W. Chang , A colon specific d

rug -de l ive ry system based on d r u g glycides and the
glycosidases of colon bac te r ia , J. Med. Chem. 27, 261
(1984).

280. M. Gibaldi and J . L. Kanig, Absorpt ion of d r u g s

t h r o u g h the oral mucosa, J. Oral Ther. Pharmac. 1,
440 (1965).

281. N. F . H. Ho and W . I . Higuchi, Quanti tat ive in te

rpre ta t ion of in vivo buccal absorpt ion of alkonoic
acids by the physical model approach , J. Pharm. Sci. 60,
537 (1971).

282. I. A. Siegel, Effect of chemical s t r u c t u r e on

nonelectrolyte penet ra t ion of oral mucosa, J. Invest.
Dermatol. 76, 137 (1981).

283. I. A. Siegel, Permeability of the oral mucosa. In ,

The Structure and Function of Oral Mucosa ( J . Meyer, C.
A. Squ ie r , and S . J . Gerson, e d s . ) , Pergamon P r
e s s , Oxford, 1984, p p . 95-108.

284. R. P . Walton, Absorpt ion of d r u g s t h rough the

oral mucosa. I I I . Fa t -wa te r solubility coefficient
of alkaloids, Proc. Soc. Exp. Biol. Med. 32, 1488 (1935).

285. I . A. Segel , K. T . Izu tsu and E. Watson,

Mechanisms of nonelectrolyte penet ra t ion across dog and
rabbi t oral mucosa, Arch. Oral Biol. 26, 357 (1981).

286. A. C. Moffat, Absorpt ion of d r u g s th rough the

oral mucosa. I n , Topics in Medicinal Chemistry, Vol. 4,
John Wiley & Sons , New York, 1971, p p . 1-26.

287. A. H. Becket t and R. D . Hossie, Buccal absorpt ion

of d r u g s . In , Handbook of Experimental Pharmacology,
Vol. 28, Par t I ( B . B . Brodie and J . R. Gillete, e d
s . ) , Spr inge r -Ver lag , Heidelberg, 1971, p p . 25
-46 .

288. S. S. Davis , P . B . Daly, J . W. Kenner ley , M. F r

i e r , J . G. Hardy and C. G. Wilson, Design and
evaluation of sus ta ined re lease formulations for oral
and buccal adminis t ra t ion, Adv. Pharmacother. 1, 17
(1982).

289. J . Abrams, Nitrate delivery systems in p e r s p e c

t i v e s , a decade of p r o g r e s s , Am. J. Med. 75,
38 (1984).

290. A. B . de Boer , L. G. J . Leede and D . D. Bre imer ,

Rectal d r u g adminis trat ion: part ial avoidance of
hepat ic f i r s t pa s s elimination, Pharm. Int. 3, 267
(1982).

291. W. A. Ritschel , H. Elconin, G. J . Alcorn, and D . D.

Denson, F i r s t p a s s elimination of lidocaine in the
rabbi t after perora l and rectal route of adminis t ra t
ion, Biopharm. Drug Disp. 6, 281 (1985).

292. L. G. J . Leede, A. G. de Boer , C D . Feijen and D .

D . Bre i mer , Site specific rectal d r u g administration
in man with an osmotic sys tem: influence on " f i r s t
-pass" elimination of lidocaine, Pharm. Res. 1, 129 (1984).

293. J . J . T u k k e r , D . J . de Blaey and G. A.

Charbon , Rectal motility and bioavailability, Pharm. Res.
1, 173 (1984).

294. F . Moolenaar and A. J . M. Schoonen, Biop harm ace ut

ics of the rectal administration of d r u g s , Pharm.
Int. 1, 144 (1980).

295. N. Senoir , Rectal administrat ion of d r u g s . In ,

Advances in Pharmaceutical Sciences, Vol. 4, Academic P r
e s s , London, 1974, p p . 363-435.

296. C J . de Blaey and J . Polderman, Rationales in the

design of rectal and vaginal delivery forms of d r u g s .
In , Drug Design, Vol. 9 (E. J . Ar iens , e d . ) ,
Academic P r e s s , New York, 1980, p p . 237-266.

297. K. Morimoto, Y. Iwamoto, T . Katashima, T . Takeeda ,

Y. Nakamoto, and K. Morisaka, Absorpt ion and
bioavailability of diclofenac after rectal administration
of diclofenac-Na gel p repara t ion in ra t and man,
Pharm. Res., 2, 166 (1985).

298. T. Nishihata , J . Ryt t ing and T. Higuchi, Enhanced

recta l a b sorption of theophyl l ine , l idocaine,
cefnetazole and levodopa by severa l ad juvan ts , J.
Pharm. Sci. 71, 865 (1982).

299. T. Nishihata , J . Ryt t ing and T. Higuchi, Effect of

salicylate on rectal absorpt ion of l idocaine, levodopa
and cefmetazole in r a t s , J. Pharm. Sci. 71, 869
(1982).

300. T . Nishihata, J . Ry t t ing , T . Higuchi , L.

Caldwell and S . J . Selk, Enhancement of rectal absorpt
ion of water-soluble ant i biotics in dogs , Int. J. Pharm.
21, 239 (1984).

301. T . Nishihata , K. Yasiu, M. Yamazaki and A. Kamada,

Effect of adjuvants on the rectal up take of bleomycin in
r a t s , J. Pharm. Dyn. 7, 278 (1984).

302. T . Nishihata , J . Ry t t ing , T . Higuchi and L.

Caldwell, Enhanced rectal absorpt ion of insulin and hepar
in in r a t s in the p resence of non-sur fac tan t ad
juvan ts , J. Pharm. Pharmacol. 33, 334 (1981).
303. T . Nishihata, G. Liversidge and T . Higuchi, Effect
of aprot inin on rectal del ivery of insul in , J. Pharm.
Pharmacol. 35, 616 (1983).

304. T . Nishihata , J . Ry t t ing , L. Caldwell, S .

Yoshioka and T . Higuch i , Adjuvant effect on rectal
absorp t ion . In , Optimization of Drug Delivery, Alfred
Benzon Symposium 17 (H. B u n d g a a r d , A. B . Hansen,
and H. Kofod, e d s . ) , Munksgaard , Copenhagen, 1982, p
p . 17-34 .

305. N. Yata, W. M. Wu, R. Yamajo, T . Murkami, Y. Higashi,

and T . Higuchi , Enhanced rectal absorpt ion of sodium
ampicillin by N-acyl der ivat ives of collagen pept ide in
r abb i t s and r a t s , J. Pharm. Sci. 74, 1058 (1985).

306. T . Nishihata , C. S. Lee, M. Yamamoto, J . Ry t t i

ng , and T. Higuchi, The effects of salicylate on the
rectal absorpt ion of phenylalanine and some p e p t i d e
s , and the effects of these p e p t ides on the rectal
absorpt ion of cefoxitin and cefmetazole, J. Pharm. Sci.
73, 1326 (1984).

307. K. Nakanishi , A. Ogata, M. Masada and T . Nadai,

Effect of non-s teroidal anti-inflammatory d r u g s on
the rectal mucosa, Chem. Pharm. Bull. 32, 1956 (1983).

308. K. Nakanishi , M. Masada and T . Nadai , Effect of

pharmaceutical adjuvants on the rectal permeabil i ty of d
r u g s I I I . Effect of repea ted administration and
recovery of t he permeabil i ty , Chem. Pharm. Bull. 31,
4161 (1983).

309. A. G. de Boer , F . Moolenenaar, L. G. J . de Leede

and D . D . Breimer, Rectal d r u g adminis t ra t ion:
clinical pharmacokinetic considerat ion, Clin.
Pharmacokin. 7, 285 (1982).

310. A. Hussain , S . Hirai, R. Bawarsh i , Nasal absorpt

ion of p ropa nolol in r a t s , J. Pharm. Sci. 73, 1300
(1984).

311. A. Hussain, S . Hirai, and C. H. Huang, Nasal absorpt

ion of tes tos te rone in r a t s , J. Pharm. Sci. 73,
1300 (1984).

312. A. Hussain, R. Kimura, C. H. Huang and T . Kashihara ,

Nasal absorpt ion of naloxone and buprenorph ine in r a t
s , Int. J. Pharm. 21, 233 (1984).
313. A. Hussain, R. Kimura, C . H. Huang and R. Mustafa,
Nasal absorpt ion of ergotamine t a r t r a t e in r a t s
, Int. J. Pharm. 21, 289 (1984).

314. K. S. E. S u , K. M. Campanale and C. L. Gr ies ,

Nasal d r u g delivery system of a q u a r t e r n a r y
ammonium compound: clofiliuum tosy la te , J. Pharm. Sci.
73, 1251 (1984).

315. A. N. F i sher , K. Brown, S . S . Davis , G. D . P a

r r , and D. A. Smith, The nasal absorpt ion of sodium
cromoglycate in the albino r a b b i t , J. Pharm.
Pharmacol. 37, 38 (1985).

316. R. L. Bronaugh and R. F . S tewar t , Methods for in v

i t ro p e r cutaneous absorpt ion s tudies V: Permeation t
h r o u g h damaged sk in , J. Pharm. Sci. 74, 1062
(1985).

317. D . L. London, W. R. Bu t t , S . S. Lynch , J . C.

Marshall , S. Owusu, W. R. Robinson and J . M. S tephenson
, Hormal r e sponse to in t ranasa l lu te iniz ing
hormone, J. Clin. Endocrinol. 37, 829 (1973).

318. J . Keenan and M. A. Chamberlain, Nasal mucosal

absorpt ion of t e t racosac t r in as indicated by a r i
se in plasma fluorogenic cor t i cos te ro ids , Br. Med.
J. 4, 407 (1969).

319. K. Muller and M. Osier , Induction of labor , a

comparison of i n t r a v e n o u s , in t ranasal and t
ransbucca l oxytocin, Acta Obstet. Gynecol Scand. 46, 59
(1967).

320. G. Bauman, A. Walser, P . A. Desaul les , F . J . A.

Paesi and L. Geller, Corticotropic action of an in t
ranasal ly applied synthet ic ACTH der iva t ive , J.
Clin. Endocrinol. 42, 60 (1976).

321. S . Hirai, T . Ikenaga and T . Matsuzawa, Nasal

absorpt ion of insulin in dogs , Diabetes 27, 296 (1978).

322. S. Hirai, T . Yashiki and H. Mima, Effect of su r fac

tan t s on the nasal absorpt ion of insulin in r a t s ,
Int. J. Pharm. 9, 165 (1981).

323. T . Nagai, Y. Nishimoto, N. Nambu, Y. Suzuki and K.

Sekine , Powder dosage form of insulin for nasal
administrat ion, J. Controlled Release 1, 15 (1984).
324. K. Morimoto, K. Morisaka and A. Kamada, Enhancement of
nasal absorpt ion of insulin and calcitonin us ing
polyacrylic acid gel , J. Pharm. Pharmacol. 37, 134
(1985).

325. K. S. E. Su , K. M. Campanale, L. G. Mendelsohn and C.

L. Gries , Nasal del ivery of polypept ides I : Nasal
absorpt ion of enkephal ins in r a t s , J. Pharm. Sci.
74, 394 (1985).

326. D. F . Proctor and G. K. Adams I I I , Physiology and

pharmacology of nasal function and mucus secre t ion ,
Pharmacol. Ther., Par t B , 2, 493 (1976).

327. G. D . P a r r , Nasal del ivery of d r u g s , Pharm.

Int. 4, 202 (1983).

328. S. Hirai, T. Yashiki , T . Matsuzawa and H. Mima,

Absorption of d r u g s from the nasal mucosa of r a t ,
Int. J. Pharm. 7, 317 (1981).

329. O. G. Rabbe , H. C. Yeh, G . J . Newton, R. F . Phalen

and D . J . Velasquez, In , Inhaled Particles IV, Par t 1,
Br i t i sh Occupational Hygiene Society, Ed inburgh ,
1977, p . 13.

330. J . W. Pa te r son , A. J . Woolcock and G. M.

Shenfield, Sta te of a r t : bronchodi la tor d r u g s ,
Am. Rev. Respir. Dis. 120, 1149 (1979).

331. K. Horsfield, S t r u c t u r e of the t

racheobronchial t r e e . In , Scientific Foundations of
Respiratory Medicine ( J . G. Scadding and G. Cummings, e
d s . ) , W. B . S a u n d e r s , Philadelphia, 1981, p p
. 54-70.

332. W. D. Fenn and H. Rahn, Handbook of Physiology:

Respiration, American Physiology Society, Washington, DC,
1973.

333. H. Von Hayek, The Human Lung, Hafer, New York, 1960.
Influence of Drug Properties on Design I 83

334. P . E . Morrow, Task group of lung dynamics:

Disposition and re tent ion models for in ternal dosimetry
of t h e human r e sp i r a to ry t r a c t , Health Phys.
12, 173 (1966).

335. M. B . Dolovich, J . Sanch is , C. Rossman and M. T.

Newhouse, Aerosol p e n e t r a n c e : a sensi t ive
index of per iphera l airway obs t ruc t ion , J. Appl.
Physiol. 40, 468 (1976).

336. S. P . Newman, F . Moren, D . Pavia, F . Little and S.

W. Clarke , Deposition of p r e s s u r i z e d suspens
ion aerosols inhaled t h r o u g h extension devices , Am.
Rev. Respir. Dis. 124, 317 (1981).

337. K. F . Lampe, Influence of disease on pharmacokinetic

parameters of inhaled s u b s t a n c e s . In , Modeling
of Inhalation Exposure to Vapors: Uptake, Distribution,
and Elimination, Vol. II (V. F i se rova-Bergerova , e d .
) , CRC P r e s s , Florida, 1983, p p . 157164.

338. J . D. Brain and P . A. Valberg , Deposition of

aerosols in the r e sp i r a to ry t r a c t , Am. Rev.
Respir. Dis. 120, 1325 (1979).

339. J . Heyder , Mechanism of aerosol part icle deposit

ion, Chest 80, 820 (1981).

340. R. Hicks , Pulmonary f ibrosis : a l le rg ies , dus t

diseases and d r u g s , Pharm. Int. 5, 304 (1984).

341. D . F . Proc tor , I . Andersen and G. Linquis t ,

Clearance of inhaled par t ic les from the human nose ,
Arch. Intern. Med. 131, 132 (1973).

342. R. E. Alber t , M. Lippmann, J . Spiegelman, C.

Strehlow, W. Briscoe, P . Wolfson, and N . Nelson, The
clearance of radioactive par t ic les from the human l u n
g s . In , Inhaled Particles and Vapors II ( C . N. Davies
, e d . ) , Pergamon P r e s s , Oxford, 1967, p p . 361.

343. C. W. LaBelle and H. Br i ege r , Pa t t e rn s and

mechanisms in the elimination of dus t from the l u n g .
I n , Inhaled Particles and Vapors ( C . N. Davies , e d .
) , Pergamon P r e s s , Oxford, 1961, p p . 356.

344. F . F . Hahn, G. J . Newton, and PI L. B r y a n t ,

In v i t ro phagocytosis of resp i rab le -s ized
monodisperse par t ic les by alveolar macrophages . In,
Pulmonary Macrophage and Epithelial Cells, CONF-760927, U
. S . Department of Commerce, Springfield, VA, 1977, p p .
424.

345. F . J . S t r ecke r , Tissue react ions in ra t l

ungs after dus t inhalaation with special r e g a r d to
bronchial dus t elimination and to the penet ra t ion of
dus t into the l u n g in te r s t i ces and lymphatic
nodes . In , Inhaled Particles and Vapors II (C . N. Davies
, e d . ) , Pergamon P r e s s , Oxford, 1967, p p . 141.

346. J . M. Lauweryns and J . H. B a e r t , Alveolar

clearance and the role of the pulmonary lymphat ics , Am.
Rev. Respir. Dis. 115, 627 (1977).

347. E. A. B . Brown, The localization, metabolism, and t h

e effects of d r u g s and toxicants in lung , Drug Metab.
Rev. 3, 33 (1974).

348. M. Simonescu, Ul t ras t ruc tura l organizat ion of

the alveolarcapillary un i t , In , Metabolic Activities
and the Lung, Ciba Foundation Symposium No. 78 ( J . Vane,
e d . ) , Amsterdam, 1980, p p . 11-26 .

349. E. E. Schneebe rge r , S t ruc tura l bas is for some

permeability p rope r t i e s of t he air-blood b a r r i
e r , Fed. Proc. Fed. Am. Soc. Exp. Biol. 37, 2471 (1978).

350. O. D . Wangensteen, L. E. Wittmers, J r . , and J . A.

Johnson , Permeability of t he mammalian blood-gas b a r r
i e r and i ts comp o n e n t s , Am. J. Physiol. 216, 719
(1969).

351. E. Taylor and K. A. Gaar, J r . , Estimation of

equivalent pore radi i of pulmonary capillary and alveolar
membranes, Am. J. Physiol. 218, 1133 (1970).

352. J . Gil, Organization of microcirculation in t he l u

n g , Ann. Rev. Physiol. 42, 177 (1980).

353. S . L. Schwar tz , Interact ion of nicotine and o ther

amines with t he endocytic and exocytic functions and
macrophages , Fed. Proc. 35, 85 (1976).

354. U. Smith and J . W. Ryan, An electron microscopic s t

u d y of t h e vascular endothelium as a si te for b radyk
in in and ATP act i vation in ra t l u n g , I n , Advances
in Experimental Medical Biology, Vol. 8 (N. Back, F . S
icuter i , and M. R. Silva, e d s . ) , 1970, p p .
249-262.

355. R. Effros, Small solutes and water . In , Lung Biology

in Health and Disease, Vol. 7 (N. C. S t aub , e d . ) ,
Marcel Dekker , New York, 1978, p p . 183-222.

356. S . J . Eunaad, L. S . Schanker , Absorption of d rugs

from the ra t l u n g , Am. J. Physiol. 223, 1227 (1972).
357. L. S . Schanker and M. J . Les s , Lung pH and
pulmonary ab sorpt ion of nonvolatile d r u g s in t h e r
a t , Drug. Metab. Dispos. 5, 174 (1977).

358. S . J . Enna and L. S. Schanker , Phenol r ed absorpt

ion from the rat lum: evidence of ca r r i e r t r a n s p
o r t , Life Sci. 12, 231 (1973).

359. T . H. Gardiner and L. S. Schanker , Absorpt ion of

disodium cromoglycate from the ra t l u n g : Evidence of
ca r r i e r t r a n s p o r t , Xenobiotica 4, 725
(1974).

360. K. R. Chapman, A. C. Braude and A. S . Rebuck ,

Anticholinergic t he rapy in asthma and chronic b ronch i t
i s , Hosp. Formulary 17, 686 (1982).

361. J . Hartiala, P . Uotila and W. Niens ted t ,

Absorption and metabolism of in t ra t racheal ly instil
led Cortisol and beclamethasone dipropionate in the
isolated perfused rat l u n g , Med. Biol. 57, 294 (1979).

362. P . A. Routledge and D . G. Shand , Presystemic d r u

g eliminat ion, Ann. Rev. Pharmacol. 19, 447 (1979).

363. R. H. Br i an t , E . W. Black well, F . M. Williams,

D . S. Davies and C. T . Dollery, The metabolism of
sympathomimetic b ronchodilator d r u g s by t h e isolated
pe r fused dog l u n g , Xenobiotica 3, 787 (1973).

364. Y. S . Bakhle , F i r s t p a s s metabolism of

endogenous and exogenous s u b s t r a t e s b y l u n g .
In , Presystemic Drug Elimination (C . F . George and D.
G. Shand , e d . ) , Bu t t e rwor th Scientific, London,
1982, p p . 147-172.

365. T . E. Picket t , T . C. Orton and M. W. Anderson , A

s tudy of t h e dynamics of imipramine accumulation in t
he isolated p e r fused rabbi t l u n g , Drug Metab.
Dispos. 3, 389 (1975).

366. D. P . Benziger and J . Edelson, Absorpt ion from the

vagina, Drug Metab. Rev. 14, 137 (1983).

367. D . J . Black and M. E. Orme, Inter individual

variabil i ty in oral cont racept ive disposit ion, TIPS
5, 480 (1984).

368. H. Okada, I . Yamazaki, Y. Ogawa, S. Hirai , T .

Yashiki , and H. Mima, Vaginal absorpt ion of a potent
luteinizing hormonere leas ing hormone analog ( leuprolide)
in r a t s I : Absorpt ion by various rou tes and absorpt
ion enhancement , J. Pharm. Sci. 71, 1367 (1982).

369. H. Okada, I . Yamazaki, T . Yashiki , and H. Mima,

Vaginal absorpt ion of a potent luteinizing
hormone-releasing hormone analogue (leuprolide) in r a t s
I I : Mechanism of absorpt ion enhancement with organic ac
ids , J. Pharm. Sci. 72, 75 (1983).

370. M. H. Burgos and C . E. Roig de Vargas l i na re s .

In , The Human Vagina (E. S . E. Hafez and T . N . Evans ,
e d . ) , Elsevier / North Holland Biomedical P r e s s ,
Amsterdam, 1978, p p . 63-69 .

371. C. E. Flowers , J r . , L . R. Beck, and W. H.

Wilborn, The cont racep t ive aspects of the anatomy,
morphology, and physiology of t h e vag ina . In , Vaginal
Contraception (G. I . Zatuchni , A. J . Sobreero , J . J .
Speidel and J . J . Sc ia r ra , e d s . ) , Harper and
Row, Hagers town, 1979, p p . 13-22 .

3 72. R. E . Trusse l l and R. F . MacDougal, Vaginal

acidity (in vivo glass electrode measurement) in late p
regnancy and i ts relation to t h e vaginal flora, Am. J.
Obstet. Gynecol. 39, 77 (1940).

373. T . Yotsuyanagi , A. Molokhia, S . Hwang, N. F . H.

Ho, G. L. Flynn and W . I . Higuchi, System approach to
vaginal del ivery of d r u g s I : Development of in s i
tu vaginal d r u g absorpt ion p r o c e d u r e , J.
Pharm. Sci. 64, 71 (1975).

374. E. Owada, C. R. Behl , S . S . Hwang, L. Suhardja , G.

L. F lynn , and W. I . Higuchi, Vaginal d r u g absorpt
ion in r h e s u s monkeys I : Development of methodology,
J. Pharm. Sci. 66, 216 (1977).

375. S . Hwang, E. Owada, T . Yotsuyanagi , L. Suhardja ,

G. L. F lynn , and W. I . Higuchi, Systems approach to
vaginal delivery of d r u g s I I : In s i tu vaginal
absorpt ion of unbranched aliphatic alcohols, J. Pharm.
Sci. 65, 1574 (1976).

376. S . Hwang, E. Owada, L. Suhardja , N. F . H. Ho, G. L.

F lynn , and W. I . Higuchi, Systems approach to vaginal
del ivery of d r u g s V: In s i tu vaginal absorpt ion of
1-alkanoic ac ids , J. Pharm. Sci. 66, 781 (1977).
377. C. R. Behl , System approach to t he s t u d y of
vaginal d r u g absorpt ion in r h e s u s monkey, P h . D
. T h e s i s , Universi ty of Michigan, Ann Arbor , 1979.

378. G. L. F lynn , N . F . H. Ho, S . Hwang, E . Owada, A.

Molokhla, C. R. Behl , W. I . Higuchi, T . Yotsuyanagi ,
Y. Shah , and J . Pa rk , In ter facing matrix re lease
and membrane absorpt ion— analysis of s teroid absorpt ion
from a vaginal device in t h e rabbi t doe . In ,
Controlled Release Polymeric formulations (D. R. Paul and
F . W. Har r i s , e d s . ) , Am. Chem. Soc, Washing ton ,
D . C . , 1976, p . 87.

379. D . R. Mishell, J r . , M. Talas , A. F . Parlow and

D. L. Moyer, Contraception by means of a Silastic vaginal
r i ng impregnated with medroxyproges terone ace ta te ,
Am. J. Obstet. Gynecol. 107, 100 (1970).

380. D. R. Mishell, J r . , M. Lumkin, S . Stone,

Inhibition of ovulation with cyclic use of proges t
roneimpregnated in t ravaginal devices , Am. J. Obstet.
Gynecol. 113, 927 (1972).

381. M. R. Henzl, D. R. Mishell, J r . , J . G. Velazquez,

and W. E. Leitch, Basic s tudies for prolonged proges
togen administration by vaginal devices , Am. J. Obstet.
Gynecol. 117, 101 (1973).

382. N. H. Lauersen and K. H. Wilson, The abortifacient

effects of a newly developed vaginal silastic device
impregnated with an 0.5% concentrat ion of 15(5)
-15-methyl -pros tag landin-F2(a lpha) methyl e s t e r in
t h e first t r imes te r , Contraception 13, 697 (1976).

383. A. Victor and D. B . Johnson , Contracept ive r i n g

s : selfadministered t reatment governed b leeding,
Contraception 16, 137 (1977).

384. D. R. Mishell, J r . , D . E. Moore, I. Roy, P . F . B

r e n n e r , and M. A. Page , Clinical performance and
endocrine profiles with cont racept ive vaginal r ings
containing a combination of estradiol and d n o r g e s t
r e l , Am. J. Obstet. Gynecol. 130, 55 (1978).

385. T . M. Jackan icz , Levonorgestrel and estradiol re

lease from an improved cont racept ive vaginal r i n g ,
Contraception 24, 323 (1981).

386. E. Diczfalusy and B-M. Landgren , Some pharmacokinetic

and pharmacodynamic p rope r t i e s of vaginal del ivery
systems tha t release small amounts of p roges togens at a
near zero-order r a t e . In , Long-Acting Contraceptive
Delivery Systems (G. I . Zatuchni , A. J . Sobre ro , J .
J . Speidel and J . J . Sc ia r ra , e d s . ) , Harper
and Row, Hagers town, 1984, p p . 213-227.

387. E. S . Nuwayser , D . L. Williams, P . M. Meier, T .

C. Wu, S. F . Merchant , and J . H. Ker r igan , A
microcapsule system for d r u g de l ive ry . I n ,
Proceedings of Drug Delivery Systems (H. L. Gabelnick, e d
. ) , U . S . Department of Health, Education, and
Welfare, Be thesda , Maryland, 1976, p p . 193-251.

388. D . L. Gardne r , A. J . Pa tnaus and D. L. F ink ,

Steroid release from microcapsules. In , Proceedings of
Drug Delivery Systems (H. L. Gabelnick, e d . ) , U . S .
Department of Health, Education, and Welfare, Be thesda ,
Maryland, 1976, p p . 193-251.

389. D . L. Gardner , D . J . F ink , and C . R. Hass ler ,

Potential del ivery of cont racept ive agen ts to t he
female rep roduc t ive t r a c t . I n , Controlled
Release of Pesticides and Pharmaceuticals (D. H. Lewis, e
d . ) , Plenum P r e s s , New York, 1981, p p . 99-109.

390. G. A. Digenis , M. J a y , R. M. Beihn, T . R. Tice,

and L. R. Beck, External sc in t ig raphy in t h e s tudy
of long-ac t ing cont racep t ive del ivery sys t ems . In
, Long-Acting Contraceptive Delivery Systems (G. I .
Zatuchni , A. J . Sobrero , J . J . Speidel , and J . J .
Sc ia r ra , e d s . ) , Harper and Row, Hagers town, 1984,
p p . 241-245.

391. A. Victor, Vaginal absorpt ion of cont racept ive s t

e r o i d s . In , Long-Acting Contraceptive Delivery
Systems (G. I . Zatuchni , A. J . Sobre ro , J . J .
Speidel and J . J . Sc ia r ra , e d s . ) , Harper and
Row, Hagers town, 1984, p p . 241-245.

392. Y. W. Chien, S. Y. Mares, J . B e r g , S . Huber , H.

J . Lamber t , and K. F . King, Controlled d r u g release
from polymeric delivery devices I I I : In v i t ro in
vivo correlat ion for in t ravaginal re lease of
ethynodiol diacetate from silicone devices in r a b b i t s
, J. Pharm. Sci. 64, 1776 (1975).

393. I . Sivin, D . R. Mishell, J r . , A. Victor, S. Diaz,

F . A. Sanchez , N. C. Nielsen, O. Akinla, T . Pyorala, E.
Cout inho, A. Faundes , S. Roy, P . B r e n n e r , T .
Ahren , M. Pavez, V. Brache , O. F . Giwa-Osagie, M. O.
Fason, B . Zausner-Guelman, E. Darze , J . C. Silva, J .
Diaz, T . M. Jackanicz , J . S t e r n , and H. Nash, A
mult icenter s tudy of levonorges t re l -es t rad io l
cont racept ive vaginal r i n g s . I I . Subjective and
objective meas u r e of effects , Contraception 24, 359
(1981).

394. G. E. Egli, and M. Newton, The t r an spo r t of

carbon par t ic les in t h e human female rep roduc t ive
t r a c t , Fertil. Steril. 12, 151 (1961).

395. D . H. de Boer , T ranspor t of par t icu la te matter

t h r o u g h the human female genital t r a c t , J .
Reprod. Fertil. 28, 295 (1972).

396. N. S. Mason, D . V. S . Gupta , D . W. Keller, R. S .

Youngqu i s t , and R. S. S p a r k s , Microencapsulation
of p roges t rone for contracept ion by in t racervica l
injection. In , Biomedical Applications of
Microencapsulation ( F . Lim, e d . ) , CRC P r e s s ,
Florida, 1984, p p . 76-84.

397. P . Lahteenmaki, H. Kurunmaki , T . Luukka inen , P .

O. A. Lahteenmaki, K. Ratsula , J . Toivonen, Development
of i n t r ace rv i cal s te ro idre leas ing sys tem. In ,
Long-Acting Contraceptive Delivery Systems (G. I .
Zatuchni , A. J . Sobre ro , J . J . Speidel , and J . J .
Sc ia r ra , e d s . ) , Harper and Row, Hagers town, MD,
1984, p p . 595-600.

398. H. M. Hasson, Morphologic features affecting IUD

performance. In , IUD Technology (E. S. E. Hafez and W. A.
A. Van Os , e d s . ) , G. K. Hall Medical Pub l i she r s
, Boston, 1980, p p . 13-19.

399. O. Puroinen and H. L. Kaihola, Uterine size measured

by u l t ra sound dur ing the menstrual cycle , Acta
Obstet. Gynecol. Scand. 54, 247 (1975).

400. H. Tatum, Clinical aspec ts of i n t r au te r ine

contracept ion: Circumspection 1976. In , Modern Trends in
Infertility and Conception Control (E. Wallach and R.
Kempers , e d s . ) , Williams and Wilkins, Baltimore,
1979, p . 333.

401. H. J . Tatum, In t r au te r ine contracept ion, Am.

J. Obstet. Gynecol. 112, 1000 (1972).

402. C. C. Chang and H. J . Tatum, Effects of i n t r au t

e r ine copper wire on resorpt ion of fe tuses in r a t s
, Contraception 11, 79 (1975).

403. F . Hefnawi, O. Kandil, G. Askalani , I . Se rou r ,

K. Zaki, F . Nasr , M. Mousa, Mode of action of the copper
IUD: effect on endometrium copper and cervical mucus sperm
migrat ion. In , Analysis of Intrauterine Contraception (
F . Hefnawi and S. Segal, e d s . ) , North-Holland Publ
ishing C o . , Amsterdam, 1975, p . 459.

404. T . Tamaya, Y. Nakata, Y. Ohno, S . Nioka, N. F u r u

t a , and H. Okada, The mechanism of action of the copper
i n t r au te r ine device, Fertil. Steril. 27, 767
(1976).

405. B . Pha r r i s s and C. Mitchell, Values of steroidal

i n t r au t e r ine contraception for developing coun t r
i e s , J. Steroid Biochem. 11, 469 (1979).

406. J . J . Sc ia r ra , A. Scommengna and G. I . Zatuchi,

Research and new developments in in t e ru t e r ine cont
racept ion . In , IUD Technology (E. S . E. Hafez and A. J
. M. Audebe r t , e d s . ) , MTP P r e s s , Lancas te r
, 1982, p p . 165-174.

407. G. F . Odland, S t ruc tu re of t he sk in . In ,

Biochemistry and Physiology of the Skin (L. A. Goldsmith,
e d . ) , Oxford University P r e s s , New York, 1983, p p
. 3 6 3 .

408. R. Scheuplein, Mechanisms of pe rcu taneous absorpt

ion I I : Trans ien t diffusion and the relat ive
importance of various routes of skin pene t ra t ion , J.
Invest. Dermatol. 45, 334 (1967).

409. R . J . Scheuplein, Mechanism of percu taneous absorp

t ion , J. Invest. Dermatol. 48, 79 (1967).

410. W. J . Albery and J . Had graf t , Percutaneous absorp

t ion : In vivo exper iments , J. Pharm. Pharmacol. 31,
140 (1979).

411. T . Higuchi , Physical chemical analysis of t h e pe

rcu taneous a b sorpt ion process from creams and ointments
, J. Soc. Cosmet. Chem. 11, 85 (1960).

412. A. M. Kligman, A biological brief on percu taneous

absorp t ion , Drug Develop. Ind. Pharm. 9, 521 (1983).

413. J . Hadgraf t , Percutaneous absorp t ion : possibilit

ies and p r o b lems, Int. J. Pharm. 16, 255 (1983).
414. R. J . Scheuplein and I . H. Blank, Permeability of
the sk in , Physiol. Rev. 51, 702 (1971).

415. R. H. Guy and H. I . Maibach, Drug delivery to local

subcutaneous s t r u c t u r e s following topical adminis
t rat ion, J. Pharm. Sci. 72, 1375 (1983).

416. J . Wepierre and J P . Marty, Percutaneous absorpt ion

of d r u g s , Trends Pharmacol. Sci. 1, 23 (1979).

417. J . Wepierre, Fac teu r s phys iques et physiologiques

in te rvenant dans l 'absorpt ion pe rcu tanee des
medicaments. In , Actualites Pharmacologiques, 31e se r i
e , Masson, Pa r i s , 1979, p p . 170-202.

418. J . E. Shaw, Development of t ransdermal the rapeu t

ic sys tems , Drug Dev. Ind. Pharm. 9, 579 (1983).

419. S. K. C h a n d r a s e d a r a n , Controlled release

of scopolamine for prophylaxis of motion s i ckeness ,
Drug Dev. Ind. Pharm. 9, 627 (1983).

420. W. R. Good, T r a n s d e r m ^ N i t r o controlled

delivery of n i t ro glycerin via t h e t ransdermal r ou t
e , Drug Dev. Ind. Pharm. 9, 647 (1983).

421. A. Karim, Transdermal absorp t ion: a unique oppor

tuni ty for a constant del ivery of n i t rog lycer in ,
Drug Dev. Ind. Pharm. 9, 671 (1983).

422. J . E. Shaw, Pharmacokinetics of n i t roglycer in and

clonidine del ivered by the t ransdermal r ou t e , Am.
Heart J. 108, 217 (1984).

423. D . L. Sekura and J . Scala, The percu taneous absorpt

ion of alkylmethyl sulfoxide, Adv. Biol. Skin 12, 257
(1972).

424. R. J . Folkman and H. I . Maibach, Percutaneous pene t

ra t ion of hydrocor t i sone with u r ea , Arch.
Dermatol. 109, 58 (1974).

425. R. E. S toughton , Enhanced percu taneous penet ra t

ion with l -dodecylazacycloheptan-2-one (Azone) , Arch.
Dermatol. 118, 474 (1982).

426. R. E. Stoughton and W. O. McClure, Azone R : A new

nontoxic enhancer of cutaneous pene t ra t ion , Drug Dev.
Ind. Pharm. 9, 725 (1983).
427. N. Baker and J . Hadgraf t , Faciliated percu taneous
absorp t ion : a model sys tem, Int. J. Pharm. 8, 193
(1981).

428. N . Bodor , J . Zupan, and S . Selk, Improved delivery

t h r o u g h biological membranes VII. Dermal del ivery
of cromoglycic acid (cromolyn) via i ts p r o d r u g s ,
Int. J. Pharm. 7, 63 (1980).

429. C. D. Yu, J . L. Fox, N. F . H. Ho, and W. I . Higuchi

, Phys i cal model of evaluation of topical p r o d r u g
del ivery-simultaneous t r a n s p o r t and bioconversion
of v idarab ine-5 f -va le ra te I I : Parame te r
determinat ions , J. Pharm. Sci. 68, 1341 (1979).

430. C. D . Yu, J . L. Fox, N. F . H. Ho, and W. I .

Higuchi , Phys i cal model evaluation of topical p r o d r
u g del ivery-s imultaneous t r a n s p o r t and
bioconversion of v idarabine-5 T -valera te I I : parame te
r determinat ions , J. Pharm. Sci. 86, 1347 (1979).

431. J . Hadgraf t , Theoretical aspects of metabolism in

the epidermis , Int. J. Pharm. 4, 229 (1980).

432. R. H. Guy and J . Hadgraf t , Percutaneous metabolism

with sa tu rab le enzyme k ine t ics , Int. J. Pharm. 11,
187 (1982).

433. R. C. Scott and P . H. D u g a r d , A potential model

for s tudy ing absorpt ion t h rough abnormal s t ra tum
corneum, J. Pharm. Pharmacol. 34, 35 (1982).

434. C. R. Beh l , E. E. Linn, G. L. F lynn , N. F . H. Ho,

W. I . Higuchi, and C. L. P ierson, Permeation of skin and
eschar by ant isept ics I I : influence of controlled b u
r n s on the permeation of phenol , J. Pharm. Sci. 72, 397
(1983).

435. J . H. Trueblood, R. M. Rossomondo, W. H. Carlton and

L. A. Wilson, Corneal contact times of ophthalmic vehic
les . Evaluation by microscint igraphy, Arch. Ophthalmol.
93, 127 (1975).

436. H. Benson , Permeability of t he cornea to topically

applied d r u g s , Arch. Ophthalmol. 91, 313 (1974).

437. J . W. Shell, Ophthalmic d r u g del ivery sys tems ,

Surv. Ophthalmol. 29, 117 (1984).
438. A. Mitra, Passive and facilitated t r a n s p o r t of
pilocarpine across the corneal membrane of the r abb i t ,
P h . D . Thes i s , Universi ty of Kansas , 1983.

439. E. Tomlinson, S . S. Davis , O. Olejnik, and C. G.

Wilson, Altered ocular disposition of sodium cromoglycate
upon ion-pa i r and complex coacervate formation with
dodecylbenzyldimethylammonium chlor ide , J. Pharm.
Pharmacol. 31, 749 (1981).

440. V. H. L . Lee, P . T . Urrea , R. E. Smith and D . J .

Schanzl in, Ocular d r u g bioavailability from topically
applied liposomes, Surv. Ophthalmol. 29, 335 (1985).

441. C. P . Wei, J . A. Anderson , and I . Leopold, Ocular

absorpt ion and metabolism of topically applied epinephr
ine and a dipivalyl e s t e r of ep inephr ine . Invest.
Ophthalmol. Vis. Sci. 17, 315 (1978) .

442. S. S. Chrai and J . R. Robinson, Ocular evaluation of

methylcellulose vehicle in albino r a b b i t s , J. Pharm.
Sci. 63, 1218 (1974). influence of Drug Properties on
Design I 91

443. T . F . Pat ton and J . R. Robinson, Ocular evaluation

of polyvinyl alcohol, J. Pharm. Sci. 64, 1312 (1975).

444. C. A. Alder , D . M. Maurice and M, E. Pa t te r son ,

The effect of viscosi ty of the vehicle on t he penetra t
ion of fluorescein into the human eye , Exp. Eye. Res. 11,
34 (1971).

445. H. W. Hui and J . R. Robinson, Effect of part icle

dissolution r a t e on ocular d r u g bioavailabili ty, J.
Pharm. Sci. 75, 280 (1986).

446. R. E . S t r a t fo rd , D . C . Yang, M. A. Redell

and V. H. L . Lee, Effects of topically applied liposomes
on disposition of epinephr ine and insul in in the albino
rabbi t eye , Int. J. Pharm. 13, 263 (1983).

447. R. E. S t r a t fo rd , D . C . Yang, M. A. Redell and

V. H. L. Lee, Ocular d is t r ibut ion of l
iposome-encapsulated epinephr ine and inulin in t h e
albino rabb i t , Curr. Eye. Res. 2, 377 (1983).

448. G. Smolin, M. Okumoto, S . Feiler , D . Condon, Idoxur

id ineliposome t h e r a p y for he rpes simplex k e r a t
i t i s , Am. J. Ophthalmol. 91, 220 (1981).
449. H. E. Schaeffer and D . L. Krohn, Liposomes in topical
d r u g de l ivery , Invest. Ophthalmol Vis. Sci. 22, 220
(1982).

450. M. Barza , J . Baum, F . Szoka, Pharmacokinetics of

subconjunct ival l iposome-encapsulated gentamicin in
normal rabbi t eye s , Invest. Ophthalmol. Vis. Sci. 25,
486 (1984).

451. J . W. Shell and R. W. Bake r , Diffusion systems for

controlled release of d r u g s to the eye , Ann.
Ophthalmol. 6, 1037 (1974).

452. R. C. Capozza, L. Sendelbeck, W. J . Balkenhol,

Prepara t ion and evaluation of a bioerodible nal t rexone
del ivery sys tem. In , Polymeric Delivery Systems:
Midland Macromolecular Monog r a p h s , Vol. 5, Gordon and
Breach , New York, 1978, p p . 5 9 7 3 .

453. H. B u n d g a a r d , D r u g t a r g e t i n g : P r
o d r u g s . I n , Topics in Pharmaceutical Sciences 1983
(D. D. Breimer and P . Spe ise r , e d s . ) , Elsevier
Science Pub l i she r s , 1983, p p . 329-343.

454. N. Bodor, Novel approaches to t he des ign of safer d

r u g s : soft d r u g s and si te-specific chemical
delivery sys tems , Adv. Drug Res. 13, 255 (1984).

455. C. R. Alving, Delivery of l iposome-encapsulated d r u

g s to macrophages , Pharmac. Ther. 22, 407 (1983).

456. C. A. Hunt , H. Kinada, M. Raede r -Sh iko r r , K.

Hirano, J . Nakamura, R. Abra , and H. Scre ier ,
Liposomes, Are they effective d r u g ca r r i e r s? I n ,
Topics in Pharmaceutical Sciences 1983 (D. D . Breimer and
P . Spe iser , e d s . ) , Elsevier Science Pub l i she r
s , 1983, p p . 257-263.

457. K . J . Widder and A. E. Senyei , Magnetic

microspheres : A vehicle for selective t a r g e t i n g
of d r u g s , Pharmac. Ther. 20, 377 (1983).

458. P . Couvreu r , B . Kante, L. Grislain, M. Roland, and

P . Speiser , Toxicity of polyalkylcyanoacrylate nanopart
ic les I I : Doxorubicinloaded nanopar t ic les . J. Pharm.
Sci. 71, 790 (1982).

459. D . C. Edwards , Ta rge t ing potential and ant ibody

conjugates , Pharmac. Ther. 23, 147 (1983).
460. R. B . Banke r t , Development and use of monoclonal
antibodies in t he t rea tment of cancer , Cancer Drug
Delivery, 1, 251 (1984).

461. R. Obr i s t , Monoclonal antibodies as d r u g ca r r

i e r s in oncology, Trends Pharmacol. Sci., 4, 375
(1983).

462. U. Zimmermann, Cellular d r u g c a r r i e r systems

and the i r p o s sible t a r g e t i n g . I n , Targeting
of Drugs (E. P . Goldberg , e d . ) , John Wiley & Sons ,
1983, p p . 153-200.

463. D. A. Lewis and H. O. Alpar , Therapeut ic

possibilities of d r u g s encapsula ted in e r y t h r o
c y t e s , Int. J. Pharm. 22, 137 (1984).

464. M. J . Poznansky, Enzyme-protein conjugates : new

possibili t ies for enzyme t h e r a p y , Pharmac. Ther.
21, 53 (1983).

465. L. Gros , H. Ringsdorf, and H. S c h u p p , Polymeric

anti tumor agen t s on a molecular and on a cellular level
, Agnew. Chem. Int. Engl. 20, 305 (1981).

466. D . P . Worth, J . N. Harvey , J . Brown, and M. R.

Lee, C-Lglutamyl-L-dopa is a dopamine p r o d r u g , relat
ively specific for t h e k idney in normal subjec ts ,
Clin. Sci. 69, 207 (1985).

467. V. J . Stella and K . J . Himmelstein, P r o d r u g

and si te-specific d r u g de l ivery , J. Med. Chem. 23,
1275 (1984).

468. J . W. Simpkins , N. Bodor, and A. Enz , Direct

evidence for bra in-specif ic release of dopamine from a
redox del ivery s y s tem, J. Pharm. Sci. 74, 1033 (1985).

469. A. W. Segeal , E. J . Willis, G. Slvain, C. D . V.

Black, and G. Gregor iadis , Morphological observa t ions
on the cellular and subcel lular dest inat ion of in t
ravascu la r ly administered liposomes, Br. Exp. Pathol.
55, 320 (1974).

470. L. R. McDougall, J . K. Dunick , M. S. McNamee, and J

. P . Kr i s s , Distr ibut ion and fate of syn the t ic
lipid vesicles in the mouse: a combined radiounclide and
spin label s t u d y , Proc. Natl. Acad. Sci. USA 71, 3487
(1974).
471. G. Gregoriadis and E. D. Neerunjun, Control of the ra
te hepat ic up take and catabolism of l iposome-entrapped
pro te ins injected into the r a t s . Possible the rapeu t
i c appl icat ions, Eur. J. Biochem. 47, 179 (1974).

472. G. Gregoriadis and E. D . Neerunjun, Homing of

liposomes to t a rge t cel ls , Biochem. Biophys. Res.
Comm. 65, 537 (1975).

473. V. T . Marchesi, T . W. Tillack, R. L. Jackson , J . P

. Seg re s t , and R. E. Scot t , Chemical character izat
ion and surface or ientation of t h e major glycoprotein of
the human e ry th rocy t e memb r a n e , Proc. Natl. Acad.
Sci. USA 69, 1445 (1972).

474. R. L . Juliano and D . J . Stamp, Lectin-mediated at

tachment of g lycoprote in-bear ing liposomes to cel ls ,
Nature 261, 235 (1976).

475. G. Weissman, D. Bloomgarden, R. Kaplan, C. Cohen, S.

Hoffs te ine , T . Collins, A. Gotlier and D . Nagle, A
general method for t he in t roduct ion of enzymes by
means of immunoglobulincoated liposomes of deficient cel ls
, Proc. Natl. Acad. Sci. USA 72, 88 (1975).

476. G. Gregor iad is , A. Meehan and M. M. Mah, In teract

ions of an t ibody-bea r ing small unilamellar liposomes
with t a rge t free ant igen in vitro and in vivo,
Biochem. J. 200, 203 (1981).

477. G. Pos te , R. Kirsch , and T . Koest ler , The

challenge of l iposome t a rge t ing in v ivo . I n ,
Liposome Technology, Vol. I I I . Targeted Drug Delivery
and Biological Interaction (G. Gregori ad i s , e d . ) ,
CRC P r e s s , Boca Raton, 1984, p p . 1-28.

478. M. J . Poznansky and R. L. Jul iano, Biological

approaches to t he controlled d r u g del ivery of d r u g
s : A critical review, Pharmacol. Rev. 36, 277 (1985).

479. R. L. Magin and M. R. Niesman, Tempera tu re -dependen

t d r u g release from large unilammellar l iposomes,
Cancer Drug Delivery 1, 109 (1984).

480. J . N. Weinstein, R. D. Klausner , T . I n n e r a r i

t y , E. Rals ton, and R. Blumental , Phase t rans i t ion
r e l ease , a new approach to the in teract ion of pro te
ins with lipid ves ic les : Application to lipop r o t e i
n s , Biochim. Biophys. Acta 647, 270 (1981).
481. V. P . Torchi l in , M. I . Ta t i sov , and V. N.
Smirnov, Magnetic Sephadex as a ca r r i e r for enzyme
immobilization and d r u g t a r ge t ing , J. Biomed.
Mater. Res. 19, 461 (1985).

482. M. Kanke , G. H. Simmons, D . L. Weiss, B . A. Biv ins

, and P . P . Deluca, Clearance of 1 4 l C r l a b e l e
d microspheres from blood and dis t r ibut ion in specific
o rgans following in t ravenuous and in t raa r t e r i a
l administration in beagle dogs , J. Pharm. Sci. 69. 755
(1980).

483. J . J . B u r g e r , E. Tomlinson, E. M. A. Mulder

and J . G. McVie, Albumin microspheres for in t r aa r t e
r i a l tumor t a r g e t i n g . I . Pha r maceutical a
spec t s , Int. J. Pharm. 23, 333(1985) .

484. R. J . W. Blanchard , I . Gro tenhuis , J . W. LaFare

, and J . F . P e r r y , Blood supply to hepat ic V2
carcinoma implants as measu red by radioactive microspheres
, Proc. Soc. Exp. Biol. Med. 118, 465 (1965).

485. B . Lindell, K. F . Aronseh , U. Rothman, and H. O.

Sjogren, The circulation in l iver t i s sue and
experimental l iver metastases before and after
embolization of t h e l iver a r t e r y , Res. Exp. Med.
171, 63-70 (1977).

486. S. Dakhil , W. Ensminger , K. Cho, Niederhuber , K.

Doan, and R. Wheller, Improved regional selectivity of
hepat ic ar ter ia l BCNU with degradable microsphers ,
Cancer 50, 631 (1982).

487. R. F . Tuma, J . O. F o r s b e r g , and B . A g e r

u p , Enhanced u p take of actinomycin D in the dog k idney
by simultaneous injection of degradable s t a rch
microspheres into the renal a r t e r y , Cancer 50, 1
(1982).

488. T . Kato, R. Nemoto, H. Mori, M. Takahash i , Y.

Tamakawa, and M. Harada, Arter ial chemoembolization with
microencapsulated an t i -cancer d r u g , JAMA 245, 1123
(1981).

489. S . Beni ta , Microcapsules: New applications and

charac te r iza t ion , Labo-Pharma. Probl. Tech. 32, 694
(1984).

490. J . T . Doluisio and L. W. D i t t e r t , Influence

of repet i t ive dosing of te t racyc l ines on biological
half-life in se rum, Clin. Pharmacol. Ther. 8, 222 (1974).
2 Chapter 2 Theory of Mass Transfer

1. D. Eisenberg and D. Crothers, Physical Chemistry with

Applications to the Life Sciences, Benjamin/Cummings, Menlo
Park, CA, 1979, Chaps. 4 and 7.

2. K . J . Laidler and J. H. Meiser, Physical Chemistry,

Benjamin/ Cumming, Menlo Park, CA, 1982, Chap. 5.

3. J. Crank, The Mathematics of Diffusion, 2nd ed . ,

Clarendon Press, Oxford, 1975.

4. R. B. Bird, W. E. Stewart, and E. N. Lightfoot,

Transport Phenomena, John Wiley & Sons, New York, 1960.

5. D. Hershey, Transport Analysis, Plenum/Rosetta, New

York, 1973.

6. R. W. Fahien, Fundamentals of Transport Phenomena,

McGrawHill, New York , 1983.

7. Y. W. Chien, Novel Drug Delivery Systems, Marcel Dekker

, New York, 1982.

8. A. Martin, J . Swarbr ick , and A. Cammarata, Physical

Pharmacy, Lea & Feb ige r , Philadelphia, 1983, C h a p .
15.

9. G. L. F lynn , S. H. Yalkowsky, and T . J . Roseman,

Mass t r a n s por t phenomena and models: Theoretical
concep ts , J. Pharm. Sci. 63, 479 (1974) .

10. R. I . Macey, Physiology of Membrane Disorders ( T . E.

Andreoli , J . E. Hoffman, and D. D. Fanes t i l , E d s .
) , Plenum Medical Book, New York, 1978, Chap . 7.

11. R. R. B u r n e t t e , A Mone-Carlo model for the pass

ive diffusion of d r u g s t h rough the stratum corneum,
Int. J. Pharm. 22:89 (1984).

12. D. Eisenberg and D . C r o t h e r s , Physical

Chemistry with Applications to the Life Sciences,
Benjamin/Cummings, Menlo Pa rk , CA, 1979, Chap . 15.

13. K. J . Laidler and J . H. Meiser, Physical Chemistry ,

Benjamin/ Cummings, Menlo Pa rk , CA, 1982, Chap . 18.

14. A. Eins te in , Investigations on the Theory of

Brownian Movement, Methuen, London, 1926.
15. C. Tanford , Physical Chemistry of Macromolecules, John
Wiley & Sons , New York, 1961, C h a p . 6.

16. L. Page , Introduction to Theoretical Physics, D . Van

Nos t rand , New York, 1928, Chap . 6.

17. M. Wu, Determination of concent ra t ion-dependent

water diffusivity in a kera t inous membrane, J. Pharm.
Sci. 72, 1421 (1983).

18. R. H. Guy, J . Hadgraf t , I . W. Kellway, and M. J .

Taylor , Calculations of d r u g release r a t e s from
spherical pa r t i c l e s , Int. J. Pharm. 11:199 (1982).

19. R. J . Scheuplein and R. L. Bronaugh , Biochemistry and

Physiology of the Skin, Vol. 2 (L. A. Goldsmith, E d . ) ,
Oxford Unive r s i t y P r e s s , New York, 1983, Chap .
58.

20. G. L. Flynn and S. H. Yalkowsky, Correlation and

predict ion of mass t r a n s p o r t across membranes I :
Influence of alkyl chain l eng th on f lux-determining p
roper t i e s of b a r r i e r and diffusant, J. Pharm.
Sci. 61, 838 (1972) .

21. T . Higuchi , Rate of release of medicaments from

ointment bases containing d r u g s in suspension, J.
Pharm. Sci. 50 (10) , 874 (1961).

22. S . J . Desai , P . Singh, A. P . Simonelli, and W. I .

Higuchi , Invest igat ion of factors influencing release
of solid d r u g d i s p e r s e d in iner t matr ices . II
Quanitation of p r o c e d u r e s , J. Pharm. Sci. 55,
1224 (1966).

23. D. R. Paul and S. K. McSpadden, Diffusional release of

a solute from a polymer matr ix, J. Memb. Sci. i :33
(1976).

24. F . Bo t t a r i , G. Di Colo, E. Nannipier i , M. F .

Sae t tone , and M. F . Seraf ini , Release of d r u g s
from ointment bases I I : in vitro re lease of benzocaine
from suspens ion type aqueous ge l s , J. Pharm. Sci. 66,
926 (1977).

25. H. Y. Ando, N. F . H. Ho, and W. I . Higuchi , Skin as

an act ive metabolizing b a r r i e r I : Theoretical
analysis of topical bioavailabili ty , J. Pharm. Sci. 66,
1525 (1977).
26. J . L. Fox, C. Yu, W. I . Higuchi, and N. F . H. Ho,
General physical model for simultaneous diffusion and
metabolism in biological membranes. The computational
approach for the s t eadys ta te case , Int. J. Pharm. 2:41
(1979).

27. J . Hadgraf t , Theoret ical a spec t s of metabolism

in the epidermis , Int. J. Pharm. 4:229, (1980).

28. R. H. Guy and J . Hadgraf t , Percutaneous metabolism

with s a t u r able enzyme k ine t ics , Int. J. Pharm.
11:187, (1982).

29. O. Kedem and A. Katchalsky, A physical in te rpre ta t

ion of the phenomenological coefficients of membrane
permeabil i ty, J. Gen. Physiol. 45, 153 (1961-62) .

30. A. Katchalsky and P . F . C a r r a n , Nonequilibrium

Thermodynamics in Biophysics, Harvard Universi ty P r e s
s , Cambridge, MA, 1965.

31 . P . S c h u s t e r , Biophysics (W. Hoppe, W.

Lohmann, H. Markl, and H. Ziegler E d s . ) , Sp r inge r
-Ver l ag , Ber l in , 1983, Chap . 8.

32. K. A. F ischer and W. S toeckenius , Biophysics (W.

Hoppe, W. Lohmann, H. Markl, and H. Ziegler E d s . ) , Sp
r inge r -Ver l ag , Ber l in , 1983, Chap . 12.

33. R. Chang, Physical Chemistry with Applications to

Biological Systems, 2nd ed . , Macmillan, New York, 1981.
4 Chapter 4 Use of Polymers in Controlled
Release of Active Agents

1. R. W. Baker and H. K. Lonsdale , Controlled re lease :

Mechanism and r a t e s . I n , Controlled Release of
Biologically Active Agents, (A. C. Tanqua ry and R. E.
Lacey, E d s . ) Plenum P r e s s , New York, 1974, p p .
1 5 7 1 .

2. T . Higuchi , Rates of release of medicaments from

ointment-bases containing d r u g s in suspens ion , J.
Pharm, Sci. 50, 874-875 (1961).

3. W. P . 0 T Neill, Membrane sys tems . In , Controlled

Release Technologies: Methods, Theory and Applications,
Vol. I (A. G. Kydonieus , E d . ) , CRC P r e s s , Boca
Raton, FL, 1980, p p . 129182.

4. F . Theeuwes and S . I . Yum, Principles of t he design

and operation of generic osmotic pumps for the delivery of
semi-solid or liquid d r u g formulations, Ann. Biomed.
Eng. 4, 343-353 (1976).

5. F . Theeuwes , Delivery of active agents by osmosis. I n

, Controlled Release Technologies: Methods, Theory and
Applications, Vol. II (A. G. Kydonieus , E d . ) CRC P r e
s s , Boca Raton, FL, 1980, p p . 195-205.

6. F . Theeuwes , Elementary osmotic pump, J. Pharm. Sci.

64, 19871991 (1975).

7. R. Langer and N. P e p p a s , Chemical and physical s t

r u c t u r e of polymers as c a r r i e r s for
controlled release of biactive agen t s : A review, Rev.
Macromol. Chem. Phys. C23, 61-126 (1983).

8. J . Heller, Controlled release of biologically active

compounds from bioerodible polymers , Biomaterials 1,
51-57 (1980).

9. J . Heller, Biodegradable polymers in controlled d r u g

de l ivery . CRC Crit. Rev. Ther. Drug Carrier Systems 1,
39-90 (1984).

10. R. V. Pe t e r s en , C. G. Anderson , S . M. F a n g ,
D . E. Gregonis , S. W. Kim, J . Feijen, J . M. Anderson
and S . Mitra, Controlled release of p roges t ins from
poly (a-amino acid) c a r r i e r s . In , Controlled
Release of Bio active Materials, (R. W. Bake r , E d . ) ,
Academic P r e s s , New York, 1980, p p . 45-60.
11. G. R. Rowland, G. J . O'Neill, and D. A. L. Davies , S
u p p r e s sion of tumour growth in mice by a d rug-an t
ibody conjugate us ing a novel approach to l inkage,
Nature (London) 255, 487488 (1975).

12. F . W. Har r i s , A. E. Aulabaugh, R. D . Case , M. K.

D y k e s , and W. A. Feld, Polymers containing pendent
herbicide subs t i t u e n t s : Preliminary hydrolys is s
t ud i e s , I n , Controlled Release Polymeric
Formulations (D. R. Paul and F . W. Har r i s , E d s . ) ,
American Chemical Society, ACS Symposium Series 33,
Washington , DC, 1976, p p . 222-230.

13. C. G. P i t t , A. R. Jeffcoat , R. A. Zweidinger, and

A. Schindler , Susta ined d r u g del ivery sys t ems . I
. The permeabili ty of poly (e-caprolactone) ,
poly(DL-lactic acid) and the i r copolymers, J. Biomed.
Mat. Res. 13, 497-507 (1979).

14. C. G. P i t t , M. M. Gratz l , A. R. Jeffcoat, R.

Zweidinger, and A. Sch ind le r , Sus ta ined d r u g del
ivery systems I I : Factors affecting re lease ra tes from
poly(e-caprolactone) and rela ted biodegradable po lyes t
e r s , J. Pharm. Sci. 68, 1534-1538 (1979).

15. C. G. P i t t , T . A. Marks , and A. Sch ind le r ,

Biodegradable d r u g del ivery systems based on aliphatic
po lyes t e r s : Application to cont racept ives and
narcot ic an tagon i s t s . I n , Controlled Release of
Bio active Materials, (R. W. Bake r , E d . ) , Academic P
r e s s , New York , 1980, p p . 19 -43 .

16. C. G. Pitt and A. Sch ind le r , The design of

controlled d r u g del ivery systems based on
biodegradable polymers . I n , Biodegradables and Delivery
Systems for Contraception, (E. S. E. Hafez, and W. A. A. v
a n O s , E d s . ) , G. K. Hall Medical Pub l i s h e r s
, Bos ton , 1980, p p . 17-46 .

17. S. J . O r y , C. B . Hammond, S. G. Yancy, W. R.

Hendren , and C. G. P i t t , The effect of biodegradable
contracept ive capsule (Capronor) containing levonorges t
re l on gonadotropin , es t rogen and p roges te rone leve
l s , Am. J. Obstet. Gynecol. 145, 600-605 (1983).

18. V. P . Torchi l in , E. G. T i shenko , V. N . Smirnov,

and E. I . Chazov, Immobilization of enzymes in slowly
soluble c a r r i e r s , J. Biomed Mat. Res. 11, 223-235
(1977).
19. I . Sjoholm, and P . Edman, Acrylic microspheres in
vivo. I . Dis t r ibut ion and elimination of
polyacrylamide micropart icles after in t r avenous and in
t raper i tonea l injection in mouse and r a t , J.
Pharmacol. Exp. Ther. 211, 656-662 (1979).

20. P . Edman, B . Ekman, and I . Sjoholm, Immobilization

of p ro te ins in microspheres of biodegradable po lyac ry
ldex t ran , J. Pharm. Sci. 69, 838-842 (1982).

21 . J . Heller, R. W. B ake r , R. F . Helwing, and M. E.

T u t t l e , Control led release of water-soluble
macromolecules from bioerodible h y d r o g e l s ,
Biomaterials 4, 262-266 (1983).

22. P . Y. Wang, and B . P . Ar l i t t , S t ruc tu ra l

requi rements for the degradat ion of condensation
polymers in vivo. In , Biomedical Applications of
Polymers, (H. P . Gregor , E d . ) , Plenum P r e s s ,
New York, 1975, p p . 173-182.

23. J . Heller and R. W. B a k e r , Theory and pract ice

of controlled d r u g delivery from bioerodible polymers .
In , Controlled Release of Bioactive Materials (R. W. B a k
e r , E d . ) , Academic P r e s s , New York , 1980, p p
. 1-17.

24. D . L. Wise, J . B . Gregory , D . M. Newberne , L. C.

Bartholow, and J . B . S t a n b u r y , Resul ts on
biodegradable cylindrical s u b dermal implants for fertil
i ty cont ro l . I n , Polymeric Delivery Systems ( R . J
. Kostelnik, E d . ) Gordon and Breach Science Pub l i s h
e r s , New York , 1978, p p . 121-138.

25. L. R. Beck, C. E. Flowers , V. Z. Pope, W. H. Wilborn,

and T . R. T ice , Clinical evaluation of an improved
injectable microcapsule contracept ive sys tem, Am. J.
Obstet. Gynecol. 147, 815-821 (1983).

26. L. R. Beck and T . R. T ice , Poly(lactic acid) and

poly (lactic acid-co-glycolic acid) contracept ive
delivery sys tems . I n , LongActing Steroid Contraception
(D. R. Mishell, J r . , E d . ) , Raven P r e s s , New
York , 1983, p p . 175-199.

27. L. C. Lappas and W. McKeehan, Synthe t ic polymers as

potential enter ic and sus ta inedre lease coa t ings , J.
Pharm. Sci. 51, 808 (1962).
28. L. C. Lappas and W. McKeehan, Polymeric pharmaceutical
coatings mater ials , I . Prepara t ion and p r o p e r t i
e s , J. Pharm. Sci. 54, 176-181 (1965).

29. L. C. Lappas and W. McKeehan, Polymeric pharmaceutical

coatings materials I I . In vivo evaluation as enter ic coa
t ings , J. Pharm. Sci. 56, 1257-1261 (1967).

30. J . Heller, R. W. B a k e r , R. M. Gale, and J . O.

Rodin, Controlled d r u g release by polymer dissolut ion,
I . Partial e s t e r s of maleic anhydr ide
copolymers—propert ies and t h e o r y , J. Appl. Polymer
Sci. 22, 1991-2009 (1978).

31. J . Heller, D. W. H. Penhale , and R. F . Helwing,

Prepara t ion of poly(or tho e s t e r s ) by the react
ion of ke tene acetals and polyols , J. Polymer Sci.,
Polym. Lett. 18, 619-624 (1980).

32. J . Heller, B. K. Fr i tz inger , S. Y. Ng, and D. W.

H. Penhale , In vitro and in vivo re lease of l evonorgres
t re l from p o l y ( o r t h o e s t e r s j . I. Linear
polymers , J. Controlled Release 1, 225-232 (1985).

33. J . Heller, B . K. F r i t z inge r , S . Y. Ng , and

D. W. H. Penhale , In vitro and in vivo re lease of
levonorges t re l from poly(or tho e s t e r s ) . I I .
Crossl inked polymers , J. Controlled Release 1, 233-238
(1985).

34. C. Shih , T . Higuchi , and K. J . Himmelstein, D r u g

del ivery from catalyzed erodible polymeric matrices of po
ly(or tho e s t e r ) s , Biomaterials 5, 237-240 (1984).

35. R. V. S p a r e r , C . Sh ih , C D . Ringeisen, and K.

J . Himmelstein, Controlled Release from erodible poly(or
tho e s t e r ) d r u g delivery sys tems , J. Controlled
Release 1, 23-32 (1984).

36. A. Conix, Aromatic po lyanhydr ides , a new class of h

igh melting fiber-forming polymers , J. Polymer Sci. 29,
343-353 (1958).

37. H. B . Rosen, J . Chang , G. E. Wnek, R. J . L inhard t

, and R. Langer , Bioerodible po lyanhydr ides for
controlled d r u g de l ivery , Biomaterials 4, 131-133
(1983).

38. K. W. Leong, B . C . B r o t t , and R. Lange r ,

Bioerodible polyanhydr ides as a d r u g ca r r i e r mat r
ix , Polymer Reprints 25(1) , 201-202 (1984).
5 Chapter 5
Pharmacokinetic/Pharmacodynamic Basis of
Controlled Drug Delivery

1. B. E. Ballard, An overview of prolonged action drug

dosage form, In, Sustained and Controlled Release Drug
Delivery Systems (J. R. Robinson, e d . ) , Marcel Dekker,
Inc . , New York, 1978, pp. 1-69.

2. P. G. Welling, Oral controlled drug administration:

Pharmacokinetic considerations, Drug Dev. Ind. Pharm. 9,
1185-1225 (1983).

3. M. Rowland, D r u g administrat ion and reg imens , I n

, Clinical Pharmacology, 2nd ed . (K. L. Melmon and H. F .
Morrelli, e d s . ) , Macmillan Publ ishing C o . , I n c
. , New York , 1978, p p . 25 -70 .

4. H. G. Boxenbaum, Physiological and pharmacokinetic

factors affecting performance of sus ta ined release
dosage forms, Drug Dev. Ind. Pharm. 8, 1-25 (1982).

5. M. Gibaldi and D . P e r r i e r , Pharmacokinetics, 2nd

ed . , Marcel D e k k e r , I n c . , New York, 1982.

6. J . G. Wagner, Fundamentals of Clinical

Pharmacokinetics. D r u g Intell igence Publicat ion,
Hamilton, IL, 1975.

7. K. J . Himmelstein and R. J . Lu tz , A review of t h e

applications of physiologically based pharmacokinetic
modeling. J. Pharmacokin. Biopharm. 7, 127 (1979).

8. P . G. Welling and M. R. Dobr inska , Dosing considerat

ions and bioavailability assessment of controlled d r u g
del ivery sys tems , I n , Sustained and Controlled Drug
Delivery Systems, 2nd ed . ( J . R. Robinson and V. H. L.
Lee , e d s . ) . Marcel Dekker , I n c . , New York,
1986, p p . 253-290.

9. J . C. K. Loo and S. Riegelman, New method for

calculating t he in t r ins ic absorpt ion r a t e of d r
u g s , J. Pharm. Sci. 57, 918-928 (1968).

10. J . G. Wagner and E. Nelson, Kinetic analysis of blood

levels and u r i n a r y excret ion in absorpt ive phase
after single doses of d r u g , J. Pharm. Sci. 53,
1392-1403 (1964).

11 . K. Yamaoka, T . Nakagawa, and T . Uno, Stat ist ical

moments in pharmacokinet ics , J. Pharmacokin. Biopharm.
6, 547-558 (1978).

12. S. Riegelman and P . Collier, The application of s tat

is t ical moment theory to the evaluation of in vivo
dissolution time and absorp tion t ime, J. Pharmacokin.
Biopharm. 8, 509-534 (1980).

13. J . G. Wagner, Linear pharmacokinetic models and

vanishing exponential t e r m s : Implication in
pharmacokinet ics , J. Pharmacokin. Biopharm. 4, 395-425
(1976).

1.4. J . G. Wagner, Application of the Wagner-Nelson

absorpt ion method to the two-compartment open model, J.
Pharmacokin. Biopharm. 2, 469-486 (1974).

15. K. K. H. Chan and M. Gibaldi, Evaluat ing d r u g

absorpt ion after oral administrat ion: Some problems and
some solut ions . Eur. J. Clin. Pharmacol. 26, 255-259
(1984).

16. F . H. Dos t , Uber ein einfaches s ta t i s t i sches

Dosis-Umsatzgesetz , Klin. Wochenschr. 36, 655-657 (1958).

17. D . J . Cu t l e r , Theory of t he mean absorpt ion

time, an adjunct to conventional bioavailability s t u d i
e s , J. Pharm. Pharmacol., 30, 476-478 (1978).

18. L. Z. Benet and R. L. Galeazzi, Noncompartmental

determination of s teady s ta te volume of d i s t r ibu t
ion , J. Pharm. Sci., 68, 1071-1074 (1979).

19. A. Rescigno and G. S e g r e , Drug and Tracer

Kinetics, Blaisdell , Waltham, MA, 1966, p p . 161-167.

20. M. Bialer , Z. M. Look, B . M. S i lber , and A.

Yacobi, The relat ionship between d r u g input and mean
res idence time in the body , Biopharm. Drug Dispos., in p
r e s s .

21 . M. Gibaldi, Prolonged-re lease medication I I ,

Perspect. Clin. Pharmacol. 2, 25-27 (1984).

22. H. C . Caldwell, W. J . Westlake, R. C. S h r i v e r ,

and E. E. Bumbier , Steady s ta te lithium blood level f
luctuations in man following administration of lithium
carbonate conventional and control led-re lease dosage
form, J. Clin. Pharmacol. 21, 106-109 (1981).
23. F . Theeuwes and W. B a y n e , Dosage form index : An
objective cr i ter ion for evaluation of control led-re
lease d r u g delivery s y s t ems , J. Pharm. Sci. 66,
1388-1392 (1977).

24. M. Gibaldi, Prolonged-re lease medication I , Perspect.

Clin. Pharmacol. 2, 17-20 (1984).

25. S . H. D . Jackson and J . M. Wright, Susta ined serum

theophyl line concentra t ions du r ing chronic twice daily
administration of a slow re lease p r e p a r a t i o n ,
Eur. J. Clin. Pharmacol. 24, 205208 (1983).

26. G. Levy , Kinetics of pharmacologic effects , Clin.

Pharmacol. Ther. 7, 362-372 (1966).

27. G. Levy, Relationship between elimination ra te of d r

u g s and r a t e of decline of the i r pharmacological
effects , J. Pharm. Sci. 53, 342-343 (1964).

28. L. B . She iner , D . R. S t ansk i , S . Vozeh, R. D .

Miller, and J . Ham, Simultaneous modeling of
pharmacokinetics and pharmacodynamics: Application to d t u
b o c u r a r i n e , Clin. Pharmacol. Ther. 25, 358-371
(1979).

29. G. Levy , Relationship between r a t e of elimination

of t ubocura r ine and ra te of decline of i ts
pharmacological ac t iv i ty , Br. J. Anaesth. 36, 694-695
(1964).

30. M. Eichelbaum, P . Bi rke l , E. Grube , U. Gutgemann,

and A. Somogyi, Effects of verapamil on P-R in te rva l s
in relation to verapamil plasma levels following single i
. v . and oral administ ra t ion and dur ing chronic t r ea
tmen t , Klin. Wochenschr. 58, 919-925 (1980).

31 . R. L. Galeazzi, L. Z. Bene t , and L. B . She ine r ,

Relationship between the pharmacokinetics and
pharmacodynamics of procainamide, Clin. Pharmacol. Ther.
20, 278-289 (1976).

32. N. H. G. Holford, P . E. Coates , T . W. Guen te r t ,

S. Riegelman, and L. B . She ine r , The effect of
quinidine and i ts metabolites on t he electrocardiogram
and systolic time i n t e rva l s : Concentration-effect re
la t ionsh ips , Br. J. Clin. Pharmacol. 11, 187-195
(1981).

33. P . J . Meffin, R. A. Winkle, T . F . Blaschke , J . F

i tzgera ld , and D . C. Har r i son , Response
optimization of d r u g dosage: Antiarrhythmic s tudies
with tocainide , Clin. Pharmacol. Ther. 22, 42-57 (1977).

34. T . Meinertz, W. Kasper , F . Kers t ing , H. J u s t ,

H. Bechtold , and E. J anchen , Lorcainide I I . Plasma
concent rat ion-effect re la t ionsh ip , Clin. Pharmacol.
Ther. 26, 187-195 (1979).

35. B . Whiting, N. H. G. Holford, and L. B . She iner ,

Quanti tat ive analysis of t he disopyramide concentrat
ion-effect re la t ionship , Br. J. Clin. Pharmacol. 9,
67-75 (1980).

36. C. J . Fal l ie rs , Pharmacodynamic and spirometric r

e sponses to sus ta inedre lease theophyll ine capsu le ,
Int. J. Clin. Pharmacol. Biopharm. 17, 125-130 (1979).

37. P . A. Mitenko and R . I . Ogilvie, Rational in t

ravenous doses of theophyl l ine , N. Engl. J. Med. 289,
600-603 (1973).

38. L. Hendeles , R. P , Ia f ra te , and M. Weinberger , A

clinical and pharmacokinetic bas is for the selection and
use of slow-release theophyll ine p r o d u c t s , Clin.
Pharmacokin. 9, 95-135 (1984).

39. M. Es le r , A. Zweifer, O. Randall , and V. DeQuat t

ro , Pathophysiologic and pharmacokinetic determinants of
the an t ihype r tens ive response to propranolol , Clin.
Pharmacol. Ther. 22, 299-308 (1977).

40. B . N . S ingh , F . M. Williams, R. M. Whitlock, J .

Collett , and C. Chew, Plasma timolol levels and systolic
time in t e rva l s , Clin. Pharmacol. Ther. 27, 159-166
(1980).

41. W. D. Hager , H. J . Pieniaszek, J r . , D. P e r r i e

r , M. Mayersohn, and V. Goldberger , Assessment of beta
blockade with propranolol , Clin. Pharmacol. Ther. 30,
283-290 (1981).

42. T . I sh izaki , J . Hirayama, K. Tawara , H. Nakaya,

M. Sa to , and K. Sa to , Pharmacokinetics and
pharmacodynamics in young normal and elderly hype r t ens
ive sub jec t s : A s t u d y us ing sotalol as a model d
r u g , J. Pharmacol. Exp. Ther. 212, 173-181 (1980).

43. D. G. McDevitt and D. G. S h a n d , Plasma concentra t

ions and the t ime-course of be ta blockade due to
propranolo l , Clin. Pharmacol. Ther. 18, 708-713 (1975).

44. R. A. Winkle, P . J . Meffin, J . W. F i tzgera ld ,

and D . C. Harr i son , Clinical efficacy and
pharmacokinetics of a new orally effective ant iar rhythmic
tocainide , Circulation 54, 884-889 (1976).

45. R. Zacest and J . Koch-Weser, Relation of propranolol

plasma level to 3-blockade dur ing oral t h e r a p y ,
Pharmacology 7, 178184 (1972).

46. B . Ablad, K. O. B o r g , G. Johnsson , C. G. R e g a

r d h , and L. Solvell , Combined pharmacokinetic and
pharmacodynamic s tudies on alprenolol and 4-hydroxy
alprenolol in man, Life Sci. 14, 693-704 (1974).

47. R. Nagashima, R. A. O'Reilly, and G. Levy , Kinetics of

p h a r macologic effects in man: The anticoagulant action
of warfar in , Clin. Pharmacol. Ther. 10, 22-35 (1969).

48. P . A. Rout ledge , P . H. Chapman, D . M. Davies , and

M. D . Rawlins, Pharmacokinetics and pharmacodynamics of
warfarin at s t e a d y s t a t e , Br. J. Clin.
Pharmacol. 8, 243-247 (1979).

49. L. R. Whitfield and G. Levy , Relationship between

concentrat ion and anticoagulant effect of hepar in in
plasma of normal sub jec t s : Magnitude and predictabi l
i ty of inter individual di f ferences , Clin. Pharmacol.
Ther. 28, 509-516 (1980).

50. J . G. Wagner, Kinetics of pharmacologic r e s p o n s

e . I . Proposed rela t ionships between response and d r
u g concentrat ion in the intact animal and man, J. Theor.
Biol. 20, 171-201 (1968).

51 . N. H. G. Holford and L. B . She iner , Kinetics of

pharmacologic r e s p o n s e , Pharmacol. Ther. 16,
143-166 (1982).

52. W. G. Kramer , A. J . Kolibash, R. P . Lewis, M. S .

Bathala , J . A. Visconti , and R. H. Reun ing ,
Pharmacokinetics of digoxin: Relationship between in tens
i ty and pred ic ted compartmental d r u g levels in man,
J. Pharmacokinet. Biopharm. 1, 47-61 (1979).

53. A. W. Kelman and B . Whiting, Modeling of d r u g

response in individual sub j ec t s , J. Pharmacokinet.
Biopharm. 8, 115-130 (1980).
54. A. V. Hill, The possible effects of t he aggregat ion
of the molecules of haemoglobin on i ts dissociation c u r
v e s , J. Physiol. (London) 40, i v v i i (1910).

55. N . H. G. Holford and L, B . She iner , Pharmacokinetic

and p h a r macodynamic modelling in vivo, Crit. Rev.
Bioeng. 5, 27 3-322 (1981).

56. V. F . Smolen, Theoret ical and computational basis for

d r u g bioavailability determinations us ing pharmacologic
da ta , I . General considerat ions and p r o c e d u r e
s , J. Pharmacokinet. Biopharm. 4, 337-353 (1976).

57. M. J . West, M. J . Kendall , and M. Mitchard, A

comparison of slow release with conventional oxprenolol:
Plasma concentra t ion and clinical effects , Br. J. Clin.
Pharmacol. 3, 439-443 (1976).

58. J . McAnish, N. S . Babe r , R. Smith, and J . Young,

Pharmacokinetic and pharmacodynamic s tudies with long-act
ing propranolol , Br. J. Clin. Pharmacol. 6, 115-121
(1978).

59. P . B . Bot t in i , E. M. Caulfield, J . G. Devane ,

E. J . Geogheran, and D . E. Panoz, Comparative oral
bioavailability of conventional propranolol t ab le t s
and a new control led-absorpt ion propranolol capsu le ,
Drug Dev. Ind. Pharm. 9, 1475-1493 (1983).

60. G. B e r n e r , F . Leuschner , H. H. Wagener, and A.

Becke r , Bioavailability of metoclopramide in a sus ta
ined release p r e p a r a t ion , Arzneim. Forsch. /Drug
Res. 34, 637-639 (1984).

61. ivi. Bia ler , M. Fr iedman, and J . D u b r o v s k y

, Comparative pharmacokinetic analysis of novel sus ta ined
release formulation of valproic acid in dogs , Drug Dispos.
5, 1-10, (1984).

62. J . P . Devissague t , S . Garba rg , M. P r o s t ,

and Y. Bogaievsky, Comparative pharmacokinetic s tudy of
two dosage forms of 5 mg t r ihexyphen idy l table ts
(Artane) and sus ta ined release capsules (Parkinane r e t
a r d ) , Therapie, 39, 231-236 (1984).

63. G. A. Har t , Aspects of t he pharmacokinetics of

slow-release lithium ca rbona te , S. Afr. Med. J. 66,
178-179 (1984).

64. R. A. Upton, J . F . Thei rce l in , T . W. Guen te r t

, L. Sansom, J . R. Powell, P . E. Coates , and S.
Riegelman, Evaluation of t he absorpt ion from some
commercial sus ta ined release theophyl line p r o d u c t
s , J. Pharmacokinet. Biopharm. 8, 149-151 (1980).

65. G. W. Houghton, M. J . Dennis , E. D . Rigler , and R.

L. Par s o n s , Comparative pharmacokinetics of ketoprofen
der ived from single oral doses of ketoprofen capsules or
a novel sus ta ined release pellet formulation, Biopharm.
Drug Dispos. 5, 203-209 (1984).

66. K. L. Liem and J . M. R. Hollander, Maintenance t he r

apy after i . v . administration of disopyramide with an
oral sus ta ined r e lease p r e p a r a t i o n , a
pharmacokinetic s t u d y , Br. J. Clin. Pharmacol. 18,
226-228 (1984).

67. J . H. Gustafson, L. Weissman, R. E. Weinfeld, A. A.

Holazo, K. C . Khoo, and S. A. Kaplan, Clinical
biavailability evaluation of a controlled release
formulation of diazepam, J . Pharmacokin. Biopharm. 9,
679-691 (1981).

68. J . C . V. Loo, N. J o r d a n , C. C h a r e t t e ,
R. Br i en , and I . J . McGilvery, Pharmacokinetic
evaluation of a conventional and controlled release
product of be tamethasone, Biopharm. Drug Dispos. 5,
97-100 (1984).

69. L. Nyberg and B . M. Kennedy , Pharmacokinetics of t e

r but aline given in slow-release t a b l e t s , Eur. J.
Respir. Dis. C Suppl. 134, 119-169 (1984).

70. E. Pe rucca , R. Grimaldi, G. Gat t i , M. Caravaggi ,

F . Crema, S. Lecchini , and G. M. F r igo ,
Pharmacokinetics and pharmacodynamic s tudies with a new
control led-re lease formulation of propranolol in normal
vo lun tee r s : A comparison with o ther commercially
available formulations, Br. J. Clin. Pharmacol. 18, 37-43
(1984).

71 . M. Va te r , G. Smith, G. W. Ahe rne , and A. R. Ai

tkenhead , Pharmacokinetics and analgesic effect of
slow-release oral morphine sulfate in vo lun t ee r s ,
Br. J. Anaesth, 56, 821-827 (1984).

72. C. G. Wilson, G. D . P a r r , J . W. Kenner ley , M. J

. Tay lor , S . S . Davis , J . G. H a r d y , and J . A.
Rees , Pharmacokinetics and in vivo sc in t igraphic
monitoring of a sus ta ined release acetyl salicylic acid
formulation, Int. J. Pharm. 18, 1-8 (1984).

73. G. Ayanoglu, P . U. Witte, and M. Badian,

Bioavailability and pharmacodynamics of a sus ta ined
release glibenclamide product (Deroctyl) in comparison to
a s t anda rd tablet formulation (Euglucon, Daoni l ) ,
Int. J. Clin, Pharmacol. Ther. Toxicol. 21, 479482 (1986).

74. L. F . Chasseaud , E. Doyle, T . Tay lor , A. D a r r a

g h , and R. F . Lambe, Bioavailability of isosorbide d
ini t ra te and i t s two monon i t r a t e metabolites
from sus ta ined release formulations, Int. J. Clin.
Pharmacol. Ther. Toxicol. 21, 514-518 (1983).

75. L. F . Chasseaud , T . Tay lor , R. M. Major, I . W.

Taylor , and V. Luckow, Pharmacokinetics of 14c_; i s o s
o r D i c l e d ini t ra te after different sus ta ined
release formulations, Arnzneim. Forsch. /Drug Res. 33,
1298-1301 (1983).

76. U. Dahls torm, C. Graffner , G. Johnsson , K. J .

Hoffman, E. Kar lsson , and P . O. Lagers t rom,
Pharmacokinetics of prenal tero l after single and
multiple administration of control led-release tab le t s
to pa t ients with congest ive hear t fai lure, Eur. J.
Clin. Pharmacol. 24, 495-502 (1983).

77. A. Ebihara , K. Tawara , and T . Oka, Pharmacodynamic

and pharmacokinetic s tudy of a s low-release formulation
of furosemide in man, Arzneim. Forsch./Drug Res. 33,
163-167 (1983).

78. B . Flouvat , F . Fodor , A. Roux, and J . R.

Bianchine, Pharmacokinetics of a sus ta ined release
trimazosin tablet formulation, Am. Heart J. 106, 1228-1234
(1983).

79. W. H. Helfand and B . L. Pejouan, New indomethacin

pharmaceut i ca l s . Pharmacokinetic profile of an oral
osmotic controlledrelease form, Ann. Pharm. Fr. 41, 401-408
(1983).

80. P . K a r t t u n e n , M. Uus i tupa , and U.

Lamminsivu, The pharmacokinetics of metformin: a comparison
of the p roper t i e s of a rap idre lease and a sus ta
inedre lease p r epa ra t i on , Int. J. Clin. Pharmacol.
Ther. Toxicol. 21, 31-36 (1983).

81 . V. W. Steini jans , K. Zech, and R. F i scher ,

Comparison of aminophylline and theophyl l ine sus ta ined
release formulations by the i r bioavailability and s t
eady s t a t e serum levels , Int. J. Clin. Pharmacol.
Ther. Toxicol. 21, 624-630 (1983).

82. Y. Santoni , R. B r u n o , M. F o r n a r i s , A. E g
r e , T . Danays , and J . P . Cano, Pharmacokinetics and
relat ive bioavailability of a new oral sus ta inedre
lease form of mexiletine in heal thy sub jec t s ,
Therapie 38, 341-344 (1983).

83. W. V. Taggar t and W. Holyoak, Steady s ta te

bioavailability of two sus ta ined release quinidine p r e
p a r a t i o n s : Quinidine gluconate v e r s u s
quinidine sulfa te , Clin. Ther. 5, 357-364 (1983).

84. P . H. Vlasses , M. L. Rocci, K. A. Por r in i , A. J .

Greenspan , and R. K. F e r g u s o n , Immediate release
and sus ta ined release procainamide: Bioavailability at s
t eady s t a t e in cardiac p a t i e n t s , Ann. Intern.
Med. 98, 613-614 (1983).

85. K. R. H. Adams, L. D . C. Halliday, R. G. Sibeon, N. B

a b e r , T . Li t t le r , and M. L T E. Orme, Clinical
and pharmacokinetic s tudy of indomethacin in s t a n d a
r d and slow-release formulations, Br. J. Clin. Pharmacol.
14, 286-289 (1982).

86. P . W. Trembath and S . W. Boobis, Pharmacokinetics of

a s u s ta ined release theophyll ine formulation, Br. J.
Clin. Pharmacol. 9, 365-369 (1980).

87. R . J . E r b , Bioavailability of control led-release

buccal and oral n i t roglycer in by digital p le
thysmography , Adv. Pharmacother. 1, 35-43 (1982).

88. R. J . Will and W. A. Colburn , Multiple-dose

pharmacokinetics of diazepam once-daily administration of
a control led-release capsu le , Ther. Drug Monit. 5,
423-426 (1983).

89. J . G. P e r k i n s , R. B r e s s l e r , D . Heather
ington , A. Cato, and J . Dickerson , Bioavailability and
safety s tudy comparing actifedsus ta ined action (SA)
capsules to Actifed immediate release (IR) t a b l e t s ,
Curr. Ther. Res. Clin. Exp. 28, 650-668 (1980).

90. W. Suess and M. Kuntze , Invest igat ions on release

and bioavailability of fluoride table ts with sus ta ined d
r u g re lease , Zentralbl. Pharm. Pharmakother. Labor.
119, 511-514 (1980).
91 . W. Suess and B . Haaser , Invest igat ion on release
and bioavailability of potassium p r e p a r a t i o n s ,
Zentralbl. Pharm. Pharmakother. Labor. 119, 503-506
(1980).

92. C. P . Charmaine, M. J . Kendall , and P . G. Welling,

Bioavailability of conventional slow-release oxprenolol in
fasted and nonfasted ind iv idua ls , Br. J. Clin.
Pharmacol. 7, 299-302 (1979).

93. R. Groning , S tudy of the bioavailability of n i t

rofuranto in . Par t 3. Comparative evaluation of
commercial sus ta ined release d r u g forms, Dtsch.
Apoth. Ztg. 119, 983-985 (1979).

94. C. P . Quaterman, M. J . Kendall , and P . G. Welling,

Plasma levels and negat ive chronotropic effect of
metoprolol following single doses of a conventional and
sus ta ined release formulation, Eur. J. Clin. Pharmacol.
15, 97-103 (1979).

95. P . L. Sharma and R. M. Sharma, Comparative

bioavailability of sus ta inedre lease and conventional t
ab le t s of hydroxye thy l theophylline in man, Int. J.
Clin. Pharmacol. Biopharm. 17, 394396 (1979).

96. W. E r k i n g , P . W. Luecker , G. Metz, M. Specker ,

and K. Wetze l sberger , Relative bioavailability of
vincamine slow-release formulation. Pharmacokinetic s tudy
in normal sub jec t s , Arzneim. Forsch. /Drug Res. 28,
2332-2336 (1978).

97. B . Y. Lee , H. Sakamoto, F . T ra ino r , G. B rody ,

and Y. W. Cho, Comparison of soft gelatine capsule v e r s
u s sus ta ined release formulation of papaver ine hydroch
lor ide : vasodilation and plasma levels , Int. J. Clin.
Pharmacol. Biopharm. 16, 32-39 (1978).

98. C D . S t e u a r t , Brompheniramine bioavailability

from two oral sus ta inedre lease nasal decongestant
formulations with identical active d r u g s but with
different release sys tems , Curr. Ther. Res. 24, 960-966
(1978).

99. D. P . Thornhi l l , Pharmacokinetics of o rd ina ry

and sus ta ined release lithium carbonate in manic pa t i
en t s after acute dosage , Eur. J. Clin Pharmacol. 14,
267-271 (1978).
100. W. J . Ti l s tone , D. H. Lawson, W. Campbell, I .
Hut ton , and T . D. Lawrie, The pharmacokinetics of
slow-release procainamide, Eur. J. Clin. Pharmacol. 14,
261-265 (1978).

101. A. J o e r g e n s e n , Comparative bioavailability

of a sus ta ined r e lease prepara t ion of amitriptyline
and conventional t a b l e t s , Eur. J. Clin. Pharmacol.
12, 187-190 (1977).

102. K. J . Simons, E. R. Simons, and E. W. Bierman,

Bioavailability of a sus ta ined release dyphyll ine
formulation, J. Clin. Pharmacol. 17, 237-242 (1977).

103. C. Graffner , G. Johnsson , and J . S jogren,

Comparative absorpt ion and pharmacokinetic s tud ies on
proxyphyl l ine in o r dinary and slow-release t a b l e t
s , Acta. Pharm. Suec. 11, 125132 (1974).

104. K. A. Java id and C. W. Hartman, Blood levels of

sulfamethizole in dogs following administration of t
ime-release table ts employing l ipase l ip id -d rug sys
t ems , J. Pharm. Sci. 61, 900902 (1972).

105. B . Muehlenbruch, H. S t r a u s s , and H. Glaubitz,

S tudies on the bioavailability of res ina tes as oral sus
ta ined release d r u g dosage forms. Par t I .
Pharmaceutical availability of d ihydrocodeine r e s i n a
t e s , Pharmazie 37, 200-203 (1982).

106. S. N. Rasmussen, S . Bondesen , E F . Hvidberg , S-H.

Hassen, V. B i n d e r , S. Halskov, and H. F lachs ,
5-aminosalicylic acid in a slow-release p repa ra t ion :
bioavailabili ty, plasma level, and excret ion in humans ,
Gastroenterology 83, 1062-1070 (1982).

107. R. J . Sawchuk, S. M. Pepin , I . E. Leppik, and R. J

. Gumnit, Rapid and slow-release phenytoin in epileptic pa
t ien ts at s t eadys t a t e : Assessment of relat ive
bioavailability util izing MichaelisMenten pa r ame te r s
, J. Pharmacokinet. Biopharm. 10, 383-391 (1982).

108. W. E. B a r r e t t , J . J . Hanigan, and D. L. S n y

d e r , The bioavailability of sus ta ined release table ts
which contain pheny lp ro panolamine and chlorpheniramine,
Curr. Ther. Res. 30, 640654 (1981).

109. J . Bourgouin , M. A. Gagnon, R. Elie, D . Dvorn ik ,

R. Gonzalez, and M. Kraml, But r ip ty l ine : Human
pharmacokinetics and comparative bioavailability of
conventional and sus ta ined release formulations,
Biopharm. Drug. Dispos. 2, 123-130 (1981).

110. R. C. Browning , V. A. John , R. J . L . Til l , and

W. Theobald , A pharmacokinetic comparison between
different slow-release formulations of Metoprolol
(Lopresor , SR and Betaloc S A ) , Br. J. Clin. Pharmacol.
12, 600-602 (1981).

111. F . Chanoine, W. Rovei, and M. Strolin Benede t t i ,

Pharmacokinet ics of heptaminol in man. Bioavailability of
sus ta ined r e lease t ab l e t , C. R. Cong. Eur.
Biopharm. Pharmacokinet. 1, 125-133 (1981).

112. M. J . Kendall , L. Lamber t , C. P . Quar te rman,

and V. A. J o h n , Pharmacokinetic and pharmacodynamic
assessment of a combined slow-release
metoprolol-chlorthalidone p repa ra t ion , J. Clin. Hosp.
Pharm. 6, 259-265 (1981).

113. H. Ledermann and B . Kaufmann, Comparative

pharmacokinetics of 400 mg bezaf ibrate after a single
oral administration of a new slow-release p repara t ion
and the cu r ren t ly available commercial form, J. Int.
Med. Res. 9, 516-520 (1981).

114. J . Marinow, W. Akpan , H. Ledermann, and U. Abshagen

, Compara t ive s tudies of t h e pharmacokinetics and
pharmacodynamics of metipranalol and slow-release
metipranolol in heal thy volunt e e r s , Herz/Kreislauf.
13, 548-554 (1981).

115. W. A. Ritschel and K. A. Hoffman, Pilot s t udy on

bioavailability of coumarin and 7-hydroxycoumarin upon
peroral adminis t ra t ion of coumarin in a sus ta ined
release dosage form, J . Clin. Pharmacol. 21, 294-300
(1981).

116. A. Yacobi, R. G. Stoll, G. C . Chao, J . E. C a r t e

r , D . M. Baaske , B . L . Kamath, A . N . Amann, and C M
. Lai , Evaluation of sus ta ined-ac t ion
chloropheniramine-pseudophedr ine dosage form in humans ,
J. Pharm. Sci. 69, 1077-1081 (1980).

117. J . J . Val lner , J . A. Kotzan, J . T . S tewar t ,

W. J . Brown, I . L. Honigberg , T . E. Needham, and S .
V. Dighe , Blood levels following multiple oral dosing of
chlorpheniramine conventional and control led-re lease p r
e p a r a t i o n s , Biopharm. Drug Dispos. 3, 95-104
(1982).
118. S . K. Baveja, K. V. Ranga Rao, and A. S ingh , Susta
ined release tablet formulation of diethylcarbamazine,
Int. J. Pharm. 19, 229-231 (1984).

119. C. Sama, A. M. Morselli Laba te , C. Chiodarell i , A.

Roda, M. Br igan t i , and E. Roda, Bioavailability of a
delayed-re lease prepara t ion of urodeoxycholic acid in
man, Curr. Ther. Res. 33, 558-564 (1983).

120. R. H. Reun ing , S. H. T . Liao, A. E. S t a u b u s ,

S . B . Aschcraf t , D . A. Downs, D . E . Har r igan , J .
N. Wiley, and D . L. Wise, Pharmacokinetic quant i ta t
ion of na l t rexone controlledrelease from a copolymer
delivery sys tem, J. Pharmacokinet. Biopharm. 11, 369-387
(1983).

121. A. A. Mishriki and D . J . Weidler, Long act ing

propranolol ( Indera l LA); pharmacokinet ic ,
pharmacodynamics and t h e r a peut ic u s e .
Pharmacotherapy 3, 334-341 (1983).

122. M. Gibaldi and P . J . McNamara, S t eadys t a t e

concentra t ions of d r u g s with shor t half-lives when
administered in ora l sus ta ined release d r u g
formulations, Int. J. Pharm. 2, 167172 (1979) .
6 Chapter 6 Dosing Considerations and
Bioavailability Assessment of Controlled
Drug Delivery Systems

I. INTRODUCTION

The success of sustained or controlled release systems for

a number

of agents has provided unprecedented impetus for this

dosage form.

With ever improving techniques and methodologies, and with

ever

increasing pressure to find novel and clinically viable

dosage forms

for new and old drugs, it has become almost mandatory to

examine

this dosage form for practically every drug in

pharmaceutical research

and development. Despite the extraordinary proliferation

of this dosage form, regu

latory authorities have exercised great caution in

suggesting guidelines

for their standardization and testing. This is

understandable when

one considers the inherent problems of making a successful

controlled

release dosage form, and possibly even greater problems of

their

standardization. Although great clinical advantages are

claimed, and sometimes

realized, for controlled release drug products, and great

advances

have been made in pharmacokinetics during the past two

decades,

most sustained or controlled release formulations are

prepared on an
empirical basis. While exceptions to this generalization
exist, as

exemplified by the work of Theeuwes and associates [1] ,

there are

few examples in the literature of controlled release dosage

form de

sign based on accepted pharmacokinetic, as well as physical

and

chemical, principles. There are a number of possible

reasons for this. One may be

that of inadequate communication between formulator and

pharmaco

kineticist, especially when their respective development

time-frames

do not coincide. Another may be the difficulty in

establishing a

relationship between in vitro and in vivo data, and this

will be dis

cussed in greater length later. The third reason may be the

un

predictable performance of oral controlled release systems

under dif

ferent dietary conditions, thereby rendering accurate

pharmacokinetic

prediction difficult. The fourth reason, again pertinent

for oral

controlled release systems, is the capricious and often

unpredictable

absorption characteristics in different regions of the GI

tract . De

spite these factors, it is unfortunate that more use is not

made of

a now rather sophisticated science to provide working

estimates at

least, and to provide precise and predictable

characteristics at best,

of a controlled release dosage form. The objectives of

this chapter are to discuss in a qualitative

sense some of the advantages and disadvantages of

controlled release

formulations, to consider some of the contentious issues

regarding the

feasibility for controlled release systems for certain

drugs, some

in vitro and in vivo aspects and models, and also to

provide some

comments on bioavailability testing. Attention will focus

primarily

on oral dosage forms.

I I . ADVANTAGES OF CONTROLLED RELEASE DOSAGE FORMS

The importance of controlled release dosage forms is

illustrated by

the list of representative compounds, separated into major

therapeutic

areas, in Table 1. As noted previously [2] , it is

interesting that

so much attention has focused on diuretic, cardiovascular,

CNS, and

respiratory drugs , and so little attention on

antimicrobial agents.

To our knowledge tetracycline is the only antibiotic that

is currently

available in sustained release form, which is marketed in

Europe as

Tetrabid R . The major reason for lack of attention in this

area is
possibly the size of the conventional dose, making a
controlled release

dosage prohibitively large. However, this is not the case

with all

antimicrobials. Many agents are given at conventional doses

of 150

mg or less, and are thus potential candidates for

controlled release

dosing. Provided that it is desirable to obtain

antimicrobial levels

above a certain minimum concentration for as long a period

as possible

for optimum therapy, there is no more reason not to produce

a con

trolled release dosage form for this class of drugs than

any other. As controlled release dosages are often more
expensive than con

ventional formulations, they cannot be justified unless

they offer some

clinical or practical advantages. Some advantages are: (a)

reduction

in dosing frequency, (b) reduced fluctuation in circulating

drug

levels, (c) increased patient compliance, (d) avoidance of

night time

dosing, (e) more uniform effect, and (f) reduction in GI

irritation

and other dose-related side effects. The ideal controlled

release

dosage form will offer all of these advantages. Clearly,

justification

is directly related to the number and extent of the

advantages com
pared to cost. The second and third advantages are concerned

with circulating drug levels, which influence many of the

other pos

sible advantages and may be predicted from pharmacokinetic

princi

ples. The fifth advantage, achieving a more uniform

pharmacological

response, is one of the major goals of controlled release

dosing.

However, there is little documentation to support this

claim and, for

the most part , improved pharmacological profiles of

controlled release

dosage forms have to be implied from blood concentration

data.

Table 1 Some Substances Available

in Controlled Release Form

Vitamins, minerals, and hormones

Ascorbic acid

Iron preparations

Methyltestosterone

Nicotinic acid

Table 1 (Continued)

[Vitamins, minerals, and hormones]

Potassium

Pyridoxine

Vitamin combinations

Diuretic and cardiovascular drugs

Acetazol amide
Ethaverine HC1

I so so r bide dinitrate

Nicotinyl alcohol

Nitroglycerin

Papaverine HC1

Pentaerythritol tetranitrate

Procainamide

Quinidine gluconate and sulfate

Reserpine

CNS drugs

Amphetamine sulfate

Aspirin

Caffeine

Chlorpromazine

Dextroamphetamine sulfate

Diazepam

Diethylpropion HC1

Fluphenazine

Indomethacin

Lithium

Meprobamate

Met hamphet amine HC1

Orphenadrine citrate

Pentobarbital

Pentylenetetrazole
Perphenazine

Phenmetrazine HC1

Pheno barbital

Phentermine HC1

Prochlorperazine

Respiratory agents

Aminophylline

Brompheniramine maleate

Carbinoxamine maleate

Table 1 (Con t inued)

[Respiratory agents]

Chlorpheniramine male ate

Combination, antitussive

Combination, expectorant

Combination, upper respiratory

Dexchlorpheniramine maleate

Dimethindene maleate

Dyphenylpraline HC1

Dyphylline

Phenylpropanolamine HC1

Psuedoephedrine HC1 and sulfate

Theophylline

Trimeprazine

Tripelennamine HC1

Xanthine combinations
Antimicrobial

Tetracycline

Gastrointestinal drugs

Belladonna alkaloids

Hexocyclium methylsulfate

Hyoscyamine sulfate

Isopropamide iodide

Prochlorperazine maleate

Tridihexethyl chloride

Other

Pyridostigmine bromide

Source: Reproduced by permission

from Ref. 2.

I I I . DISADVANTAGES OF CONTROLLED RELEASE DOSAGE FORMS

Controlled release dosage forms have several potential

disadvantages.

They include cost, unpredictable and often poor in vitro—in

vivo corre

lations, dose dumping, reduced potential for dosage

adjustment, and

increased potential for first-pass clearance and also of

poor systemic

availability in general. For oral dosage forms there is the

additional

disadvantage that the effective drug release period is

influenced and

limited by GI residence time. The high cost of sustained

release dosage forms must again be
taken into account when the advantages and disadvantages of
a par

ticular drug formulation are being considered. In vitro—in

vivo cor

relations for conventional dosage forms are often poor, and

this prob

lem has occupied the minds of many for a long time. For
controlled

release dosages, in which the rate of release is

deliberately reduced

to achieve drug release over a greater region of the GI

tract with

potential reduction in systemic availability, there is no

reason to sus

pect that in vitro—in vivo correlations would not be worse.

Dose dumping is a phenomenon whereby the relatively large

quantity of medication in a controlled release formulation

is rapidly

released, introducing potentially toxic quantities of drug

into the

systemic circulation. This has been reported for a

bronchodilator

[3], However, dose dumping should not be a problem with good

manufacturing practice and the types of rigid controls that

have be

come standard in industry. For the same reason, it is also

prudent to

indicate in product labeling relevant statements concerning

alteration

of the dosage form by the patient prior to its ingestion (

e . g . , chewing

or grinding and dispersing in food or liquids). Reduced

potential for dosage adjustment is a major disadvantage
of some controlled release products, and this should be
considered

when preparing controlled release formulations for drugs

that are

available in a variety of strengths in conventional

dosages. The

controlled release formulation should also be available in

a variety

of strengths or in a form that can easily be subdivided

without losing

controlled release properties. Hepatic metabolism is a

saturable process. Saturable elimination

has been reported for only a small number of drugs

following intra

venous administration, including alcohol, phenytoin,

carbamazepine,

valproate, theophylline, and probenecid. These observations

have

been based on drug /concentration dependent elimination

rates. The

small number of drugs that have exhibited this phenomenon

indicates

that most drugs do not achieve drug levels that saturate

hepatic metab

olizing enzymes at therapeutic dose levels. After oral

dosing, on the

other hand, drug reaches the liver via the portal vein at
far greater

concentrations than normally observed in the systemic

circulation.

In fact, the levels may be high enough to exceed the

capacity of the

hepatic metabolizing enzymes. Thus, the higher the oral

dose the
greater the possibility of saturating hepatic drug
metabolizing en

zymes. Conversely, the smaller the dose, or the slower the

dose is

released from the formulation, the smaller the possibility

of satura

ting first pass metabolism. The potential for reduced drug

availabil

ity due to first-pass metabolism is therefore greater with

controlled

or sustained release formulations than with conventional

dosages. Reduced drug absorption is an intrinsic hazard
with all controlled

release dosage forms. Apart from the obvious limitation of

GI resi

dence time, a controlled release formulation is likely to

cause a

fraction of administered drug to be released in regions of

the GI

tract that are distal to the optimum absorptive region of

the small

intestine. The so called "absorption window" becomes

important,

and may give rise to unsatisfactory drug absorption in vivo

despite

excellent release characteristics in vitro. There is

generally poor

agreement in estimates of effective GI residence time for

drug absorp

tion. This may vary for different drugs and formulations

depending

on (a) absorption efficiency in distal regions of the

intestine and
(b) susceptibility of the drug or dosage form to intestinal
bacterial

degradation. The transit time of a dosage form through the

gastrointestinal

tract depends not only on the physical characteristics of

the formulation

but also on physiological factors [4 -6 ] . Stomach

emptying is perhaps

the single most important factor controlling the overall

transit time.

Following food intake, the stomach enters the T fed mode'

in which

liquids and digested material are readily emptied but solid

materials

are selectively retained until particle size is reduced to

about 2 mm

in diameter [7] f When digestion is complete, the stomach

enters the

'fasting mode' in which intense contractions (part of the

interdiges

tive myoelectric complex or housekeeper) recur briefly in a

2-hr cycle

and result in complete emptying of any residual or

indigestible material

from the stomach [5] . Hence, gastric residence time of a

slowly

eroding or nondisintegrating dosage form may differ

substantially

between fed and fasting modes. Gastric residence times of

such

formulations also appear to increase as the caloric content

of the

ingested meal increases; times reported for an osmotic

delivery device,
for instance, range from about 10 hr when given after a
heavy break

fast to as little as 0.5 hr after a very light meal [8,10].

Notwithstand

ing direct effects of food on the absorption process,

administration

of sustained-release dosage forms with food therefore has

the poten

tial for increasing the duration and extent of absorption

of a drug,

particularly if the optimum absorption region is in the

small intestine.

Hence, bioavailability studies should be conducted under

both fasting

and nonfasting conditions.

IV. COMPOUNDS THAT ARE UNSUITABLE FOR CONTROLLED RELEASE

Some characteristics that may make a drug a poor candidate

for con

trolled release dosing are given in Table 2. For drugs with

an

elimination half-life of less than two hours, as well as

those that

are administered in large doses, a controlled release

dosage form

may contain a prohibitively large quantity of drug. On the

other

hand, drugs with elimination half-lives of 8 hr or more are

sufficient

ly sustained in the body from conventional doses, and

controlled

release is generally not necessary. Dose dumping of a very

potent
drug or of a compound with a narrow therapeutic index may
give

rise to very high circulating drug levels, with possibly

disastrous

consequences. Absorption of poorly water-soluble drugs is

often dissolution

rate-limited. Incorporating such compounds into controlled

release

formulations is therefore unrealistic and may reduce

overall absorption

efficiency. Administering drugs like warfarin, whose

pharmacological

effect is delayed relative to its blood profile, offers no

clinical ad

vantage. Similarly, incorporating drugs such as

fluorouracil, and

perhaps some beta lactam antibiotics and thiazide diuretics

that appear

to exhibit an "absorption window" may reduce absorption

efficiency.

Problems of first-pass hepatic clearance of

sustained-release drugs

has been discussed. While the above comments may provide

useful guidelines for de

cision making regarding the feasibility of controlled

release dosage

forms, they may not apply in specific situations. For

instance, many

of the drugs in Table 1 have very short elimination

half-lives, while

others have half-lives greater than 8 hr . The best

example of the former is nitroglycerin. The present

consensus is that nitroglycerin has a short biological

half-life of
Table 2 Characteristics That May Make

a Drug Unsuitable for Controlled Release

Dosing

1. Short elimination half-life

2. Long elimination half-life

3. Narrow therapeutic index

4. Large doses

5. Poor absorption

6. Active absorption

7. Low or slow solubility

8. Time course of circulating drug levels different to

that of pharmacological effect

9. Extensive first-pass clearance

Table 3 Some Categories of Oral Controlled Release Dosage

Forms

Category Product Active Ingred ien t

Slow erosion with

initial fast re lease

dose Tedra l SA

Erosion core only

Repeat action tab le t s Chlor-Trimeton Tenuate Dospan

Pellets in capsules

Pellets in tab le t s

Leaching Com bid T h e o d u r Desbutal Gradumet

Ion-exchange res ins Biphetamine

Complexation
Microencapsulation

Flotation- diffusion

Osmotic del ivery Rynatan Nit ro span Valrelease

Acutrim Theophyl l ine , ephedr ine HC1, phenobarbi ta l
Diethylpropion HC1 Pseudoephedr ine su l fa te ,
chlorpheniramine maleate Isopropamide iodide, p r o
chlorperazine maleate Theophyll ine Methamphetamine HC1,
pentobarbi ta l sodium Amphetamine, dextroamphetamine
Chlorpheniramine, phenyl e p h r i n e , and pyrilamine t
annates Nitroglycerin Diazepam Phenylpropanolamine HC1

about 10 min and tha t it unde rgoes considerable f i r s t

-pa s s hepatic

metabolism. Nitroglycerin is therefore given by the buccal

route for

t reatment of angina pa in . Bucally administered d r u g

avoids f i rs t

pass metabolism and e n s u r e s rapid availability of act

ive d r u g to the

c i rculat ion. There a re t h u s two excellent reasons

why ni t roglycer in

should not be given in a controlled release dosage forms

and par t i cu

larly not by the oral r o u t e . However, most of the

dosage forms of

n i t roglycer in a re controlled re lease in n a t u r e

and both oral and t r a n s

dermal rou tes a re u s e d . The reason for th i s appa

ren t anomaly lies

in the indication for th i s d r u g . Buccal

administration is used to p ro

vide high c i rcula t ing levels of n i t roglcycer in to

rel ieve acute pain of

angina , while controlled re lease is used as p rophy lax i

s . It is claimed
tha t with oral doses sufficient compound escapes f i r s t
pa s s metabolism

to provide adequate circulating drug levels to prevent

angina. Trans

dermal dosing is claimed to provide the additional

advantage of not

only delivering drug slowly but also avoiding first-pass

hepatic me

tabolism. These various claims are under regulatory review.

Controlled release of drugs that have long biological
half-lives is

difficult to rationalize. The most plausible reason is that

by reducing

the absorption rate it is possible to prevent the

occurrence of high

peak drug levels shortly after dosing. This may be

important for

drugs that have a narrow therapeutic index, but is less

important

for drugs that exhibit a relatively flat dose-response

profile. The

current active interest in controlled drug release,

together with im

proved technology, has given rise to a rush of new

formulations.

Examples of well established and also more novel oral

dosage forms

are summarized in Table 3. Undoubtedly, this list will

increase fur

ther as more novel dosage forms are introduced.

Microencapsulation

and osmotic pressure systems will likely find more

applications.

Other products that prolong GI residence time, either by

means of

adhesion or by the use of low density hydrated gels have

been intro

duced (Susadrin®, Valrelease®). These types of dosage forms

may

undergo extensive development in the future.

V. IN VITRO CONSIDERATIONS

Despite the large variety of formulations devoted to oral

controlled

drug release, and also the varied physical properties that

influence

drug release from these formulations, the number of kinetic

models

necessary to describe overall drug release is relatively

small. The

four major release patterns are illustrated in Figure 1.

The release patterns can be divided into those that release
drug

at a slow zero- or first order-rate and those that provide

an initial

rapid dose, followed by slow zero- or first-order release

of sus

tained component. Formulations that release drug at a slow

first

order or zero-order rate are more common than those

containing a

fast-release component. Arguments presented later in this

chapter

will show that this is appropriate from a pharmacokinetic

viewpoint. The sustained nature of drug release from these
dosage forms

presents problems in the development of in vitro

dissolution stand
ards. Dissolution is now accepted as an in vitro standard
for drug

release from conventional dosage forms. The use of such

tests to

determine drug product bioavailability or bioequivalence

has been

advocated by the United States Food and Drug Administration

[11].

While dissolution rate has proven to be an excellent

criterion for

product uniformity, it has been less successful in

predicting product

bioavailability [12-14]. For conventional oral drug

products, in vitro dissolution criteria

are based on the fastest possible dissolution rate. The

situation is

ZERO ORDER Time FIRST ORDER Time

INSTANT RELEASE,

THEN ZERO ORDER Time INSTANT RELEASE, THEN FIRST ORDER

Time

Fig. 1 Drug release characteristics from oral controlled

release

formulations. (Reproduced by permission from Ref. 2.)

quite different, however, for controlled release products

for which

the optimum dissolution rate is not the fastest that can be

obtained,

but rather an intermediate value that will hopefully result

in prolonged

release of drug in vivo. Thus for these products a

dissolution win

dows is required, and deviation from the optimum rate can

be in terms
of being too fast or too slow, Given (a) the enormous
variety of formulations that are currently

available, (b) the different release patterns indicated in

Figure 1,

and (c) the rapid development of other novel drug release

forms such

as the osmotic pump, adhesion formulations, and hydrated

gels, it

is not surprising that there are currently limited

compendial (USP

XXI, 1985) guidelines for in vitro dissolution tests for

controlled

release products. Also due to the relatively poor

correlations that

are generally observed between in vitro and in vivo

characteristics,

bioavailability and bioequivalence determinations must

currently be

carried out in vivo.

V I . IN VIVO CONSIDERATIONS

In this section, attention will focus on the

pharmacokinetics associated

with the four release patterns shown in Figure 1, the

blood-level

profiles that may be achieved from these dosage forms, and

how

these profiles may be influenced by GI transit time. Drugs

may obey single- or multi-compartment pharmacokinetic

models depending on their affinity for various body

tissues. Multi

compartment characteristics are more readily identified

after rapid
drug administration compared to slow administration as the
distribution

phase is not obscured by absorption processes. Slow

absorption of

drugs from controlled release formulations generally

precludes de

scription of resulting drug profiles by kinetic models more

complex

than the simple one-compartment model. That approach will

be used

here. For ease of presentation the following simplifying

assumptions

are made: (a) drug absorption, metabolism, and excretion

are first

order processes, (b) drug absorption and elimination are

irreversible,

(c) drug that is released into the GI tract is completely

absorbed in

its unchanged form, and (d) drug release from the sustained
release

formulation is rate-limiting in the absorption process.

The model is shown in Scheme I [15].* In this scheme, D s

denotes slowly released drug, Dj denotes instantaneously

released Scheme I

drug, A denotes unchanged drug in the body, B denotes

cumulative

amount of drug excreted in urine or metabolized, k a is a

first-order

rate constant for drug transfer from the absorption site

into the

systemic circulation, VLQ and k r are zero-order (ko) or

first-order

(k r ) rate constants for release of drug from D s ,

respectively, and
k e i is a first-order rate constant for elimination of
drug by combined

urinary excretion, metabolism, etc.

*In the original model an additional absorption step was

incorporated

for the slowly released component D s , However, as k 0 or

k r are

generally significantly smaller than k a , deletion of that

step does not

significantly affect resulting drug profiles [15].

A. First-Order Release

1. Single Dose

The amount of drug in the body following a single dose is

given

by Eq. (1), in which k r is the rate constant governing

absorption

(k r « k a ) . T k t k t"| s r el r Le - e J D k (1)
k - k n r el Eq. (1) can be converted to describe drug
concentration, C, by

adding the distribution volume, V, to the denominator, as

in Eq. (2). FT Le ' e J D k r k .t k t" s r | el . r ,
( 2 ) V(k « r el With this model, drug profiles can be
influenced by the absorption

and elimination rate constants, as shown in Figures 2 and

3, respec

tively. From Figure 3, the drug profile is markedly

influenced by

its biological half-life ( t i /2 = In 2/k e i ) . The peak

level, A m a x , and

time of peak level, T m a x , both increase as the

half-life increases.

The curves generated with k e i = 0.3 hr"* and 0.5 h r" l

have the same
elimination slopes with values of 0.2 hr" 1 . This is an
example of the

"flip-flop" model, where k e i > k r [16] and where the

apparent elimina

tion slope is controlled by the rate at which drug is

released from

the formulation. This is a common situation with controlled

release

formulations. From Figure 2, for a given value of k e ]_,

drug profiles are lowered

and more prolonged as k r is reduced. In this case, A m a

x is reduced

while T m a x is prolonged as the drug release rate

constant is reduced. Reduction in the value of A m a x
(or C m a x ) in controlled release

products is of concern, particularly for drugs that have a

well de

fined minimum effective concentration in the body. The

controlled

release dose, D s , that is necessary in order to achieve

the same

Amax as its fast release counterpart can be calculated by

Eq. (3)

[15]. For a drug with an elimination t^/2 of four hr (k e i

= 0.17 (3) D s D. l fe) / k el \ \ k - k / \ el a
/ , •fe) t k « Ik k , \ r el TIME (hours)

Fig. 2 Drug levels following a single dose. Curves

generated from

Eq. (1) with D s = 100 mg, k e i = 0.2 h r" 1 , and k r =

0.05, 0 .1 , 0.3,

and 0.5 h r 1 . (Reproduced by permission from Ref. 15.)

hr" 1 ) and a k a of 1.0 h r" 1 and a controlled release

rate constant k r
of 0.5 hr" 1 (release t i / 2 = 1.4 h r ) , a controlled
release dose would

have to be 1.2 times greater than the fast release dose to

achieve

the same A m a x . If k r were reduced further to 0.2 h r

1 (release

t i / 2 = 3.5 h r ) , then the controlled release dose

would have to be

1.8 times the fast release dose. A k r of 0.1 hr" 1 ,

which is practical

only in cases of prolonged GI residence time, would require

a 2.5-fold

dose increase.

2. Repeated Dose

The same rules govern drug accumulation following repeated

doses

of both controlled release and conventional dosage forms.

Provided

the dosage interval T is less than the time taken for all
drug to be

cleared from the body, accumulation will occur with each

subsequent

dose until steady state is reached. The time taken to reach

steady state

is controlled by the drug elimination rate and is

independent of the

absorption or drug release rate (k r , k a > k e j ) .

Thus, prolonging

the absorption of a drug by controlled release does not

influence its

accumulation rate. As it takes 4.3 x t i /2 to reach 95%

of steady state the number

of doses required to attain this condition depends upon the

relation

ship between the dosage interval and the elimination

half-life. For

a compound that is dosed once every half-life it will take

between

four and five doses to reach 95% of steady-state. If drug

is admin

istered every second half-life, 95% of steady state will be

achieved

between two and three doses. The major difference between

controlled and conventional dosage

forms is in the maximum A^ax anc * minimum A m j n values

at steady

state. These values are obtained from Eqs. (4) and (5), and
the

time of peak values, T ^ a x is given by Eq. (6). TIME

(hours)

Fig. 3 Drug levels following a single dose. Curves generated

from Eq. (1) with D s = 100 mg, k r = 0.2 hr" 1 , and k e

l = 0.05,

0.1, 0.3, and 0.5 hr" 1 . (Reproduced by permission from

Ref. 15.) A = D max s 1 - e -k T el y 1 e ) k T L
k e l ( l e r ) J el k k el r (4) 0 0 min oo max
D k s r k - k t r el 1 k - k , r el 1 In k T el
e e k T el . - e 1 r ~ k i T l k r ( l - e e l ) k T
L v 1 6 r >. k T r k e T r (5) (6) From Eq . ( 6
) , the time of peak level increases as the release

ra te is decreased . For example, if k e i = 0.17 h r " 1

and x is 12 h r ,

k r values of 0 . 5 , 0 .2 , and 0.1 h r * 1 would yield

T ^ a x values of 2 . 3 ,

3 .9, and 4.4 h o u r s , r espec t ive ly , compared to

two hours with a con

ventional formulation with a k a of 1.0 h r "* . T h u s ,

a ten-fold de
crease in t he absorpt ion ra te constant yields only a
2.2-fold increase

in t h e value of T ^ a x . It is generally believed tha t

controlled d r u g release resu l t s in

lower C m a x and h igher C m ^ n va lues compared to

conventional re lease .

However, th is is not always t h e case . Consider F igure

4. A con

ventional dosage form of d r u g ( k a = 1.0 h " 1 , k e l

= 0.1 h r " 1 ) admin

i s t e red 100 mg every six hours yields peak and t r o u

g h amounts of

t h e d r u g in the body of 105 and 54 mg , respec t ive

ly . A controlled

release dose ( k r = 0.5 h r " 1 ) administered 200 mg

every 12 h r r e su l t s

in increased peak and decreased t r o u g h leve ls . The

value of k r

would need to be r educed to ca 0.25 h r " 1 in o r d e r

to obtain similar

peak and t r o u g h levels to those from the conventional

dosage form.

B . Zero-Order Release

1. Single Dose

The amount of d rug in the body following a single dose is

given by

Eq . ( 7 ) , in which k Q is t he ra te constant govern

ing absorpt ion

(ko « k a ) . A-M!-.-*'] (7) el

A(mg) 12 18 24 Time (hours)

Fig. 4 Drug levels at steady-state during repeated doses,

400 mg
per day in divided doses, of a conventional formulation (k
a = 1.0

h r ' l ) and controlled release formulations (k r = 0.5

hr~l [ — 1 and

0.25 hr" l [ ] , T = 6 hr for the conventional formulation

and 12

hr for the others, and k e j = 0 . 2 h r " l ) .

(Reproduced by permission

from Ref. 2.) Eq. (7) can be converted to describe drug

concentrations as in

Eq. (8) . C = k o r v i v i r ; L l e J el (8) Drug

profiles from this type of dosage form are influenced by

the rate at which drug is released from the dosage form and
also the

elimination rate, as shown in Figures 5 and 6. It is clear

from Fig

ure 5 that , while drug levels are directly proportional to

the con

trolled release rate , the time course of accumulation

following a single

dose is independent of release rate and is dependent solely

on the

elimination rate constant. It is also clear that , even

with a short 160I20H

A(mg) 80H 4 0 H Time (hours)

Fig. 5 Accumulation of drug in the body from a single dose

of

zero-order release formulations (k 0 = 10,20,30, and 40

mg'hr" 1 and

k e j = 0.25 h r " 1 ) . (Reproduced by permission from

Ref. 2.)

drug elimination half-life of 2.8 h r , plateau drug levels

are not
achieved with a GI residence time of 12 hr . To achieve a
plateau

level, the residence time would have to be increased to

20-25 hr .

For drugs with longer elimination half-lives, it is

unlikely that plateau

drug levels are achieved from a single dose. For example a

drug

with a t i / 2 of 10 hr would have to be released

continuously for 45

hours before steady-state levels were approached. This

argument is illustrated in Figure 6. A drug with an elimina

tion t i /2 of 1.7 hr (k e i = 0.4 hr" 1 ) will approach

steady state at

12 h r . A drug with a t i / 2 of 7 (k e j = 0.1 hr" 1 )

will not achieve

steady state at 24 hr . These examples illustrate the

misconception

that it is possible to achieve plateau or steady-state drug

levels

with a single dose of a zero-order release formulation.

When a zero-order formulation has released all of its
medication,

or when the partially spent formulation is voided in the

feces, drug

levels decline at a first-order rate regardless of whether

or not

steady-state levels have been reached.

with elimination half-lives of 2 hr (k e i :

0.087 hr~l) are shown in Figure 7.

2. Repeated Dose Typical profiles for drugs 0.35 hr" 1 )

and 8 hr (k e l :
Despite the discontinuous nature of drug levels from
zero-order re

lease formulations, as shown in Figure 8, the dependency of

both

the ascending and descending components of the curves on

drug

elimination half-life lends itself to sustained and

controlled levels of

medication with repeated dosing. Consider the two

situations in Figure 7. If the drug with the

shorter half-life is administered every 12 hr as in Figure

8, then 9 0 n 60H

A(mg) 30H Time (hours)

Fig. 6 Accumulation of drug in the body from a single dose

of a

zero-order release formulation (k 0 = 10 [Link]"! and k e j

= 0.1-0.4

h r " 1 ) . (Reproduced by permission from Ref. 2.) 8 0 n

A(mg) Time (hours)

Fig. 7 Drug levels during and after a single dose of a

zero-order

release dosage form (ko = 10 mg hr~l , release time T = 12

hr , and

k e l = 0.087 and 0.35 h r " 1 ) . (Reproduced by

permission from Ref, 2.)

plateau drug levels are maintained with successive doses.

If the

drug with the longer half-life is given every 12 hr , then,

as shown

in Figure 9, accumulation will continue with successive

doses until the

steady-state level is achieved. Ninety-five percent of

steady-state
level will be reached at 4.3 x t^ /2 , or between the
fourth and fifth

doses. Once steady-state is reached, plateau drug levels,

with

minimal fluctuation, can theoretically be obtained.

Zero-order release

formulations thus represent an ideal controlled release

system and

several recently introduced products are based on this

principle.

Obviously, actual blood levels obtained in vivo will depend

not only

on drug release rate, but also on drug stability,

absorption efficiency

from various regions of the GI tract , and a host of other

factors. From this discussion on first-order and
zero-order release sys

tems , it is clear that , whether considering single dose

or multiple

dose, the time taken to achieve desired levels in the body

depends

on the elimination rate constant. The slower the

elimination, the

more time will be required to reach steady-state. Methods

for

calculating appropriate loading doses under a variety of

situations

are well documented [17]. A number of formulations have

been designed incorporating a

fast release drug component in addition to a controlled

release com

ponent. While such formuations may be useful when

administered
either as single doses or as widely spaced intermittent
doses, their

usefulness for repeated dosages in order to maintain drug

levels in

the body is less obvious. The next sections will consider

some ad

vantages and disadvantages of this type of dosage form.

C . Zero-Order Release with a Fast Release Component

1. Single Dose

Incorporation of a fast release component into a controlled

release for

mulation is intended to rapidly obtain a desired drug level

in the body

and to maintain this level by means of the controlled

release component.

A(mg) Time (hours)

Fig. 8 Drug levels during 12-hourly repeated doses of the

rapidly

eliminated dosage form from Figure 7. Solid lines indicate

total drug

levels while dashed lines indicate the individual levels

from successive

doses. (Reproduced by permission from Ref. 2.) Time (hours)

Fig. 9 Drug levels during 12-hourly repeated doses of the

slowly

eliminated dosage form from Figure 7. Solid lines indicate

total drug

levels while dashed lines indicate the individual levels

from successive

doses. (Reproduced by permission from Ref. 2.) The

pharmacokinetics associated with this type of drug release

are complex because of contributions from both the fast and

slow

release components. Although the temporal relationship

between

initiation of release of the two components may vary,

discussions

here will assume that release of both components starts

simultaneously. Again assuming k 0 << k a , the amount of
drug in the body follow

ing a single dose is given by Eq, (9). D.k T k t k t l k r

k Al A i a el a o L el The two parenthetical terms on the
right hand side of this equa

tion represent the contributions of the fast and slow

release compo

nents. The first portion is similar to Eq. (1) (released by

first-order

process) while the second portion is identical to Eq. (7)

(zero-order

release). The quantity of drug in the controlled release

component,

D s , is given by k 0 T, where T is the duration of drug

release. The

drug profile obtained from a single dose is a composite of

a rapidly

increasing and then declining component and of a slowly

increasing

component. This dosage form is ideally suited for all drugs

other

than those with very short elimination half-lives, that

would not

achieve steady-state without a fast release component.

With this dosage form, both the rate of deline in drug
levels from

the fast-release component and the rate of increase in

levels from the
slow zero-order release component are controlled by the
drug elimina

tion rate constant [Eq. (9 ) ] . Several methods have been

described

to calculate the proportions of Di and D s that are

required to rapidly

achieve and maintain therapeutic drug levels [18-21], The

most

recent method is based on the assumption that the fast

release com

ponent should provide the quantity of drug that would yield

the

desired therapeutic response at steady-state, A s s , as in

Eq. (10)

[21]. D. = A = k / k , (10) l ss o el This approach

ignores the possible additive effect from the fast

and slow release components at early times and may yield

drug levels

higher than the desired steady-state levels shortly after

dosing.

However, this effect is likely to be slight, and the method

is simple

and practical. Application of the method is demonstrated

for theophylline. Theo

phylline has an elimination t i / 2 of approximately 4 hr

(k e i = 0.17 hr" 1 )

and a distribution volume of 32 liters [22] . A

steady-state level of

5 yg/ml is thus equivalent to A s s = B\ = 160 mg, and ko

= 160 x

0.17 = 27.2 mg/hr [Eq. (10)]. Substitution into Eq. (9) and
assign

ing k a = 1.3 h r" l [22] and a zero-order release time of

12 hr yields
the drug levels in Figure 10. The required level of 5 yg/ml
is

achieved by 2 hr and maintained through 12 hr , after which

time the

zero-order component is exhausted of drug. Levels then fall

expon

entially at a rate determined by k e i«

Ctpg/ml ) Time (hours)

Fig. 10 Plasma theophylline concentration profile from a

single dose

of an oral formulation containing 160 mg as a fast-release

component

and a slow component releasing 27.2 [Link]" 1 during 12 hr

. Solid

lines indicate total drug levels while dashed lines

indicate the con

tributions from individual components. (Reproduced by

permission

from Ref. 2.) The above method clearly is successful in

rapidly achieving a

desired drug level, but the level reached is only one half
the minimum

therapeutic concentration of 10 yg/ml. This is intentional

and reflects

two problems associated with controlled release drug

formulations.

The first is dose size. Rapidly obtaining and then

maintaining a

theophylline level of 5 yg/ml for a 12-hr period requires

(160 +

27.2 x 12) mg or ca. 500 mg. This is probably the upper

limit for
a single oral dosage unit. A theophylline level of 10 yg/ml
under

the same conditions would require a total dose of 1000 mg

(320 mg

as Dj and 680 mg as D s released over 12 h r ) . This is

too large for

a single dosage unit, but can be obtained by giving 2 x 500

mg units .

Similarly 15 yg/ml and 20 yg/ml levels can be obtained with

three

and four dosage units , respectively. Thus, whatever the

dosage

size for a drug, multiples of a minimum drug level are

achieved by

taking the appropriate number of tablets. While this

process is sim

ple, the reverse is not. It is often not possible to

subdivide single

controlled release formulations to achieve a smaller dose.

Thus, it

is appropriate for maximum flexibility in dosing to prepare

controlled

release dosage forms in the smallest practical dosage units.

2. Repeated Dose

The objective with repeated doses for this case is not so

much to

achieve increasing drug levels with each subsequent dose,

but to

maintain plauteau levels obtained with the initial dose. It

is at this

point that the argument for a fast release component in an

oral con

trolled release dosage form becomes tenuous, While

formulations that release all of the drug at a slow, zero

order rate yield continuous drug levels with no peaks or

troughs

with repeated doses at intervals equal to the total release

time of

each dose (Figs. 8 and 9), this type of drug level pattern
cannot

be achieved when a fast release component is added.

Consider the theophylline example again. If this
formulation were

taken every 12 hr , then, unlike the situation in Figure 8,

there

would be sharp increases in drug levels with successive

doses and

undue accumulation may occur if drug levels do not return

to re

quired C s s levels at the end of each dosing interval.

This is demon

strated in Figure 11 using a dosing interval of 12 hr and

the same

kinetic values as in Figure 10. Although a plateau level of

ca. 5

yg/ml is rapidly achieved with the initial dose, levels are

transiently

increased to 8.7 and 9.2 yg/ml shortly after the second and
third

doses, respectively. This could clearly give rise to

transient yet

potentially toxic side effects after each dose with this

type of

formulation. Several approaches may be used to prevent

transient fluctuations

in drug levels with this type of formulation. One can

minimize the
transient increase by decreasing the loading dose in all
doses after

the first, or by administering the dosages at time

intervals greater

than the zero-order release period. Unfortunately, these

approaches

are either impractical from a formulation viewpoint or

cumbersome

with respect to drug administration. A more realistic

approach is

not to include a fast-release component at all, but rather

to administer

a conventional dosage form initially to establish

therapeutic levels,

followed by repeated doses of a zero-order controlled

release dosage

form to maintain constant levels with minimum fluctuation.

For the theophylline example, an initial conventional dose
of 300

mg, together with (a) a zero-order release formulation that

releases

600-650 mg during 12 hr and (b) subsequent 12-hourly doses

of the

controlled release formulation, would rapidly achieve and

maintain a

theophylline plasma level of ca. 10 yg/ml.

D. F i rs t -Order Release with a Fast Release Component

2. Single Dose

Both the fast and slow components of this dosage form

release drug

at a first-order rate. If release of both components starts

simul
taneously, the resulting drug profiles are described by Eq.
(11).

10.0

7.5 H

C(pg/ml)

5.0-^

2.5HJ Time (hours)

Fig. 11 Plasma theophylline concentration profile from

three succes

sive doses of the formulation in Figure 10. Pharmacokinetic

param

eters are the same as in that figure. Dosage interval is 12

hr .

Solid lines indicate total drug levels while dashed lines

indicate

the individual levels from'successive doses. (Reproduced by

per

mission from Ref. 2 . ) . D k r , x i +1 D k r k t"| i a

k t k t s r k t r el (ID This equation is the sum of two
separate, simultaneous first

order absorption and elimination profiles, with different

apparent

absorption rate constants k a and k r . With this pattern

of drug release, which is probably more common

than the previous model, a strong argument can be made for

delaying

the release of the slow component until some time later

compared to

the fast component. Consider the profiles in Figure 12. In

this

figure the slow component is threefold greater in size than

the fast
component. The curve generated when all the dose is in the
fast

release form is included for comparison. When k r = 0.5 k

a there is

a negligible sustained effect, and drug profiles are not

significantly

prolonged until k r is reduced to 0.1 k a . Unfortunately,

between 25

and 50% of the slow release proportion may not be absorbed

due to

limited GI residence time so that the sustained component

during 12

24 hr would be lost. An alternative method to achieve

prolonged circulating drug profiles

with this type of formulation is to delay release of the

slow component 80 -, 6 0

A(mg) 40-^ 20 a r \ \ b A a b c d Dj = 100 mg k

r = 0 . 5 h r H k r = 0 .25hr _ l k r =0.1 hr" 1 16
20 24 Time (hours)

Fig. 12 Drug levels following single oral doses of a dosage

form

containing fast and slow first-order release components,

released

simultaneously. The pharmacokinetic values are as follows:

D^ =

25 mg, D s = 75 mg, k a = 1.0 h r " l , k e l = 0.17 h r"

l ( t i /2 = 4 h r ) ,

and k r = 0.1, 0.25, and 0.5 h r 1 . The curve obtained

when Dj =

100 mg and D s = 0 mg is also shown. (Reproduced by

permission

from Ref. 2.)

to provide a second input at a certain time after the

release of the fast
component. Arguments can then be made for fast or slow
release of

the second drug component. The first of these is similar to

admin

istering repeated doses of a conventional dosage form

except that

the second portion will be released lower down the GI t

ract . The

second component therefore will be less susceptible to

gastric degra

dation but more susceptible to poor absorption from distal

parts of

the intestine, bacterial degradation, and limited GI

transit time.

Apart from these problems, which may be drug specific, the

general

pharmacokinetic treatment from two- or three- step fast

release formu

lation does not differ conceptually from repeated doses of

conven

tional dosage forms. The alternative approach of a

delayed, controlled-release com

ponent is also a viable method to maintain drug levels. The

principal

C(/ /g/ml) Time (hours)

Fig. 13 Plasma theophylline concentration profiles from a

single

dose of an oral formulation in which first-order release of

the slow

component is initiated when plasma levels from the fast

release com

ponent are at a maximum. The curves are calculated from

Equation
12 with the value of t for the slow component reduced by T
m a x =

1.8 hr. The pharmacokinetic values are as follows: k a =

1.3 hr~l ,

k e l = 0.17 h r ' 1 , V = 32L, Di = 200 mg, and D s =

160 mg ( k r = 0.125

h r " 1 ) , 320 mg (k r = 0.063 h r " 1 ) , 640 mg ( k r

= 0.031 h r " 1 ) , and

1280 mg (k r = 0.016 h r " 1 ) . (Reproduced by permission

from Ref.

2.) 5 -j 4 A 3 -H

C(//g/ml) 2 I i I o-r 0 12 24 Time (hours)

Fig. 14 Predicted plasma theophylline concentration profile

from a

single dose of an oral formulation in which first-order

release of the

slow component is initiated when release of the fast

component is 99%

complete. The pharmacokinetic values are as follows: Di =

200 mg,

D s = 180 mg, k a = 1.3 hr" 1 , k e l = 0.17 hr" 1 , and

k r = 0.3 hr" 1 .

Delay time for the slow component is four hours. Solid

lines indicate

total drug levels while dashed lines indicate the

individual levels from

the two components. (Reproduced by permission from Ref. 2.)

questions in this approach are: (a) when should the slow

release

component be released and (b) what are the optimal

proportions of

drug in the fast and slow release components. Regarding the

first

question, two possible approaches are (a) to release the

second com

ponent when levels from the first component are at a

maximum, or

(b) to release the second component when essentially all of

the first

component has been released [20]. The first approach is

based on the argument that if the slow com

ponent can approximate zero-order release, then initiating

the second

component when the drug levels from the fast component are
at a

peak should yield a plateau effect similar to that achieved

with the

third case. This approach does not work well in practice.

First

order release approximates zero-order only when the amount

of drug

is large and the first-order release rate constant is

small. This is

illustrated for the theophylline example in Figure 13. An

ideal pla

teau affect is achieved only when D s is six-fold greater

than Dj and

k r is reduced to 0.016 h r 1 . This is wasteful as only

20% of the

slowly released dose would be absorbed during a 12 hour

period,

and only 30% during 24 hr . The second approach of

releasing the slow component when most

of the fast component has been released is more realistic.

If the
delay is equal to the time when Di is essentially
completely released,

then drug level curves similar to those shown in Figure 14

can be

achieved. In this example the slow release component is

released

four hours, or 7.5 absorption half-lives, after the fast

component.

Despite the fluctuations in drug levels, reasonably

sustained levels

are obtained using a relatively small maintenance dose.

This type

of formulation is also efficient from a drug utilization

viewpoint. In

this example, approximately 80% of the sustained dose would

be ab

sorbed by 12 hr, and absorption would be quantitative in 24

hr,

2. Repeated Dose

A dosage form that contains fast and slow first-order

release com

ponents presents the same problems for multiple dosing

regimens as

those described for the preceding case (Case C). For that
model

it was shown that more satisfactory multiple dose drug

profiles are

C(/ /g /ml) 4H Time (hours)

Fig. 15 Predicted plasma theophylline concentration profile

during

repeated doses of the formulation in Figure 14. (Reproduced

by per

mission from Ref. 2.) t t n 1 r 0 12 24 36 Time (hours)

Fig. 16 Predicted plasma theophylline concentration profile
during

repeated doses of the oral formulation in Figure 14. Dj has

been

reduced to 100 mg for the second and third doses [x= 12 h r

] . (Re

produced by permission from Ref. 2.)

obtained without a fast release component. In the present

case, a

variety of multiple dose profiles can be obtained by

judicious selection

of drug quantities and release rates [15]. Consider the

formulation in Figure 14. Multiple doses of this

formulation could be given with the sustained and fast drug

compo

nents unchanged, or with the quantity Dj reduced to

compensate

for drug remaining in the body from the previous dose.

Typical

profiles are shown in Figures 15 and 16. The profile in

Figure 15 shows that, once again, repeated dosing

of a formulation containing a fast release component that

yields the

required therapeutic profile after the initial dose will

lead to marked

oscillation, the possibility of yielding toxic levels

shortly after each

dose, and also undue accumulation with repeated dosing. If,

on the

other hand, the amount of drug in the fast component is

appropriately

reduced [15], then the more acceptable profile in Figure 16

is ob
tained. Thus, by judicious dose adjustment, drug levels can
be

generated, at least in theory, to oscillate within a

relatively narrow

range.

C(//g/ml) 2-J It is impractical to have varying amounts

of instantly released

drug in different tablets, so that one is presented with a

compromise

of either achieving required levels rapidly and accepting

the wide

range of drug levels subsequently, or achieving the ideal

drug pro

file at steady-state and accepting a delay in achieving

that level.

It is not possible to rapidly achieve required drug levels

and then

maintain them with minimum oscillation from this type of

formulation.

V I I . BIOAVAILABILITY TESTING

Bioavailability is generally defined as the rate and extent

of absorp

tion of unchanged drug from its site of application to the

general cir

culation. Bioavailability is necessarily defined in terms

of a specific

drug moiety, usually the active therapeutic entity, which

may be

the unchanged drug or , as with prodrugs for instance, a

metabolite.

In contrast, the term "absorption" often refers to net

transport of
drug-related mass from its site of application into the
body. Hence,

a compound may be completely absorbed but only partially

bioavailable

as would occur, for example, with a pharmacologically

active agent

which is efficiently absorbed from the gut to the portal

circulation

but undergoes extensive first-pass degradation to inactive

metabolites

in the liver before it reaches the systemic circulation.

When low

bioavailability is caused by incomplete absorption,

pharmaceutical op

timization of the dosage form may be warranted to improve

absorption

characteristics of the drug and thereby also its

bioavailability.

Throughout this chapter, it is assumed that the orally

administered

drug is the pharmacologically active agent which is

absorbed in

unchanged form so that absorption and bioavailability are

synonymous. The assessment of extent of absorption from a
sustained-release

formulation does not differ fundamentally from that for

standard,

immediate-release dosage forms. Mass balance dictates that

the amount

of drug absorbed must be equivalent to the amount of drug

eliminated.

In other words, after a single oral dose the bioavailable

fraction

(F x ) of the administered oral dose (D x ) is equivalent

to the product

of the plasma clearance (CL) of the drug and the total area
under

the plasma drug concentration curve (AUC X ): F X D X =

[Link] X (12) Once the CL of the drug is known, F X can
be determined. CL

is estimated in a separate reference treatment following an

intra

venous dose of the drug (X = i .v . ) since F** v - in Eq.

(12) i s , by

definition, unity. In this case, the "absolute

bioavailability" of the

oral dose is determined. When intravenous dose

administration is

not possible an oral solution or other reference

standard(s) is used

and the "relative bioavailability" determined: F X /F S =

(AUC X /AUC S ).(D S /D X ) (13)

Equation (13) is valid as long as CL X = CL S ;

alternatives to the con

stant clearance assumption have been delineated [23,24].

Equation (13) provides an estimate of the extent of
absorption

but gives no information on the rate, or time-course, of

the absorp

tion (input) process. Equivalence in rate of absorption

between

immediate-release and reference formulations is often

inferred from

the observed maximum and time of maximum plasma drug

concentration

(Cmax> t m a x ) . The two formulations are termed

"bioequivalent" if

their rate and extent of absorption are similar. Since rate

is inten

tionally modulated in a sustained release formulation, it i

s , by defini

tion, not bioequivalent to an immediate release dosage

form. Rather,

an objective of bioavailability testing of

sustained-release formulations

is to document in a quantitative sense how the input

process has

been modulated. Again, mass balance considerations provide

one

means to determine the absorption, or input, profile of the

drug.

The amount of drug absorbed through time t after dose

administration

A(t) , must be equal to the sum of that which is in the

body at time

t , B ( t ) , and that which has been eliminated from the

body by time

t . That i s , A(t) = V.C(t) + CL . A U C 0 ^ (14)

where B(t) is given by the product of the volume of

distribution of

the drug, V, and its plasma concentration at time t , C( t

) , and the

cumulative amount eliminated is the product of drug

clearance and the

area under the curve from time 0 to 5, AUC 0_> t. The

absorption

profile [A(t) vs_ t] is obtained by successive application

of Eq. (14)

to each of the plasma sampling time points. The

experimental design

should accomodate a plasma sampling scheme sufficient to

define the

entire time course of the absorption process. Equation

(14) is applicable for drugs which exhibit monoexponen

tial disposition kinetics and is known as the Wagner-Nelson

method

[25] for estimating the time course of absorption. The

method is

model-dependent and requires estimates of V and CL obtained

follow

ing an i .v . dose. If i .v . dose administration is not

feasible, the

amount of drug absorbed relative to its distribution volume

can be

obtained as: A(t)/V = C(t) + k . AUC (15)

since CL/V is the elimination rate constant of the drug (k

e i ) . Ap

plication of Eq. (15) requires an estimate of the true

value of k e i .

With conventional, fast release dosage forms, where k a >

k e j , k e j is

obtained from the terminal slope of the log-concentration

versus time

profile (k e i = 0.693/t 1/2) • With a sustained release

formulation,

where a prolonged absorption phase is intended, the

observed terminal

portion of the profile may not be free from the effects of

absorption

and, in the extreme, may represent the release rate

constant of drug

from the formulation (k r ) as shown in Figures 2 and 3,

where k r <

k e j . Notwithstanding intersubject variability in k e i ,

comparison of

the plasma profile after the sustained-release formulation

with that

after an immediate release formulation would provide

assurance that

the proper k e i is used. When drug disposition kinetics

are more complex than a one

compartment model, the amount of drug in the body term in

Eq. (14)

must account for drug in the peripheral as well as central

compart

ments, as has been described for biexponential [26,27] or

more com

plex [28] disposition models. Owing to the absence of

suitable in vitro tests for sustained re

lease drug products, and also the uncertain relationship

between

in vitro release and in vivo absorption, bioavailability

and bioequiva

lence testing of sustained and controlled release products

must be

conducted in vivo in man. The FDA requirements for

bioequivalency testing between con

trolled release and conventional release products, or

between two

controlled release products, have been set out in the

Federal Register

[11] . The regulations provide the following guidelines to

assist in

conducting and presenting bioequivalence studies in support

of a New

Drug Application for controlled release products. The

purpose of an in vivo bioavailability study involving a
drug
for which a controlled release claim is made is to
determine if all of

the following conditions are met: 1. The drug product

meets the controlled release claims made for i t . 2. The
bioavailability profile established for the drug product
rules out the occurrence of any dose dumping. 3. The drug
product's steady-state performance is equivalent to a
currently marketed non-controlled release or controlled
release drug product that contains the same active drug
ingredient or therapeutic moiety and that is subject to an
approved full New Drug Application. 4. The drug product's
formulation provides consistent pharmacokinetic performance
between individual dosage units. The reference material(s)
for such a bioavailability study shall

be chosen to permit an appropriate scientific evaluation of

the

controlled release claims made for the drug product. The

reference

material shall be one of the following or any combination

thereof: 1. A solution or suspension of the active drug
ingredient or therapeutic moiety 2. A currently marketed
non-controlled release drug product containing the same
active drug ingredient or therapeutic moiety and
administered according to the dosage recommendations in the
labeling of the noncontrolled release drug product 3. A
currently markedted controlled release drug product subject
to an approved full New Drug Application containing the
same active drug ingredient or therapeutic moiety and
administered according to the dosage recommendations in
the labeling proposed for the controlled release drug
product 4. Another reference material that is appropriate
for valid scientific reasons The guidelines have been
described recently by Malinowski [29] .

It is the position of the FDA that the above requirements

apply to

essentially all controlled release prescription as well as

over-the

counter (OTC) products. It is important to note that , in

vivo tests

must be done at steady-state, as pointed out in item 3.

Single dose
data are insufficient. However, single dose data have been
accepted

for some OTC products in the past. In addition to in vivo

data, the FDA requires in vitro data to

ensure lot uniformity and hopefully to provide information

that is

predictive of in vivo bioavailability. The key elements of

in vitro

tes ts , as outlined by Malinowski, are method

reproducibility, correct

choice of dissolution medium, maintenance of perfect sink

conditions,

and control of solution hydrodynamics. The FDA are

concerned with the possibility of dose dumping,

and criteria for evaluating this consists essentially of

administering

the quantity of drug contained in the controlled release

product as

an immediate release bolus dose. The rate of absorption

from the

test formulation should be substantially slower compared to

the bolus

dose. Whether testing a new controlled release formulation

against con

ventional release or another controlled release product,

similar cri

teria for bioequivalence apply, notwithstanding the

different dosage

intervals for slow release and fast release products. One

problem that is being addressed by the FDA is that of thera

peutic equivalence. The current guidelines indicate that

for two

products to be therapeutically equivalent thay must by

definition be

bioequivalent with the same rate and extent of absorption.

Thus,

for therapeutic equivalence, the reference product needs to

be an

approved controlled release formulation, and the blood

level curves

from the test and reference products should be

statistically super

imposable. Products that do not meet these criteria

exactly, as well

as situations where a controlled release product is

compared to a

conventional formulation, need to be considered on a case

by case

basis.

V I I I . CONCLUSIONS

The development of sustained or controlled release products

is now

one of the most active research areas in the pharmaceutical

industry.

Controlled release has inherent advantages and

disadvantages, and

these should be considered together before embarking on a

formula

tion program for a drug candidate. Controlled release

formulations

have developed principally for cardiovascular, CNS , and

respiratory

drugs. The antimicrobial drugs have been largely neglected.

For

drugs such as nitroglycerin, the particular indication has

to be
considered as well when assessing the merits of controlled
release

compared to conventional release. Despite the ever

increasing number of controlled release products

available in the United States and elsewhere, there have

been few

attempts to predict in vivo drug level data from in vitro

or theo

retical release patterns, or to address the unique problems

that ac

company single and repeated doses of these dosage forms.

There

are some notable exceptions. Attempts to develop a truly

zero-order

release dosage form have found expression in the osmotic

pump [30,

31] and also in a matrix system for controlled release

[32]. Basic pharmacokinetic principles can be used in the
development

of controlled release prducts to achieve desirable release

properties.

Different criteria may apply when one is considering single

and

repeated doses. The methods described here, while containing

some simplifying assumptions, provide a rational basis for

controlled

release dosage design. The methods represent a compromise

between

ideality and practical feasibility. They may not always

apply to in

dividual cases. Some drugs may exhibit a marked apparent

absorp

tion window or may be susceptible to bacterial degradation

in the

lower GI t ract , thus reducing absorption efficiency. The

opposite

effect occurs with formulations designed to extend GI

transit time.

First-pass clearance may also be important for drugs that

undergo

extensive hepatic metabolism or are excreted extensively in

the bile. In the final analysis, controlled release dosage
forms are entering

an era of unprecedented sophistication, not only in terms

of new

dosage forms but also in terms of more rigid testing and

characteri

zation with respect to in vitro—in vivo relationships,

predicted and

actual release patterns, and

pharmacokinetic/pharmacodynamic rela

tionships. Appreciation and application of simple kinetic

principles,

similar to those descr ibed in th i s c h a p t e r , i s

an essent ial component

of controlled release development and offers a g rea te r

oppor tun i ty for

success compared to t he empirical approach .

1. F . Theeuwes , D r u g delivery sys tem, Pharmac. Ther.

13, 149191 (1981).

2. P . G. Welling, Oral controlled d r u g adminis trat

ion: Pharmacokinet ic cons idera t ions , Drug Dev. Ind.
Pharm. 9, 1185-1225 (1983).

3 . L. Hendeles, R. P . I a f ra te , and M. Weinberger , A

clinical and pharmacokinetic basis for t h e selection and
use of slow release theophyll ine p r o d u c t s , Clin.
Pharmacokin. 9, 95-135 (1984).
4. A. F . Hofmann, J . H. Dressman, C. F . Code, and K. F .
Witztum, Controlled e n t r y of oral administered d r u g
s : Physiological cons idera t ions , Drug Dev. Ind.
Pharm. 9, 1077-1109 (1983).

5. K. A. Kelly, Motility of t h e stomach and gastro

duodenal junct ion . I n , Physiology of the
Gastrointestinal Tract (L. R. Johnson , E d . ) , Raven P
r e s s , New York, 1981, Chap . 12, p p . 393-410.

6. J . W. Fa ra , Gastrointest inal t r ans i t of solid

dosage forms, Pharm. Tech. 7 ( S u p p l . ) , 23-26
(1983).

7. J . H. Meyer, H. Ohash i , D . J e h n , and J . B .

Thomson, Size of l iver par t ic les emptied from the
human stomach, Gastroenterology, 80, 1489-1496 (1981).

8. S . S . Davis , J . G. Hardy , M. J . Tay lor , D . R.

Whalley, and C. G. Wilson, A comparative s tudy of t he
gas t rointes t inal t r a n sit of a pellet and tablet
formulation, Int. J. Pharm. 21, 167177 (1984).

9. S. S . Davis , J . G. Hardy , M. J . Tay lor , D. R.

Whalley, and C. G. Wilson, The effect of food on the gast
rointes t inal t r ans i t of pellet and an osmotic device
(Osmet) , Int. J. Pharm. 21, 331-340 (1984).

10. S . S . Dav i s , J . G. Hardy , M. J . Tay lor , A.

Stockwell, D . R. Whalley, and C. G. Wilson, The in vivo
evaluation of an osmotic device (Osmet) u s ing gamma sc
in t i g r aphy , J. Pharm. Pharmacol. 36, 740-742 (1984).

11. Drug p r o d u c t s , bioequivalence requi rements and

in vivo bioavailability p r o c e d u r e s , Fed. Register
42, 1624-1653 (1977).

12. C. MacLeod, H. Rabin , J . Ruedy , M. Caron , D.

Zarowny, and R. O. Davies, Comparative bioavailability of
t h r e e b r a n d s of ampicillin, Can. Med. Assoc. J.
107, 203-209 (1972).

13. P . G. Welling, R. B . Pate l , U. R. Pate l , W. R.

Gillespie, W. A. Cra ig , and K. S . A lbe r t ,
Bioavailability of tolazamide from t ab l e t s :
Comparison of in vitro and in vivo r e s u l t s , J.
Pharm. Sci. 71, 1259-1263 (1982).

14. R. B . Pate l , M. C. Rogge , A. Selen, T . J . Goehl,

V. P . Shah, V. K. P r a s a d , and P . G. Welling,
Bioavailability of hydrocor t i sone from commercial 20 mg
t a b l e t s , J. Pharm. Sci. (in p r e s s ) .

15. P . G. Welling and M. R. Dobr inska , Multiple dosing

of sus ta ined release s y s t e m s . In , Sustained and
Controlled Release Drug Delivery Systems ( J . R.
Robinson, E d . ) , Marcel Dekker , I n c . , New York ,
1978, p p . 631-716.

16. M. Gibaldi and M. A . Schwar tz , The pharmacokinet ics

of penamecillin, Br. J. Pharmacol. Chemother. 28, 360-366
(1966).

17. M. Gibaldi and D. P e r r i e r , Pharmacokinetics,

Marcel D e k k e r , I n c . , New York, 1975, p . 108.

18. E. Nelson, A note on mathematics of oral sus ta inedre

lease p r o d u c t s , J. Amer. Pharm. Assoc. (Sci. Ed)
46, 572-573 (1957).

19. M. Rowland and A. H. Becke t t , Mathematical t rea

tment of oral sus ta inedre lease d r u g formulations, J.
Pharm. Pharmacol. 16 (Suppl.), 156T-162T (1964).

20. J . R. Robinson and S. P . E r ik sen , Theoret ical

formulation of sus ta ined release dosage forms, J. Pharm.
Sci. 55, 1254-1263 (1966).

21 . M. R. Dobrinska and P . G. Welling, Blood levels from

a sus ta inedre lease dosage form, J. Pharm. Sci. 64,
1728-1729 (1975).

22. J . W. J e n n e , E. Wyze, F . S . Rood, and F . M.

MacDonald, Pharmacokinetics of theophyl l ine: Application
to adjustment of t h e clinical dose of aminophylline,
Clin. Pharacol. Ther. 13, 349-360 (1972).

23. K. C. Kwan and A. E. Til l , Novel method for

bioavailability assessment , J. Pharm. Sci. 62, 1494-1497
(1973).

24. S. Hwang and K. C. Kwan, F u r t h e r considerat ions

on modelindependent bioavailability estimation, J. Pharm.
Sci. 69, 77-80 (1980).

25. J . G. Wagner and E. Nelson, Percent absorbed time

plots der ived from blood level and /o r u r i n a r y
excret ion da t a , J. Pharm. Sci. 52, 610-611 (1963).

26. J . C. K. Loo and S . Riegelman, New method for

calculating t he in t r ins ic absorpt ion ra te of d r u
g s , J. Pharm. Sci. 57, 918928 (1968).

27. H. G. Boxenbaum and S . A. Kaplan, Potential source of

e r r o r in absorpt ion r a t e calculat ions , J.
Pharmacokin. Biopharm. 3, 257-264 (1975).

28. K. C. Kwan, Pharmacokinetic considerat ions in the

design of controlled and sus ta ined release d r u g del
ivery sys tems . In , Sustained and Controlled Release
Drug Delivery Systems ( J . R. Robinson, E d . ) , Marcel
D e k k e r , I n c . , New York, 1978, Chap . 8, p p .
605-607.

29. H. J . Malinowski, Biopharmaceutics aspec ts of t he

regula tory review of oral control led-re lease d r u g p
r o d u c t s , Drug. Dev. Ind. Pharm. 9, 1255-1279
(1983).

30. W. B a y n e , V . Place, F . Theeuwes , J . D. Roge r

s , R. B . Lee, R. O . Davies , and K. C. Kwan, Kinetics
of osmotic ally control led indomethacin del ivery systems
after r epea ted dos ing , Clin. Pharmacol. Ther. 32,
270-276 (1982).

31. J . D . R o g e r s , Biopharmaceutical evaluation of

"Osmosin," Curr. Med. Res. Op. 8(Suppl. 2 ) , 38-54
(1983).

32. P . O. Fagers t rom, T . Mells t rand, and N. Svedmyr ,

Absorpt ion of theophyl l ine from conventional and sus ta
inedre lease t a b l e t s , Int. J. Clin. Pharmacol. 19,
128-131 (1981).
7 Chapter 7 Regulatory Assessment

1. USP Modified Release Dosage Form Policy. United Sta tes

Pharmacopeia! Convention publ icat ion; 1985-USP XXI,
Published by USP, Rockville, MD, 1984.

2. J . P . Skelly and W. H. B a r r ; Short course in

controlled release dosage forms; biopharmaceutic
considerat ions in des igning and evaluat ing novel d r u
g delivery sys t ems , Academy of Pharmaceutical Sciences
National Meeting Symposium, Miami Beach , Flor ida,
November, 1983.

3. Controlled Release Dosage Forms " Issues and Cont rovers

ies" (Sep t . 29 -Oc t . 1, 1985) Cosponsored by Food and
Drug Admini s t ra t ion , Academy of Pharmaceutical
Science, and American Association for Clinical Pharmacology
& T h e r a p e u t i c s , Washington, DC.

4. W. H. B a r r , Bioavailability of solid oral dosage

forms and clinical r esponse to d r u g t h e r a p e y ,
in J . Swarbr ick , e d . , Current Concepts in the
Pharmaceutical Sciences; Dosage Form Design and
Bioavailability. Lea & Feb iger , Philadelphia, 1973.

5. S. S. Davis , Principles and pharmacokinetic

applications of ex te rna l visualization techniques—Use of
sc in tography in the d e velopment and optimization of
dosage forms; 24th Internat ional Indus t r ia l
Pharmaceutical Conference, Tapatio S p r i n g s , Boerne ,
TX, 1984.

6. J . Gummitt, and R. J . Sawchuk, FDA contrac t number

223-76-3019,

7. United States Pharmacopeial Convention publ ica t ions;

1985-USP XXI, publ i shed by USP; Rockville, MD.

8. M. A. Osman, R. B . Pate l , D . S . I rwin , and P . G.

Welling, Absorption of theophyll ine from enter ic coated
and sus ta ined release formulations in fasted and non-fas
ted sub jec t s , Biopharm. Drug Dispos. 4, 63-72 (1983).

9. A. P . S ip s , R. M. Edelbroek, S . Kuls tad , F . A.

de Wolff, and J . H. Dijkman, Food does not affect
bioavailability of theophyl line from Theolin Re ta rd ,
Eur. J. Clin. Pharmacol. 26, 405-407 (19 84).

10. N . H. Leeds , P . Gal, A. A. Puroh i t , and J . B .

Water, Effect of food on the bioavailability and p a t t e
r n of release of a s u s ta ined release theophyll ine t
ab le t , J. Clin. Pharmacol. 22, 196200 (1982).

11 . M. Lagas and J . H. G. Jonkman, Greatly enhanced

bioavailability of theophyl l ine on pos tprandia l
administration of a sus ta ined r e lease tablet, Eur. J.
Clin. Pharmacol. 24, 761-767 (1983).

12. S . Pedersen and J . Moeller-Peter s e n , Influence of

food on the absorpt ion r a t e and bioavailability of a
sus ta ined release theophyll ine p repa ra t i on ,
Allergy 37, 531-534 (1982).

13. S. Pedersen and J . Moeller-Peter s e n , Er ra t ic

absorpt ion of a slow release Theophylline Sprinkle p r o
d u c t , Pediatrics 74, 534-538 (1984).

14. L. Hendeles, M. Weinberger , G. Milavetz, M. Hill, and

L. Vaugh a n , Food induced "dose dumping" from a
once-a-day theophyl line p roduc t as a cause of theophyll
ine toxic i ty , Chest 87, 758-765 (19 85).

15. A. Karim, Univers i ty of Maryland Th i rd Annual

Conference on Cur ren t Concepts in Biopharmaceutics and
Clinical T r i a l s , Pharmacokinetic and pharmacodynamic
considerat ions in des igning bioavailability and clinical
efficacy s t u d i e s , Balt imore, MD , October 2 4 ,
1984.

16. J . G. Wagner, Wagner-Nelson equat ion , J. Pharm. Sci.

52, 610 (1963).

17. J . G. Wagner, Pharmaceutic absorpt ion plots from oral

data alone or oral in t ravenous data and an exact
Loo-Reigelman equat ion , J. Pharm. Sci. 72, 838 (1983).

18. V. K. P r a s a d , V. P . Shah , P . Knigh t , H. J .

Malinowski, B . E. Cabana , and M. C . Meyer, Importance
of media selection in establishment of in vitro/in vivo re
la t ionships for quinidine gluconate , Int. J. Pharm. 13,
1-7 (1983).

19. M. C . Meyer, A. B . S t r a u g h n , P . Lieberman,

and J . T . Jacob, Serious bioavailability problem with a
generic prolonged release quinidine gluconate p r o d u c
t , J. Clin. Pharmacol. 22, 131-134 (1982).

20. J . P . Skelly, L. A. Yamamoto, V. P . Shah , M. K.

Yau, and W. H. B a r r , Topographical dissolution
character izat ion for controlled release products-—A new
techn ique . Drug Dev. Ind. Pharm. 12, 1159-1175 (1986).

21 . J . P . Skelly, M. K. Yau, J . S . Elkins , L. A.

Yamamoto, V. P . Shah , and W. H. B a r r , In vitro
topographical character izat ion as a pred ica tor of in
vivo controlled release quinidine gluconate bioavailabili
ty, Drug Dev. Ind. Pharm. 12, 1177-1201 (1986).

22. J . P . Skel ly , Bioavailability of sus ta ined

release dosage forms — relat ionship with in vitro d
issolut ion, Academy of Pharmaceutical Sciences Meeting,
Minneapolis, MN, 1985.

23. V. Shah , V. K. P r a s a d , C. Freeman, J . P . Skel

ly , and B . E. Cabana, Phenytoin I I : In vitro/in vivo
bioequivalence s t a n d a r d for 100 mg phenyto in
sodium capsu le s , J. Pharm. Sci. 72, 309310 (1983).

24. V. P . Shah , N. T y n e s , L . A. Yamamoto, and J . P

. Skel ly , In vitro dissolution profile of t ransdermal n
i t roglycer in patches us ing paddle method, Int. J .
Pharm. 32, 243-250 (1986).
8 Chapter 8 Novel Chemical Approaches for
Sustained Drug Delivery

1. A. A. Sinkula and S. H. Yalkowsky, Rationale for design

of biologically revers ib le d r u g der iva t ives : P r
o d r u g s , J. Pharm. Sci. 64, 181 (1975).

2. N. Bodor, Novel approaches in p r o d r u g des ign ,

Drugs of Future, 6, 165 (1981).

3 . N. Bodor , Novel approaches for the design of membrane

t r a n s por t p roper i t e s of d r u g s . I n , Design
of Bio-Pharmaceutical Properties Through Pro-Drugs and
Analogs (E. B . Roche, E d . ) , APhA, Washington, DC,
1977, Chap . 7, p p . 98-135.

4. V. Stella, P r o d r u g s : An overview and definition.

I n , Prodrugs as Novel Drug Delivery Systems ( T .
Higuchi and V. Stella, E d s . ) , ACS Symposium Ser ies ,
vol . 14, American Chemical Socie t y , Washington, DC,
1975, p p . 1-115.

5. A. A. Sinkula , Methods to achieve sus ta ined d r u g

del ivery: The chemical approach . In , Sustained and
Controlled Release Drug Delivery Systems ( J . R.
Robinson, E d . ) , Marcel Dekke r , New York, 1978, p p .
411-555.

6. A. A. Sinkula , The chemical approach to achieve sus ta

ined d r u g de l ivery . I n , Optimization of Drug
Delivery (H. B u n d g a a r d , A. B . Hansen, and H.
Kofod, E d s . ) , Alfred Benzon Symposium 17, Munksgaard
, Copenhagen , 1982, p p . 199-210.

7. N. Bodor , Novel approaches in p r o d r u g des ign . I

n , Optimization of Drug Delivery (H. B u n d g a a r d ,
A. B . Hansen , and H. Kofod, E d s . ) , Alfred Benzon
Symposium 17, Copenhagen , 1982, p p . 156-174.

8. K. Miescher, A. Wettstein, and E. T s c h o p p , The

activation of t he male sex hormones , Biochem. J . 30, 53
(1982).

9. N* Bodor , K. B . Sloan, Y . N . Kuo, and T . Higuchi ,

Controlled del ivery of theophyl l ine : Chemistry of
7-acyl-and 7,8 T -acylditheophyll ine de r iva t ives , J .
Pharm. Sci. 67, 1045 (1978).

10. N. Bodor , Soft d r u g s : S t ra teg ies for design

of low toxicity d r u g s , Proceedings of the Cent re de
Rechercher s Clin Midy Symposium on Drug Metabolism and
Drug Design: Quo Vadis? , Montpellier, November 26 -27 ,
1981.

11. N. Bodor , Soft d r u g s : S t ra teg ies for design

of safer d r u g s . I n , Strategy in Drug Research, Vol.
4 ( J . A. K. Buisman, E d . ) , Elsevier Scientific
Company, Amsterdam, 1982, p p . 137164.

12. N. Bodor , Designing safer d r u g s based on the soft

d r u g app roach , Trends Pharmacol. Sci. 3, 53 (1982).

13. N. Bodor , The soft d r u g approach , Chemtech 14, 28

(1984).

14. A. M. Kligman and K. H. Kaidbey, Hydrocort isone rev i

s i t ed : An historical and experimental evaluat ion,
Cutis 22, 232 (1978).

15. N. Bodor , K. B . Sloan, R. J . Li t t le , S. H. Selk

and L. Caldwell, Soft d r u g s 4: 3-spirothiazolidines of
hydrocor t i sone and i t s de r iva t ives , Int. J.
Pharm. 10, 307 (1982).

16. K. B . Sloan, N. Bodor, and R . J . Li t t le , 1 3 C

NMR spect roscopy of 4,5 and 5,6-double bond isomers of sp
i ro-3-s te ro ida l ketone de r iva t ives : The
determination of the s t r u c t u r e s of s teroidal
thiazol idines, Tetrahedron 37, 3467 (1981).

17. K. B . Sloan, N. Bodor , and J . Zupan, Acylation of

the 4 ,5 and 5,6-double bond isomers of 3-steroidal thiazol
idines, Tetrahedron 37, 3463 (1981).

18. N. Bodor and K. B . Sloan, Soft d r u g s V: Thiazol

idine-type der iva t ives of p roges te rone and t e s to
s t e rone , J. Pharm. Sci. 71, 514 (1982).

19. N. Bodor and K. B . Sloan, Thiazolidine p r o d r u g s

for the improved del ivery of anti-inflammatory cor t i cos
te ro ids , U . S . Pa t en t , 4,239,757, December 16,
1980.

20. J . Gi ra rd , A. Ba rb i e r , and C. Lafille,

Inhibition of t e s tos te rone metabolism and l
ipogenesis in animal sebaceous glands by p r o ges t e rone
, Arch. Dermatol. Res. 269, 281 (1980).

21. S. E. Rappopor t , Blood Brain Barrier in Physiology

and Medicine, Raven P r e s s , New York , 1976.
22. R. A. Fishman, Car r i e r t r a n s p o r t of glucose
between blood and cerebrospina l fluid, Am. J. Physiol.
206, 836 (1964).

23. N. Bodor, H. H. Fa r ag , and M. E. B r e w s t e r ,

Site-specific sus ta ined release of d r u g s to the b r
a i n , Science 214, 1370 (1981).

24. N. Bodor and H. H. F a r a g , Improved del ivery t h

rough biological membranes I I : A redox chemical d rug
-de l ive ry system and i t s u s e for brain-specif ic
del ivery of phenyle thylamine, J. Med. Chem. 26, 313
(1983).

25. N. Bodor and H. H. F a r a g , Improved del ivery t h r

o u g h biological membranes 13: Brain-specif ic del ivery
of dopamine with d ihydropyr id ine pyridinium salt t y p
e redox del ivery sys tem, J. Med. Chem. 26, 528 (1983).

26. M. Kormano, Distr ibut ion of injected L-3 ,4 -d

ihydroxypheny lanme (L-dopa) in the adult ra t t es t i s
and epididymis, Acta Physiol. Scand. 71, 125 (1967).

27. M. Kormano, Dye permeabili ty and alkaline phospha tase

activity of tes t icular capillaries in the postnata l r a
t , Histochemie 9, 327 (1967).

28. D. W. Fawcet t , L. V. Leav, and P . M . Heidger ,

Electron microscopic observat ion of the s t r u c t u r a
l components of the bloodtest is barrier, J. Reprod.
Fertil. 10 (Suppl.), 105 (1970).

29. N . Dym and D. W. Fawcet t , The bloodtes t is b a r r

i e r in the r a t and the physiological compart mentation
of the seminiferous epithelium, Biol. Reprod. 3 , 308
(1970).

30. N. Bodor and H. F a r a g , Improved del ivery t h r o

u g h biological membranes XIV: Brain-specif ic sus ta
ined del ivery of t e s to s te rone us ing a redox
chemical del ivery sys tem, J. Pharm. Sci. 73, 385 (1984).

31. N . Bodor and A. M. AbdelAlim, Improved del ivery t h r

o u g h biological membranes XIX: Novel redox ca r r i e r
s for b r a i n specific chemical del ivery sys t ems ,
Int. J. Pharm. (in p r e s s ) .

32. N. Bodor and A. M. AbdelAlim, Improved del ivery t h r

o u g h biological membranes XX: Nicotinamide
dihydronicotinamide based es te r l inked redox ca r r i e
r sys tems , Int. J. Pharm. (in p r e s s ) .
9 Chapter 9 Design and Fabrication of
Oral Controlled Release Drug Delivery
Systems

1. R. D. Cowsar , In t roduct ion to controlled re lease .

I n , Controlled Release of Biologically Active Agents (A.
C. Tanquary and R. E. Lacey, E d s . ) , Plenum, New York,
1974.

2. The United States Pharmacopeia, 20th r e v . , Mack Publ

ishing C o . , Eaton, PA, 1980, p . 959.

3. A. C. Shah, C. B . Peot , and J . F . Ochs , Design and

evaluation of a ro t a t ing filter-stationary baske t in
vitro dissolution tes t appara tus I : Fixed fluid volume
sys tem, J. Pharm. Sci. 62, 671 (1973).

4. H. Weintraub and M. Gibaldi, Rotat ing-f lask method for

dissolution ra te determinations of aspir in from various
dosage forms, J. Pharm. Sci. 59, 1792 (1970).

5. J . E. T ings t ad , E. Gropper , L. Lachman, and E.

Shami, Dissolution r a t e s tud ies III : Effect of type
and in tes i ty of agitation on dissolution r a t e , J.
Pharm. Sci. 62, 293 (1973).

6. E. O. Kruger and E. B . Vliet, In vitro t e s t i ng of

timed release t ab le t s and capsu le s , J. Pharm. Sci.
51, 181 (1962).

7. P . B . Chemburkar , R. D. Smyth, D. B . Shah , R. S.

Jos l in , A. Polk, and N. H. Reavey-Cant well, Correlat
ions between dissolution charac te r i s t i cs and absorpt
ion of methaqualone from solid dosage forms, J. Pharm.
Sci. 65, 529 (1976).

8. S. S t avchansky , J . T . Doluisio, A. Mastin, C.

Martin, B . Cabana , S. Dighe, and A. Loper , Correlation
of in vivo bioavailability of e ry thromycin s t ea ra t e
table ts with in vitro t e s t s , J. Pharm. Sci. 69, 1309
(1980).

9. H. Schneider , C. H. Night ingale , R. Quintr i l iani ,

and D. R. F lanagan, Evaluation of an oral pro longed-re
lease antibiotic formulation, J. Pharm. Sci. 67, 1620
(1978).

10. S. E r ik sen , Susta ined action dosage forms. I n ,

The Theory and Practice of Industrial Pharmacy, 1st e d .
(L. Lachman, H. A. Lieberman, and J . L. Kanig, E d s . )
, Lea & Febiger , Philadelphia, 1970.

11. H. B . Hopfenberg , Controlled re lease from erodible s

l a b s , cyli n d e r s , and s p h e r e s . I n ,
Controlled Release Polymeric Formulations (D. R. Paul and
F . W. Har r i s , E d s . ) , American Chemical Society,
Washington, DC, 1976, p . 26.

12. J . T . C a r s t e n s e n , Dissolution of sol ids .

I n , Pharmaceutics of Solids and Solid Dosage Forms,
Wiley-Inter sc ience , New York , 1977, p . 63.

13. K. R. Heimlich, D. R. MacDonnell, T . L. F lanagan, and

P . D. O 'Br ien , Evaluation of a sus ta ined release
form of pheny lp ropanolamine hydrochlor ide by u r ina ry
excret ion s tud ie s , J. Pharm. Sci. 50, 232 (1961).

14. S. Benita and M. Donbrow, Coacervation of e thy l

cellulose, the role of polyisobutylene and the effect of i
t s concent ra t ion , J . Colloid Interface Sci. 77, 102
(1980).

15. Y. Takeda , N. Nambu, and T . Nagai, Microencapsulation

and bioavailability in beagle dogs of indomethacin, Chem.
Pharm. Bull. 29, 264 (1981).

16. S. Benita and M. Donbrow, Dissolution ra te control of

the r e lease kinet ics of water-soluble compounds from
ethyl cellulose film-type microcapsules , Int. J. Pharm.
12, 251 (1982).

17. J . P . Benoit , J . Y. Drouin, F . Puis ieux , F .

Brunel le , M. Dubo is , and M. Beaufi ls , Selective
embolization of the renal a r t e ry of the ra t by c ross
l inked serum/albumin microcapsules . I n , Microspheres
and Drug Therapy, Elsevier , Amsterdam, 1983.

18. S. Beni ta , Microcapsules: New applications and charac

ter iza t ion , Labo-Pharma-Propl. Tech. 32, 694 (1984).

19. K. R. Heimlich, D. R. MacDonnell, A. Polk, and T . L.

Flanagan, Evaluation of an oral sus ta ined re lease
dosage of t r imeprazine as measured by u r ina ry excre t
ion , J. Pharm. Sci. 50, 213 (1961).

20. J . G. Wagner, O. S. C a r p e n t e r , and E. J .

Collins, Sustained action oral medication. I . A quant i
ta t ive s tudy of prednisolone in man, in the dog and in
vitro, J. Pharmacol. Exp. Ther. 129, 101 (1960).
21. J . F . Nash and R. E. C a b t r e e , Absorption of t
r i t ia ted d -desoxyephedr ine in sus ta inedre lease
dosage forms, J. Pharm. Sci. 50, 134 (1961).

22. E. Rosen and J . V. Swintosky, Prepara t ion of a

(35)S-labelled t r imeprazine t a r t r a t e sus ta ined
action p roduc t for i t s evaluation in man, J. Pharm.
Pharmacol. 12, 237 (1960).

23. L. E. Hollister, Studies of delayed-act ion medication.

I . Meprobamate administered as compressed tab le t s and
as two delayedaction capsu les , N. Engl. J. Med. 266, 281
(1962).

24. E. Rosen , P . Tannenbaum, T . Ellison, S. M. F r e e ,

and A. P . Cros ley , Absorption and excret ion of
radioactively t agged dextroamphetamine sulfate from a sus
ta inedre lease p r epa ra t i on , JAMA 194, 145 (1965).

25. A. A. Sugerman and E. Rosen, Absorpt ion efficiency and

excret ion profile of a prolonged-act ion form of
chlorpromazine, Clin. Pharmacol. Ther. 5, 561 (1964).

26. E. Rosen , T . Ellison, P . Tannenbaum, S. M. F r e e ,

and A. P . Cros ley , Comparative s t udy in man and dog
of the absorpt ion and excret ion of dextroamphetamine-C14
sulfate in sus ta inedre lease and nonsus ta inedre lease
dosage forms, J. Pharm. Sci. 56, 365 (1967).

27. E. Rosen , A. Polk, S. M. F r e e , P . J . Tannenbaum,

and A. P . Cros ley , Comparative s t udy in man of the
absorpt ion and excret ion of amobarbital-C14 from sus t a
inedre l ease and nonsus ta inedre lease dosage forms, J.
Pharm. Sci. 56, 1285 (1967).

28. S. Khalil and S. Elgamal, In vitro re lease of aspir in

from va r i ous wax-coated formulations, J. Pharm.
Pharmacol. 23, 72 (1971).

29. J . Royal, In vitro method for the determination of the

ra te of re lease of amphetamine sulfate from sus ta ined
re lease medication, Drug Standards 26, 41 (1958).

30. J . Royal , A comparision of in vitro r a t e s of

release of severa l b r a n d s of dextroamphetamine
sulfate sus ta ined re lease capsu les , Drug Standards
27, (1959).

31. J . Campbell, E. Nelson, and D. G. Chapman, Cri ter ia

for oral sus ta ined re lease medication with par t i cu
la r reference to amphetamine, Can. Med. Assoc. J. 81, 15
(1959).

32. R. A Nash and A. D. Marcus , An in vitro method for the

evaluation of sus ta ined re lease p r o d u c t s , Drug
Standards 28, 1 (1960).

33. E. Vliet, A sugges t ed in vitro p rocedure for measur

ing the ra te of d r u g re lease from timed re lease tab
le t s and capsu les , Drug Standards 27, 92 (1959).

34. A. Beckett and G. T u c k e r , A method for the

evaulation of some oral pro longed-re lease forms of
dextroamphetamine in man us ing u r i n a r y excret ion
da ta , J. Pharm. Pharmacol. 18, 725 (1966).

35. J . A. Campbell, Evaluation of sus ta ined-ac t ion re

lease r a t e s , Drug Cosmetic Ind. 87, 620 (1960).

36. S. Benita and M. Donbrow, Release kinet ics of spar

ingly soluble d r u g s from e thyl cellulose walled
microcapsules . Theophyll ine microcapsules , J. Pharm.
Pharmacol. 34, 77 (1982).

37. M. Donbrow and S. Beni ta , Release kinet ics of spar

ingly soluble d r u g s from ethyl cellulose walled
microcapsules. Salicylamide microcapsules , J. Pharm.
Pharmacol. 34, 547 (1982) .

38. M. Oyaalpar and V. Walters, The prolongation of the in

vitro dissolution of a soluble d r u g (phenethicil l in
potassium) by microencapsulation with e thyl cellulose, J.
Pharm. Pharmacol. 33, 419 (1981).

39. I . Ja lsenjak, J . R. Nixon, R. Senjkovic, and I .

Stivic, Sus ta inedre lease dosage forms of
microencapsulated isoniazid, J. Pharm. Pharmacol. 32, 678
(1980).

40. M. A. Green , One y e a r s ' exper ience with sus ta

ined release antihistamine medication, Ann. Allergy 12,
273 (1954).

41. H. L. R o g e r s , Treatment of allergic conditions

with sus ta ined re lease chlorprophenpyr idamine maleate,
Ann. Allergy 12, 266 (1954) .

42. D. Berkowitz , The effect of a long-ac t ing prepara t

ion (Spansule) of belladonna alkaloids on gas t r ic
secret ion of pa t ien t s with pept ic u lcer ,
Gastroenterology 30, 608 (1956).

43. S. Morrison, The use of a sus ta ined release t ranqui

l i ze r anticholinergic combination in pat ients with d i
s tu rbed digest ive function, Am. J. Gastroenterol. 29,
518 (1958).

44. H. V. Graham, Ant ihyper tens ive effects of r e se rp

ine in sus ta inedre lease form: a comparative s t u d y ,
J. Am. Geriatr. Soc. 6, 671 (1958).

45. S. H. B u r n e s s , Clinical evaulation of a sus ta

ined release belladonna p repa ra t i on , Am. J. Dig. Dis.
22, 111 (1955).

46. J . Vasconcellos and A. A. Kur land, Use of sus ta

inedre lease chlorpromazine in the management of
hospitalized chronic psychot ic p a t i e n t s , Dis.
Nerv. Sys. 19, 173 (1958).

47. J . C. Colber t , Controlled Action Drug Forms,

Chemical Technology Review No. 24, Noyes Data C o r p . ,
Park Ridge , NJ, 1974.

48. J . C. Johnson , Tablet Manufacture, Chemical

Technology Review No. 30, Noyes Data C o r p . , Park Ridge
, NJ , 1974.

49. W. A. Ri tschel , Peroral solid dosage forms with

prolonged act ion. I n , Drug Design, Vol. 4 (E . J . Ar
ien , E d . ) , Academic, New York , 1973, Chap . 2, p .
37.

50. D. R. Paul and F . W. H a r r i s , Controlled Release

Polymeric Formulations, ACS Symposium Series 33, American
Chemical Society, Washington DC, 1976, p . 27.

51. D. W. Doer r , E. R. Ser ies , and D. L. Deardorff ,

Tablet coati n g s : Cellulosic high polymers , J. Am.
Pharm. Assoc. (Sci. Ed.) 43, 433 (1954).

52. L. P . Gagnon, H. G. DeKay, and C. O. Lee , Coating of

g ranules , Drug Standards 23, 47 (1955).

53. S. S. Ahsan and S. M. Blaug , A s t u d y of tablet

coat ing u s ing polyvinylpyrrol idone and acetylated
monoglyceride, Drug Standards 26, 29 (1958).

54. J . R. Nixon and S. E. Walker, The in vitro evaluation

of gelatin coacervate microcapsules , J. Pharm. Pharmacol.
23, 1475 (1971).

55. J . G. Wagner, W. Veldkamp, and S. Long, Enter ic coa t

ings . IV. In vitro t e s t i ng of granules and table ts
coated with s tyrene-maleic acid copolymer, J. Am. Pharm.
Assoc. (Sci. Ed.) 49, 128 (1960).

56. J . D. A n d r a d e , Hydrogels for Medical and

Related Applications, ACS Symposium Series 31 , American
Chemical Society, Washingt o n , DC, 1976, p . 88.

57. J . A. Bakan and J . L. Ande r son ,

Microencapsulation. I n , The Theory and Practice of
Industrial Pharmacy, 2nd ed . (L. Lachman, H. A. Lieberman,
and J . L. Kaing, E d s . ) , Lea & Feb iger , Phi
ladelphia, 1967, Chap . 13, Par t I I I .

58. T . M. Feinblatt and E. A. Fe rguson , Timed-dis

integrat ion capsu les : an in vivo roen tgenographic s t u
d y , N. Engl. J. Med. 254, 940 (1956).

59. T . M. Feinblatt and E. A. F e r g u s o n , Timed-dis

integrat ion capsules (Tympcaps) : A fu r the r s t u d y .
An in vivo roen tgenog r a p h ^ s t u d y , blood level s
t udy and relief of anginal pain with pen tae ry th r i to
l t e t r a n i t r a t e , N. Engl. J. Med. 256, 331
(1957).

60. D. M. Green , Tablets of coated aspir in microspherules

: A new dosage form, J . New Drugs 6, 294 (1966).

61 . F . Steigmann, L. KaminsM, and S. Nasa t i r ,

Clinical-experimental evaulation of a prolonged act ing
ant ispasmodic-sedat ive , Am. J. Dig. Dis. 4, 534 (1959).

62. T . J . Mellinger, Serum concentra t ion of

thioridazine after different oral medication forms, Am. J.
Psychiatry 121, 1119 (1965).

63. L. E. Hollister, Studies of prolonged-act ion

medication. I I . Two phenothiazine t ranqui l ize rs
(thioridazine and chlorpromazine) administered as coated
tab le t s and prolonged action p r e p a r a t i o n s ,
Curr. Ther. Res., 4, 471 (1962).

64. T . J . Mellinger, E . M. Mellinger, and W. T . Smith,

Thioridazine blood levels in pa t i en t s rece iv ing
different oral forms, Clin. Pharmacol. Ther. 6, 486
(1965).
65. N. D. Vest re and B . C. Schiele, An evaluation of s
low-release and regu la r thioridazine and two medication
schedules , Curr. Ther. Res. 8, 585 (1966).

66. K. R. Magee and M. R. Westerberg , Treatment of

myasthenia gravis with prolonged-act ion Mestinon,
Neurology 9, 348 (1959).

67. L. J . Cass and W. S. F r ede r ik , Clinical

comparison of a sus ta ined- and a r egu la r r e l ease
asp i r in , Curr. Ther. Res. 7, 673 (1965).

68. L. J . Cass and W. S. F r ede r ik , A clinical

evaluation of a sus ta inedre lease asp i r in , Curr.
Ther. Res. 7, 683 (1965).

69. A. F . Kydonieus , E d . , Controlled Release

Technologies: Methods, Theory, and Applications, Vol. I I ,
CRC P r e s s , I n c . , Boca Raton, FL, 1980.

70. C. Banse , J . J . Ben tz , C. B r o s s a r d , G.

Cognyl , J . C. Cru b e z y , F . Herbemont, L. Thankh T h
u y , and R. Sarfa t i , Microencapsula t ion , Sci.
Technol. Pharm. 7, 73 (1978).

71 . J . A. Bakan and J . A. Ande r son ,

Microencapsulation. I n , Theory and Practice of
Industrial Pharmacy, 2nd ed . (L. Lachman, H. A. Lieberman,
and J . L. Kanig, E d s . ) , Lea & Febiger , Phi
ladelphia, 1967, p . 420.

72. A. Kondo, Microcapsule Processing and Technology ( J .

W. Van Va lkenburg , E d . ) , Marcel Dekke r , New York ,
1979, p . 35.

73. C. T h i e s , Microencapsulation. I n , McGraw-Hill

Yearbook of Science and Technology, McGraw-Hill, New York
, 1979, p . 12.

74. C. T h i e s , Physicochemical aspec t s of

microencapsulat ion, Polymer Plast. TechnoL Eng. 5, 1
(1975) .

75. A. Watanabe and T . Hayashi , Microencapsulation

techniques of Fuji Photo Film Co. L t d . , and the i r
appl icat ions. I n , Microencapsulation ( J . R. Nixon, E
d . ) , Marcel Dekker , New York, 1976, C h a p . 2.

76. H. G. B u n g e n b e r g de J o n g , Complex colloid

sys tems . I n , Colloid Science, Vol. II (H. R. K r u y t
, E d . ) , Elsevier , New York , 1949, Chap . 10.

77. M. S. Har r i s , Prepara t ion and release charac te r

i s t i c s of po tas sium chloride microcapsules , J.
Pharm. Sci. 70, 391 (1981).

78. T . Kondo, Microcapsules: Thei r p repara t ion and p r

o p e r t i e s . I n , Surface and Colloid Science, Vol.
10 (E. Matijevic, E d . ) , Plenum P r e s s , New York ,
1978, Chap . 1.

79. T . M. S. C h a n g e , Artificial Cells ( T . C. Char

l e s , E d . ) , Char les C. Thomas, Springfie ld , IL,
1972.

80. G. Langer and G. Yamote, U . S . Patent # 3,159,874,

1964.

81. J . A. Bakan , Microcapsule d r u g delivery sys tems .

I n , Polymers in Medicine and Surgery (R. L. Kronentha l ,
Z. Ose r , and E. Martin, E d s . ) , Plenum, New York ,
1975, p . 213.

82. B . D. S e a r s , U . S . Patent # 4,145,410, 1979.

83. J . L. Shank , U . S . Patent # 4,001,480, 1977.

84. V. H. S a g g e r s , I . F . Chasseaud , and A. J .

Copper , Plasma concen t ra t ions , durat ion of
analgelsia, and bioavailability of microencapsulated
aspirin ( L e v i u s ) , Clin. Trials J. 9, 36 (1972).

85. L. Kuhns and K. Hospes , Klinische b e d e u t u n g

and Anwendung eines Kaliumdefizit-Testes u n t e r B e r u
c k s r c h t i g u n g der Therapie mit F redn i son ,
Schweiz. Med. Wochenschr. 86, 783 (1956).

86. E. B . Draper and C. H. Becker , Some wax formulations

of a sulfaethylthiadiazole p roduced by aqueous dispers
ion for p r o longed-re lease medication, J. Pharm. Sci.
55, 376 (1966).

87. I . C. Robinson and C. H. Becker ,

Sulfaethylthiadiazole re lease from synthe t ic wax pro
longed-re lease pa r t i c l e s . I . Effect of d i spe r
san t concent ra t ion , J. Pharm. Sci. 57, 49 (1968).

88. P . M . John and C. H. Becker , Surfactant effects of s

p r a y congealed formulations of sulfaethyl
thiadazole-wax, J. Pharm. Sci. 57, 584 (1968).
89. A. G. Cusimano and C. H. Becker , Spray-congealed
formulat ions of sulfaethylthiadazole and waxes for pro
longed-re lease medication: effect of wax, J . Pharm. Sci.
57, 1104 (1968).

90. Y. Raghuna than and C. H. Becke r , Spray-congealed

formulat ions of sulfaethylthiadazole and waxes for pro
longed-re lease medication: effect of modifiers, J. Pharm.
Sci. 57, 1748 (1968).

91. I . S. Hamid and C. H. Becker , Release s tudy of

sulfaethylthiadazole from a tablet dosage form p r e p a r
e d from sp ray congealed formulations of SETD and wax, J.
Pharm. Sci. 59, 511 (1970) .

92. Y. Kawashima, H. Ohno , and H. Takenaka , Prepara t ion

of spher ica l matrices of p ro longedre lease d r u g s
from liquid s u s pens ion , J. Pharm. Sci. 70, 913 (1981).

93. J . Heller and P . V. T r e s c o n y , Controlled d r

u g re lease by polymer dissolution I I : Enzyme-mediated
del ivery device, J. Pharm. Sci. 68, 919 (1979).

94. F . Alhaique, F . M. Riccierie , E . Santucci , V.

Crescenz i , and A. Gamini, A possible pH-control led d r
u g delivery system based on a der ivat ive of t he
polysacchar ide sceleroglucan, J. Pharm. Pharmacol. 37,
310 (1985).

95. C. Graffner , G. Johnson , and J . S jogren ,

Pharmacokinetics of procainamide in t ravenous ly and
orally as conventional and slow release t a b l e t s ,
Clin. Pharmacol. Ther. 17, 414 (1975).

96. E. DeRi t te r , Evaluation of nicotinic alcohol

Timespan table ts in humans by u r ina ry excret ion t e s
t s , Drug Standards 28, 33 (1960).

97. E. G. Rippie and J . R. Johnson , Regulation of

dissolution r a t e by pellet geometry, J. Pharm. Sci. 58,
428 (1969) .

98. D. Brooke and R. J . Washkuhn, Zero-order d r u g del

ivery sys tems : theory and prel iminary t e s t i n g ,
J. Pharm. Sci. 66, 159 (1977).

99. D. S. T . Hsieh, W. D. Rh ine , and R. Lange r ,

Zero-order control led-re lease polymer matrices for
micro- and macromolecu le s , J. Pharm. Sci. 72, 17 (1983).
100. R. A. Siegel and R. Lange r , Controlled re lease of
polypept ides and o ther macromolecules, Pharm. Res. 1, 2
(1984).

101. P . I . Lee, Novel approach to ze ro -o rder d r u g

del ivery via immobilized nonuniform d r u g dis t r ibut
ion in glassy hyd roge l s , J. Pharm. Sci. 73, 1344
(1984).

102. C. B r o s s a r d , D. Lefort Des Ylousas , D.

Duchene , F . Puis ieux , and J . T . C a r s t e n s e n
, Dissolution of a soluble d r u g subs tance from vinyl
polymer matr ices , J. Pharm. Sci. 72, 162 (1983).

103. G. L. F lynn , S. H. Yalkowsky, and T . J . Roseman,

Mass t r a n s p o r t phenomena and models: Theoret ical
concep t s , J. Pharm. Sci. 63, 479 (1974).

104. S. Benita and M. Danbrow, Effect of polyisobutylene on

e thyl cellulose-walled microcapsules: Wall s t r u c t u r
e and th ickness of salicylamide and theophyll ine
microcapsules , J. Pharm. Sci. 71, 205 (1982).

105. H. Takenaka , Y. Kawashima, and S. Y. Lin, Polymorphs

of s p r a y d r i e d microencapsulated sulfamethoxazole
with cellulose acetate phtha la te and colloidal silica,
montmorillonita, or t a lc , J. Pharm. Sci. 70, 1256
(1981).

106. F . Lim and R. D. Moss, Microencapsulation of l iving

cells and t i s s u e s , J. Pharm. Sci. 70, 351 (1981).

107. M. Arakawa and T . Kondo, Prepara t ion of

hemolysate-loaded p o l y ( N . , N-Llys inediyl
terephthaloyl ) nanocapsu les , J. Pharm. Sci. 70, 354
(1981).

108. T . I sh izaka , K. Endo, and M. Koishi, Prepara t ion

of egg albumin microcapsules and microspheres , J. Pharm.
Sci. 70, 358 (1981).

109. J . Krue te r and E. Liehl, Long-term s tudies of

microencapsulated and adsorbed influenza vaccine nan op a r
t i c les , J. Pharm. Sci. 70, 367 (1981) .

110. J . W. McGinity, A. Mart in, G. W. Cuff, and A. S.

Combs, Influences of matrices on nylon-encapsula ted
pharmaceut ica ls , J. Pharm. Sci. 70, 372 (1981).
111. J . R. Nixon, In vitro and in vivo re lease of
microencapsulated chlorothiazide, J. Pharm. Sci. 70, 376
(1981).

112. Y. Nozawa and S. W. Fox , Microencapsulation of

methylylmal and two der iva t ives , J. Pharm. Sci. 70,
385 (1981).

113. H. Takenaka , Y. Kawashima, and S. Y. Lin, Prepara t

ion of en ter ic -coated microcapsules for tab le t ing by
s p r a y d r y i n g technique and in vitro simulation of
d r u g release from the tablet in GI t r a c t , J.
Pharm. Sci. 69, 1388 (1980).

114. H. Takenaka , Y. Kawashima, and S. Y. Lin,

Micromeritic p roper t i es of sulfamethonazole
microcapsules p r e p a r e d by gelatin-acacia coacervat
ion, J. Pharm. Sci. 69, 513 (1980).

115. D. M. Green , Tablets of elated aspir in micro spheru

les—A new dosage form, J. New Drugs 6, 294 (1966).

116. A. Williams, Sustained Release Pharmaceuticals, Nayes

Development Co rp , P a r k Ridge , NJ , 1969.

117. J . C. Colber t , Controlled Action Drug Forms,

Chemical Technology Review No. 24, Nayes Data Corporat ion,
Pa rk Ridge , N J , 1974.

118. J . C. Johnson , Tablet Manufacturer, Chemical

Technology Review No. 30, Nayes Data Corporat ion, Pa rk
Ridge , NJ, 1974.

119. Y. Samuelov, M. Donbrow, and M. Fr iedman, Susta ined

release of d r u g s from ethylcel lulose-polyethylene
glycol films and kinet ics of d r u g re lease , J .
Pharm. Sci. 68, 325 (1979).

120. G. Kal ls t rand and B . Ekman, Membrane-coated t a b

l e t s : A system for t he controlled re lease of d r u g
s , J. Pharm. Sci. 68, 325 (1979).

121. S. Borodkin and F . E. T u c k e r , D r u g release

from h y d r o x y propy l cellulose-polyvinyl acetate
films, J. Pharm. Sci. 63, 1359 (1974).

122. M. Yoshida, M. Kumakura, and I . Kaetsu , Controlled

Drug dissolution by radiat ion induced polymerization in
the p resence of dimethylaminoethyl methacrylate-methyl
methacrylate copolymer or methacrylic acid-methyl acrylate
copolymer, J. Pharm. Sci. 68, 860 (1979) .

123. S. Borodkin and F . E. T u c k e r , Linear d r u g

release from laminated hyd roxypropy l cellulose-poly
vinyl acetate films, J. Pharm. Sci. 64, 1289 (1975).

124. P . L. Madan, Clofibrate microcapsules II : Effect of

wall th ickness on re lease cha rac te r i s t i c s , J.
Pharm. Sci. 70, 430 (1981).

125. L. A. Luzzi, M. A. Zoglio, and M. V. Maulding, Prepara

t ion and evaluation of the prolonged re lease p roper t i
e s of nylon microcapsules , J. Pharm. Sci. 59, 338
(1970).

126. N. Mason, C. Th i e s , and T . J . Ciero , In vivo

and in vitro evaluation of a microencapsulated narcotic an
tagonis t , J. Pharm. Sci. 65, 847 (1976).

127. P . L. Madan, D. K. Madan, and J . C. P r i ce ,

Clofibrate microcapsu les : Prepara t ion and re lease ra
te s t u d i e s , J. Pharm. Sci. 65, 1476 (1976).

128. M. Donbrow and M. Fr iedman, Timed release from

polymeric films containing d r u g s and kinet ics of d r
u g re lease , J. Pharm. Sci. 64, 76 (1975).

129. G. M. Zentner , J . R M C a r d i n a l , and D. E.

Gregonis , Proges t in permeation t h r o u g h polymer
membranes I I I : Polymerization solvent effect on p roges
te rone permeation t h r o u g h hydrogel memb r a n e s ,
J. Pharm. Sci. 68, 794 (1979).

130. G. M. Zentner , J . R. Card ina l , and S. W. Kim,

Progest in permeation t h r o u g h polymer membranes I :
Diffusion s tud ies on plasma-soaked membranes , J. Pharm.
Sci. 10, 1347 (1978).

131. M. Yoshida, M. Kumakura , and I . Kae tsu , Drug ent

rapment for controlled re lease in radiat ion-polymerized
b e a d s , J. Pharm. Sci. 68, 628 (1979).

132. M. Nakamo, K. J u n i , and T . Ar i ta , Controlled d

r u g permeation I : Controlled re lease of butamben th
rough silicon membrane by complexation, J. Pharm. Sci. 65,
709 (1976).

133. T . Higuchi , Rate of release of medicaments from

ointment bases containing d r u g s in suspens ion , J.
Pharm. Sci. 50, 847 (1961).
134. W. A. Ri tschel , Influence of formulating factors on
d r u g safety of t imed-release ni t roglycer in t ab l e
t s , J. Pharm. Sci. 60, 1683 (1971).

135. H. E. H u b e r , L. B . Dale, and G. L. C h r i s t e

n s e n , Utilization of hydrophi l ic gums for the
control of d r u g release from tablet formulations I :
Disintegrat ion and dissolution behavior , J. Pharm. Sci.
55, 974 (1966).

136. H. Lapidus and N. G. Lordi , Some factors affecting

the r e lease of a water-soluble d r u g from a compressed
hydrophil ic mat r ix , J. Pharm. Sci. 55, 840 (1966).

137. A. Dakkur i , L. D. Bu t l e r , and P . P . Deluca,

Sustained r e lease from ine r t wax matrices I I I :
Effect of povidone on tr ipelennamine hydrochlor ide re
lease , J. Pharm. Sci. 67, 357 (1978).

138. J . W. McGurr i ty , L. A. Hunke , and A. B . Combs,

Effect of water soluble c a r r i e r s on morphine
sulfate release from a silicone polymer, J. Pharm. Sci. 68,
662 (1979).

139. N. Salib, S. Abd El -Fa t t ah , and M. El-Massik,

Prepara t ion and in vitro evaluation of controlled
release mepyramine male a t e -ca r bopol 934 en t r apped
sys tems , Pharm. Ind. 45, 902 (1983).

140. F . W. Goodhar t , R. H. McCoy, and F . C. Ninger ,

Release of a water soluble d r u g from a wax matrix t
imed-release t a r g e t , J. Pharm. Sci. 63, 1748 (1974).

141. S. J . Desai , A. P . Simonelli, and W. I . Higuchi ,

Invest igat ion of factors influencing release of solid d
r u g d i spe r sed in ine r t matr ices , J. Pharm. Sci.
54, 1459 (1965).

142. S . J . Desai , P . S ingh , A. P . Simonelli, and W .

I . Higuchi , Invest igat ion of factors inf luencing
release of solid d r u g d is p e r s e d in ine r t
matrices I I I : Quanti tat ive s tud ies involving the
polyethylene plast ic matr ix , J. Pharm. Sci. 55, 1230
(1966).

143. S . J . Desai , P . S ingh , A. P . Simonelli, and W.

I . Higuchi , Invest igat ion of factors inf luencing
release of solid d r u g d i s pe r sed in ine r t matr
ices . IV: Some s tud ies involving the polyvinyl chloride
matr ix , J. Pharm. Sci. 55, 1235 (1966).

144. K. A. Java id , J . H. F incher , and C. W. Hartman,

Timedre lease table ts employing
lipase-lipid-sulfamethizole systems p r e p a r e d by sp
ray -congea l ing , J. Pharm. Sci. 60, 1709 (1971).

145. K. A. Javaid and C. W. Hartman, Blood levels of

sulfamethizole in dogs following administration of t
imed-release table ts employing l ipase l ip id -drug sys
tems , J. Pharm. Sci. 61, 900 (1972).

146. S. Er iksen , Sustained action dosage forms. I n , The

Theory and Practice of Industrial Pharmacy 1st ed . (L.
Lachman, H. A. Lieberman, and J . L. Kanig, E d s . ) ,
Lea & Feb ige r , Philadelphia, 1970.

147. S. Motycka and J . G. Naira , Influence of wax coat

ings on r e lease ra te of anions from ion-exchange res in
b e a d s , J. Pharm. Sci. 67, 500 (1978).

148. S. Motycka, C. J . L. Newth, and J . G. Na i rn ,

Prepara t ion and evaluation of microencapsulated and
coated ion-exchange res in beads containing theophyl l ine
, J. Pharm. Sci. 74, 643 (1985).

149. Y. R a g h u n a t h a n , L. Amsel, O. Hinsvack, and

W. B r y a n t , Sus ta inedre lease d r u g del ivery
systems I : Coated ionexchange res in system for
phenylpropanolamine and o the r d r u g s , J. Pharm. Sci.
70, 379 (1981).

150. R. J . Timko and N. G. Lordi , In vitro evaluation of

t h r e e commercial sus ta inedre lease papaver ine
hydrochlor ide p r o d u c t s , J. Pharm. Sci. 67, 496
(1978).

151. A. M. Pede r son , U . S . Patent #3,917,813.

152. H. Bechgaard and S. Baggesen , Propoxyphene and norp

ropoxyp h e n e : Influence of t ype of controlled re lease
formulation on i n t r a - and in te rsubjec t va r ia t
ions , J. Pharm. Sci. 69, 1327 (1980).

153. A. M. Pede r son , German Patent #2,414,868.

154. F . Theeuwes and T . Higuchi , U . S . Patent

#3,916,899.

155. F . Theeuwes , Evolution and design of ra te-cont ro l

led osmotic forms, Curr. Med. Res. Opin. , 8 (Suppl.), 220
(1983).

156. F . Theeuwes , D. Swanson, P . Wong, P . Bonsen , V.

Place, K. Heimlich, and K. C. Kwan, Elementary osmotic
pump for indomethacin, J. Pharm. Sci. 72, 253 (1983).

157. F . Theeuwes , Oral dosage form des ign : S ta tus and

goals of oral osmotic systems technology, Pharm. Int. 5,
293 (1984).

158. J . C. Johnson , Sustained Release Medication, Noyes

Data Corpora t ion , Park Ridge NJ, 1980, p . 116.

159. A. Zaffaroni, A. S. Michaels, and F . Theeuwes , U . S

. Pa ten t #4,096,238.

160. F . Theeuwes , U . S . Patent #4,111,202.

161. R. W. Ba k e r , U . S . Pa tent #3,952,741.

162. R. Gale, S. K. C h a n d r a s e k a r a n , D.
Swanson, and J . Wright , Use of osmotically active
therapeut ic agen t s in monolithic s y s tems, J. Memb.
Sci. 7, 319 (1980).

163. K. Heilmann, Innovations in d r u g del ivery sys tems

, Curr. Med. Res. Opin., 8 (Suppl. 2), 3 (1984).

164. J . D. Roge r s , Osmosin t a b l e t s , Curr. Med.

Res. Opin., 8 (Suppl. 2) , 38-46 (1983).

165. A. R. Phymer , J . A. Sromovsky, C. Dicenta, and C. B

. Har t , Osmosin tablets, Curr. Med. Res. Opin., 8,
(Suppl. 2), 62 71 (1983).

166. W. Bayne , V. Place, F . Theeuwes , J . D . Roge r s ,

R. B . Lee , R. O. Davies , and K. C. Kwan, Kinetics of
osmotically controlled indomethacin delivery systems after
r epea ted dos ing , Clin. Pharmacol. Ther. 32, 270
(1982).

167. J . D. Roge r s , R. B . Lee, P . R. Souder , R. K. Fe

rguson , R. O. Davies , F. Theeuwes , and K. C. Kwan,
Pharmacokinetic evaluation of osmotically controlled
indomethacin del ivery s y s tems in man, Int. J. Pharm.
16, 191 (1983).

168. J . M. Hinton, J . E. Lenna rd Jones , and A. C.

Young, A New Method for S tudying Gut Transi t Times Using
Radioopaque Markers , Gut, 10, 842 (1969).

169. K. Pa rk and J . R. Robinson, Bioadhesive polymers as

p la t forms for oral-control led d r u g de l ivery :
Method to s tudy bioadhes ion , Int. J. Pharm. 19, 107
(1984).

170. K. P a r k , H. S. Ching , and J . R. Robinson,

Alternat ive ap proaches to oral controlled d r u g de l
ivery : Bioadhesive and in-situ sys tems . In , Recent
Advances in Drug Delivery Systems ( J . M. Anderson and S.
W. Kim, E d . ) , Plenum, New York , 1984, p p . 163.

171. H. S. C h ' n g , H. P a r k , Kelly, and J . R.

Robinson, Bioadhesive polymers as platforms for oral
controlled d r u g del ivery I I : Synthes i s and
evaluation of some swelling, waterinsoluble bioadhesive
polymers , J. Pharm. Sci. 74, 399 (1985).

172. M. A. Longer , H. S. Ch f ng , and J . R. Robinson,

Bioadhesive polymers as platforms for oral controlled d r
u g delivery I I I : Oral del ivery of chlorothiazide u s
ing a bioadhesive polymer, J. Pharm. Sci. 74, 406, (1985).

173. H. Bechgaard and K. Ladefoged, Distr ibution of

pellets in the gas t ro in tes t ina l t r a c t . The
influence on t r ans i t time exer ted by the dens i ty or
diameter of pe l l e t s , J. Pharm. Sci. 30, 690 (1978).

174. S. Watanabe, M. Kayano, Y. I sh ino , and K. Miyao, U

. S . Patent #3,976,197.

175. P . R. Sheth and J . L. Tossounian , U . S . Patent

#4,126,672.

176. P . R. Sheth and J . Tossounian , The hydrodynamically

balanced system (HBS) : A novel d r u g del ivery system
for oral u s e , Drug Dev. Ind. Pharm. 10, 313 (1984).

177. P . R. Sheth and J . L. Tossounian , U . S . Patent

#4,167,558.

178. P . R. Sheth and J . L. Tossounian , U . S . Pa tent

#4,140,755.

179. R. M. Ha r r i gan , U . S . Patent #4,055,178.

10 Chapter 10 Parenteral Products

1. K . J . Widder and A. E. Senyei , Magnetic microspheres

: A vehicle for selective t a rge t i ng of d r u g s ,
Pharmac. Ther. 20, 377 (1983).

2. M. Pfeffer, R. D . Smyth, K. A. Pit tman, and P . A.

Nardella, Pharmacokinetics of subcu taneous and in t
ramuscular butorphanol in d o g s , J. Pharm. Sci. 69, 801
(1980).

3. L. Ilium and S. S. Davis , The t a rge t ing of d r u g

s parentera l ly by use of microspheres , J. Parent. Sci.
Tech. 36, 242 (1982).

4. J . Zeidman. In , Cancer Biology Reviews, Metastasis, an

Overview ( I . J . Marchalonis, M. G. Hanna, et a l . , E d
s . ) , Raven, New York, 1982, p p . 1-27.

5. J . M. Yoffey and F . C. Cour t ice , Lymphatics, Lymph

and the Lymphomyeloid Complex, Academic P r e s s , New
York, 1970.

6. J . E. Gray . In , Sustained and Controlled Release Drug

Delivery Systems ( J . R. Robinson, E d . ) , Marcel
Dekker , New York, 1978, p p . 351-410.

7. K. Hirano and H. Yamada, Studies on the absorpt ion of p

rac t i cally waterinsoluble d r u g s following injection
VI: Subcutaneous absorpt ion from aqueous suspens ions in
r a t s , J. Pharm. Sci. 71, 500 (1982).

8. K. Hirano, T . Ichihashi , and H. Yamada, Studies on the

a b s o r p tion of practically waterinsoluble d r u g s
following injection V: Subcutaneous absorpt ion in r a t s
from solutions in water immiscible oils , J. Pharm. Sci.
71, 495 (1982).

9. S. S. Ober , H. C. Vincent , D. E. Simon, and K. J . F

reder ick , A Theological s tudy of procaine penicillin G
depot p r epa ra t i ons , J. Am. Pharm. Assoc. Sci. Ed.
47, 667 (1958).

10. C. Hansch and W. J . Dunn , I I I , Linear re la t

ionships between lipophilic cha rac te r and biological
act ivi ty of d r u g s , J. Pharm. Sci. 61, 1 (1972).

11. T . Fujita, J . Iwasa, and C. Hansch, A new subs t i

tuen t constant der ived from part i t ion coefficients,
J. Am. Chem. Soc. 86, 5175 (1964).
12. S. Feldman, Physiochemical factors influencing d r u g
absorpt ion from the in t ramuscular injection s i te ,
Bull. Parent. Drug Assoc. 28, 53 (1974).

13. D. L. Coleman, R. N. King, and J . D. Andrade , The

foreign body react ion: A chronic inflammatory r e s p o n
s e , J. Biomed. Mater. Res. 8, 199 (1974).

14. R. Langer , H. Brem, and D. Tappe r , Biocompatibility

of polymeric delivery systems for macromolecules, J.
Biomed. Mater. Res. 15, 267 (1981).

15. J . H. Ratcliffe, I . M. Hunneybal l , A. Smith, C. G.

Wilson, and S. S. Davis , Prepara t ion and evaluation of
biodegradable polymeric systems for t he in t r a -a r t i
cu l a r del ivery of d r u g s , J. Pharm. Pharmacol. 36,
431 (1984).

16. K. Merr i t t , Role of medical materials , both in

implant and s u r face appl icat ions, in immune response
and in res i s tance to inject ion, Biomaterials 5, 47
(1984).

17. L. Spr incl , M. Kuskova, J . Roda, and J . Kral icek,

The biocompatibility of polyvinylpyrrol idone in t es t
implantation, J. Biomed. Mat. Res. 16, 95 (1982).

18. J . D. Bobyn , G. J . Wilson, D. C. MacGregor, R. M.

Pilliar, and G. C. Weatherly, Effect of pore size on the
peel s t r eng th of at tachment of f ibrous t i s sue to
porous-sur faced implants , J. Biomed. Mat. Res. 16, 571
(1982).

19. B . F . Matlaga and T . N . Sal thouse, Ul t ras t ruc

tura l observa t ions of cells at the interface of a b
iodegradable polymer: Polyglactin 910, J. Biomed. Mat.
Res. 17, 185 (1983).

20. T . N . Sal thouse, Some aspec t s of macrophage

behavior at the implant in te r face , J. Biomed. Mat.
Res. 18, 395 (1984).

21. M. N. Helmus, D. F . Gibbons, and R. D. J o n e s , The

effects of surface cha rge on ar ter ia l thrombosis , J.
Biomed. Mat. Res. 18, 165 (1984).

22. R. G. Buck les , Biomaterials for d r u g del ivery sys

tems , J. Biomed. Mat. Res. 17, 109 (1983).
23. D. L. Coleman, D. E. Gregonis , and J . D. Andrade ,
Bloodmaterials in te rac t ions : The minimum interfacial
free ene rgy and the optimum polar /apolar rat io h y p o
t h e s e s , J. Biomed. Mat. Res. 16, 381 (1982).

24. R. E. Baier , A. E. Meyer, J . R. Natiella, R. R.

Natiella, and J . M. C a r t e r , Surface proper t i es
determine bioadhesive outcomes: Methods and r e s u l t s
, J . Biomed. Mat. Res. 18, 337 (1984).

25. S. W. Kim, Heparinized polymers for improving blood

compatibili t y , MD&DI, 99 (1984).

26. V. L. Gott , J . D. Whiffen, and R. C. Dat ton, Heparin

bonding on colloidal graphi te su r f aces , Science 142,
1297 (1963).

27. M. F. A. Goosen and M. V. Sefton, Proper t ies of a

hepa r in poly (vinyl alcohol) hydrogel coat ing, J.
Biomed. Mat. Res. 17, 359 (1983).

28. N. A. Peppas and E. W. Merrill , Development of

semicrystall ine PVA hydrogels for biomedical appl icat
ions, J. Biomed. Mat. Res. 11, 423 (1977).

29. H. R. Lager ren and J . C. Er iksson , Plastics with a

stable s u r face monolayer of c rossl inked hepar in :
Prepara t ion and evaluat ion , TASAIO 17, 10 (1971).

30. G. Schmer, The biological activity of covalently

immobilized hep a r in , TASAIO 18, 321 (1972).

31. I . Danishefsky and F . Tzeng , Preparat ion of hepar

inl inked agarose and i t s in teract ion with plasma,
Thromb. Res. 4, 237 (1974).

32. J . Heller, R. F. Helwing, R. W. Baber , and M. E. Tu t

t l e , Controlled release of water-soluble macromolecules
from bioerodible hyd roge l s , Biomaterials 4, 262
(1983).

33. J . Kopecek, Controlled bio degr ad ability of

polymer—a key to d r u g del ivery sys t ems ,
Biomaterials 5, 19 (1984).

34. R. E. Thompson and R. A. Hecht , Studies on a

long-action vitamine B-12 p repa ra t i on , Am. J. Clin.
Nutr. 7, 311 (1959).

35. M. J . Romans ky and G. E. Rit tman, A method for

prolonging the action of penicil l in, Science 100, 196
(1944).

36. E. Kruger -Th iemer , W. Diller, L. Dett l i , P . B u

n g e r , and J . Seydel , Demonstration des einfluses de
r e ive issb indung and der ionisation duf die
pharmacokonetik am kombineirten gaskinet ischen modell
nach van ' t Hoff und Langmuir , Antibiot. Chemother. 12,
171 (1964).

37. E. Kruger -Thiemer and P. B u n g e r , The role of the

rapeu t ic regimen in dosage des ign . Part I ,
Chemotherapia 10, 61 (1965— 1966).

38. E. Kruger -Thiemer and P. B u n g e r , The role of the

rapeu t ic r e g i men in dosage des ign . Part I I ,
Chemotherapia 10, 129 (1965— 1966).

39. E. Kruger -Th iemer , P. B u n g e r , L. Dett l i , P

. Sp r ing , and E. Wempe, Dosage regimen calculation of
chemotherapeutic agen t s . Part I I I . Sulfasymazine,
Chemotherapia 10, 325 (1965-1966).

40. T. Higuchi and R. Kuramoato, S tudy of possible complex

formation between macromolecules and cer ta in
pharmaceuticals I , J. Am. Pharm. Assoc. (Sci. Ed.) 43,
393 (1954).

41. T. Higuchi and R. Kuramoto, S tudy of possible complex

formation between macromolecules and cer ta in
pharmaceuticals I I , J. Am. Pharm. Assoc. (Sci. Ed) 43,
398 (1954).

42. A. Choay and H. Choay, Prolongation des effets de l '

insuline pa r association a la po lyvinypyrro l idone ,
Ann. Pharm. Fr. 5, 520 (1947).

43. K. E ik -nes , A . , Sandbe rg , F . H. Ty le r , and

L. T . Samuels, Changes in plasma level of 17-hydroxycort
icosteroids induced by ACTH. I I I . Effects of var ious
vehicles and modes of administrat ion , J. Clin.
Endocrinol. Metab. 18, 882 (1958).

44. M. H. Malone, R. D. Gibson, and T. S. Miya, A

pharmacologic s tudy of the effects of var ious
pharmaceutical vehicles on the action of orally
administered phenobarb i t a l , J. Pharm. Sci. 49, 529
(1960).

45. G. Hangard , K. Ki rkeby , and P. Lingjaerde, The

potency of repos i tory ACTH p r e p a r a t i o n s ,
Acta Med. Scand. 168, 205 (1960).

46. C. Davison, J . L. Guy, M. Levi t t , and P. K. Smith,

The d i s t r ibut ion of cer ta in non-narcot ic analgesic
agents in the CNS of severa l spec ies , J. Pharmacol.
Exp. Tlner. 134, 176 (1961).

47. P. Hedner , On the effect of long-act ing cort

icotrophin p r e p a r a t ions , Acta Endocrinol. 43, 499
(1963).

48. M. Friedman, Comparison of durat ion of activity of cor

t icot rophingelatin and cor t icotrophin-carboxymethylcel
lulose, Br. Med. J. Hi, 409 (1967).

49. A. Pekkar inen and U. K. Rinne, Comparison of different

longact ing cort icotrophin p repara t ions in the two-day
cort icotrophin tes t in man, Acta Pharmacol. , Suppl. 25,
1 (1967).

50. G. Levy and R. H. Reuning , Effect of complex formation

on d r u g absorpt ion . I . Complexes of salicylic acid
with absorbable and nonabsorbable compounds, J. Pharm.
Sci. 53, 1471 (1964).

51. G. Levy and T. Matosuzawa, Effect of complex formation

on d r u g absorpt ion . I I . Lipid-soluble dye
complexes, J. Pharm. Sci. 54, 1003 (1965).

52. G. Levy, K. E. Miller, and R. H. Reuning, Effect of

complex formation on d r u g absorpt ion . I I I .
Concentra t ion- and d r u g dependent effect of a nonionic
su r fac t an t , J. Pharm. Sci. 55, 394 (1966).

53. R. H. Reuning and G. Levy, Effect of complex formation

on d r u g absorpt ion . IV. Role of i n t r agas t r i c
diffusion in the absorpt ion of free and
caffeine-complexed salicylic acid from the ra t s tomach,
J. Pharm. Sci. 56, 843 (1967).

54. G. Levy and J . A. Anello, Effect of complex formation

on d r u g absorpt ion. V. Studies on the mechanism of the
secobarbi tal absorp t ion-enhanc ing effect of
polysorbate 80 in goldfish, J. Pharm. Sci. 57, 101 (1968).

55. G. Levy and E. J . Mroszczak, Effect of complex

formation on d r u g absorpt ion . VI. Drug permeation t h
r o u g h an artificial lipid b a r r i e r , J. Pharm.
Sci. 57, 235 (1968).
56. R. H. Reuning and G. Levy, Effect of complex formation
on d r u g absorpt ion . IX. Determination of the in tes t
inal t r ans fe r ra te constant of the
salicylamide-caffeine complex, J. Pharm. Sci. 58, 79
(1969).

57. J . A. Anello and G. Levy, Effect of complex formation

on d r u g absorpt ion . X. Effect of polysorbate 80 on
the permeabili ty of biological membranes, J. Pharm. Sci.
58, 721 (1969).

58. W. L. Hayton and G. Levy, Effect of complex formation

on d r u g absorpt ion. XIII. Effect of constant
concentrat ions of N , N d i n propylpropionamide on
prednisolone absorpt ion from the ra t small i n t e s t i
ne , J. Pharm. Sci. 61, 367 (1972).

59. Y. P. Chow and A. J . Repta , Compexation of

acetaminophen with methyl x a n t h i n e s , J. Pharm.
Sci. 61, 1454 (1972).

60. H. C. Hagerdorn , B . N. J e n s e n , and N. B .

Kramp, Protamine insu l ina te , JAMA 106, 111 (1936).

61. R. E. Thompson, Sustained release of pa ren te ra l d r

u g , Bull. Parent. Drug Assoc. 14, 6 (1960).

62. R. A. Nash , Formulation of pharmaceutical suspens ions

I , Drug Cosmetic Ind. 97, 843 (1965).

63. R. E. Collard, Formulation and manufacture of cort

icosteroid p r e p a r a t i o n s , Pharm. J. 186, 133
(1961).

64. V. G. Folglia, J . C. Penhos , and E. Montuori,

Relation of c r y s tal size to es t rogenic activity of pa
rahydroxyprop iophenone , Endocrinology 57, 559 (1955).

65. R. W. Bates and C. Loury , Effect of part icle size of

suspens ion of e s t rogen c rys ta l s on dura t ion of e
s t r u s , Proc. Soc. Exp. Biol. Med. 73, 576 (1950).

66. F . H. Buckwalter and H. L. Dickison, The effect of

vehicle and part icle size on absorpt ion by the in t
ramuscular route of p r o caine penicillin G s u s p e n s
i o n s , J. Am. Pharm. Assoc. (Sci. Ed.) 47, 661 (1958).

67. J . Mullins and T. Macek, Some pharmaceutical p roper t

i e s of novobiocin, J. Am. Pharm. Assoc. (Sci. Ed.) 49,
245 (1960).

68. A. J . Aguiar and J . C. Zelmer, Dissolution behavior

of polymorphs of chloramphenicol palmitate and mefenamic
acid, J. Pharm. Sci. 58, 983 (1969).

69. W. E. Hamlin, E. Nelson, B. E. Bal lard , and J . G.

Wagner, Loss of sensi t iv i ty in d is t inguish ing real
differences on dissolution ra t e s due to inc reas ing in
tens i ty of agi tat ion, J. Pharm. Sci. 51, 432 (1962).

70. J . W. Poole, G. Owen, J . Silverio, J . N. Freyhof,

and S. B. Roseman, Physicochemical factors influencing the
absorpt ion of the anhydrous and t r i h y d r a t e forms
of ampicillin, Curr. Ther. Res. 10, 292 (1968).

71. J . Haleblian and W. McCrone, Pharmaceutical

applications of polymorphism, J. Pharm. Sci. 58, 911
(1969).

72. N. B . Shah and B . B . She th , Effect of polymers on

dissolution from d r u g suspens ions , J. Pharm. Sci. 65,
1619 (1976).

73. H. Seager , The effect of methylcellulose on the

absorpt ion of ni t rofurantoin from the gas t ro intes t
inal t r a c t , J. Pharm. Pharmacol. 20, 968 (1968).

74. A. T . Florence, P. H. Elworthy, and A. Rahman, The

influence of solution viscosity on the dissolution ra te
of soluble sal ts and the measurement of an "effective" v
iscos i ty , J. Pharm Pharmacol. 25, 779 (1973).

75. J . H. R. Woodland, S. Yolles, D. A. Blake, M. Helrich,

and F . J . Meyer, Long act ing del ivery systems for
narcotic an tagon i s t s , J. Med. Chem. 16, 897 (1973).

76. W. R. Martin and V. L. Snadquis t , A sus ta ined

release depot for narcot ic an tagon i s t s , Arch, Gen.
Psychiatry 30, 31 (1974).

77. S. Yolles, T. D. Leafe, J . H. R. Woodland, and F . J .

Meyer, Long act ing del ivery systems for narcotic an
tagonis t s . I I . Release r a t e s of nal t rexone from
poly(lactic acid) composites, J. Pharm. Sci. 64, 348
(1975).

78. S. Yolles, Controlled release of biologically active

agen t s . I n , Polymers in Medicine and Surgery (R. L.
Kronentha l , Z. Oser , and E. Martin, E d s . ) , Plenum,
New York, 1975, p p . 245-261.

79. S. Yolles, Time-release depot for ant icancer d r u g s

: Release of d r u g s covalently bonded to polymers , J.
Parent. Drug Assoc. 32, 188 (1978).

80. V. Lenae r t s , P . Couvreu r , D. Chr i s t i

aens-Leyh , E. Jo i r i s , M. Roland, B . Rollman, and P.
Speiser , Degradation of poly( isobutyl cyanoacryla te)
nanopar t ic les , Biomaterials 5, 65 (1984).

81. K. R. Sidman, W. D. S tebe r , A. D. Schwope, and G. R.

Schnaper , Controlled release of macromolecules and
pharmaceut i cals from syn the t i c polypept ides based on
glutamic acid, Biopolymers 22, 547 (1983).

82. J . W. McGinity, A. Martin, G. W. Cuff, and A. B .

Combe, In fluences of matrixes on nylon-encapsula ted
pharmaceut ica ls , J. Pharm. Sci. 70, 372 (1981).

83. N. Mason, C. Th ies , and T. J . Cicero, In vivo and In

vitro evaluation of a microencapsulated narcotic an
tagonis t , J. Pharm. Sci. 65, 847 (1976).

84. S. Beni ta , J . P. Benoil, F . Puis ieux, and C. Th ie

s , Charac te r i zation of drugloaded po ly (d , l l ac t
ide ) microspheres , J. Pharm. Sci. 73, 1721 (198 ) .

85. T. Ish izaka , K. Endo, and M. Koishi, Prepara t ion of

egg albumin microcapsules and microspheres , J. Pharm.
Sci. 70, 358 (1981).

86. J . M. Gallo, C. T. Hung , and D. G. P e r r i e r ,

Analysis of albumin microsphere p repa ra t ion , Int. J.
Pharm. 22, 63 (1984).

87. P. A r t u r s s o n , P. Edman, T. Laakso, and I .

Sjoholm, Charac te r ization of polyacryl s t a r ch
microparticles as ca r r i e r s for prote in and d r u g
s , J. Pharm. Sci. 73, 1507 (1984).

88. Y. Kawashima, S. Y. Lin, A. Kasai, H. Takenaka , K.

Matsunami, Y. Nochida, and H. Hirose, Drug release p roper
t i es of the microcapsules of adriamycin hydrochlor ide
with ethylcellulose p repa red by a phase separat ion t
echn ique , Drug Dev. Ind. Pharm. 10, 467 (1984).

89. I . Jalsenjak and T. Kondo, Effect of capsule size on

permeabili ty of gelatin-acacia microcapsules toward
sodium chlor ide , J. Pharm. Sci. 70, 456 (1981).
90. T. Ishizaka and M. Koishi, In vitro d r u g release
from egg albumin microcapsules, J. Pharm. Sci. 72, 1057
(1983).

91. P. L. Madan, Clofibrate microcapsules I I : Effect of

wall th ickness on release cha rac te r i s t i c s , J.
Pharm. Sci. 70, 430 (1981).

92. J . Sjovall, R. Sjoqvist , B . Huitfeldt , and H.

Nyqvis t , Correlation between the bioavailability of
microencapsulated bacampicillin hydrochlor ide in suspens
ion and in vitro microcapsule dissolut ion, J. Pharm. Sci.
73. 141 (1984).

93. M. C. B i s se ry , F. Valeriote, and C. Th ies , In

vitro lomustine release from small poly (
(3-hydroxybutyrate) and poly ( d , 1lactide) microspheres .
I n , 11th International Symposium on Controlled Reelase
Bioactive Materials, (W. E. Meyers and R. L. Dunn , E d s
. ) , Controlled Release Society, I n c . , 1984, p . 25.

94. P . Edman and I . Sjoholm, Acrylic microspheres in vivo

VI: Antitumor effect of mi crop art icles with immobilized
L- asparaginase against 6C3HED lymphoma, J. Pharm. Sci.
72, 654 (1983).

95. Y. Nozawa and S. W. Fox, Microencapsulation of methyl

glyoxal and two de r iva t ives , J. Pharm. Sci. 70, 385
(1981).

96. J . R. Nixon, In vitro and in vivo re lease of

microencapsulated chlorothiazide, J. Pharm. Sci. 70, 376
(1981).

97. A. T. Florence, A. W. J e n k i n s , and A. H.

Loveless , Approaches to the formulation of a long-ac t
ing in t ramuscular injection, J. Pharm. Pharmacol. Suppl.
25, 121P (1973).

98. J . D. Scheu, G. J . Sperandion , S. M. Shaw, R. R.

Landolt , and G. E. Peck, Use of microcapsules as t
imed-released p a r e n tera l dosage form: Application as
radiopharmaceutical imaging agen t , J. Pharm. Sci. 66,
172 (1977).

99. M. S. H a r r i s , Preparat ion and release charac te

r i s t ics of p o t a s sium chloride microcapsules , J.
Pharm. Sci. 70, 391 (1981).
100. L. R. Beck, D. R. Cowsar, D. H. Lewis, J . W. Gibson,
and C. E. Flowers, New long-ac t ing injectable
microcapsule con t ra ceptive sys tem, J. Obstet. Gynecol.
135, 419 (1979).

101. H. Takenaka , Y. Kawashima, and S. T. Lin,

Micromeritic p r o p er t ies of sulfamethoxazole
microcapsules p r epa red by gelat inacacia coacervat ion,
J. Pharm. Sci. 69, 513 (1980).

102. L. M. S a n d e r s , J . S. Kent , G. I. McRae, B .

H. Vickery , T. R. Tice , and D. H. Lewis, Controlled re
lease of a luteinizing hormone-releas ing hormone analogue
from poly (d , l l a c t i de co glycolide) microspheres ,
J. Pharm. Sci. 73, 1294 (1984).

103. P . Rambourg, J . Levy, and M. C. Levy,

Microencapsulation I I I : Prepara t ion of i nve r t a se
microcapsules , J. Pharm. Sci. 71, 759 (1982).

104. M. C. Levy, P. Rambourg, J . Levy, and G. Pot ron ,

Microencapsulation IV: Crossl inked hemoglobin
microcapsules , J. Pharm. Sci. 71, 759 (1982).

105. T . Konda, M. Arakawa, and B. Tamamushi,

Poly(phthaloyl L-lysine) microcapsules containing
hemoglobin solution: Artificial red blood cells. I n ,
Microencapsulation ( J . R. Nixon, E d . ) , Marcel Dekker
, New York, 1976, p . 163.

106. T. M. S. Chang , Semipermeable microcapsules as

artificial cells: Clinical applications and p e r s p e c
t i v e s . In , Microencapsulation ( J . R. Nixon, E d .
) , Marcel Dekker , New York, 1076, p . 57.

107. P . Edman and I . Sjoholm, Prolongation of effect of

asparaginase by implantation in polyacrylamide in r a t s
, J. Pharm. Sci. 70, 684 (1981).

108. P. Edman and I . Sjoholm, Acrylic microspheres

in-vivo. V. Immunological p roper t i e s of immobilized
asparaginase in micropart ic les , J. Pharm. Sci. 71, 576
(1982).

109. B . Ekman, C. Lefter , and I . Sjoholm, Incorporat ion

of micromolecules in micropart icles: Preparat ion and cha
rc t e r i s t i c s , Biochemistry 15, 5115 (1976).

110. M. V. Sefton, L. R. Brown, and R. S. Langer ,

Ethylene-vinyl acetate copolymer microspheres for
controlled release of macromolecules, J . Pharm. Sci. 73,
1859 (1984).

111. J . Kreu te r and E. Lichl, Long-term s tudies of

microencapsulated and adsorbed influenza vaccine nanopar t
ic les , J. Pharm. Sci. 70, 367 (1981).

112. F . Lim and R. D. Moss, Microencapsulation of l iving

cells and t i s s u e s , J. Pharm. Sci. 70, 351 (1981).

113. T . M. S. Chang , Artificial cells in medicine and

biotechnology, Appl. Biochem. Biotech. 10, 5 (1984).

114. A. M. Sun , G. M. Oshea, M. F . A. Goosen, and H.

Gharapet ian , Microencapsulation of l iving cells as
long-term hormone and enzyme del ivery sys tem. In , 11th
International Symposium on Controlled Release Bioactive
Materials (W. E. Meyer and R. L. Dunn , E d s . ) ,
Controlled Release Society Ic . , 1984, p . 55.

115. P . A r t u r s o n , T. Laakso, and P. Edman, Acrylic

microspheres in vivo IX: Blood elimination kinetics and
organ dis t r ibut ion of microparticles with different
surface cha rac te r i s t i c s , J. Pharm. Sci. 72, 1415
(1983).

116. A. W. Segal, E . J . Willis, J . E. Richmond, G.

Slavin, C. D. V. Black, and G. Gregor iadis ,
Morphological observa t ions on the cellular and
subcellular dest inat ions of in t ravenous ly administe
red liposomes, Br. J. Exp. Pathol. 55, 320 (1974).

117. L. R. McDougall, J . K. Dunnick , M. S. McNamee, and J

. P. Kr i s s , Distr ibut ion and fate of syn the t ic
lipid vesicles in the mouse: A combined radionuclide and
spin label s t u d y , Proc. Natl. Acad. Sci. USA 71, 3487
(1974).

118. P. Edman and I . Sjoholm, Acrylic microspheres in vivo

VIII: Distr ibution and elimination of po lyacry ldext ran
par t ic les in mice, J. Pharm. Sci. 72, 796 (1983).

119. P . Edman, I . Sjoholm, and U. B r u n k , Acrylic

microspheres in vivo VII: Morphological s tud ies on mice
and cul tured macrop h a g e s , J. Pharm. Sci. 72, 658
(1983).

120. M. Kanke, I . Sniecinske, and P. P. DeLuca, Interact

ion of microspheres with blood cons t i tuen t s : I .
Uptake of po lys ty rene sphe re s by monocytes and
granulocytes and effect on immune respons iveness of
lymphocytes , J. Parent. Sci. Tech. 37, 210 (1983).

121. T . Tanaka , K. Taneda , H. Kobayashi , K. Okumura, S.

Muranih i , and H. Sezaki , Application of liposomes to the
pharamceutical modification of the d is t r ibut ion
charac te r i s t i cs of d r u g s in the r a t , Chem.
Pharm. Bull. 23, 3069 (1975).

122. G. Gregoriadis and E. D. Neerunjun, Homing of

liposomes to t a rge t cel ls , Biochem. Biophys. Res.
Commun. 65, 537 (1975).

123. R. L. Juliano and D. Stamp, Lectin-mediated at

tachment of g lycoprote in-bear ing liposomes to cel ls ,
Nature 261, 235 (1976).

124. G. Weissman, D. Gloomgarden, R. Kaplan, C . Cohen, S.

Hoffs te in , T . Collins, A . Gotlieb, and D . Nagle, A
general method for the int roduct ion of enzymes by means
of immunoglobulin coated liposomes of deficient cel ls ,
Proc. Natl. Acad. Sci. USA 72, 88 (1975) .

125. T . Kato, R. Nemoto, H. Mori, K. Iwata, S. Sato, K.

Unno, A. Goto, M. Harada , M. Homma, M. Okada, and T .
Minowa, An approach to magnetically controlled cancer
chemotherapy. I I I . Magnetic control of ferromagnetic
mitomycin C microcapsules in the a r t e r y , J. Jpn. Soc.
Cancer Ther. 15, 28 (1980).

126. T . Kato, R. Nemoto, H. Mori, and I . Kumagai, Susta

inedrelease p rope r t i e s of microencapsulated mitomycin
C with e thy l cellulose infused into the renal a r t e r y
of the dog, Cancer 46, 14 (1980).

127. T . Kato, R. Nemoto, H. Mori, M. Takahash i , and Y.

Tamakawa, T ransca the t e r ar ter ia l chemoembolization
of renal cell carcinoma with microencapsulated mitomycin
C, J. Urol. 125, 19 (1981).

128. K. Widder, G. Floure t , and A. Senyei , Magnetic

microspheres : Synthes is of a novel paren te ra l d r u g
c a r r i e r , J. Pharm. Sci. 68, 79 (1979).

129. K . J . Widder, A. E. Senyei , and D . G. Scarpell i ,

Magnetic microspheres : Model system for site specific d r
u g del ivery in vivo, Proc. Soc. Exp. Biol. Med. 158, 141
(1978).

130. F . Ishii i , A. Takamura, and S. Noro, Magnetic

microcapsules for in vitro t e s t ing as ca r r i e r for
in t ravascu la r administration of ant icancer d r u g s
: Prepara t ion and physicochemical p r o p e r t i e s ,
Chem. Pharm. Bull. 32, 678 (1984).

131. P . L. Kronick, G. L . Campbell, and K. Joseph ,

Magnetic microsphe re s p r epa red by redox polymerization
used in a cell separation based on gangl iosides , Science
200, 1074 (1978).

132. A. E. Senyei , S. D. Reich, C. Gonczy, and K. J .

Widder, In vivo k ine t ics of magentically t a rge ted
low-dose doxorubicin , J. Pharm. Sci. 70, 389 (1981).

133. K . J . Widder, A . E. Senyei , and D. F . Ranney,

Magnetically responsive microspheres and o ther c a r r i
e r s for the biophysical t a rge t ing of anti tumor a g
e n t s , Adv. Pharmacol. Chemo. 16, 213 (1979).

134. K . J . Widder, A. E. Senyei , and B . Sea r s ,

Experimental methods in cancer t he r apeu t i c s , J.
Pharm. Sci. 71, 379 (1982).

135. K . J . Widder, A. E. Senyei , H. Ovadia, and P . Y.

Pater son, Specific cell b inding us ing staphylococcal
prote in A magnetic microspheres , J. Pharm. Sci. 70, 387
(1981).

136. R. Deanesly and A. S . P a r k e s , Note on the

subcutaneous a b sorption of oils by r a t s and mice, with
special reference to the assay of oes t r in , J .
Physiol. 78, 155 (1973).

137. W. E . Brown, V. M. Wilder, and P . Schwartz , A s

tudy of oils used for in t ramuscular injections, J. Lab.
Clin. Med. 29, 259 (144) .

138. W. G. Waggoner and J . H. F incher , Influence of HLB

values of su r fac tan t s on ephedr ine release from
emulsified liquid s y s tems, J. Pharm. Sci. 60, 1830
(1971).

139. K. Kakemi, T . Sezaka, S. Muraniski , H. Ogata , and

S. Isemura , Mechanism of absorpt ion of d r u g s from oi
lin-water emulsions I, Chem. Pharm. Bull. 20, 708 (1972).

140. P . J . Carr igan and T . R. Ba t e s ,

Biopharmaceutics of d r u g s administered in l
ipid-containing dosage forms. I . GI absorpt ion of
griseofulvin from an oi l in-water emulsion in the r a t ,
J. Pharm. Sci. 62, 1476 (1973).

141. G. Ln , F . Sadik, W. F . Gilmore, and J . H. F incher

, Influence of hydrophil ic-l ipophil ic balance values of
su r fac tan t s on ephedr ine absorpt ion and release from
emulsified systems after oral administrat ion to dogs , J.
Pharm. Sci. 63, 666 (1974).

142. T . R. Bates and J . A. Sequeira , Bioavailability of

micronized griseofulvin from corn oi l in-water emulsion,
aqueous suspension and commercial tablet dosage forms in
humans , J. Pharm. Sci. 64, 793 (1975).

143. D. Hal lberg, I . Holm, and A. L. Abel, Fat emulsion

for in t r a venous nu t r i t ion , Postgrad. Med. J. 43,
307 (1967).

144. H. C. Meng, Use of fat emulsions in paren te ra l nu t

r i t ion , Drug Intell. Clin. Pharm. 6, 321 (1972).

145. C. L . Fo r tne r , W. R. Grove, D. Bowie, and M. D.

Walker, Fat emulsion vehicle for in t r avenous
administration of an aqueous insoluble d r u g , Am. J.
Hosp. Pharm. 32, 582 (1975).

146. R. E . Counsell and R. C. Pohland, Lipoproteins as

potential si te-specific del ivery systems for diagnostic
and the rapeu t ic a g e n t s , J. Med. Chem. 25,
1115-1120 (198 2) .

147. G. W. Halber t , J . F . B . S tua r t , and A. T .

Florence, The incorporation of l ipid-soluble antineoplast
ic agen t s into microemulsions—protein-free analogues of
low densi ty l ipoprotein , Int. J. Pharm. 21, 219 (1984).

148. J . Welsh, K. C. Caiman, J . F . S tua r t , J .

Clegg, J . M. Stewar t , C . J . Packard , H. G. Morgan,
and J . Shepard , Low dens i ty l ipoprotein up take by
tumors , Clin. Sci. (London) 63, P44 (198 2 ) .

149. D. Gal, P . E . MacDonald, J . E . Po r t e r , and E.

R. Simpson, Cholesterol metabolism in cancer cells in
monolayer c u l t u r e . IV. LDL metabolism, Int. J.
Cancer 28, 315-319 (1981).

150. M. R. Hilleman, Critical appraisal of emulsified oil

adjuvants applied to viral vacc ines , Prog. Med Virol. 8,
131 (1966).

151. J . F r eund and M. V. Bonato, The effect of paraffin

oil, lanolin-like subs tances and killed tuberc le bacilli
on immunization with d iphther ic toxoic and Bac t .
Typhosum, J. Immunol. 48, 325 (1944).

152. J . E . Salk, M. Contakos , A. M. Lauren t , M.

Sorenson, A. J . Rapalski , I . H. Simmons, and H. Sandber
t , Use of adjuvants in s tudies on influenza
immunization, JAMA 151, 1169 (1953).

153. J . F r e u n d , Mode of action of mineral oil ad

juvan ts , Adv. Tuberc. Res. 7, 130 (1956).

154. F . M. Davenpor t , Applied immunology of mineral oil

ad juvan ts , J. Allergy 32, 111 (1961).

155. W. I . Higuchi , Rate of solute t r a n s p o r t out

of emulsion droplets in micron size r a n g e , J. Pharm.
Sci. 53, 405 (1964).

156. J . L . Windheuser, M. L . Bes t , and J . H. Pe r r i

n , Evaluation of sus ta ined action pa ren te ra l
emulsions, Parent. Drug Assoc. Bull. 24, 286 (1970).

157. A. F . Brodin , D. R. Kaval iunas , and S. G. F r a n

k , Prolonged d r u g release from multiple emulsions,
Acta Pharm. Suec. 15, 1 (1978).

158. C . J . Eenoy, L . A. Elson, and R. Schneider ,

Multiple emulsions, a suitable vehicle to provide susta
ined release of cancer chemotherapeu t ic a g e n t s , Br.
J. Pharmacol. 45, 135P (1972).

159. T . Yoshioka, K. Ikeuchi , M. Hashida, S. Muranishi ,

and H. Sezaki, Prolonged release of bleomycin from paren
te ra l gelatin spherein-o i l in -water multiple
emulsion, Chem. Pharm. Bull. 30, 1408 (198 2 ) .

160. A. J . Collings and R. Schneider , The multiple

emulsion formulation for the slow release of d r u g s ,
Br. J. Pharmacol. 38, 469P (1970).

161. A. T . Florence and D. Whitehill, The formulation and

stabil i ty of multiple emulsions, Int. J. Pharm. 11, 211
(1982).

162. M. Akimoto and Y. Morimoto, Use of magnetic emulsion

as a novel d r u g ca r r i e r for chemotherapeutic a g e
n t s , Biomaterials 4, 49 (1983).

163. E . Muler, J . M. Lamers-Stahlhofen, and H. J . Van

Der Molen, Interact ion between s teroids and membranes .
Uptake of s teroids and steroid su lphates by resealed e
ry th rocy te ghos t , J". Steroid Biochem. 4, 369 (1973).

164. J . D. Gardner and A. G. Levy, T ranspo r t of dibasic

amino acids by human e r y t h r o c y t e s , Metabolism
21, 413 (1972).

165. W. C. Wise, Maturation of membrane funct ion: T

ranspor t of amino acid by ra t e ry th ro id cells , J.
Cell Physiol. 87, 199 (1975).

166. J . M. Oliver, and A . R. P . Pater son, Nucleoside t

r a n s p o r t . I . A medicated process in human e r y t
h r o c y t e s , Can. J. Biochem. 49, 262 (1971) .

167. J . C . Goldsmith, M. E. S. Roer , and E. P . O r r i

n g e r , A new treatment s t r a t egy for hemophilia B :
Incorporat ion of factor IX into r ed cell ghos t , Am. J.
Hematol. 7, 119 (1979).

168. G. M. Ih ler , E ry th rocy te c a r r i e r s ,

Pharmac. Ther. 20, 151 (1983).

169. G. L . Dale, Resealed e r y t h r o c y t e s as d r u

g c a r r i e r s . In , Drug Delivery Systems (R . L .
Jul iano, E d . ) , Oxford Univers i ty P r e s s , New
York, 1980, p p . 237.

170. G. D. Eytan and E . Eytan , Fusion of proteoliposomes

and cells , J. Biol. Chem. 255, 4992 (1980) .

171. M. B . F iddler , L . D . S. Hudson, and R. J .

Desnick, Immunological evaluation of repea ted
administration of e r y t h r o c y t e en t r apped prote
in to C311/HeJ mice, Biochem. J. 168, 141 (1977).

172. L . D . S . Hudson, M. B . Fiddler , and R . J .

Desnick, Enzyme t h e r a p y . X . Immune response
induced by enzyme- and bufferloaded liposomes in C3H/HeJ
Gus mice, J. Pharmac. Exp. Ther. 208, 507 (1979).

173. D. A. Tyrre l l and B . E. Ryman, The ent rapment of

the rapeu t ic agen t s in resealed e ry th rocy t e "ghos
t s" and the i r fate in vivo, Biochem. Soc. Trans. 4, 6 7
7 ( 1 9 7 6 ) .

174. G. P . Royer , T . K. Lee, and T . D . Sokoloski,

Entrapment of bioactive compounds within nat ive albumin b
e a d s , J. Parent. Sci. Tech. 37, 34 (1983).
175. M. J . Poznansky and L . G. Cleland, Biological
macromolecules as c a r r i e r s of d r u g s and
enzymes. In , Drug Delivery Systems (R . L. Jul iano, E d
. ) , Oxford Univers i ty P r e s s , New York, 1980, p p
. 253.

176. T . K. Lee, T . D. Sokoloski, G. P . Royer , Serum

albumin b e a d s : An injectable, b iodegradable system
for the susta ined release of d r u g s , Science 213, 233
(1981).

177. M. F . A . Goosen, Y. F . Leung , S. Chou, and A. M.

Sun, Insulin-albumin microbeads: An implantable, b
iodegradable system, Biomat. Med. Dev. Act. Org. 10, 205
(1982).

178. O. Vaizolglu and P . Speiser , Intell igent d r u g

del ivery sys tems , TIPS 3, 28 (1982).

179. A. Troue t , D. D. De Campeneere, R. Baura in , M. H y

b r e c h t s , and A. Zenebergh . In , Drug Carriers in
Biology and Medicine, Academic P r e s s , London, New
York and San Francisco , 1979, p . 87.

180. S. G. Vitals , M. Masquelier, and C O . Pe te r son ,

Low densi ty l ipoprotein (LDL) for the t a rge t ing of
ant icancer agen t s to malignant cells with high LDL
recep tor ac t iv i ty . In , 11th International Symposium
on Controlled Release Bioactive Materials (W. E. Meyers and
R. L . Dunn , E d s . ) , Controlled Release Society, I n
c . , 1984, p p . 23.

181. J . Pi tha , Nucleic acid and sulfate and phosphate

polyanions, In , Anionic Polymeric Drugs (L . G. Donaruma,
R. M. Ot tenb r i t e , and O. Vogel, E d s . ) , John
Wiley & Sons, I n c . , New York, 1980.

182. A. D . Bangham, M. M. Stan d i sh , and J . C .

Watkins, Diffusion of univalent ions across the lamellae
of swollen phosphol ipids , J. Mol. Biol. 13, 238 (1965) .

183. D. Papahadjopoulos and J . W. Watkins, Phospholipid

model memb r a n e s . I I . Permeability p roper t i e s
of h y d r a t e d liquid c r y s t a l s , Biochem.
Biophys. Acta 135, 639 (1967).

184. A. D. Bangham, Membrane models with phosphol ip ids ,

Prog. Biophy. Mol. Biol. 18, 29 (1968).
185. D. Papahadjopoulos and N. Miller, Phospholipid model
membrane. I. S t ruc tu ra l charac te r i s t i cs of h y
d r a t e d liquid c r y s t a l s , Biochim. Biophys. Acta
135, 624 (1967).

186. S. M. Gru n e r , R. P . Lenk, A. S. Janoff, and M. J

. Os t ro , Novel multi layered lipid ves ic les :
Comparision of physical cha r ac ter i s t ics of
multilamellar liposomes and stable plurilamellar vesic les
, Biochemistry 24, 2833 (198 5 ) .

187. A. Goundalker , T . Ghose, and M. Mezei, Covalent b

inding of ant ibodies to liposomes us ing a novel lipid
der iva t ive , J. Pharm. Pharmacol. 36, 465 (1984) .

188. L . S. Rao, Liposomal dosage form development-some

practical cons idera t ions , J. Parent. Sci. Tech. 37, 72
(1983) .

189. G. Gregor iadis , P . D . Leathwood, and B . E. Ryman,

Enzyme ent rapment in liposomes, FEBS Lett. 14, 95 (1971).

190. G. Gregoriadis and B . E . Ryman, Lysosomal

localization of (3-fructofuranosidase-containing liposomes
injected into r a t s , Biochem. J. 129, 123 (1972).

191. G. Gregoriadis and B . E. Ryman, Fate of pro te

in-conta in ing liposomes injected into r a t s : An
approach to the t reatment of s torage d isease , Eur. J.
Biochem. 24, 48 5 (1972).

192. G. Gregor iadis , D. Putman, L. Louis , and E. D.

Neerunjun, Comparative effect of non -en t r apped and l
iposome-entrapped neuraminidase injected into r a t s ,
Biochem. J. 140, 323 (1974).

193. G. Gregoriadis and E. D. Neerunjum, Homing of

liposomes to t a rge t celU, Biochem. Biophys. Res. Comm.
65, 537 (1975).

194. G. Gregor iadis , Drug ent rapment in liposomes, FEBS

Lett. 36, 292 (1973) .

195. R. L. Juliano and D. Stamp, The effect of par t ic le

size and cha rge on the clearance r a t e s of liposomes
and liposome encapsulated d r u g , Biochem. Biophys. Res.
Commun. 63, 651 (1975).

196. G. Deliconstant inos, G. Ramantanis , and D. K.

Todorou, Interact ion of 99m Tc-labeled liposomes with
Walker tumor cells in vitro. Liposome-medicated introduct
ion of thal iblast ine into r e s i s t an t Walker tumor
cells , Gen. Pharmacol. 124, 407 (1983) .

197. A. W. Segal, E . J . Wills, J . E. Richmond, G. Slown,

C. D. V. Black, and G. Gregor iadis , Morphological
observa t ions on the cellular and subcellular dest inat
ion of in t ravenous ly administered liposomes, Br. J.
Exp. Pathol. 55, 320 (1974).

198. A. Cudd and C. Nicolau, Electron microscope s tudy of

the fate of liposomes in-vivo. In , 11th International
Symposium on Controlled Release Bioactive Materials (W. E.
Meyer and R. L . Dunn, E d s . ) , Controlled Release
Society, I n c . , 1984, p . 40.

199. R. M. Abra , C. A. Hunt , and D. T . Lau, Liposome

disposition in-vivo. VI . Delivery to the l u n g , J.
Pharm. Sci. 73, 203 (1984).

200. P . Speiser . In , Frontiers of Biology, Vol. 6 (A.

Neuberger and E. L. Tatum, E d s . ) , Elsevier /North
Holland Biomedical P r e s s , New York, 1979, p . 653.

201. P . Couvreu r , P . Tu lkens , M. Roland, A . T roue t

, and P . Speise r , Nanocapsules : A new type of
lysosomotropic ca r r i e r , FEBS Lett. 84, 323 (1977).

202. P . Couvreu r , B . Kante , V. L e n a e r t s , Y.

Scail teur , M. Roland, and P . Speiser , Tissue dis t r
ibut ion of anti tumor d r u g s associated with
polyalkylcyanoacrylate nanopar t ic les , J. Pharm. Sci.
69, 199 (1980).

203. L . Ilium and S. S. Davis , Effect of the nonionic

surfac tant poloxamer 338 on the fate and deposition of po
lys tyrene microsphe re s following in t ravenous
administrat ion, J. Pharm. Sci. 72, 1086 (1983) .

204. D. Leu, B . Manthey, J . K r e u t e r , P . Speiser ,

and P . P . DeLuca, Distr ibut ion and elimination of
coated polymethyl [2 1 4 C] methacrylate nanopar t ic les
after in t ravenous injection in r a t s , J. Pharm. Sci.
73, 1433 (1984).

205. M. Arakawa and T . Konda, Prepara t ion of hemolysate

loaded poly (N,N-Llys ine di terephthaloyl) nanocapsules ,
J. Pharm. Sci. 70, 354 (1981).

206. F . Theeuwes and S. I . Yum, Principles of the design

and operat ion of gener ic osmotic pumps for the del ivery
of semisolid or l iquid d r u g formulations, Ann. Biomed.
Eng. 4, 343 (1976).

207. F . Theeuwes , The elementary osmotic pump, J. Pharm.

Sci. 64, 198 7 (1975).

208. E. L . P . Uhlig, W. F . Gray don, and D r . W. Zingg,

The e lect roosmotic actuation of implantable insulin
micropumps, J. Biomed. Mat. Res. 17, 931 (1983) .

209. P . J . B lackshear , F . D. Dorman, P . L .

Blackshear J r . , R. L . Varco, and H. Buchwald, A
permanently implantable, selfrecyc l ing , low flow, cons
tant r a te mult ipurpose infusion pump of simple des ign
, Surg. Forum 21, 136 (1970).

210. P . J . Blackshear , F . D. Dorman, P . L . Blackshear

J r . , R . L . Varco, and H. Buchwald, The design and
initial t e s t ing of an implantable infusion pump, Surg.
Gynecol. Obstet. 134, 51 (1972).

211. P . J . Blackshear , T. D. Rohde, F . Pros i , and H.

Buchwald, The implantable infusion pump: a new concept in
d r u g del ivery , Med. Prog. Tech. 6, 149 (1979).

212. S. A. Varia, S. Schul ler , and V. J . Stella,

Phenytoin p r o d r u g s IV: Hydrolysis of var ious
3(hydroxymethyl ) phenytoin e s t e r s , J. Pharm. Sci.
73, 1075 (1984).

213. S . A. Varia and V. J . Stella, Phenytoin p r o d r u

g s V: In vivo evaluation of some water-soluble phenytoin
p r o d r u g s in dog, J. Pharm. Sci. 73, 1080 (1984).

214. S. A . Varia and V. J . Stella, Phenytoin p r o d r u

g s VI: In vivo evaluation of a phosphate e s t e r p r o
d r u g of phenytoin after pa ren te ra l administration
to r a t s , J. Pharm. Sci. 73, 1087 (1984).

215. S. A. Varia, S. SchuUer, K . B . Sloan, and V. J .

Stella, Phenytoin p r o d r u g s III : Water-soluble p r
o d r u g for oral a n d / o r pa ren te ra l u s e , J.
Pharm. Sci. 73, 1068 (1984).

216. Y. Yamoaka, R. D . Robe r t s , and V. J . Stella,

Low-melting phenytoin p r o d r u g s as a l ternat ive
oral del ivery modes for pheny to in : A model for o ther
high-melt ing spar ingly water soluble d r u g s , J.
Pharm. Sci. 72, 400 (1983).
217. M. Johansen and H. B u n d g a a r d , P r o d r u g s
as d r u g del ivery sys tems . XXV: Hydrolysis of
oxazolidines—A potential new p r o d r u g t y p e , J.
Pharm. Sci. 72, 1294 (1983).

218. U. Klixbull and H. B u n d g a a r d , P r o d r u g s

as d r u g del ivery sys tems . XXX. 4-Imidazolidinones as
potential b iorevers ib le der iva t ives for the
a-aminoamide moiety in p e p t i d e s , Int. J . Pharm.
20, 273 (1984) .

219. R. A. Lipper , S. M. Machkovech, J . C . Drach , and W

. I . Higuchi , Inhibition of d r u g metabolism by a p r
o d r u g : 9-$~Darabinofuranosyladenine 5 f -valerate as
an inhibi tor of adenosine deaminase. Mol. Pharmacol., 14,
366 (1978) .

220. V. J . Stella, Drug subs tances in par t icu lar p r o

d r u g problems and methods of approach. In, Formulation
and Preparation of Dosage Forms ( J . Polderman, E d . ) ,
Elsevier /North-Holland Biomedical P r e s s , New YOrk,
1977, p . 9 1 .

221. R. A. Siegel and R. Lange r , Controlled release of

polypept ides and o ther macromolecules, Pharm. Res. 1, 1
(1984).

222. K. S. E . Su, K. M. Campanale, L . G. Mendelsohn, G. A

. Kerchn e r , and G. L . Gr ies , Nasal del ivery of
polypept ides I : Nasal absorption of enkephalins in ra ts
, J. Pharm. Sci. 74, 394 (198 5).

223. V. Bocci, A. Naldini, F . Corradeschi, and E.

Lencioni, Colorectal administration of human interferon-A,
Int. J. Pharm. 24, 109 (1985).

224. H. Okada, I. Yamazaki, T. Yashiki, T. Shimamoto, and

H. Mima, Vaginal absorption of a potent luteinizing
hormonereleasing hormone analogue (leuprolide) in rats IV:
Evaluation of the vaginal absorption and gonadotropin
responses by radioimmunoassay, J. Pharm. Sci. 73, 298
(1984).
11 Chapter 11 Implantable Therapeutic
Systems

1. R. Deanesly and A. S. P a r k e s , Comparative Activit

ies of compounds of the andros te rone t e s tos t e rone
se r i e s , Biochem. J. 30, 291 (1936).

2. R. Deanesly and A. S. P a r k e s , Factors influencing

the effectivenes s of administered hormones, Proc. Roy.
Soc. (London) S. B. 124, 279 (1937).

3. B . E. Ballard and E. Nelson, Prolonged-action

pharmaceut icals . In , Remington's Pharmaceutical
Sciences, 15th e d . (A. Osol et a l . , E d s . ) , Mack,
Easton, PA, 1975, Chap . 91 .

4. M. B . Shimkin and J . White, Absorpt ion ra te of

hormonecholesterol pe l le t s , Endocrinology 29, 1020
(1941).

5. F . Fuenzalida, Absorption of s teroids from

subcutaneously implanted table ts of the pu re hormone and
of the hormone mixed with cholesterol , J. Clin.
Endocrinol. 10, 1511 (1950).

6. A. F . Pi , A. Oriol, L . H. Lasso , M. Maqueo, R. I .

Dorfman, and F . A. K i n d , Inhibition of ferti l i ty
in mice by steroid implants , Acta Endocrinol. 48, 602
(1965).

7. Physicians' Desk Reference, 33rd e d . , Medical

Economics C o . , Oradell , NJ, 1979.

8. E. L. Way, H. H. Loh, and F . H. Shen, Simultaneous

quant i ta tive assessment of morphine tolerance and
physical dependence , J. Pharmacol. Exp. Ther. 167, 1
(1969).

9. F . H. Shen, H. H. Loh, and E. L. Way, Brain serotonin t

u r n over in morphinetolerant and dependent mice, J.
Pharmacol. Exp. Ther. 175, 427-434 (1970).

10. S. Algeri and E. Costa , Physical dependence on

morphine fails to increase serotonin t u r n o v e r ra te
in ra t b r a i n , Biochem. Pharmac. 20, 8 77 (1971).

11. I . Marshall and D. G. Grahame-Smith, Evidence against

a role of bra in 5-hydroxytryptamine in the development of
physical dependence upon morphine in mice, J. Pharmacol.
Exp. Ther. 179, 634-641 (1971).
12. J . Blasig, A. Herz , K. Reinhold, and S.
Zieglgansberger , Development of physical dependence of
morphine in respec t to time and dosage and quantification
of the prec ip i ta ted withdrawal syndrome in r a t s ,
Psychopharmacologia 33, 19-38 (1973).

13. T . J . Cicero and E. R. Meyer, Morphine pellet

implantation in r a t s : Quanti ta t ive assessment of
tolerance and dependence , J. Pharmacol. Exp. Ther. 184,
404-408 (1973).

14. E. Wei, H. H. Loh, and E. L . Way, Quanti tat ive aspec

t s of precipated abs t inence in morphine dependent r a t
s , J. Pharmacol. Exp. Ther. 184, 398-403 (1973).

15. K. S. Hui and M. B . Robe r t s , An improved

implantation pellet for rapid induction of morphine
dependence in mice, J. Pharm. Pharmacol. 27, 569 (1975).

16. H . N . Bha rgava , Rapid induction and quant i ta t

ion of morphine dependence in the ra t by pellet
implantation, Psychopharmacology 52, 55-62 (1977).

17. H . N . B h a r g a v a , Quantitation of morphine

tolerance induced by pellet implantation in the r a t , J.
Pharm. Pharmacol. 30, 133 (1978).

18. J . Folkman, Controlled d r u g release from polymers ,

Hosp. Practice 13, 127-133 (1978).

19. J . Folkman and D. M. Long, J r . , The use of silicone

r u b b e r as a c a r r i e r for prolonged d r u g t h e
r a p y , J. Surg. Res. 4, 139142 (1964).

20. J . Folkman and D . M. Long, J r . , Drug pacemakers in

the t r ea t ment of hea r t block, Ann. NY Acad. Sci. 8,
857 (1964).

21. P . B a s s , R. A. Pu rdon , and J . N. Wiley,

Prolonged administration of a t ropine or histamine in a
silicone r u b b e r implant, Nature 208, 591 (1965).

22. K. G. Powers , The use of silicone r u b b e r implants

for the s u s tained release of antimalarial and
antischistosomal a g e n t s , J Parasitology 51, 53
(1965).

23. P . J . Dziuk and B . Cook, Passage of s teroids th

rough silicone r u b b e r , Endocrinology 78, 208-211
(1966).

24. F . A. K i n d , G. Benagiano, and I . Anges ,

Sustained release hormonal p repara t ions I . Diffusion
of var ious s teroids th rough polymer membranes, Steroids
11, 673 (1968).

25. C M . Clifford, C. E. Yunke r , and M. D. Corwin,

Control of the louse Polyplax serrata with systemic insect
icides administered in silastic r u b b e r implants , J.
Econ. Entomol. 60, 1210 (1967).

26. J . Folkman, W. Reiling, and G. Williams, Chronic

analgesia by silicone r u b b e r diffusion, Surgery 66,
194 (1969).

27. T . S. Gaginella and P . B a s s , Nicotine: Release

from silicone r u b b e r implants in vivo, Res. Commun.
Chem. Pathol. Pharmacol. 7, 213 (1974).

28. J . Folkman, D. M. Long, J r . , and R. Rosembaum, A

new diffusion p rope r ty useful for general anes thes ia ,
Science 154, 148 (1966).

29. J . Folkman and V. H. Mark, Diffusion of anes the t ics

and o ther d r u g s th rough silicone r u b b e r :
Therapeut ic implications, Trans. NY Acad. Sci. 30, 1187
(1968).

30. P . Siegel and J . R. Atkinson, In vivo chemode

diffusion of L-dopa , J. Appl. Physiol. 30, 900 (1971).

31. Y. W. Chien, In t r au te r ine control led-re lease d

r u g adminis t ra t ion. In , Novel Drug Delivery
Systems: Fundamentals, Development Concepts and Biomedical
Assessments, Marcel Dekker , I n c . , New York, 1982,
Chap . 4.

32. Y. W. Chien, Ocular control led-re lease d r u g

adminis t ra t ion. In , Novel Drug Delivery Systems:
Fundamentals, Developmental Concepts and Biomedical
Assessments, Marcel Dekker , I n c . , New York, 198 2,
Chap . 2.

33. Y. W. Chien, Int ravaginal control led-re lease d r u g

adminis t ra t ion. In , Novel Drug Delivery Systems:
Fundamentals, Developmental Concepts and Biomedical
Assessments, Marcel Dekker , I n c . , New York, 198 2,
Chap . 3.
34. Y. W. Chien, Methods to achieve sus ta ined d r u g de
l ivery—The physical approach : Implants . In , Sustained
and Controlled Release Drug Delivery Systems ( J . R.
Robinson, E d . ) , Marcel Dekker , I n c . , New York,
1978, Chap . 4.

35. Y. W. Chien, Controlled administration of e s t ru s

synch ron i z ing agen t s in l ives tock. In , Novel Drug
Delivery Systems: Fundamentals, Developmental Concepts and
Biomedical Assessments, Marcel Dekker , I n c . , New
York, 1982, Chap . 8.

36. D. S. T . Hsieh, N. Smith, and Y. W. Chien,

Subcutaneous controlled administration of estradiol from
compudose implants: In vitro and in vivo evaluat ions . In
, Proceeding of 11th International Symposium on Controlled
Release of Bioactive Materials (W. E. Meyers and R. L.
Dunn, E d s . ) , The Controlled Release Society, I n c .
, Lincolnshire , IL, 1984, p p . 134-135.

37. Y. W. Chien and H . J . Lambert , Method for making a

microsealed del ivery device , U . S . pa tent 3,992,518
(Nov. 16, 1976).

38. Y. W. Chien and H. J . Lambert , Microsealed

pharmaceutical del ivery dev ices , U . S . pa ten t
4,053,580 (Oct . 11, 1977).

39. Y. W. Chien, Microsealed d r u g del ivery sys tems :

Theoretical apsec t s and biomedical a s se s smen t s .
In , Recent Advances in Drug Delivery Systems ( J . M.
Anderson & S. W. Kim, E d s , ) , Plenum, New York, 1984,
p p . 367-38 7.

40. Y. W. Chien, Fundamentals of control led-re lease d r u

g administ r a t ion . In , Novel Drug Delivery Systems:
Fundamentals, Developmental Concepts, and Biomedical
Assessments, Marcel Dekker , I n c . , New York, 198 2,
Chap . 9.

41 . F . Theeuwes , Elementary osmotic pump, J. Pharm. Sci.

64, 1987 (1975).

42. F . Theeuwes and S. I . Yum, Principles of the design

and oper ation of generic osmotic pumps for the del ivery
of semisolid or liquid d r u g formulations, Ann. Biomed.
Eng. 4, 343 (1976).

43. Y. W. Chien, Implantable control led-re lease d r u g

del ivery s y s tems. In , Novel Drug Delivery Systems:
Fundamentals, Developmental Concepts, and Biomedical
Assessments, Marcel Dekker , I n c . , New York, 1982,
Chap . 7.

44. P . J . Blackshear , T . D. Rohde, J . D . Grot l ing,

F . D. Dorman, P . R. P e r k i n s , R. L . Varco, and H.
Buchwald, Control of blood glucose in experimental d
iabetes by means of a totally implantable insulin infusion
device , Diabetes 28, 634 (1979).

45. P . J . Blackshear , T . D. Rohde, R. L. Varco, and H.

Buchwald, One yea r of cont inuous heparinizat ion in the
dog us ing a totally implantable infusion pump, Surg.
Gynecol. Obstet. 141, 176 (1975).

46. Implantable pump for morphine, Am. Pharmacy NS24 ( 8 )

, 20 (1984).

47. D. S. T . Hsieh and R. Langer , Zero-order d r u g del

ivery s y s tems with magnetic cont ro l . In , Controlled
Release Delivery Systems ( T . J . Roseman and S. Z.
Mansdorf, E d s . ) , Marcel Dekker , I n c . , New York,
1983, Chap . 7.

48. J . Kost , K. W. Leong, and R. Langer , Ultrasonic

controlled polymeric del ivery sys tems . In , Proceedings
of 11th International Symposium on "Controlled Release of
Bioactive Materials" (W. E. Meyers and R. L . Dunn , E d s
. ) , The Controlled Release Society, I n c . ,
Lincolnshire , IL, 1984, p . 84.

49. A. D. Schwope and D. L. Wise, Development of d r u g

del ivery systems for u s e in t rea tment of narcot ic
addict ion. In , Dynatech Quarterly Report (No. 1361) to
NIDA J anua ry 16, 1976.

50. D. L . Wise, T . D. Fellmann, J . E. Sanderson , and R.

L. Wentwor th , Lactic/glycolic and polymers . In , Drug
Carriers in Biology and Medicine (G. Gregor iad is , E d .
) , Academic P r e s s , New York, 1979, Chap . 12.

51. J . Heller, Controlled d r u g release from poly (or

tho e s t e r s ) . In , Proceedings of 11th International
Symposium on Controlled Release of Bioactive Materials (W.
E. Meyers and R. L. Dunn, E d s . ) , The controlled
Release Society, I n c . , Lincolnshire , IL, 1984), p .
128.

52. C. C. Chang and F . A. K i n d , Sustained release

hormonal p r e p ara t ions (3)-biologic effectiveness of
6-methyl -17a-ace toxypregna-4 , 6 -d iene-3 , 20-dione,
Steroids 12, 689-696 (1968).

53. A. C u a d r o s , A. Br inson , and K. Sundaram,

Progestat ional act ivi ty of megestrol
acetate-polydimethylsi loxane (PDS) capsules in r h e s u
s monkeys , Contraception 2, 29 (1970).

54. C. C. Chang and F . A. K i n d , Sustained release

hormonal p repa ra t ion : 4. Biologic effectiveness of s
teroid hormones, Fertil. Steril. 21, 134 (1970).

55. V. Zbuzkova and F . A. K i n d , Sustained release

hormonal p r e p pa ra t i ons : 11. Biological effect
iveness , Endocrinologia Experimental 4, 215 (1970).

56. F . A. K i n d , H . J . Ringold, and R. J . Dorfman,

Pi tu i tary gonadotrophin inhibition by subcutaneously
administered s t e ro ids , Acta Endocrinol. 36, 83
(1961).

57. F . A. K ind and R. I . Dorfman, Pi tu i tary

gonadotrophin in inhibi tory action of neut ra l s t e ro
ids , Acta Endocrinol. 46, 300 (1964).

58. C. R. Moore and D. Pr ice , Some effects of t es tos te

rone and tes tos te rone propionate in the r a t , Anat.
Rec. 71, 59 (1938).

59. F . A. K i n d , I . Angee, C. C. Chang , and H. W.

Rudel , Sus tained release hormonal p r e p a r a t i o n s
: 9. Plasma levels and accumulation into var ious t i s
sues of 6-methyl-17a-acetoxy-4,6p r e g n a d i e n e 3 ,
20-dione after oral administration or absorpt ion from
polydimethylsiloxane implants , Acta. Endocrinol. 64, 508
(1970).

60. G. H. Bell, J . N. Davidson, and H. Sca rborough ,

Textbook of Physiology and Biochemistry, 5th e d . ,
Livingston, London, Chap . 35.

61. B . Bloch and G. W. Has t ings , Plastics Materials in

Surgery, 2nd e d . , Thomas, Springfield, IL, 1972, Chap .
VI.

62. V. Menken, Biochemical Mechanisms in Inflammation,

Thomas, Springfield, IL, 1956.

63. E. M. Coutinho, D. A. M. Fe r r e i r a , H. P r a t e
s , and F . A. K i n d , Excretion of [6-14c] megestrol
acetate (6-methyl-17-acetoxyp r e g n a 4 , 6 -d iene-3 ,
20-dione) released from subcutaneous silastic implants in
women, J. Reprod. Fertil. 23, 345 (1970).

64. G. Benagiano, M. Ermini, L . Carenza , and G. Rolfini,

Studies on sus ta ined contracept ive effects with
subcutaneous polydimethylsiloxane implants . 1. Diffusion
of megestrol acetate in humans , Acta Endocrinol. 73, 335
(1973).

65. G. Benagiano and M. Ermini, Continuous s teroid t rea

tment by subdermal polysiloxane implants , Acta. Eur.
Fertil. 3, 119 (1972).

66. V. Mirkovitch, Bioelectric phenomena, thrombosis and p

las t ics : A review of c u r r e n t knowledge ,
Cleveland Clin. Q. 30, 241 (1963).

67. V. Mirkovitch, R. E. Beck, and P . G. A n d r u s , The

zeta potentials and blood compatibility charac te r i s t i
cs of some selected sol ids, J. Surg. Res. 4, 395 (1964).

68. J . Folkman and D. M. Long, J r . , The use of silicone

r u b b e r as a c a r r i e r for prolonged d r u g t h e
r a p y , J. Surg. Res. 4, 139 (1964).

69. J . Folkman and D. M. Long, J r . , Drug pacemakers in

the t r e a t ment of hea r t block, Ann. NY Acad. Sci.
Ill, 857 (1963-1964).

70. R. Schuhman and H. D. T a u b e r t , Long-term

application of s teroids enclosed in dimethyl-poly
siloxane (S i las t ic ) : In vitro and in vivo exper
iments , Acta Biol. Med. Germ. Band 24, Seite 897 (1970).

71. R. H. Hall, Acute toxicity of inhaled beryl l ium:

observa t ions cor re la t ing toxicity with
physiochemical p roper t i e s of beryllium oxide d u s t
, Arch. Ind. Hyg. 2, 25 (1950).

72. H. LeVeen and J . R. Barber io , Tissue reaction to

plast ics and in s u r g e r y with special reference to
Teflon, Ann. Surg. 12, 974 (1949).

73. F . C. Usher and S. A. Wallace, Tissue reaction to p

las t i cs : A comparison of Nylon, Orion, Dacron, Teflon
and Marl ex , Am. Med. Assoc. Arch. Surg. 76, 997 (1958).

74. N. E. St inson, Tissue reaction induced in guinea p igs

by pa r t i c ulate polymethylacrylate , polyethylene and
nylon of the same size r a n g e , Br. J. Exp. Pathol. 46,
135 (1965).

75. C. Tie tze , Evaluation of i n t r au t e r ine devices

, 9th P rog re s s Report of the Cooperative Statistical
Program, Studies in Family Planning 55, 1 (July 1970).

76. L. L . Doyle, Hormone-releasing s i l icone-rubber in t

r au te r ine cont racept ive dev ices : Effect of
incorporation of var ious compounds on i n t r au t e r ine
devices in r a t s , Am. J. Obstet. Gynecol. 121, 405
(1975).

77. L. L. Doyle and T . H. Clewe, Preliminary s tudies on

the effect of hormone-re leas ing in t r au te r ine
devices , Am. J. Obstet. Gynecol. 101, 564 (1968).

78. C. C. Boll inger, Bacterial flora of the nonpregnan t u

t e r u s : A new cu l tu re t echn ique , Obstet.
Gynecol. 23, 251 (1964).

79. M . I . Buchman, A s tudy of the in t r au te r ine

cont racept ive device with and without an extracervical
appendage or tai l , Fertil. Steril. 21, 348 (1970).

80. H. Lehfeldt , In t r au te r ine cont racept ion:

Tailed v s . tail less dev ices . In , Extrail du Livre
Jubilaire Offert au Dr. Jean Dalsace, Masson et c ie , Pa
r i s , 1966, p p . 199-213.

8 1 . J . R. Wilson, C. C. Boll inger , and W. J . Ledger ,

The effect of an in t r au te r ine cont racept ive device
on the bacterial flora of the endometrial cav i ty , Am.
J. Obstet. Gynecol. 90, 726 (1964).

82. H. J . Tatum, F . H. Schmidt, D. PhiUips, M. McCarty,

and W. M. O'Leary, The Dalkon Shield c o n t r o v e r s y
: S t ruc tura l and bacteriological s tudies of IUD ta i
l s , JAMA 231, 711 (1975).

83. J . Folkman, W. Reiling, and G. Williams, Chronic

analgesia by silicone r u b b e r diffusion, Surgery 66,
194 (1969).

84. B . S. Oppenheimer, F u r t h e r s tudies of polymers

as carcinogenic agen t s in animals, Cancer Res. 15, 333
(1955).

85. BuH. Dow Corning Centre Med. Res. 5, 7 (1963).

86. P . J . Dzuik and B . Cook, Passage of s teroids t h
rough silicone r u b b e r , Endocrinology 78, 208 (1966).
12 Chapter 12 Transdermal Therapeutic
Systems

3. 1982 Indust r ia l Pharmaceutical R & D Symposium on

Transdermal Controlled Release Medication, R u t g e r s '
College of Pharmacy, Piscataway, NJ, J a n u a r y 14-15 ,
1982, Drug Dev. Ind. Pharm. 9 ( 4 ) , 497-744 (1983).

4. World Congress of Clinical Pharmacology Symposium on

Transder mal Delivery of Cardiovascular Drugs, Washington,
D . C . , Augus t 5, 1983, Am. Heart J. 108 ( 1 ) ,
195-236 (1984).

5. S. W. Jacob and C. A. Francone , Structure and Function

of Man, 2nd e d . , W. B . Saunders C o . , Philadelphia,
1970, p p . 5 5 60.

6. P . Zanowiak and M. R. Jacobs , Topical ant iinfect ive

p r o d u c t s . In , Handbook of Nonprescription Drugs,
7th ed . ( S . C. Lait in, E d . ) , American
Pharmaceutical Association, Washington, DC, 1982, p p .
525-529.

7. Y. W. Chien, Logics of t ransdermal controlled d r u g

adminis t rat ion, Drug Dev. Ind. Pharm. 9, 497 (1983).

8. E. K. Kas t rup and J . R. Boyd, Drug: Facts and

Comparisons, 1983 e d . , J . B . Lippincott C o . , S t .
Louis , 1983, p p . 1634-1708.

9. J . E. Shaw, W. Bayne , and L. Schmidt, Clinical

pharmacology of scopolamine, Clin. Pharmacol. Ther. 19,
115 (1976).

10. P . W. Armst rong , J . A. Armst rong , and G. S.

Marks; Pharmacokinetic-hemodynamic s tudies of n i t
roglycer in ointment in congest ive hear t fai lure, Am.
J. Cardiol. 46, 670 (1980).

11. R. Si t ruk-Ware, B . deLignieres , A. Basdevan t , and

P . MauvaisJ a r v i s , Absorption of pe rcu taneous
oestradiol in postmenopausal women, Maturitas 2, 207 (198
0 ) .

12. Y. W. Chien, Novel Drug Delivery Systems: Fundamentals,

Developmental Concepts and Biomedical Assessments, Marcel
Dekker , I n c . , New York, 1982, Chap . 5.

13. D. R. Sanvordeker , J . G. Cooney, and R. C. Wester, T

r a n s dermal n i t roglycer in pad , U . S . pa ten t
#4,336,243 ( June 22, 198 2 ) .

14. P . R. Kesha ry , Y. C. Huang, and Y. W. Chien, unpubl

i shed da ta , personal communication, 1984.

15. K. H. Valia and Y. W. Chien, Long-term skin permeation

kinet ics of es t radio l : ( I ) Effect of d rugs solubil
izer-polyethylene glycol 400, Drug Dev. Ind. Pharm. 10,
951 (1984).

16. K. H. Valia and Y. W. Chien, Long-term skin permeation

kinet ics of es t rad io l : ( I I ) Kinetics of skin u p
t a k e , b ind ing and metabolism, Drug Dev. Ind. Pharm.
10, 991 (1984).

17. W. R. Good; Transde rm-Ni t ro : Controlled del ivery

of n i t roglycerin via the t ransdermal r ou t e , Drug
Dev. Ind. Pharm. 9, 647 (1983).

18. A. Gera rd in , J . Hir tz , P . Fankhause r , and J .

Moppert , Achievement of sus ta ined plasma concent ra t
ions of n i t roglycer in (TNG) in man by a t ransdermal
therapeut ic sys tem. In , APhA/APS 31st National Meeting
Abstracts, 11 ( 2 ) , 84 (1981).

19. J . E. Shaw, Pharmacokinetics of n i t roglycer in and

clonidine delivered by the t ransdermal r ou t e , Am.
Heart J. 108, 217 (1984).

20. M. A. Weber and J . I . M. D r a y e r , Clinical exper

ience with r a t e controlled delivery of an t ihyper t ens
ive t he r apy by a t ransdermal sys tem, Am. Heart J.
108, 231 (1984).

21. D . A r n d t s and K. A r n d t s , Pharmacokinetics

and pharmacodyamics of t ransdermal ly administered
clonidine, Eur. J. Clin. Pharmacol. 26, 79 (1984).

22. S. Hwang, E. Owada, L. Suhardja , N. F . H. Ho, G. L. F

lynn , and W. I . Higuchi , Systems approach to vaginal
del ivery of d r u g s V: In situ vaginal absorpt ion of
1-alkanoic ac ids , J. Pharm. Sci. 66, 781 (1977).

23. L . Schenkel , J . Ba les t ra , L . Schmitt , and J .

Shaw, Transdermal oestrogen subs t i tu t ion in the
menopause. In , Second International Conference on Drug
Absorption—Rate Control in Drug Therapy, Universi ty of E
d i n b u r g h , Ed inbu rgh , Scotland, September 21 -23
, 1983, p . 41.
24. L. R. Laufer , J . L. De Fazio, J . K. H. Lu, D. R.
Meldrum, P. Eggena , M. P. Sambhi, J . M. Hershman, and H.
L. J u d d , Est rogen replacement t he r apy by t
ransdermal estradiol adminis t rat ion , Am. J. Obstet.
Gyncol. 146, 533 (1983).

25. T. J . Roseman, R. M. Benne t t , J . J . Biermacher,

M. E. Tu t t l e , and C. H. Spilman, Design cr i te r ia
for carbopost methyl controlled release devices . In ,
Proceedings of 11th International Symposium on Controlled
Release of Bioactive Materials (W. E. Meyers and R. L.
Dunn, E d s . ) , F t . Lauderdale , FL, 1984, p . 50.

26. Y. W. Chien, Novel Drug Delivery Systems, Marcel Dekker

, I n c . , New York, 198 2, Chap . 9.

27. A. D. Kei th , Polymer matrix considerat ions for t

ransdermal de v ices , Drug Dev. Ind. Pharm. 9, 605 (1983).

28. Y. W. Chien and H . J . Lambert , Microsealed

pharmaceutical del ivery devices , U . S . pa ten t
#3,946,106 (March 23, 1976).

29. Y. W. Chien and H. J . Lambert , Method for making a

microsealed del ivery device , U . S . pa tent #3,992,518
(November 16, 1976).

30. Y. W. Chien and H. J . Lambert , Microsealed

pharmaceutical del ivery device , U . S . pa ten t
#4,053,580 (October 11, 1977).

31. A. Karim, Transdermal absorp t ion : A unique oppor

tuni ty for cons tant del ivery of n i t rog lycer in ,
Drug Dev. Ind. Pharm. 9, 671 (1983).

32. Y. W. Chien, Microsealed d r u g del ivery sys tems:

Theoretical a spec t s and biomedical a s se s smen t s .
In , International Symposium on Recent Advances in Drug
Delivery Systems ( J . M. Anderson and S. W. Kim, E d s .
) , Plenum, New York, 1984, p . 367.

33. Y. W. Chien, Long-term controlled navel administration

of t e s to s te rone , J. Pharm. Sci. 73, 1064 (1984).

34. S. J . Davidson, L. D. Nichols, A. S. Obermayer , M. B

. Allen, E. J . Murphy, and R. N. Hurd , Developing a
controlled release dual-antibiot ic wound d r e s s i n g
. In , Proceedings of 11th International Symposium on
Controlled Release of Bioactive Materials (W. E. Meyers
and R. L. Dunn, E d s . ) , F t . Lauderda le , FL, 1984, p
p . 58, 60.

35. A. C. Humes, A hydrophi l ic polymeric r e se rvo i r

for t ransdermal d r u g de l ivery . In , APhA/APS
Midwest Regional Meeting Abstract, April 2, 1984, Chicago,
IL, p . 4.

36. H. Durrheim, G. L. F lynn , W. I . Higuchi, and C. R.

Behl , Permeation of ha i r less mouse skin I :
Experimental methods and comparison with human epidermal
permeation by alkanols , J . Pharm. Sci. 69, 781 (1980).

37. Y. W. Chien, P . R. Kesha ry , Y. C. Huang, and P . P .

Sarpotda r , Comparative controlled skin permeation of n i
t roglycer in from marketed t ransdermal del ivery sys
tems, J. Pharm. Sci. 72, 968 (1983).

38. K. Tojo, M. Ghannam, Y. Sun , and Y. W. Chien, In t r

ins ic r a t e s of permeation and release th rough
polymeric d r u g del ivery sys t ems . In , APS/APhA 37th
National Meeting Abstracts, vol . 14, No. 2, 1984, p .
193.

39. D . E. Magnuson, personal communication, 1983.

40. Y. W. Chien, Pharmaceutical considera t ions of t

ransdermal n i t ro glycerin de l ivery : The var ious
approaches , Am. Heart J. 108, 207 (1984).

41 . J . E. Shaw, S. K. Chand ra seka ran , A. S. Michaels,

and L. Taskovich , Controlled t ransdermal de l ivery , in
vitro and in vivo. In , Animal Models in Dermatology (H .
Maibach, E d . ) , Churchil l Livingston, Ed inbu rgh ,
1975, Chap . 14.

42. P . W. Armst rong , J . A. Armst rong , and G. S. Marks

, Blood levels after sublingual n i t rog lycer in ,
Circulation 59, 585 (1979).

43. A. S. Michaels, S. K. Chand ra seka ran , and J . E.

Shaw, Drug permeation th rough human sk in : Theory and in
vitro exper i mental measurement, AICHE J., 21, 985 (1975).

44. Dr . A. D. Kei th , personal communication 1983.

45. P . R. Kesha ry , Y. C. Huang, and Y. W. Chien,

Mechanism of t ransdermal controlled n i t roglycer in
adminis t ra t ion: ( I II) Control of skin permeation ra
te and optimization, Drug Dev. Ind. Pharm., 11, 1213
(1985).
13 Chapter 13 Microparticulate Drug
Carriers

1. E. S . Vitet ta , K. A. Krolick, M. Miyama-lanab, W.

Cushley , and J . W. Uhr , Immunotoxins: A new approach to
cancer t h e r a p y , Science 219, 644-650 (1983).

2. D. C. Edwards , P . E. Thorpe , and A. J . S. Davies ,

Ant ibodytoxin conjugates as potential therapeut ic a g e n
t s , In , Targeting of Drugs (G . Gregor iadis , J .
Senior , and A. T roue t , e d s . ) , Plenum P r e s s ,
New York, 198 2, p p . 83 -96 .

3 . M . J . Poznansky and L. G. Cleveland, Biological

macromolecules as c a r r i e r s of d r u g s and
enzymes, In , Drug Delivery Systems (R . Jul iano, e d . )
, Oxford Univers i ty P r e s s , New York, 1980, p p .
253-315.

4. Langer , R . , Implantable controlled release eys tems ,

Pharm. Ther. 21, 35-52 (1983).

5. Y. W. Chien, Controlled d r u g release from polymeric

del ivery system, In , Drug Delivery Systems (R. Jul iano,
e d . ) , Oxford P r e s s , New York, 1980, p p . 11-63 .

6. R. L . Juliano and D. Layton, Liposomes as a d r u g del

ivery s y s tem, In , Drug Delivery Systems (R. L. Jul
iano, e d . ) , Oxford Univers i ty P r e s s , New York,
1980, p p . 189-236.

7. K . J . Widder and A. E . Senyei , Magnetic microspheres

: A vehicle for selective t a rge t i ng of d r u g s ,
Pharm. Ther. 20:377396 (1983).

8. G. M. Ih ler , E ry th rocy te c a r r i e r s , Pharm.

Ther. 20:151-170 (1983).

9. A. Abuchowski and F . F . Davies , Soluble

polymer-enzyme add u c t s , In , Enzymes as Drugs ( J .
Holcenberg and R. Robe r t s , e d . ) , Wiley, New York,
1981, p p . 367-384.

10. L. Gros , H. Ringsdorf , and H. Schupp , Polymer anti

tumor agen t s on a molecular and on a cellular level ,
Angew. Chem. Int. Ed. Engl. 20:305-325 (1981).

11. M. S. Poznansky and R. L. Jul iano, Biological

approaches to the controlled del ivery of d r u g s : A
critical review, Pharm. Rev. 36:277-336 (1984).
12. P . Rambourg, J . Levy , and M. C. Levy, Preparat ion
of inver tase microcapsules, J. Pharm. Sci. 71:753-60
(1982).

13. T . M. S. Chang and N. Malave, The development and

first clinical use of semipermeable microcapsules
(artificial cells) as a compact artificial k idney ,
Trans. Am. Soc. Artif. Intern. Organs 16:141-148 (1970).

14. A. D. Bangham, Liposomes, Ann. Rev. Biochem. 41:753

(1972).

15. R. L. Jul iano, In terac t ions of p ro te ins and d r

u g s with liposomes, In , Liposomes, (M. Os t ro , e d .
) , Marcel Dekker , New York, 1983, p p . 53-86.

16. S. L. Regen, Polymerizable l ip ids , Ann. NY Acad.

Sci. (in p r e s s ) .

17. R. L . Jul iano, S. L . Regen, M. Singh, M. J . Hsu,

and A. S ingh , Stability p roper t i e s of
photopolymerized liposomes, Biotechnology 1:882-885
(1983).

18. J . Fendler and H. Tundo , Polymerized s u r f a c t a

n t s , Ace. Chem. Res. 17:3 (1984).

19. R. L. Juliano and D . Stamp, In terac t ions of d r u g

s with lipid membranes, Biochim. Biophys. Acta 586:137-145
(1979).

20. A. G. Lee, Effects of cha rged d r u g s on the phase t

rans i t ion tempera ture of phospholipid b i l aye r s ,
Biochim. Biophys. Acta 514:95-104 (1978).

21. F . Szoka, J r . and D. Papahadjopoulos, Comparative p

roper t i e s and methods in p repara t ion of lipid
vesicles ( l iposomes), Ann. Rev. Biophys. Bioeng.
9:467-508 (1980).

22. D. W. Deamer and P . S. Us te r , Liposome p repa ra t

ion : Methods and mechanism, In , Liposomes (M. Os t ro ,
e d . ) , Marcel Dekker , New York, 1982, p p . 2 7 5 1 .

23. F . J . T . Fi ldes , Liposomes, the indust r ia l

viewpoint, In , Liposomes: Physical Structure to
Therapeutic Applications (G. Knight , e d . ) , Elsevier ,
Amsterdam, 1981, p p . 465-48 5.
24. G. Gregor iadis , C. Ki rby , and J . Senior,
Optimization of l iposome behavior in vivo, Biol. Cell
47:11-18 (1983).

25. R. C. Oppenheim, Nanopart ic les , in Drug Delivery

Systems (R. Jul iano, e d . ) , Oxford Univers i ty P r e
s s , New York, 1980, p p . 177-188.

26. K . J . Widder, A. E. Senyei , and B . S e a r s ,

Experimental methods in cancer t h e r a p e u t i c s , J.
Pharm. Sci. 71:379-38 7 (1982).

27. P . A. Kramer , Albumin microspheres a re vehicles for

achieving specificity in d r u g de l iver ies , J. Pharm.
Sci. 63:646-647 (1974).

28. W. E. Long, H. Iwata, T . A. Lindheimer, and E. P .

Goldberg, Preparat ion of hydrophi l ic albumin
microspheres us ing polymeric d i spe rs ing a g e n t s ,
J. Pharm. Sci. 71:1323-1328 (1982).

29. P. Edman and I. Sjoholm, Acrylic microspheres in vivo.

VI: Antitumor effect of microparticles with immobilized
L-asparaginase against 6C3HED lymphoma, J. Pharm. Sci.
72:654-658 (1983).

30. P . A r t u r s o n , T . Laskso , and P . Edman,

Acrylic microspheres In vivo. IX: Blood elimination kinet
ics and organ dis t r ibut ion of microparticles with
different surface cha rac t e r i s t i c s , J. Pharm.
Sci. 72:1415-1420 (1983).

31 . K. Widder, G. Floret , C , and A. Senyei , A . :

Magnetic micros p h e r e s : syn thes i s of a novel pa
ren te ra l d r u g c a r r i e r , J. Pharm. Sci.
68:79-83 (1979).

32. M. C , Levy, P . Rambourg, J . Levy, and G. P t ron ,

Microencapsula t ion. IV: c ross l inked hemoglobin
microcapsules, J. Pharm. Sci. 71:759-762 (1982).

33. J . Heller, R. F . Helwing, R. W. Bake r , and M. E. Tu

t t l e , Controlled release of water-soluble
macromolecules from bioerodible hyd roge l s ,
Biomaterials 4:262-266 (1983).

34. G. Ih ler , R. H. Glen, and F . W. Schnure , Enzyme

loading of e r y t h r o c y t e s , Proc. Natl. Acad.
Sci. USA 70:2663-2666 (1973).
35. U. Zimmermann, Jahresbericht der Kern forschungsanlage,
Julich GmbH, 1973, p p . 55-58 .

36. S . J . Updike , R. T . Wakamija, and E . N .

Lightfoot, Asparag i nase en t r apped in red blood cel ls
: Action and surv iva l , Science 193:681-683 (1976).

37. K. Kinosita and T . Y. T s u n g , Survival of sucrose

loaded e r y th rocy tes in the c i rculat ion, Nature
272:258-260 (1978).

38. G. Dale, Resealed e r y t h r o c y t e s as d r u g c

a r r i e r s , In , Drug Delivery Systems (R . Jul iano,
e d . ) , Oxford Univers i ty P r e s s , New York, 1980,
p p . 237-252.

39. J . D. Humphreys and G. M. Ih ler , Encapsulation of d

r u g s , enzymes and DNA within human and mouse e r y t h
r o c y t e s , In , Optimization of Drug Delivery, Alfred
Benzon Symposium 17 (H. B u n d g a a r d , A. B . Hansen,
and H. Kofod, e d s . ) , Munksgaa rd , Copenhagen, 198 2,
p p . 270-284.

40. U. Zimmerman, G. Pilwat, and B . Esse r , The effect of

encapsulation in red blood cells on the d is t r ibut ion
of methotrexate in mice, J. Clin. Chem. Clin. Biochem.
15:135-147 (1978).

41. P . Seeman, Trans ient holes in the e ry th rocy te

membrane d u r i n g hypotonic hemolysis and stable holes
in the membrane after lysis by saponin and lysoleci thin,
J. Cell Biol. 32:55-70 (1967).

42. M. B. Fiddler , L. D. S. Hudson, J . G. White, and R. J

. Desnick, Comparison of methods for enzyme entrapment in
human e r y t h r o c y t e s , J. Clin. Lab Med.
96:307-317 (1980).

43. J . P. Durocher , R. D. Payne , and M. E. Conrad , Role

of sialic acid in e ry th rocy te s u r v i v a l , Blood
45:11-20 (1975).

44. F. Ki rkpa t r ick , Spec t r in : Cur ren t u n d e r

s t a n d i n g of i ts phys ica l , biochemical and
functional p r o p e r t i e s , Life Sci. 19:1-18 (1976).

45. C. W. M. Haest , G. Plasa, D. Kamp, and B . Deut icke,

In t ra and intermolecular c ross l inking of membrane pro
te ins in intact e ry th rocy t e s and ghos t s by
SH-oxidizing a g e n t s , Biochim. Biophys. Acta
469:226-230 (1977).

46. A . J . Schroit and I . J . Fidler , Effects of

liposome s t r u c t u r e and lipid composition on the
activation of the tumoricidal p r o p er t ies of
macrophages , Cancer Res. 42:161-167 (198 2 ) .

47. N . Simionescu and M. Simionescu, The cardiovascular

system, In , Histology (L . Weiss, e d . ) , Elsevier ,
New York, 1983, p p . 371-433.

48. N . F r e u d e n b e r g , K. H. Riese, and M. A. F r

e u d e n b e r g , The Vascular Endothelial System,
Gustav F isher , S t u t t g a r t , 1983.

49. M. B u n d g a a r d , T ranspo r t pa thways in capi l

lar ies . In search of p o r e s , Ann. Rev. Physiol.
42:325-335 (1980).

50. C. C. Michel, Fil tration coefficients and osmotic

reflection coefficients of the walls of single mesenteric
capi l lar ies , J. Physiol. 309:341-355 (1980).

51. A. Mar t inez-Hernandez , The basement membrane in the

microvasculature, , In , Microcirculation (R. Effros, H.
Schmid-Shonben, and J . Ditzel, e d s . ) , Academic P r e
s s , New York, 1981, p p . 125146.

52. G. Poste and R. Ki r sh , Site specific d r u g

delivery in cancer t h e r a p y , Biotechnology 1:869-878
(1983).

53. C. Meuret , Kinetics of mononuclear phagocytes in man,

Hematol. Bluttransfus. 27:11-122 (1981).

54. E. Unanue , Regulatory role of macrophages in antigenic

stimulat ion, Adv. Immunol. 31:1-121 (1981).

55. D. O. Adams, Macrophage activation and secre t ion ,

Fed. Proc. 41:2193-2197 (1982).

56. B . M. Altura and T. M. Saba, Pathophysiology of the

Reticuloendothelial System, Raven P r e s s , New York,
1981.

57. D. L. Knook and E. Wisse, Sinusoidal Liver Cells,

Elsevier , Amsterdam 1982.

58. Y . J . Kao and R. L. Jul iano, Interact ion of

liposomes with the reticuloendothelial sys tem: Effects of
blockade on the clearance of la rge unilamellar ves ic les
, Biochim. Biophys. Acta 677:453461 (1981).

59. M. J . Hsu and R. L. Jul iano, Interact ion of

liposomes with the reticuloendothelial system I I . Non
specific and recep tor mediated up take of liposomes by
mouse peri toneal macrophages , Biochim. Biophys. Acta
720:411-419 (1982).

60. S. C. Si lvers te in , R. M. Steinman, and Z. A. Cohn,

Endocytos i s , Ann. Rev. Biochem. 46:669-722 (1977).

61. R. M. Steinman, I . S. Mellman, W. A. Muller, and Z. A.

Cohn, Endocytosis and the recycl ing of plasma membrane,
J. Cell Biol. 96:1-27 (1983).

62. J . D. Lambris and C D . Ross , Assay of membrane

complement r ecep to r s with C3b and C3d coated f
luorescent microspheres , J. Immunol. 128:186-191, 1982.

63. P . Stahl and S. Gordon, Expression of mannosyl fucosyl

r eceptor function for endocytosis in cu l tu red pr imary
macrophages and the i r h y b i r d s , J. Cell Biol.
93:49-54 (1982).

64. C M . Cunningham, M, Kingzet te , R. L. R icha rds , C.

R. Alving, T . F . Lint , and H. Gewurz, Activation of
human complement by liposomes: A model for membrane
activation of the alt e rna t ive pa thway, Immunology
122:1237-1242 (1979).

65. A. Allison, Macrophage activation and non specific

immunity, Int. Rev. Exp. Pathol. 18:303-346 (1978).

66. J . W. Harr i s and R. W. Kellermeyer, The Red Cell,

Harvard Universi ty P r e s s , Cambridge, MA, 1970.

67. P . Machy, J . B a r b e t , and L. D. Leserman,

Differential endocytosis of T and B lymphocyte surface
molecules evaluated with an t ibody-bear ing f luorescent
liposomes containing methot rexa te , Proc. Natl. Acad.
Sci. USA 79:4148-4152 (1982).

68. P . Machy, M. P i e r r e s , J . B a r b e t , and L.

D. Leserman, Drug t r ans fe r into lymphoblasts mediated
b y liposomes bound to d i s t inct s i tes on H-2 encoded
I-A, I -E, and K molecules, J. Immunol. 129:2098-2101
(1982).

69. R. L. Jul iano, G. Lopez-Beres te in , R. Hopfer, R.

Mehta, K. Mehta, and K. Mills, Selective toxicity of and
enhanced the ra peut ic efficacy of liposomal amphotericin
B , Ann. NY Acad. Sci. 446:390-402 (1985).

70. R. L. Juliano and D. Stamp, Effects of par t ic le size

and cha rge on the c learance ra t e s of liposomes and
liposome encapsulated d r u g s , Biochem. Biophys. Res.
Commun. 63:651-658 (1975).

71. G. Gregor iad is , L. D. Ki rby , P . La rge , A.

Meehan, and J . Senior, Targe t ing of liposomes: S tudy
of influencing fac tors , In , Targeting of Drugs ( C .
Gregor iadis , J . Senior, and A. T r o u e t , e d s . )
, Plenum Publ ishing C o r p . , New York, 1982, p p .
155-184.

72. C. F . Gotfredsen, S. Frokjaer , E. L. Hjorth, K. D. Jo

rgensen , and M. C. Debroux-Guisse t , Disposition of
intact liposomes of different compositions and of
liposomal degradat ion p r o d u c t s , Biochem.
Pharmacol. 32:3381-3387 (1983).

73. F . Roerd ink , J . R e g t s , B . Van Leeuwen, and G.

Scherphof, In t rahepat ic up take and process ing of in t
ravenous ly injected small unilamellar phospholipid
vesicles in r a t s , Biochim. Biophys. Acta 770:195-202
(1984).

74. I . R. Har t , W. E. Fogler , G. Pos te , and I . J .

Fidler , Toxicity s tudies of liposome encapsula ted
immunomodulators administered in t ravenous ly to dogs and
mice, Cancer Immunol. Immunother. 10:57-196 (1981).

75. T . M. Allen, L. Murray , S. MacKeigan, and M. Shah,

Chronic liposome administration in mice: Effects on
reticuloendothelial function and t i ssue d i s t r ibu t
ion , J. Pharmacol. Exp. Ther. 229: 267-275 (1984).

76. G. Lopez-Beres te in , L. Kasi , M. G. Rosenblum, T .

Haynie, M. J a h n s , H. Glenn, R. Mehta, G. M. Mavligit,
and E. M. Hersh , Clinical pharmacology of 99mTc-labeled
liposomes in pat ients with cancer , Cancer Res. 44:375-378
(1984).

77. G. Pos te , Liposome t a rge t ing in vivo: Problems

and oppor tuni t i e s , Biol. Cell 47:19-37 (1983).

78. L. Ilium and S. S. Davies, The organ up take of in t

ravenous ly administered colloidal par t ic les can be a l
tered us ing a non-ionic surfac tant (Poloxamer 388), FEBS
Lett. 167:79-82 (1984).

79. R. L. Jul iano, Interact ion of liposomes with the re t

iculoendothelial sys tem: Implications for the controlled
del ivery of d r u g s , In , Optimization of Drug
Delivery (H. B u n d g a a r d , A. B . Hansen, and H.
Kofod, e d s . ) , Munskgaard , Copenhagen, 1981, p p .
405415.

80. C . R. Alving, Delivery of l iposome-encapsulated d r u

g s to macrop h a g e s , Pharmacol. Ther. 22:407-424
(1983).

81. I . J . Fidler and G. Pos te , Macrophage-mediated des

t ruc t ion of malignant tumor cells and new s t ra teg
ies for the t he rapy of metastatic d isease , Spring Sem.
Immunopathol. 5:161-174 (1982).

82. G. Pos te , R. Ki r sh , W. E. Fogler , and I . J .

Fidler , Activation of tumoricidal p roper t i e s in
mouse macrophages by lymphokines encapsulated in
liposomes, Cancer Res. 39:881-892 (1979).

83. I. J . Fidler , The rapy of spontaneous metastases by

in t ravenous injection of liposomes containing
lymphokines , Science 208:1469— 1471 (1980).

84. I . J . Fidler , S. Sone, W. E. Fogler , and Z. L. B a

r n e s , Eradication of spontaneous metastases and
activation of alveolar macrophages by in t r avenous
injection of liposomes containing muramyl d ipept ide ,
Proc. Natl. Acad. Sci. USA 78:1680-1684 (1981).

84. K. Mehta, R. L. Jul iano, and G. Lopez-Beres te in ,

Stimulation of macrophage pro tease secret ion via
liposomal delivery of muramyl dipept ide der iva t ives to
intracel lular s i t e s , Immunology 51: 517-527 (1984).

86. G. Lopez-Beres te in , K. Mehta, R. Mehta, R. L. Jul

iano, and E. M. Her sh , Activation of human monocytes by
liposome encapsulated muramyl dipept ide analogs , J.
Immunol. 130:15001502 (1983).

87. C. Pidgeon, R. D. Schre iber , and R. M. Schul tz ,

Macrophage act ivat ion: Synergism between hybridoma MAF
and poly Ipoly C del ivered by liposomes, J. Immunol.
131:311-314 (1983).

88. S. D. Deodhar , S. Gautam, B . Yen Lieberman, and D. R

o b e r t s , Macrophage activation and generation of
tumoricidal activity by liposome-associated human C-react
ive p ro te in , Cancer Res. 44: 305-310 (1984).

89. S. D. Deodhar , K. James, T . Chiang , M. Ed inger ,

and B . P . Ba rna , Inhibition of lung metastases in mice
bea r ing a malignant fibrosarcoma by t reatment with
liposomes containing human C-react ive p ro te in , Cancer
Res. 4:5084-5088 (1982).

90. P . S. Thombre and S. D. Deodhar , Inhibition of l iver

metastases in murine colon adenocarcinoma by liposomes
containing human C-react ive protein or c r u d e
lymphokine, Cancer Immunol. Immunother. 16:145-150 (1984).

91. W. C. Koff, S. D. Showlater, D. A. Seniff, and B .

Hampar, Lysis of he rpes v i rusinfec ted cells by
macrophages act ivated with free or l iposome-encapsulated
lymphokine produced by a murine T cell hybr idoma, Infect.
Immunol. 42:1067-1072 (1983).

92. Y. Hashimoto, M. Sugawara , T . Musakuo, and H. Hojo,

Antitumor effect of actinomycin D en t rapped in liposomes
bea r ing subun i t s of tumor-specific monoclonal
immunoglobulin M ant ibody, Cancer Res. 43:5328-5334
(1983).

93. S. B . Kaye, Liposomes-problems and promise as

selective d r u g c a r r i e r s , Cancer Treat. Rev.
5:27-150 (1981).

94. J . N. Weinstein, Liposomes as d r u g c a r r i e r s

in cancer t h e r a p y , Cancer Treat. Rep. 68:127-135
(1984).

95. J . Khato, A. A. del Campo, and S. M. Sieber , Ca r r i

e r activity of sonicated small liposomes containing
melphalan to regional lymph nodes of r a t s ,
Pharmacology 26:23-40 (1983).

96. J . W. Babbage and M. C. Berenbaum, Increased therapeut

ic efficiency of a l ipid-soluble alkylat ing agent
incorpora ted in liposomes, Br. J. Cancer 45:830-834
(1982).

97. P . Large and G. Gregor iadis , Phospholipid

composition of small unilamellar liposomes containing
melphalan influences d r u g action in mice bea r ing PC6
tumors , Biochem. Pharmacol. 32:1315-1318 (1983).

97. J . Hi ldebrand, J . M. R u y s s c h a e r t , and C.

Laduron , Antitumor act ivi ty of a waterinsoluble
compound en t rapped in liposomes on L1210 leukemia in
mice, J. Natl. Cancer Inst. 70:1081-1086 (1983).

99. A. Rahman, A. Kess ler , N. More, B . Sikic, G. Rowden,

P . Woolley, and P . S. Schein, Liposomal protect ion of
adriamycininduced cardiotoxici ty in mice, Cancer Res.
40:1532-1537 (1980).

100. E. A. Forssen and Z. A. Tokes , Use of anionic

liposomes for the reduct ion of chronic doxorubicininduced
cardiotoxici ty , Proc. Natl. Acad. Sci. USA 78:1873-1877
(1981).

101. A. Gabizon, A. Dagan, D. Goren, Y. Barenholz , and Z.

F u k s , Liposomes as in vivo c a r r i e r s of
adriamycin: Reduced cardiac up take and p r e s e r v e d
anti tumor activity in mice, Cancer Res. 42:4734-4739
(1982).

102. E. H. Herman, A. Rahman, V. J . F e r r a n s , J . A.

Vick, and P . S. Schein, Prevent ion of chronic
doxorubicin cardiotoxici ty in beagles by liposomal
encapsulat ion, Cancer Res. 43:54275432 (1983).

103. E. A. Forssen and Z. A. Tokes , Attenuat ion of dermal

toxicity of doxorubicin by liposome encapsulat ion, Cancer
Treat. Rep. 67:481-484 (1983).

104. R. Olson, E. Mayhew, D. Maslow, Y. Rustum, and F .

Szoka, Character iza t ion , toxicity and therapeut ic
efficacy of adriamycin encapsulated in liposomes, Eur. J.
Cancer Clin. Oncol. 18:167176 (1982).

105. E. A. Forssen and Z. A. Tokes , Improved therapeu t ic

benef i ts of doxorubicin by entrapment in anionic
liposomes, Cancer Res. 43:546-550 (1983).

106. A. Gabizon, D. Goren, Z. R u k s , Y. Barenholz , A.

Dagan, and A. Meshorer , Enhancement of adriamycin del
ivery to l iver metastatic cells with increased
tumoricidal effect us ing liposomes as d r u g c a r r i e
r s , Cancer Res. 43:47 30-4735 (1983).

107. T . R. Tr i t ton and G. Yee, The ant icancer agent

adriamycin can be actively cytotoxic without en te r ing
cel ls , Science 217: 248-250 (1982).

108. C. R. Alving, E. A. Steck, W. L. Chapman, V. B .

Waits, L. D. Hendr icks , G. M. Swar tz , and W. L.
Hanson, Therapy of leishmaniasis: super ior efficacies of
liposome encapsula ted d r u g s , Proc. Natl. Acad. Sci.
USA 75:2959-2963 (1978).

109. C . D. V. Black, C. J . Watson, and R. J . Ward, Use

of pentostam liposomes in the chemotherapy of experimental
leishmanias i s , Trans. Roy. Soc. Trop. Med. Hyg.
71:550-552 (1977).

110. R. R. C. New, M. L. Chance , S. C. Thomas, and W. P e

t e r s , Antileishmanial act ivi ty in antimonials en t r
apped in liposomes, Nature 272:55-56 (1978).

111. C. R. Alving, E. A. Steck, W. L. Chapman, J r . , V. B

. Waits, L. D. Hendr icks , G. M. Swar tz , J r . , and W.
L. Hanson, Liposomes in leishmaniasis: the rapeut ic
effects of antimonial d r u g s , 8-aminoquinolines, and
te t racyc l ine , Life Sci. 26:2231-2238 (1980).

112. R. R. C. New, M. L. Chance , and S. Heath ,

Antileishmanial activity of amphotericin and o ther
antifungal agen t s en t rapped in liposomes, J.
Antimicrob. Chemother. 8:371-381 (1981).

113. J . V. Desiderio and S. G. Campbell,

Liposome-encapsulated cephalothin in the t reatment of
experimental murine salmonellosis , J. Reticuloendothel.
Soc. 34:279-287 (1983).

114. J . V. Desiderio and S. G. Campbell, In t raphagocut

ic killing of Salmonella typhimurium by l
iposome-encapsulated cephalothin , J. Infect. Dis.
148:563-570 (1983).

115. J . R. Graybil l , P . C. C raven , R. L. Taylor , D.

M. Williams, and W. E. Magee, Treatment of murine
cryptococcosis with liposome-associated amphotericin B ,
J. Infect. Dis. 145:748-752 (1982).

116. G. Lopez-Beres te in , R. Mehta, R. L. Hopfer, K.

Mills, L. Kasi , K. Mehta, V. Fains te in , M. Luna, E. M.
Her sh , and R. Jul iano, Treatment and prophylax is of
disseminated infection due to Candida albicans in mice
with l iposome-encapsulated amphotericin B , J. Infect.
Dis. 147:939-945 (1983).

117. R. Mehta, G. Lopez-Beres te in , R. Hopfer, K. Mills,

and R. L. Jul iano, Liposomal amphotericin B is toxic to
fungal cells bu t not to mammalian cel ls , Biochim.
Biophys. Acta 77:230-234 (1984).
118. R. L. Hopfer, K. Mills, R. Mehta, G. Lopez-Beres te in
, V. Fains te in , and R. L. Jul iano, In vitro antifungal
act ivi t ies of amphotericin B and liposome encapsulated
amphotericin B , Antimicrob. Agents Chemother. 24:387-389
(1984).

119. G. Lopez-Beres te in , R. L. Hopfer, R. Mehta, K.

Mehta, E. N . Hersh , and R. L. Jul iano, Prophylaxis of
Candida albicans infections in neut ropenic mice with
liposome encapsulated amphotericin B , Antimicrob. Agents
Chemother. 25:366-367 (1984).

120. P . D. Edman and I . Sjoholm, Prolongation of effect

and a spa r aginase b y implantation in polyacrylar ide in
r a t s , J. Pharm. Sci. 70:684-685 (1981).

121. T . Kato, R. Nemoto, H. Mori, K. Iwata, S. Sato, K.

Unno, A. Goto, M. Harada, M. Homma, M. Okada, and T .
Minowa, An approach to magnetically controlled cancer
chemotherapy. I I I . Magnetic control of ferromagnetic
mitomycin C microcapsules in the a r t e r y , J. Jpn. Soc.
Cancer Ther. 15:28-32 (1980).

122. T . Kato, R. Nemoto, H. Mori, and I. Kumagai, Sus ta

ined-re lease p r o p e r t i e s , of microencapsulated
mitomycin C with ethylcellulose infused into t he renal a
r t e r y of the dog, Cancer 46:14-21 (1980).

123. T . Kato, R. Nemoto, H. Mori, M. Takahash i , and Y.

Tamakawa, T ransca the t e r ar ter ia l chemoembolization
of renal cell carcinoma with microencapsulated Mitomycin
C, J. Urol. 125:19-24 (1981).

124. K. E. Roge r s , B . I . C a r r , and Z. A. Tokes ,

Cell sur facemediated cytotoxici ty of polymer-bound
adriamycin against d r u g res i s tan t hepa tocy tes ,
Cancer Res. 43:2741-2748 (1983).

125. K. E. Rogers and Z. A. Tokens, Novel mode of

cytotoxici ty obtained by coupling inactive anthracycl ine
to a polymer, Biochem. Pharmacol. 33:605-608 (1984).

126. Z. A. Tokes , K. E. Rogers , and A. Rembaum, Synthes

is of adrimaycin-coupled polyglutara ldehyde microspheres
and evaluation of the i r cytostat ic ac t iv i ty , Proc.
Natl. Acad. Sci. USA 79:2026-2030 (1982).

127. E. Beu t l e r , G. L. Dale and W. L. Kull,

Replacement t he rapy in Gaucher ' s d i sease , In ,
Therapy in Genetic Diseases (R. Desnick, e d . ) Alan Liss
, New York, 1980, p p . 369-381.
14 Chapter 14 Selective Endocytosis of
Macromolecular Drug Carriers

1. C. DeDuve, T . DeBarsy , B . Poole, A. Troue t , P . Tu

lkens , and F . Van Hoof, Lysosomotropic a g e n t s ,
Biochem. Pharmacol. 23, 2495 (1974).

2. T. P . Stossel , Endocytosis . In , Receptors and

Recognition Series A, Vol. 4 ( P . Cuat recasas and M. F .
Greaves , E d s . ) , Chapman and Hall, London, 1977, p p
. 105-141.

3. S. C. Si lvers te in , R. M. Steinman, and Z. A. Cohn,

Endocytos i s , Annu. Rev. Biochem. 46, 669 (1977).

4. J . M. Besterman and R. B . Low, Endocytosis : A review

of mechanism and plasma membrane dynamics, Biochem. J.
210, 1 (1983).

5. R. M. Steinman, I. S. Mellman, W. A. Muller, and Z. A.

Cohn, Endocytosis and recycl ing of plasma membrane, J .
Cell Biol. 96, 1 (1983).

6. R. Duncan and J . Kopecek, Soluble synthet ic polymers

as po tential d r u g c a r r i e r s , Ad. Polymer Sci.
57, 51 (1984).

7. R. Duncan, Biological effects of soluble syn the t ic

polymers as d r u g c a r r i e r s , CJRC Crit. Rev.
Ther. Drug Carrier Systems 1, 281 (1985).

8. F . M. Griffin J r . , J . A. Griffin, J . E. Leider,

and S. C. Silv e r s t e i n , Studies on the mechanism of
phagocy tos i s . 1. Requirements for circumferential at
tachment of par t ic le -bound l igands to specific r ecep
to r s on the macrophage plasma membrane, J. Exp. Med.
142, 1263 (1975).

9. A. C. Allison and P. Davies , Mechanisms of endocytosis

and exocytos is . In , Transport at the Cellular Level (M.
A. Sleigh and D. H. J e n n i n g s , E d s . ) , Society
for Experimental Biology, Symp. 28, Cambridge Universi ty
P r e s s , Cambridge, 1974, p p . 419-446.

10. M. K. P r a t t e n , R. Duncan, and J . B . Lloyd,

Adsorpt ive and pass ive pinocytic up t ake . In , Coated
Vesicles ( C . J . Ockleford and A. Whyte, E d s . ) ,
Cambridge Univers i ty P r e s s , Cambridge, 1980, p p .
179-218.
11. K. E. Williams, E. M. Kidston, F . Beck, and J . B.
Lloyd, Quanti tat ive s tudies of pinocytosis 1. Kinetics
of up take of [125j]polyvinylpyrrol idone by ra t yolk sac
cu l tu red in vitro, J. Cell Biol. 64, 113 (1975).

12. R. Duncan, P . Rejamanova, J . Kopecek, and J . B .

Lloyd, Pinocytic uptake and intracel lular degradat ion of
N ( 2 h y d r o x y propyl)methacrylamide copolymers. A
potential d r u g del ivery sys tem, Biochim. Biophys.
Acta 678, 143 (1981).

13. R. Duncan, H. C. Cable, P . Rejmanova, and J . Kopecek,

Tyrosinamide res idues enhance pinocytic cap tu re of N ( 2
h y d r o x y propyl)methacrylamide copolymers, Biochim.
Biophys. Acta 799, 1 (1984).

14. A. V. S. Robe r t s , K. E. Williams, and J . B. Lloyd,

The pinocytosis of 125i-i a D eiled poly(vinylpyrrol idone)
[ l^C] sucrose and colloidal [ 1 9 8 Au] by ra t yolk sac
cu l tured in vitro, Biochem. J. 168, 239 (1977).

15. J . F. Bridges and J . F . Woodley, The uptake of

[125j]polyvinylpyrrol idone by adult ra t gut in vitro* In
, Maternofoetal Transmission, Vo. 2 (W. A. Hemmings, E d .
) , Elsevier , Amsterdam, 1979, p p . 249-257.

16. M. K. P r a t t e n , K. E. Williams, and J . B .

Lloyd. A quan t i t a tive s tudy of pinocytosis and
intracel lular proteolysis in ra t per i toneal
macrophages , Biochem. J. 168, 365 (1977).

17. R. M. Steinman and Z. A. Cohn, The interact ion of

soluble horse rad i sh peroxidase with mouse peri toneal
macrophages in vitro, J. Cell Biol. 55, 186 (1972).

18. P. J . Edelson, R. Zweibel, and Z. A. Cohn, The

pinocytic ra te of act ivated macrophages , J. Exp. Med.
126, 941 (1975).

19. R. Duncan, D. S tar l ing , F. Rypacek, J . Drobnik ,

and J . B. Lloyd, Pinocytosis of po ly (a , $ (N-2
-hydroxye thy l ) -DL-aspa r t a mide and a tyramine der
ivat ive by ra t visceral yolk sacs cu l tured in vitro,
Biochim. Biophys. Acta 717, 248 (1982).

20. A. T. Moore, K. E. Williams, and J . B. Lloyd, The

effect of chemical t rea tments of albumin and orosomucoid
on ra te of c learance from the ra t bloodstream and ra te
of pinocytic cap tu re by ra t yolk sac cu l tured in
vitro, Biochem. J. 164, 607 (1977).
21. G. E. Ibbotson and K. E. Williams, Rate of pinocytic
cap tu re of macro molecular s u b s t r a t e s by ra t
yolk sac incubated in se rumfree cu l tu re medium,
Biochem. J. 178, 785 (1979).

22. G. Ashwell and J . Harford, Carbohydra te specific

recep tors of the l iver , Annu. Ref. Biochem. 51, 531
(1982).

23. A. L. Schwartz , S. E. Fr idovich, and H. F. Lodish,

Kinetics of internalizat ion and recycl ing of the
asialoglycoprotein receptor in a hepatoma cell l ine , J.
Biol. Chem. 257, 4230 (1982).

24. H. Tol leshaug, T. Be rg , M. Nilsson, and K. R. Norum,

Uptake and degradat ion of l ^ I l a b e l e d
asialofetuin by isolated ra t hepatocy te s , Biochim.
Biophys. Acta, 499, 73 (1977).

25. P. Stahl , Lysosomes and mononuclear phagocy te s . In

, Receptors and Recognition Series B , Vol. 15 ( P . Cuat
recasas and T. Roth, E d s . ) , Chapman and Hall, London,
1983, p p . 141-165.

26. K. Von F igura , H. Kresse , U. Meinhard, and D.

Holtfrerich, Studies on secret ion and endocytosis of
macromolecules by cul t i vated skin f ibroblas ts ,
Biochem. J. 170, 313 (1978).

27. K. Ullrich and K. Von Figura , Endocytosis of

$-N-acetylglucosaminidase from secret ions of
mucolipidosis-II and -III f ibroblasts by non-parenchymal
ra t l iver cel ls , Biochem. J. 182, 245 (1979).

28. P . Stahl and S. Gordon, Expression of a

mannosyl-fucosyl receptor for endocytosis on cu l tured pr
imary macrophages and the i r h y b r i d s , J. Cell
Biol. 93, 49 (1982).

29. J . B. Lloyd and K. E. Williams, Non-specific adsorpt

ive pinocytos i s , Biochem. Soc. Trans. 12, 527 (1984).

30. B . M. F. Pearse and M. S. B r e t s c h e r , Membrane

recycl ing by coated ves ic les . Annu. Rev. Biochem. 50,
85 (1981).

31. A. Helenius, J . Mellman, D. Wall and A. Hubbard ,

Endosomes, Trends in Biochem. Sci. July, 245 (1983).
32. I. Pastan and M. C. Willingham, Receptor-mediated
endocytos is : coated p i t s , receptosomes and Golgi,
Trends in Biochem. Sci. July, 250 (1983).

33. C. R. Hopkins , The importance of the endosome in

intracel lular t raf f ic , Nature 305, 684 (1983).

34. J . N. Limet, Y-J . Schneider , J P . Vaerman, and A.

Troue t , Binding, up take and intracel lular p rocess ing
of polymeric ra t immunoglobulin A by cu l tu red ra t
hepa tocy tes , Eur. J. Biochem. 125, 437 (1982).

35. J C . Sibile, J -N . Octave, Y-J . Schneider , A. Troue

t , and R. R. Cr ichton, Transfe r r in prote in and iron
uptake by cu l tured hepat o c y t e s , FEBS Lett. 150,
365 (1982).

36. P . L. Zeitlin and A. L. Hubba rd , Cell surface d is t

r ibut ion and intracel lular fate of asialoglycoproteins
. A morphological and biochemical s t udy of isolated ra t
hepatocytes and monolayer c u l t u r e s , J. Cell Ciol.
92, 634 (1982).

37. J . P . Reeves , The mechanism of lysosomal

acidification. In, Lysosomes, Vol. 7 ( J . T. Dingle, R.
T. Dean, and W. Sly, E d s . ) , Elsevier , Amsterdam,
1984, p p . 175-200.

38. R. T. Dean, Lysosomes, Edward Arnold (Pub l i shers ) L

t d . , London, 1977.

39. J . T. Dingle ( E d . ) , Lysosomes: A Laboratory

Handbook, 2nd ed . North Holland Publishing Company,
Amsterdam, 1977.

40. M. Geisow, Lysosome proton pump identif ied, Nature

298, 515 (1982).

41. J . B . Lloyd, A s tudy of permeability of lysosomes to

amino acids and small pep t i de s , Biochem. J. 121, 245
(1971).

42. C. N. Hales, K. Docher ty , and G. A. Maguire, Sugar t

r a n s por t in lysosomes. In , Lysosomes in Biology and
Pathology, Vol. 7, ( J . T. Dingle, R. T . Dean, and W.
Sly, E d s . ) , Elsevier Science Publ ishers B . V . ,
Amsterdam, 1984, p p . 165—174.

43. J . Drobnik and F. Rypacek, Soluble synthe t ic

polymers in biological sys tems , Adv. Polymer Sci. 57, 1
(1984).

44. K. E. Williams, E. M. Kidston, F. Beck, and J . B.

Lloyd. Quanti tat ive s tudies of p inocytos is , I I .
Kinetics of prote in u p take and digestion by ra t yolk
sac cu l tu red in vitro, J. Cell Biol. 64, 123 (1975).

45. G. Livesey and K. E. Williams, Hydrolysis of an

exogenous ^ 2 ^I-labeled prote in by ra t yolk s a c s ,
Biochem. J. 184, 519 (1979).

46. J . M. Besterman, J . A. Ai rha r t , R. C. Wood wor th

, and R. B . Low, Exocytosis of pinocytosed fluid in cu l
tu red cel ls : Kinetic evidence for rapid t u r n o v e r
and compart mentation, J. Cell Biol. 91, 716 (1981).

47. U. Weisbecker, G. E. Ibbotson, G. Livesey, and K. E.

Williams, The fate of homologuos l 2 ^Ilabel led
immunoglobulin G within r a t visceral yolk sacs incubated
in vitro, Biochem. J. 214, 815 (1983).

48. G. Gregor iadis , E d . , Drug Carriers in Biology and

Medicine, Academic P r e s s , London, 1979.

49. G. Gregor iadis , J . Senior, and A. Troue t , E d s .

, Targeting of Drugs, Plenum P r e s s , New York, 1982.

50. G. Gregoriadis and J. Senior, E d s . ,

Receptor-Mediated Targeting of Drugs, Plenum P r e s s ,
New York, 1984.

51. H. B u n d g a a r d , A. B. Hansen, and H. Kofod, E d

s . , Optimization of Drug Delivery, Munksgaard ,
Copenhagen, 1982.

52. R. Baura in , M. Masquelier, D. Deprez-De Campeneere,

and A. Troue t , Targe t ing of daunorubicin by covalent
and r e v e r sible l inkage to ca r r i e r p r o t e i n
s , lysosomal hydrolys is and an t i tumoral activity of
conjugates p r e p a r e d with peptidic spacer a rms ,
Drugs Exp. Clin. Res. 9, 303 (1983).

53. A. Troue t , R. Baura in , D. Deprez-De Campaneere, M.

Masquelier, and P . P i rson , Targe t ing of antitumoral
antiprotozoal d r u g s by covalent l inkage to prote in c
a r r i e r s . In , Targeting of Drugs (G. Gregor iadis ,
J . Senior , and A. Troue t , E d s . ) , Plenum p r e s s
, New York, 1982, p p . 19-30.

54. M. C. Garne t t , M. J . Embleton, E. Jacobs , and R.

W. Baldwin, Preparat ion and p roper t i e s of a d r u g
c a r r i e r a n t i b o d y conjugate showing selective
an t ibody-d i rec ted cytotoxici ty in vitro, Int. J.
Cancer 31, 661 (1983).

55. B. C. F. Chu and J . M. Whiteley, Control of solid

tumor metastases with a high molecular weight der ivat ive
of methot rexa te , J. Natl. Cancer Inst. 62, 79 (1979).

56. K. Motycka, K. Slavik, J . E. Dyr , A. Balcarova, and

Z. Vodrazka , The chemotherapy of C-3H mice bear ing
Gardner lymphosarcoma with bovine fibrinogen methotrexate
de r iva t ive , Neoplasma 28, 3 (1981).

57. L. Fiume, C. Busi , and A. Matlioli, Targe t ing of ant

iviral d rugs by coupling with protein c a r r i e r s ,
FEBS Lett. 153, 6 (1983).

58. A. Troue t , D. Deprez-De Campeneere, and C. De Duve ,

Chemot h e r a p y th rough lysosomes, with a
DNA-daunorubicin complex, Nature 239, 110 (1972).

59. A. Trouet and G. Sokal, Clinical s tudies with

daunorubicin-DNA and adriamycin DNA complexes: A review,
Cancer Treat Rep. 63, 895 (1979).

60. R. Hulhoven and C. Harveng t , Distr ibution of

daunorubicin i n t r a venously injected or in t ravenous
ly infused as free d r u g and as a complex with DNA in r
a b b i t s , Pharmacology 24, 253 (1982).

61. R. Arnon , E. Hurwitz , and M. Sela, Antibodies as ca r

r i e r s for oncostatic mater ials , Rec. Res. Cancer
Res. 75, 236 (1980).

62. K. A. Krolick, D. Yuan, and E. S. Vitet ta , Specific

killing of a human b reas t carcinoma cell line by a
monoclonal ant ibody coupled to the A-chain of r i c in ,
Cancer Immunol. Immunother. 12, 39 (1981).

63. C. H. J . Ford , C. E. Newman, J . R. Johnson , C. S.

Woodhouse , T. A. Reeder , G. F. Rowland, and R. G.
Simmonds, Localization and toxicity s t u d y of a
vindesine-ant i -CEA conjugate in pa t ien ts with
advanced cance r , Br. J. Cancer. 47, 35 (1983).

64. M. J . Poznanzky, R. Singh, and B . Singh, Insul in:

Carr ier potential for enzyme and d r u g t h e r a p y ,
Science 223, 1304 (1984).
65. J . M. Varga , N. Asato, S. Lande, and A. B . Le rne r
, Melanotropin-daunomycin conjugate shows receptor-media
ted cytotoxicty in cu l tu red murine melanoma cel ls ,
Nature 267, 56 (1977).

66. W. T. Shier , Lectins as d r u g c a r r i e r s . In ,

Drug Carriers in Biology and Medicine (G. Gregor iadis , E
d . ) , Academic Press I n c . , New York, 1979, p p .
44-70 .

67. T. Kitao and K. Hatto, Concanavalin A as a ca r r i e r

of daunomyc in , Nature 265, 81 (1977).

68. J . P . Remon, R. Duncan, and E. Schacht , Polymer-drug

combinat ions : Pinocytic uptake of modified polysacchar
ides conta ining procainamide moieties by ra t visceral
yolk sacs cu l tured in vitro, J. Controlled Release 1, 47
(1984).

69. E. Schacht , Use of polysacchar ides as d r u g c a r r

i e r s , Ann. Natl. Acad. Sci. (in p r e s s ) .

70. M. Konieczny, D. Charytonowicz, and A. D. Inglot ,

Search for ca r r i e r s for non-covalent b inding of in
ter feron among 1,3,5 tr iazine der ivat ives of d e x t r
a n , Arch. Immunol. Ther. Exp. 30, 1 (1982).

71. A. Berns te in , E. Hurwitz , R. Maron, R. Arnon, M.

Sela, and M. Wilchek, Higher antitumor efficacy of
daunomycin when linked to d e x t r a n , in vivo and in
vitro s t u d i e s , J. Natl. Cancer Inst. 60, 379
(1978).

72. E. Hurwitz , M. Wilchek, and J . Pi tha , Soluble

macromolecules as ca r r i e r s of daunomycin, J. Appl.
Biochem. 2, 25 (1980).

73. H. J P . Ryser and W-C. Shen, Conjugation of

methotrexate to poly(L-lys ine) increases d r u g t r a n
s p o r t and overcomes d r u g res i s tance in cu l
tured cel ls , Proc. Natl. Acad. Sci. USA 75, 3867 (1978).

74. B . C. F. Chu and S. B. Howell, Pharmacological and t h

e r a p e u tic p roper t i e s of ca r r i e r bound
methotrexate against tumor confined to a th i rd space body
compartment, J. Pharmacol. Exp. Ther. 219, 389 (1981).

75. F. Zunino, F. Giulliani, G. Savi , T. Dasdia, and R.

Gambetta, Antitumor activity of daunorubicin linked to
poly-L-aspar t ic acid, Int. J. Cancer. 30, 465 (1982).
76. F. Zunino, G. Savi , F. Giuliani, R. Gambetta, R.
Supino, S. Tinelli, and G. Pezzoni, Comparison of anti
tumor effects of daunorubicin covalently l inked to
poly-L-amino acid c a r r i e r s , Eur. J. Cancer Clin.
Oncol. 20, 421 (1984).

77. M. Havranova, D. Cechova, V. Saudek, M. Metalova, and J

. Drobnik , A high molecular mass der ivat ive of t ryps
in-ka l l ik re in inhibitor for potential medical u s e ,
Hoppe-Seyler's Z. Physiol. Chem. 363, 295 (1982).

78. T. Hirano, H. Ringsdorf , and D. S. Zaharko, Antitumor

activity of monomeric and polymeric cyclophosphamide der
ivat ives compa red with in vitro hyd ro ly s i s , Cancer
Res. 40, 2263 (1980).

79. M. P rzyby l sk i , E. Fell, H. Ringsdorf, and D. Z.

Zaharko, Pharmacologically active polymers , 17. Synthesis
and Characterizat ion of polymeric der ivat ives of the
antitumor agent methot r e x a t e , Makromol. Chem. 179,
1719 (1978).

80. J . Kopecek, P. Rejmanova, R. Duncan, and J . B. Lloyd,

Controlled release of d r u g model from N(2 -hydroxypropy
l )me thac ry l amide copolymers, Ann. NY Acad. Sci. 446,
93 (1985).

81. B-U. Von Specht , H. Sainfeld, and W. Brende l ,

Polyvinylpyrrolidone as a soluble ca r r i e r of p r o t e
i n s , Hoppe-Seyler's Z. Physiol. Chem. 354, 1659 (1973).

82. J C . Soutif, F. Mouity-Moussounda, and J . C . Brosse

, Polymeric ca r r i e r s of glycerol de r iva t ives , 2.
Chlorambucil der ivat i ve s , Makromol. Chem. 4, 61
(1983).

83. J . Pato , M. Azori, and F. Tudos , Polymeric p r o d r

u g s . 2. Synthesis by coupling of d rugs via spacer g r o
u p , Makromol. Chem. Rapit Commun. 4, 25 (1983).

84. H. Ringsdorf , S t ruc tu re and proper t i es of

pharmacologically active polymers , J. Polymer Sci.
Polymer Symp. 51, 135 (1975).

85. J . Kopecek, Synthesis of tai lor-made soluble

polymeric d r u g c a r r i e r s . I n , Recent Advances
in Drug Delivery Systems ( S . W. Kim and J . M. Anderson
, E d s . ) , Plenum P r e s s , New York, 1984 p p .
41-62.
86. A. T roue t , R. Baura in , D. Deprez-De Campeneere, D.
Layton, and M. Masquelier, DNA, Liposomes and prote ins as
ca r r i e r s for antitumoral d r u g s . In , Recent
Results in Cancer Research, Vol. 75 (G. Mathe and F. M.
Muggia, E d s . ) , Sp r inge r -Ver l ag , Berl in ,
1980, p p . 229-235.

87. L. Gros , Biological act ivi ty of polymers . In ,

Encyclopedia of Polymer Science ( J . I. Kroschwitz, E d .
) , John Wiley & Sons I n c . , New York, 1984 (in p r e s
s ) .

88. M. Masquelier, R. Baura in , D. Deprez-De Campeneere,

and A. Troue t , Antitumor act ivi ty of daunorubicin
linked to prote ins : Biological and antitumor p roper t i
e s of peptidic der iva t ives of daunorubicin used as in
te rmedia tes . In , Current Chemotherapy and
Immunotherapy, Proceedings of the 12th Internat ional
Congress of Chemotherapy, Florence, I taly, 19-24 July
1981, p . 1428.

89. A. Troue t , M. Masquelier, R. Baura in , and D.

Deprez-De Campeneere, A covalent l inkage between
daunorubicin and p r o teins tha t is s table in serum and
revers ib le by lysosomal h y d ro lyses , as requ i red
for a lysosomotropic d r u g c a r r i e r conjuga te : In
vitro and in vivo s t u d i e s , Proc. Natl. Acad. Sci.
USA 79, 626 (1982).

90. R. Duncan, J . Kopecek, and J . B. Lloyd, Development

of N-(2-hydroxypropyl ) -methacry lamide copolymers as ca
r r i e r s of therapeut ic a g e n t s . In , Polymers in
Medicine: Biomedical and Pharmacological Applications (E.
Chiellini and P. Guist i , E d s . ) , Plenum P r e s s ,
New York, 1983, p p . 97-114.

91. J . Kopecek, Biodegradation of polymers of biomedical u

s e . In, IUPAC Macromolecules (H. Benoit and P. Rempp, E
d s . ) , Per gamon P r e s s , New York, 1982, p p .
305-320.

92. J . Kopecek and P. Rejmanova, Enzymatically degradable

bonds in synthet ic polymers . In, Controlled Drug
Delivery Vol. 1 ( S . D. Bruck , E d . ) , CRC P r e s s ,
Boca Raton, FL, 1983, p p . 81-124.

93. J . Kopecek, Controlled biodegradabil i ty of

polymers—A key to d r u g del ivery sys t ems ,
Biomaterials 5, 19 (1984).
94. J . Kopecek, P. Rejmanova, and V. C h y t r y ,
Polymers containing enzymatically degradable b o n d s ,
1. Chymotrypsin catalyzed hydrolys is of p-ni t roani l
ides of phenylalanine and tyros ine a t tached to s
ide-chains of copolymers of N ( 2 h y d r o x y p r o p y l
) methacrylamide, Makromol. Chem. 182, 799 (1981).

95. P. Rejamnova, J . Kopecek, R. Duncan, and J . B. Lloyd,

Sus ceptibil i ty of oligopeptide sequences in N ( 2 h y d
r o x y p r o p y l ) methacrylamide copolymers to degradat
ion by ra t plasma and se rum, Biomaterials 6, 45 (1985).

96. R. Duncan, J . B. Lloyd, and J . Kopecek, Degradation

of side chains of N-(2-hydroxypropyl )methacry lamide
copolymers by lysosomal enzymes, Biochem. Biophys. Res.
Commun. 94, 824 (1980).

97. R. Duncan, H. C. Cable, J . B . Lloyd, P. Rejmanova,

and J . Kopecek, Degradation of s ide-chains of N ( 2 h y
d r o x y p r o p y l ) methacrylamide copolymers by
lysosomal th io l -p ro te inases , Biosci. Rep. 2, 1041
(1982).

98. R. Duncan, H. C. Cable, J . B . Lloyd, P. Rejmanova,

and J . Kopecek, Polymers containing enzymatically
degradable b o n d s , 7. Design of oligopeptide s
ide-chains in poly N-2 (hy droxypropyl)methacrylamide
copolymers to promote efficient degradat ion by lysosomal
enzymes, Makromol. Chem. 184, 1997 (1983).

99. P. Rejmanova, J . Pohl, M. B a u d y s , M. Kostka, J .

Kostka, and J . Kopecek, Degradation of oligopeptide
sequences in N-(2-hydroxypropyl )methacry lamide
copolymers by bovine spleen cathepsin B , Makromol. Chem.
184, 2009 (1983).

100. P. Rejmanova, J . Pohl, V. Subr , M. B a u d y s , V.

Kostka, and J . Kopecek, (unpubl ished r e s u l t s ) .

101. I. Schechter and A. B e r g e r , On the size of

active site in p r o t e a s e s . 1 Papain , Biochem.
Biophys. Res. Commun. 27, 157 (1967).

102. W-C. Shen and H . J P . Ryse r , Cis-aconityl spacer

between daunomycin and macromolecular c a r r i e r s : A
model of pH-sens i tive l inkage re leasing d r u g from a
lysosomotropic conjugate , Biochem. Biophys. Res. Commun.
102, 1048 (1981).
103. B. Ballou, R. J . Taylor , W-C. Shen, M. Lieber t , H.
J P . Ryse r , D. Solter, and T. R. Hakala, Daunomycin t a
rge t ing to the MH-15 teratocarcinoma us ing anti SSEA-1.
, Fed. Proc. 42, 685 (1983).

104. J . Black, Systemic effects of biomaterials,

Biomaterials 5, 11 (1984).

105. B. Rihova, K. Ulbrich, J . Kopecek, and P . Mancal,

Immunogenicity of N-(2-hydroxypropyl )methacry lamide
copolymers— Potential hapten or d r u g c a r r i e r s ,
Folia Microbiol. 28, 217 (1983).

106. B. Rihova, J . Kopecek, K. Ulbrich, M. Pospisil , and

P. Mancal, Effect of chemical s t r u c t u r e of N(2
-hydroxypropy l )me thac ry la mide copolymers on the
immune response of inbred s t ra ins of mice, Biomaterials
(in p r e s s ) .

107. B. Rihova and I. Riha, Immunological problems of

polymerbound d r u g , CRC Crit. Rev. Ther. Drug Carrier
Systems 1, 311 (1985).

108. T. J . Gill III and W. Kunz, The immunogenicity of

vinyl polymers , Proc. Natl. Acad. Sci. USA 61, 490 (1968).

109. M. Sela, S. Fuchs , and R. Arnon, Studies on the

chemical basis of the antigenici ty of p r o t e i n s .
5. Syn thes i s , cha rac terization and immunogenicity of
some multichain and linear polypept ides containing t y
ros ine , Biochem. J. 85, 223 (1962).

110. E. Reske-Nielsen, M. Bojsen-Moller, M. Ve tne r , and

J . C. Hansen, Poly v inylpyrro l idone-s tor age d i
sease , Acta Path. Microbiol. Scand. Sect. A. 8, 397
(1976).

111. A. E. F. H. Meijer and R. G. J . Willinghagen, The

activity of g lucose-6-phospha tase , adenosine t r i p h
o s p h a t a s e , succinic dehydrogenase , and acid
phospha tase after dex t ran or polyvinylpyrrol idone
uptake by the l iver in vivo, Biochem. Pharmacol. 12, 973
(1963).

112. K. Ulbrich, J . Strohalm, and J . Kopecek, Polymers

containing enzymatically bonds . 3. Poly N(2 -hydroxypropy
l )me thac ry l amide chains connected by oligopeptide
sequences cleavable by t r y p s i n , Makromol. Chem.
182, 1917 (1981).
113. P. Rejmanova, B . Obere igner , and J . Kopecek,
Polymers containing enzymatically degradable bonds . 2.
Poly N-( 2 -hydroxypropyl)methacrylamide chains connected
by oligopeptide sequences cleavable by chymotryps in ,
Makromol. Chem. 182, 1899 (1981).

114. K. Ulbrich, E. I. Zacharieva, B. Obere igner , and J .

Kopecek, Polymers containing enzymatically degradable b o
n d s . V. Hydrophilic polymers degradable by papa in ,
Biomaterials 1, 199 (1980).

115. S. A. Car t l idge , R. Duncan, J . B. Lloyd, P.

Rejmanova, and J . Kopecek, Pinocytic cap tu re and int
racel lular degradat ion of poly N-(2-hydroxypropyl
)methacry lamide chains connected by oligopeptide s
equences . Abst ract from the Internat ional Conference on
Biomedical Polymers, Durham, U . K . , Ju ly , 1982.

116. J . Kopecek, I. Cifkova, P. Rejmanova, J . Strohalm, B

. Obere igne r , and K. Ulbrich, Polymers containing
enzymatically de gradable bonds . 4. Preliminary
experiments in vivo, Makromol. Chem. 182, 2941 (1981).

117. G. Poste , Liposome t a rge t i ng in vivo: Problems

and oppor tun i t i e s , Biol. Cell 47, 19 (1983).

118. R. Duncan, M. K. P ra t t en , H. C. Cable, H.

Ringsdorf , and J . B. Lloyd, Effect of molecular size of
1 2 5 I label led p o l y v i n y l pyrrol idone) on i ts
pinocytosis by ra t visceral yolk sacs and ra t peri
toneal macrophages , Biochem. J. 196, 49 (1981).

119. S. A. Car t l idge , R. Duncan, P. Rejmanova, J .

Kopecek, and J . B. Lloyd, Pinocytosis of soluble crossl
inked N ( 2 h y d r o x y propyl)methacrylamide copolymers
by ra t visceral yolk sacs and ra t in tes t ine cu l tu
red in vitro, Effect of molecular weight on up take and
intracel lular degrada t ion , J. Controlled Release 3, 55
(1986).

120. G. S. Vince and R. T. Dean, Comparative s tudies on

the endocytosis of pro te ins in kidney tubule cel ls ,
Biochem. Soc. Trans. (in p r e s s ) .

121. R. Duncan and M. K. P r a t t e n , Pinocytosis :

Mechanism and regula t ion . In Mononuclear Phagocytes:
Physiology and Pathology (R. T. Dean and W. J e s s u p , E
d s . ) , Elsevier Biomedical P r e s s , Amsterdam 1985,
p p . 2 7 5 1 .
122. M. K. P r a t t e n , R. Duncan, and J . B . Lloyd, A
comparative s t udy of the effects of polyamino acids and
dex t r an der ivat ives on pinocytosis in the ra t yolk
sac and the ra t peri toneal macrop h a g e , Biochim.
Biophys. Acta 540, 455 (1978).

123. R. Duncan, M. K. P r a t t e n , and J . B. Lloyd,

Mechanism of polycation stimulation of p inocytos is ,
Biochim. Biophys. Acta, 587, 463 (1979).

124. H. J P . Ryse r , A membrane effect of basic polymers

dependent on molecular s ize , Nature 215, 934 (1967).

125. T. Kooistra, A Duursma, J . M. W. Bouma, and M. Grube

r , Effect of size and charge on endocytosis of lysozyme
der ivat ives by sinusoidal ra t l iver cells in vivo,
Biochem. Biophys. Acta 631, 439 (1980).

126. J . Sinke, J . M. W. Bouma, T. Kooistra, and M. G r u

b e r , Endocytosis and breakdown of 1 2 5 I label led
lactate dehydrogenase isoenzyme M4 by ra t l iver and
spleen in vivo, Biochem. J. 180, 1 (1979).

127. T. Kooistra, M. K. P r a t t e n , and K. E. Williams,

Endocytosis of simple prote ins by ra t yolk sacs and by
ra t peri toneal macrophages incubated in vitro, Acta Biol.
Med. Germ. 40, 1637 (1981).

128. G. Livesey and K. E. Williams, Heterogenicity of b

inding s i tes for adsorpt ive pinocytosis of simple prote
ins by ra t yolk s a c s , Eur. J. Biochem. 122, 147
(1982).

129. R. Duncan, H. C. Cable, F. Rypacek, J . Drobnik , and

J . B. Lloyd, Enhancement of adsorpt ive pinocytosis of a
po lyaspar ta mide by incorporat ion of tyramine r e s i d
u e s , Biochem. Soc. Trans. 12, 1064 (1984).

130. F . Rypacek, J . Drobnik, V. Chmelar, and J . Kalal,

The renal excret ion and re tent ion of macromolecules.
The chemical s t r u c t u r e effect, Pflilgers Arch. 392,
211 (1982).

131. F. Rypacek , J . Drobnik , and J . Kalal, Progess in

model s tudies in cellular u p t a k e , Ann. NY Acad.
Sci. (in p r e s s ) .

132. C. H. C. M. B u y s , A. S. H. De Jong , J . M. W.
Bouma, and M. Grube r , Rapid up take by l iver sinusoidal
cells of serum albumin modified with re tent ion of i t s
compact conformation, Biochim. Biophys. Acta 392, 95
(1975).

133. R. Blomhoff, W. Eskild, and T. Ber , Endocytosis of

formaldeh y d e t r e a t e d serum albumin via scavenger
pathway in l iver endothelial cel ls , Biochem. J. 218, 81
(1984).

134. M. K. P r a t t e n , R. Duncan, H. C. Cable, R.

Schnee , H. R ings dorf, and J . B. Lloyd, Pinocytic up
take of divinylether-maleic anhydr ide ( p y r a n
copolymer) and i ts failure to stimulate p inocy tos i s ,
Chem. Biol. Interact. 35, 319 (1981).

135. K. Park and J . R. Robinson, Polymer binding to

epithelial cel ls . In , Optimization of Drug Delivery (H.
Bundgaa rd , A. B . Hansen, and H. Kofod, E d s . ) ,
Munksgaard , Cophenhagen , 1982, p p . 35-52.

136. K. Pa rk , H. S. Ch 'ng , and J . R. Robinson,

Alternat ive a p proaches to oral controlled d r u g de l
ivery : bioadhesives and in-situ sys tems . In , Recent
Advances in Drug Delivery Systems ( S . W. Kim and J . M.
Anderson , E d s . ) , Plenum P r e s s , New York, 1984.

137. D. A. Tirrel l and P. M. Boyd, Interact ion of synthe

t ic polymers with cell membranes and model membrane sys t
ems , 1. Differential scanning calor imetry, Makromol.
Chem. Rabid Commun. 2, 193 (1981).

138. J . Vermeersch, L. R u y s , E. Schacht , J . P .

Remon, and R. Duncan, Synthesis and biological evaluation
of procainamide containing polysacchar ides , Abst rac t
from the 26th Microsymposium on Macromolecules on Polymers
in Medicine and Biology, P r a g u e , July 9 -12 , 1984,
p p . S4-1 to S4-4.

139. E. F . Neufeld and G. Ashwell, Carbohydra te

recognition s y s tems for receptor-media ted p inocytos is
. In , The Biochemistry of Glycoproteins and Proteoglycans
(W. J . Lennarz , E d . ) , Plenum P r e s s , New York,
1980, Chap. 6.

140. P . Cuatrecasas and T. Roth, E d s . , Receptors and

Recognition Series B , Vol. 15, Receptor-Mediated
Endocytosis, Chapman and Hall, London, 1983.

141. M. Monsigny, C. Kieda, and A-C. Roche, Membrane

glycoprot e i n s , glycolipids and membrane lectins as
recognition signals in normal and malignant cel ls , Biol.
Cell. 47, 95 (1983).

142. M. I. Horowitz, E d . , The Glycoconjugates, Vol. IV.

Glycoproteins, Glycolipids and Proteoglycans, Part B ,
Academic P r e s s , New York, 1982.

143. G. Ashwell and A. G. Morell, The role of surface ca

rbohydra tes in the hepat ic recognit ion and t r a n s p
o r t of c i rcula t ing glycop r o t e i n s , Adv.
Enzymol. 41, 99 (1974).

144. A. G. Morell, R. A. I rv ine , I. S tern l ieb , I. M.

Sche inberg , and G. Ashwell, Physical and Chemical s
tudies on ceruloplasmin V. Metabolic s tudies on sialic
acid-free ceruloplasmin in vivo, J. Biol. Chem. 243, 155
(1968).

145. A. L. Hubbard , G. Wilson, G. Ashwell, and H. S

tukenbrok , An electron microscope autoradiographic s tudy
of the ca rbohydra t e recognit ion systems in the ra t l
iver . I. Distr ibution of 1 2 5 I l i gands among the l
iver cell t y p e s , J. Cell. Biol. 83, 47 (1979).

146. T. Tanabe , W. E. P r ice r , J r . , and G. Ashwell,

Subcellular membrane topology and t u r n o v e r of ra t
hepatic b inding protein specific for as ialoglycoproteins
, J. Biol. Chem. 254, 1038 (1979).

147. C. J . S teer , E. S. Kempner, and G. Ashwell,

Molecular size of the hepat ic receptor for
asialoglycoproteins determined in si tu by radiation inact
ivat ion, J. Biol. Chem. 256, 5851 (1981).

148. H. B. Haimes, R. J . S tocker t , A. G. Morell, and A.

B. Novikoff, Carbohydrate-speci f ied endocytos is :
Localization of ligand in the lysosomal compartment, Proc.
Natl. Acad. Sci. USA 78, 6936 (1981).

149. W. M. P a r t r i d g e , A. J . Vant ler le , R. T .

Naruse , G. F ie ra r , and A. Costin, In vivo
quantification of recep tor mediated u p take of
asialoglycoproteins by ra t l iver , J. Biol. Chem. 258,
990 (1983).

150. K. Kawaguchi, M. Kuhlenschmidt , S. Roseman, and J .

C. Lee, Differential up take of D-galactosyl- and
D-glucosyl-neoglycoprote ins by isolated ra t hepa tocy te
s , J. Biol. Chem. 256, 2230 (1981).

151. M. Deschuyteneer , J P . Pr ice ls , and R.

Mosselmans, Galactosespecific adsorpt ive endocytos is : An
u l t r a s t ruc tu r a l quali tative and quant i ta t
ive s t udy in cu l tu red ra t hepa tocy tes , Biol. Cell.
50, 17 (1984).

152. C. J . Steer and G. Ashwell, Studies on a mammalian

hepatic b inding protein specific for asialoglycoproteins,
J. Biol. Chem. 255, 3008 (1980).

153. K. Br idges , J . Harford, G. Ashwell, and R. D.

Klausner , Fate of receptor and ligand d u r i n g
endocytosis of asialoglycoprote ins by isolated hepa tocy
tes , Proc. Natl. Acad. Sci. USA 79, 350 (1982).

154. J . U. Baenziger and D. Fiete , Recycling of the

hepatocyte asialoglycoprotein receptor does not r equ i re
del ivery of ligand to lysosomes, J. Biol. Chem. 257, 6007
(1982).

155. D. B . Cawley, D. L. Simpson, and H. R. Herschman,

Asialoglycoprotein receptor mediates the toxic effects of
an asialofetulin d ip ther ia toxin fragment A conjugate on
cu l tured ra t hepatocy te s , Proc. Natl. Acad. Sci. USA
78, 3383 (1981).

156. L. Fiume, C. Busi , and A. Matlioli, Lactosaminated

human serum albumin as hepatotropic d r u g c a r r i e r
. Rate of uptake by mouse l iver , FEBS Lett. 146, 42
(1982).

157. K. F u r n u n o , N. Miwa, and K. Kato,

Receptor-mediated i n t ro duction of pepsta t in-as ia
lofetuin conjugate into liposomes of ra t hepa tocy tes ,
J. Biochem. 93, 249 (1983).

158. R. Duncan, J . Kopecek, P . Rejmanova, and J . B.

Lloyd, Tar get ing of N-(2-hydroxypropyl )methacry lamide
copolymers to l iver incorporat ion of galactose r e s i d
u e s , Biochim. Biophys. Acta 755, 518 (1983).

159. R. Duncan, J . B. Lloyd, P . Rejmanova, and J .

Kopecek, Methods of t a rge t i ng N-(2-hydroxypropyl
)methacry lamide copolymers to par t icu lar cell t y p e s
, Makromol. Chem. Suppl. 9, 3 (1985).

160. H. Kolb and V. Kolb-Bachafen, A lectin-l ike receptor

on mammalian macrophages , Biochem. Biophys. Res. Commun.
85, 678 (1978).

161. R. Terada i ra , V. Kolb-Bachofen, J .

Schlepper-Schafer , and H. Kolb, Galactose-part icle recep
tor on l iver macrophages . Quantitation of par t ic le u
p t a k e , Biochim. Biophys. Acta 759, 306 (1983).

162. P . Stahl , P . H. Schles inger , J . Rodman, and T.

Doebber , Recognition of lysosomal glycosidases in vivo
inhibi ted by modified g lycoprote ins , Nature 264, 86
(1976).

163. P. Stahl , H. Siz, J . S. Rodman, P. Schles inger , D.

R. P. Tulsiani , and O. Tous te r , Evidence for specific
recognit ion si tes mediating clearance of lysosomal
enzymes in vivo, Proc. Natl. Acad. Sci. USA 73, 4045
(1976).

164. D. T. Achord, F. E. Bro t , and W. S. Sly, Inhibition

of the ra t clearance system for agalacto-orosomucoid by
yeast mannans and by mannose, Biochem. Biophys. Res.
Commun. 77, 409 (1977).

165. D. T . Achord , F. E. Bro t , C. E. Bell, and W. S.

Sly, Human B-g lucuronidase : In vivo clearance and in
vitro up take by a glycoprotein recognition system on
reticuloendothelial cel ls , Cell 15, 269 (1978).

166. Y. C. Lee, C. P . Stowell, and M. K. Kran tz ,

2-Imino-2-methoxye thyl -Lth ioglyeos ides : New reagen t s
for a t taching s u g a r s to p r o t e i n s ,
Biochemistry 15, 3956 (1976).

167. R. T. Lee and Y. C. Lee, Preparat ion and some

biochemical p roper t i es of neoglycoproteins produced by
reduct ive amination of thioglycosides containing co-a
ldehydoaglycan, Biochemistry 19, 156.

168. P. D. Stahl , J . S. Rodman, J . M. Miller, and P. H.

Schles inger , Evidence for receptor-media ted b inding of
g lycoprote ins , glyconjugates and lysosomal glycosidases
by alveolar macrophages , Proc. Natl. Acad. Sci. USA 75,
1399 (1978).

169. V. S h e p h e r d , J. C. Lee, P. H. Schles inger ,

and P. Stahl , L-Fucoseterminated glycoconjugates are
recognized by p inocytosis r ecep to r s on macrophages ,
Proc. Natl. Acad. Sci. USA 78, 1019 (1981).

170. P . Stahl , P . Schles inger , E. S igardson , J . S.

Rodman, and Y. C. Lee, Receptor-mediated pinocytosis of
mannose glyconjugates by macrophages: character izat ion
and evidence for receptor recyc l ing , Cell 19, 207
(1980).

171. Y. Maynard and J . U. Baenziger , Oligosaccharide

specific endocytosis by isolated ra t hepatic
reticuloendothelial cel ls , J. Biol. Chem. 256, 8063
(1981).

172. Y. Mizuno, Y. Kozutsumi, T. Kowasaki, and I .

Yamashina, Isolation and character izat ion of a
mannan-binding protein from rat l iver , J. Biol. Chem.
256, 4247 (1981).

173. R. Townsend and P. Stahl , Isolation and character

izat ion of a mannose/N-acetylglucosamine/fucose-binding
protein from ra t l iver , Biochem. J. 194, 209 (1981).

174. J . Wild, D. Robinson, and B . Winchester, Isolation

of mannosebinding prote ins from human and rat l iver ,
Biochem. J. 210, 167 (1983).

175. J P . Pr iee ls , S. V. Pizzo, L. R. Glasgow, J . C.

Paulson, and R. L. Hill, Hepatic recep tor tha t
specifically binds oligosacchar ides containing fucosyl a l
-3 -N-ace ty l glucosamine l inkages , Proc. Natl. Acad.
Sci. USA 75, 2215 (1978).

176. E. F . Neufeld, T. W. Lim, and L. J . Shapiro, Inher i

ted d i s o rde r s of lysosomal metabolism, Annu. Rev.
Biochem. 44, 357 (1975).

177. A. Kaplan, D. T. Achord, and W. S. Sly, Phosphohexoxyl

components of a lysosomal enzyme are recognized by
pinocytosis r ecep tors on human f ibroblas ts , Proc.
Natl. Acad. Sci. USA 74, 2026 (1977).

178. W. S. Sly, The up take and t r a n s p o r t of

lysosomal enzymes. In, The Glycoconjugates, Vol. IV (M. I
. Horowitz, E d . ) , Academic P r e s s , New York, 1982,
p p . 3 -25 .

179. K. Ullrich, G. Mersmann, M. Fleischer , and K. Von

Figura , Epithelial ra t l iver cells have cell surface r
ecep to r s recognizing a phosphory la ted ca rbohydra te
on lysosomal enzymes, HoppeSeyler's Z. Physiol. Chem. 359,
1591 (1978).

180. H. D. F ischer , A. Gonzalez-Noriega, W. S. Sly, and

D. J . Morre, Phosphomannosylenzyme recep tors in ra t l
iver , J. Biol. Chem. 255, 9608 (1980).
181. T. Feizi, Monoclonal antibodies reveal sacchar ide s t
r u c t u r e s of glycoproteins and glycolipids as
differentiation and tumorassociated an t igens , Biochem.
Soc. Trans. 12, 545 (1984).

182. A. C. Roche, M. Barzi lay, P . Midoux, S. J u n q u a

, N. Sharon , and M. Monsigny, Sugar-specif ic endocytosis
of glycoproteins by Lewis lung carcinoma cel ls , J. Cell
Biochem. 22, 131 (1983).

183. J . L. Goldstein and M. S. Brown, The low densi ty l

ipoprotein pathway and i ts relation to a therosc le ros i
s , Annu. Rev. Biochem. 46, 897 (1977).

184. E. L. Biermann and J . J . Albers , Lipoprotein uptake

by cul t u r ed human ar ter ia l smooth muscle cel ls ,
Biochim. Biophys. Acta 388, 198 (1975).

185. D. B. Weisnstein, T. E. Carew, and D. S te inberg ,

Uptake and degradat ion of low densi ty l ipoprotein by
swine ar ter ia l smooth muscle cells with inhibition of
cholesterol b iosyn thes i s , Biochim. Biophys. Acta 424,
404 (1976).

186. E. A. Kirsten and J . A. Watson, Regulation of 3 h y d

r o x y 3 methylglutaryl coenzyme A reduc tase in hepatoma
t i s sue cu l tu re cells by serum l ipoprote ins , J.
Biol. Chem. 249, 6104 (1974).

187. A. M. Fogelman, J . Edmond, J . Seager , and G.

Popjak, Abnormal induction of 3-hydroxy-3-methylgutamyl
coenzyme A reduc ta se in leukocytes from subjects with he
terozygous h y p e r cholesterolemia, J. Biol. Chem. 250,
2045 (1975).

188. G. Gregor iadis , Old d r u g s in new clothing,

Nature 310, 186 (1984).

189. R. J . Desnick, S. R. Thorpe , and M. B . Fiddler ,

Toward en zyme the r apy for lysosomal s torage d i seases
, Physiol. Rev. 56, 57 (1976).

190. G. Gregor iadis , Liposomes in the t h e r a p y of

lysosomal s torage d i seases , Nature 275, 695 (1978).

191. M. J . Poznansky and D. Bhardwaj , Antibody-mediated t

a rge t i ng of a l ,4 -g lucos idase-a lbumin polymers to
ra t hepa tocy tes . A model for enzyme t h e r a p y ,
Biochem. J. 196, 89 (1981).
192. M. J . Poznansky and D. Bhardwaj ,
1,4-Glucosidase-albumin polymers : In vitro p roper t i e
s and advantages for enzyme r e placement t h e r a p y ,
Can. J. Physiol. Pharmacol. 58, 322 (1980).

193. G. Poste and I. J , Fidler , Stimulation of macrophage

mediated des t ruc t ion of lung metastases by
administration of immunomodulators encapsulated in
liposomes. In , Liposomes, Drugs and Immunocompetent Cell
Functions ( C . Nicolau and A. Paraf, E d s . ) , Academic
P r e s s , New York, 1981, p p . 147-162.

194. P . P i rson, R. F . Ste iger , R. Baura in , M.

Masquelier, and A. Troue t , Antimalarial activity of
liposomal primaquine and p e p tidic der ivat ives of pr
imaquine . In , The Host Invader Interplay (H. Van den
Bossche, E d . ) , Elsevier/North-Holland Biomedical P r e
s s , Amsterdam, 1980, p p . 663-667.

195. M. J . Poznansky , M. Shandl ing, M. A. Salkie, J .

Elliott, and E. Lau, Advantages in the use of
L-asparaginase-albumin polymer as an antitumor agen t ,
Cancer Res. 42, 1020 (1982).

196. R. R. C. New, M. L. Chance , and S. Heath, Liposome

the rapy for experimental cutaneous and visceral
leishmaniasis , Biol. Cell 47, 59 (1983).

197. V. L. Shephe rd , P . D. Stahl , P . Bernol , and M.

Rabinovitch, Receptor mediated e n t r y of beta
glucoronidase into the pa ras i to phorus vacuoles of
macrophages infected with Leishmaniamexicana-amozonesis, J.
Exp. Med. 157, 147 (1983).
15 Chapter 15 Antibodies for Drug Delivery

1. V. T. DeVita and R. S. Hellman, E d s . , Cancer,

Principles and Practice of Oncology, J . B . Lippincott &
C o . , Philadelphia, 1982.

2. W. Ensminger , J . Niederhuber , S. Dakhil , J . Thra l

l , and R. Wheeler, Totally implanted d r u g delivery
system for hepatic a r terial chemotherapy, Cancer Treat.
Rep. 65, 393 (1981).

3. B . Himmelweit, Ed. The Selected Papers of Paul Ehrlich,

Pe rga mon P r e s s , Oxford, 1957.

4. E. J . Foley, Antigenic p roper t i es of

methylcholanthreneinduced tumors in mice of the s t ra in
or ig in , Cancer Res. 13, 835 (1953).

5. R. Prehn and D. Main, Immunity to methylcholanthrene

induced sarcomas, J. Natl. Cancer Inst. 18, 768 (1957).

6. H. O. Sjogren, Transplanta t ion methods as a tool for

detection of tumor specific an t i gens , Prog. Exp. Tumor
Res. 6, 289 (1965).

7. T. P . Gold and S. Freedman, Demonstration of

tumor-specific ant igens in human colonic carcinoma by
immunological tolerance and absorption t echn iques , J.
Exp. Med. 121, 439 (1965).

8. G. I. Abelev, S. D. Perova , A. P. Khramkova, Z. A.

Postni hova , and I. S. I r t i n , Production of embyronal
crglobulin by t ransp lan tab le mouse hepatomas,
Transplantation 1, 174 (1963).

9. K. E. Hellstrom and I. Hellstrom, Cellular immunity

against tumor specific an t igens , Adv. Cancer Res. 12,
167 (1969).

10. G. Mathe, T. B . Loc, and J . B e r n a r d , Medecine

experimentale— Effet s u r la leucemie 1210 de la Souris d
'une combinaison pa r diazotation d 'A-methopter ine et de
y-globulines de hamsters p o r t e u r s de celle leucemia
pa r he te rogref fe , Acad. Sc. C. R. 246, 1626 (1958).

11. T. Ghose, S. T. Novell, A. Guclu, D. Cameron, A. Bodur

tha , and A. S. MacDonald, Immunochemotherapy of cancer
with chlorambuci l -carry ing an t ibody , Br. Med. J. 3,
495 (1972).
12. F. Hurwitz , R. Levy, R. Maron, M. Wilchek, R. Arnon,
and M. Sela, The covalent b inding of daunomycin and
adriamycin to ant ibodies , Cancer Res. 35, 1175 (1975).

13. F . Hurwitz , R. Kashi , and M. Wilcheck,

Platinum-complexed ant i tumor immunoglobulins tha t
specifically inhibit DNA s y n thes is of mouse tumor cel
ls , J. Natl. Cancer Inst. 69, 47 (1982).

14. G. Kohler and C. Milstein, Continuous cu l ture of

fused cells sec re t ing antibodies of predef ined specif
ici ty, Nature 256, 495 (1975).

15. K. E. Hellstrom, I. Hellstrom, and J . P. Brown, Human

tumorassociated ant igens identified by monoclonal an t
ibodies . In , Springer Seminars in Immunopathology
Series, Mechanisms of Host Resistance in Cancer, Vol. 5
(R. W. Baldwin, e d . ) , Spr inge r -Ver lag , New York,
1982, p . 127.

16. S. M. Larson , J . A. Carrasqui l lo , K. A. Krohn, J .

P . Brown, R. W. McGuffin, J . M. F e r e n s , M. M.
Graham, L. D. Hill, P. L. Beaumier, K. E. Hellstrom, and
I. Hellstrom, Localization of p97 specific Fab fragments
in human melanoma as a basis for r ad io the rapy , J.
Clin. Invest. 72, 2101 (1983).

17. H. F. Sea r s , J . Mattis, and D. Her lyn, Phase I

clinical t r ia l with monoclonal ant ibody in the t
reatment of gas t rointes t inal tumors , Lancet 1, 762
(1982).

18. R. K. Oldham, K. A. Foon, A. C. Morgan, C. S.

Woodhouse, R. W. Schraff, P . G. Abrams, M. Fe r , C. S.
Schoenberger , M. Far re l l , E. Kimball, and S. A.
Sherwin, Monoclonal antibody t h e r a p y of malignant
melanoma: In vivo localization in cutaneous metastasis
after in t ravenous administrat ion, J. Clin. Oncol. 2,
1235 (1984).

19. G. E. Goodman, P. L. Beaumier, I. Hellstrom, B . Fe

rnyhough , and K. E. Hellstrom, Phase I t r ial of murine
monoclonal an t i bodies in pa t ients with advance
melanoma, J. Clin. Onocol. 3, 340 (1984).

20. F. K. J a n s e n , H. E. Blythman, D. Ca r r i e r e ,
P. Casellas, P. Gros , O. Gros , J . C. Lauren t , F .
Paloucci, B . Pau, P. Poncelet , G. Richer , H. Vidal, and
G. A. Voisin, Immunotoxins: Hybrid molecules combining
high specificity and potent cy to toxic i ty , Immunol.
Rev. 62, 185 (1982).

21. Vitetta and J . W. Uhr , The potential use of

immunotoxins in t r a n s planta t ion , cancer t h e r a p
y , and immunoregulation, Transplant 37, 535 (1984).

22. K. E. Hellstrom and I. Hellstrom, Monoclonal

anti-melanoma antibodies and the i r possible clinical u s
e . In , Monoclonal Antibodies for Cancer Detection and
Therapy (R. W. Baldwin, E d . ) , Academic P r e s s , New
York, 1984 p . 17.

23. G. Galfre, S. C. Howe, C. Milstein, G. W. Bu tche r ,

and J . C. Howard, Antibodies to major histocompatability
ant igens produced by hybr id cell l ines , Nature 266,
550 (1977).

24. H. Koprowski and Z. Steplewski , Human solid tumor ant

igens defined by monoclonal ant ibodies . In , Monoclonal
Antibodies and T-Cell Hybridomas (G. J . Hammerling, U.
Hammerling, and J . F . Kearney , E d s . ) , Elsevier ,
North-Holland, 1981, p . 161.

25. K. E. Hellstrom, J . P . Brown, and I. Hellstrom,

Monoclonal antibodies to tumor an t igens . In ,
Contemporary Topics in Immunobiology, Vol. II (N. L.
Warner, E d . ) , Plenum P r e s s , New York, 1980, p .
117.

26. P . Thammana and M. D. Scharff, Immunoglobulin heavy

chain class switch from IgM to IgG in a hybridoma, Eur. J.
Immunol. 13, 614 (1983).

27. J . P. Brown, P. W. Wright, C. E. Har t , R. G.

Woodbury, K. E. Hellstrom, and I. Hellstrom, Protein ant
igens of normal and malignant human cells identified by
immunoprecipitation with monoclonal an t ibodies , J.
Biol. Chem. 255, 4980 (1980).

28. T . Brodin , I. Hellstrom, K. E. Hellstrom, K. A.

Karlsson, H. O. Sjogren, N. S t romberg , and J . T h u r
i n , Mouse monoclonal an t i bodies with specificity for
the melanoma-associated ganglioside d is i
alyllactosylceramide (GD3) also react with the s t r u c t
u r a l analogue disialylparagloboside. Biochim. Biophys.
Acta 837, 349 (1985).

29. L. Olsson and H. S. Kaplan, Human-human hybridomas p r

o d u c ing monoclonal antibodies of predefined antigenic
specifici ty, Proc. Natl. Acad. Sci. USA 77, 5429 (1980).
30. C. Croce, A. Linnenbach, W. Wall, Z. Steplewski , and
H. Koprowski , Production of human hybridomas secre t ing
antibodies to measles v i r u s , Nature 288, 488 (1980).

31. J . Schlom, D. Wunderlich, and Y. A. Teramoto,

Generation of human monoclonal antibodies react ive with
human mammary ca r cinoma cel ls , Proc. Natl. Acad. Sci.
USA 77, 6841 (1980).

32. A. W. Siadak and M. E. Lostrom, Cell-driven viral t

ransformat ion , in Human Hybridomas and Monoclonal
Antibodies (E. G. Engleman, S. K. H. Foung, J . Larr ick ,
and A. Raubi t schek , e d s . ) , Plenum Publ i sh ing ,
1985, p . 167.

33. D. Colcher, P . Horan Hand, M. Nuti , and J . Schlom, A

spec trum of monoclonal antibodies react ive with human
mammary tumor ceUs, Proc. Natl. Acad. Sci. USA 78, 3199
(1981).

34. R. J . Cote, D. M. Morrissey, A. N. Houghton, E. J .

Beat t ie , and H. F . Oet tgen , Generation of human
monoclonal antibodies react ive with cellular an t i gens
, Proc. Natl. Acad. Sci. USA 80, 2026 (1983).

35. T. Tai , L. D. Cahan, J . C. Paulson, R. E. Saxton, and

R. F. I r ie , Human monoclonal ant ibody against
ganglioside G D 2 : Use in development of enzyme-linked
immunosorbent assay for the monitoring of anti-Gj^2 in
cancer p a t i e n t s , J. Natl. Cancer Inst. 73, 627
(1984).

36. S. L. Morrison, M. J . Johnson , L. A. Herzenbe rg ,

and V. T. Oi, Chimeric human antibody molecules: Mouse an
t igen-b ind ing domains with human constant region
domains, Proc. Natl. Acad. Sci. USA 81, 6851 (1984).

37. I. Hellstrom, V. Brankovan , and K. E. Hellstrom, An

IgGl an t i body to a human melanoma-associated antigen has
s t r o n g ant i tumor effects in vitro and in vivo, Proc.
Natl. Acad. Sci. 82, 1499 (1985).

38. G. Klein, H. O. Sjogren, E. Klein, and K. E. Hellstrom,

Demons t ra t ion of res i s tance against
methylcholanthreneinduced s a r comas in the pr imary
autochthonous hos t , Cancer Res. 20, 1561 (1960).

39. K. D. Bageshaw, Third Gordon Hamilton-Fairley Memorial

Lect u r e . Tumour markers—Where do we go from here? Br.
J. Cancer 48, 167 (1983).

40. J . P. Brown, R. G. Woodbury, C. E. Har t , I.

Hellstrom, and K. E. Hellstrom, Quanti tat ive analysis of
melanoma-associated antigen p97 in normal and neoplastic t
i s s u e s , Proc. Natl. Acad. Sci. USA 78, 539 (1981).

41. J . P . Brown, K. Nishiyama, I. Hellstrom, and K. E.

Hellstrom, S t ruc tura l character izat ion of human
melanoma-associated antigen p97 us ing monoclonal an t
ibodies , J. Immunol. 127, 539 (1981).

42. D. J . Slamon, J . B. DeKernion, I. M. Verma, and M. J

. Cline, Expression of cellular oncogenes in human
maligancies, Science 224, 256 (1984).

43. R. T. Schimke, Gene amplification, d r u g res is tance

and cance r , Cancer Res. 44, 1735 (1984).

44. J . M. Klitzman, J . P. Brown, K. E. Hellstrom, and I.

Hellstrom, Antibodies to murine leukemia v i rus gp70 and
p 15(E) in s e ra of BALB/c mice immunized with syngeneic
chemically induced s a r comas, J. Immunol. 124, 2552
(1980).

45. I. Hellstrom, K. E. Hellstrom, N. Rollins, V. K. Lee,

and G. T. Nepom, Monoclonal antibodies to cell surface ant
igens shared by chemically induced mouse b ladder
carcinomas Cancer Res., 45, 2210 (1985).

46. L. A. S t e r n b e r g e r , The unlabelled antibody

pe rox idase ant iperoxidase (PAP) method. In ,
Immunocytochemistry, John Wiley & Sons, I n c . , New
York, 1979, p . 104.

47. H. J . Gar r igues , W. Ti lgen, I . Hellstrom, W.

Ranke , and K. E. Hellstrom, Detection of a human
melanoma-associated an t igen , p97, in histological sect
ions of pr imary human melanomas, Int. J. Cancer 29, 511
(1982).

48. P. L. Beaumier, K. A. Krohn, J . A. Carrasqui l lo , J

. Eary , I. Hellstrom, K. E. Hellstrom, W. B. Nelp, and S.
M. Larson, Melanoma localization in nude mice with
monoclonal Fab against p97 J. Nucl. Med. 26, 1172 (1985).

49. F. Buchegge r , C. M. Haskell, M. Sch reye r , B . R.

Scazziga, S. Randin , S. Car re l , and J P . Mach,
Radiolabeled fragments of monoclonal antibodies against
carcinoembryonic ant igen for localization of human colon
carcinoma grafted into nude mice, J. Exp. Med. 158, 413
(1983).

50. D. Her lyn , J . Powe, A. Alavi, J . A. Mattis, M. Her

lyn, C. E r n s t , R. Vaum, and H. Koprowski,
Radioimmunodetection of human tumor xenograf ts by
monoclonal ant ibodies , Cancer Res. 43, 2731 (1983).

51. M. O. Nelson, F. H. DeLand, D. Shocat, S. J . Benne t t

, and D. M. Goldenberg , External imaging of gas t r i c
-cancer metastases with rad io labe led CEA and CSAp ant
ibodies , N. Engl. J. Med. 7, 309 (1983).

52. J P . Mach, F. Buchegge r , M. Forni , J . R i t scha

rd , C. Berche , J -L . Sch reye r , C. Gi radrde t , R.
S. Accolla, and S. Car re l , Use of rad io labe led
monoclonal anti-CEA antibodies for the de tection of human
carcinomas by ex te rna l photoscanning and tomoscint
igraphy, Immunol. Today 2, 239 (1981).

53. J . F. Chatal , J . C. Saccavini , P. Fumoleau, J . Y.

Douillard, C. Cu r t e t , M. Kremer, B. Le Mevel, and H.
Koprowski, Immunoscint igraphy of colon carcinoma, J. Nucl.
Med. 25, 307 (1984).

54. S. M. Larson, J . P . Brown, P. W. Wright, J . A.

Carrasqui l lo , I. Hellstrom, and K. E. Hellstrom,
Imaging of melanoma with 1 3 1 I label led monoclonal ant
ibodies , J. Nucl. Med. 24, 123, (1983).

55. S. M. Larson, J . A. Carrasqui l lo , K. A. Krohn, R.

W. McGuffin, I. Hellstrom, K. E. Hellstrom, and D. Lys t e
r , Diagnostic imaging of malignant melanoma with
radiolabeled ant i tumor ant i bodies , JAMA 249, 811
(1983).

56. S. Fe r rone , S. P. Giacomini, P . G. Natali, D. Rui

te r , G. B u r a g gi , L. Callegaro, and U. Rosa, A high
molecular weight-melanoma associated ant igen (HWM-MAA)
defined by monoclonal ant ibodies: A useful marker to
radioimage tumor lesions in pa t ien ts with melanoma. In
, Proceedings of the First International Symposium on
Neutron Capture Therapy, Brookhaven National Laboratories
(R. G. Fairchild and G. L. Brownell, E d s . ) , 1983, p p
. 174-183.

57. J . A. Carrasqui l lo , K. A. Krohn, P. Beaumier, R. W.

McGuffin, J . P. Brown, K. E. Hellstrom, and I. Hellstrom,
Diagnosis and t he r apy of solid tumors tumors with rad
io labe led Fab , Cancer Treat. Rep. 68, 317 (1984).
58. S. M. Larson , J . A. Carrasqui l lo , R. W. McGuffin,
K. A. Krohn, J . M. F e r e n s , L. D. Hill, P . L.
Beaumier, K. E. Hells t rom, and I. Hellstrom, Use of
I^Sl-labelled, murine Fab against a high molecular weight
ant igen of human melanoma: Preliminary expe r i ence .
Radiology 155, 487 (1985).

59. D. S. E t t i nge r , S. E. O r d e r , M. D. Wharam,

M. K. P a r k e r , J . L. Klein, and P . K. Leichner ,
PhaseI I s t u d y of isotoic immunoglobulin t h e r a p y
for pr imary l iver cance r , Cancer Treat. Rep. 66, 289
(1982).

60. I. Hellstrom, K. E. Hellstrom, and T. H. Shephe rd ,

Cellmediated immunity against ant igens common to human
colonic carcinomas and fetal gut epithelium, Int. J.
Cancer 6, 346 (1970).

61. D. L. Morton, R. A. Malmgren, E. C. Holmes, and A. S.

Ketcham, Demonstration of antibodies against human
malignant melanoma by immunofluorescence. Surgery 64, 233
(1968).

62. I . Hellstrom, K. E. Hellstrom, G. E. Pierce , and J .

P . S. Yang, Cellular and humoral immunity to different
types of human neoplasms, Nature 220, 1352 (1968).

63. I . Hellstrom and K. E. Hellstrom, Cell-mediated react

iv i ty to human tumor type associated an t igens : Does
it exis t? J. Biol. Response Modifiers, 2, 310, 1983.

64. R. C. Bas t , J r . , T. L. Klug, E. St . John , E.

Jenison, J . M. Niloff, H. Laza rus , R. S. Berkowitz, C.
T. Griffi ths, L. P a r k e r , V. R. Zurawski , and R. C.
Knapp, A radioimmunoassay us ing a monoclonal ant ibody to
monitor the course of epithelial ovarian cance r , N.
Engl. J. Med. 309, 883 (1983).

65. R. A. Miller, D. G. Maloney, R. Warnke, and R. Levy, T

rea t ment of B-cell lymphoma with monoclonal ant
iidiotypic an t ibody, N. Engl. J. Med. 306, 517 (1981).

66. H. Shiku, T. Takahash i , H. F . Oet tgen , and L. J .

Old, Cell surface ant igens of human malignant melanoma: I
I . Serological t yp ing with immune adherence assays and
definition of two new surface an t i gens , J. Exp. Med.
144, 873 (1976).

67. G. Klein, P . Clifford, E. Klein, and E. S t je rnsward

, Search for tumor-specific immune react ions in Burk i t
t ' s lymphoma pat ients by the immunofluorescence reac t
ion , Proc. Natl. Acad. Sci. USA 55, 1628 (1966).

68. R. W. Baldwin, E d . , Springer Seminars in

Immunopathology Series, Mechanisms of Host Resistance in
Cancer S p r i n g e r Ver lag , New York, 1982

69. R. W. Baldwin, E d . , Monoclonal Antibodies for Cancer

Detection and Therapy, Academic P r e s s , New York
(1985).

70. R. A. Reisfeld and S. Fe r rone , E d s . , Melanoma

Antigens and Antibodies, Plenum P r e s s , New York,
1982.

71. G. Reithmum, H. Koprowski, S. von Kleist , and K. Munk,

Eds . Contribution to Oncology, Genes and Antigens in
Cancer Cells , Ka rge r /Base l , Vol. 19, 1984.

72. M. F. Greaves , Analysis of the clinical and biological

significance of lymphoid phenbtypes in acute leukemia,
Cancer Res. 42, 4752 (1981).

73. J . Ri tz , J . M. Pesando , J . Notis-McConarty, H.

Laza rus , and S. F . Schlossman, A monoclonal ant ibody
to human acute lymphoblast ic leukemia an t igen , Nature
283, 583 (1980).

74. J . Ri tz , J . M. Pesando, J . Notis-McConarty, J .

Clavell, L. A. Sallan, and S. F. Schlossman, Use of
monoclonal antibodies as diagnostic and the rapeu t ic
reagen ts in acute lymphoblastic leukemia, Cancer Res. 41,
4771 (1981).

75. S. E. Sallen, J . Ritz , J . Pesando, R. Gelbar, C.

O'Brien, S. Hitchcock, F. Coral, and S. F . Schlossman,
Cell surface an t igens ; prognost ic implications in
childhood acute lymphoblastic leukemia, Blood 55, 395
(1980).

76. V. Raso, J . Ritz , M. Basala, and S. F. Schlossman,

Monoclonal ant ibody-r ic in A chain conjugate selectively
cytotoxic for cells bear ing the common acute
lymphoblastic leukemia an t igen , Cancer Res. 42, 457
(1982).

77. J . Ritz, J . M. Pesando, J . Notis-McConarty, and S.

F. Schlossman, Modulation of human acute lymphoblastic
leukemia ant igen induced by monoclonal ant ibody in
vitro. J. Immunol. 125, 1506 (1980).

78. R. Su the r l and , D. Delia, C. Schnieder , R. Newman,

J . Kemshead , and M. Greaves , Ubiquitous cell surface
glycoprotein on tumor cells is prol i ferat ion-associated
recep tor for t r a n s f e r r i n , Proc. Natl. Acad.
Sci. USA 78, 4515 (1981).

79. P. J . Mc Alpine and D. Bootsma, Report of the

committee on the genetic const i tut ion of chromosomes,
2, 3, 4, and 6. Oslo Conference (1981): Sixth Internat
ional Workshop on Human Gene Mapping, Cytogenet. Cell
Genet. 32, 121 (1982).

80. I. S. Trowbridge and F. Lopez, Monoclonal ant ibody to

t r a n s ferr in receptor blocks t r ans fe r r i n b
inding and inhibi ts human tumor cell g rowth , Proc.
Natl. Acad. Sci. USA 79, 1175 (1982).

81. I. Royston, J . A. Majda, S. M. Bai rd , B. L. Meserve,

and J . C. Griff i ths, Human T cell ant igens defined by
monoclonal ant ibodies : the 65,000 dalton ant igen of T
cells (T65) is also found on chronic lymphocytic leukemia
cells bea r ing surface immunoglobulin, J. Immunol. 125,
725 (1980).

82. R. A. Miller and R. Levy, Response of cutaneous T cell

lymphoma to t he r apy with hybridoma monoclonal an t ibody
, Lancet 2, 8240 (1981).

83. I. D. Berns te in , R. C. Nowinski, M. R. Tarn, B .

McMaster, L. L. Houston, and E. A. Clark , Monoclonal ant
ibody t he r apy of mouse leukemia. In , Monoclonal
Antibodies (R . H. Kennet t , T. G. McKearn, and K. B .
Bechtol , E d s . ) , Plenum P r e s s , New York, 1980, p
p . 275.

84. P . A. B u n n , J r . , J . A. Carrasqui l lo , A. M.
Keenan, R. W. Schroff, K. A. Foon, S. M. Hsu, A. F .
Gazdar , J . C. Reyno lds , P. Pe ren t e s i s , and S. M.
Larson, Imaging of T-cell lymphoma by radiolabeled
monoclonal an t ibody , Lancet, 2, 1219, (1984).

85. K. E. Hellstrom, I. Hellstrom, and J. P . Brown,

Monoclonal antibodies to melanoma-associated an t igens .
In , Monoclonal Antibodies and Cancer (G. L. Wright, E d .
) , Marcel Dekker , I n c . , New York, 1984, p p . 31-47
.

86. R. G. Woodbury, J . P . Brown, S. M. Loop, K. E.

Hellstrom, and I. Hellstrom, Analysis of normal and
neoplastic human t i s sues for the tumor-associated prote
in p97, Int. J. Cancer 27, 145 (1981).

87. I. Hellstrom, J . P. Brown, and K. E. Hellstrom,

Monoclonal antibodies to two determinants of
melanoma-antigen p97 act s y n ergist ical ly in
complement-dependent cytotoxic i ty , J. Immunol. 127, 157
(1981).

88. G. T. Nepom, K. A. Nelson, S. L. Holbeck, I. Hellstrom,

and K. E. Hellstrom, Induct ion of immunity to a human
tumor marker by in vivo administration of ant iidiotypic
antibodies in mice, Proc. Natl. Acad. Sci. USA 81, 2864
(1984).

89. J . P . Brown, R. M. He wick, I. Hellstrom, K. E.

Hellstrom, R. F. Doolittle, and W. J. Dreye r , Human
melanoma-associated ant igen p97 is s t ruc tu ra l ly and
functionally related to t r a n s f e r r i n , Nature 296,
171 (1982).

90. G. Plowman, J . P . Brown, C. A. Enns , J . Schroder ,

B . Nikinmaa, H. H. Suss man, K. E. Hellstrom, and I.
Hellstrom, Ass ignment of the gene for human
melanoma-associated ant igen p97 to chromosome 3, Nature
303, 70 (1983).

91. J . P . Brown, T. M. Rose, J . W. Fors t rom, I.

Hellstrom, and K. E. Hellstrom, Isolation of a cDNA clone
for human melanomaassociated antigen p97. In , Molecular
Biology of Tumor Cells, 1984, ( B . Wahren, e d . ) ,
Raven P r e s s , New York 1985, p . 157.

91a. T. M. Rose, G. D. Plowman, D. B. Teplow, W. J . Dreye

r , K. E. Hellstrom, and J . P . Brown, Primary s t r u c
t u r e of the human melanoma-antigen p97 (melanotransferr
in) deduced from the mRNA sequence , Proc. Natl. Acad.
Sci. USA, 83, 1261 (1986).

92. M. J . Atass i , Precise determination of the en t i re

antigenic s t r u c t u r e of lysozyme: molecular features
of prote in antigenic s t r u c t u r e s and potential of
surface stimulation synthesis—A powerful new concept for
prote in b inding s i t e s , Immunochemistry 15, 909
(1978).

93. T. F. Bumol and R. A. Reisfeld, Unique g lycoprote

in-pro teoglycan complex defined by monoclonal ant ibody on
human melanoma cel ls , Proc. Natl. Acad. Sci. USA 79,
1245 (1982).

94. K. Imai, B. S. Wilson, A. Bigot t i , P . G. Natali,

and S. Fe r rone , J . , A 94,000-dalton glycoprotein
expressed by human melanoma and carcinoma cel ls , J.
Natl. Cancer Inst. 69, 761, 1982.

95. I . Hellstrom, H. J . Ga r r igues , L. Cabasco, G. H.

Mosely, J . P. Brown, and K. E. Hellstrom, Studies of a
high molecular weight human melanoma-assocated an t igen ,
J. Immunol. 130, 1467 (1983).

96. A. H. Ross , M. Her lyn , C. S. E r n s t , D. G u e r

r y , J . Bennicell , B. F . D. Ghr i s t , B . Atkinson,
and H. Koprowski, Immunoassay for melanoma-associated
proteoglycan in the se ra of pa t ients us ing monoclonal
and polyclonal an t ibodies , Cancer Res. 44, 4642 (1984).

97. G. Schul tz , T. F . Bumol, and R. A. Reisfeld,

Monoclonaldirected effector cells selectively lyse human
melanoma cells in vitro and in vivo, Proc. Natl. Acad.
Sci. USA 80, 5407 (1983).

98. W. G. Dippold, K. O. Lloyd, L. T. C. Li, H. Ikeda, H.

F. Oe t tgen , and L. J . Old, Cell surface ant igens of
human malignant melanoma: Definition of six antigenic
systems with mouse monoclonal ant ibodies , Proc. Natl.
Acad. Sci. USA 77, 6114 (1980).

99. K. O. Pukel , L. R. Lloyd, W. G. T rabas sos , W. G.

Dippold, H. F . Oet tgen , and L. J . Old, GD3, a
prominent ganglioside of human melanoma. Detection and
character iza t ion by mouse monoclonal an t ibody , J.
Exp. Med. 155, 1133 (1982).

100. M-Y. Yeh, I. Hellstrom, J . P . Brown, G. A. Warner, J

. A. Hansen, and K. E. Hellstrom, Cell surface ant igens
of human melanoma identified by monoclonal an t ibody ,
Proc. Natl. Acad. Sci. USA 76, 2927 (1979).

101. E. Nudelman, S. Hakomori, R. Kannagi , S. Levery ,

M-Y. Yeh, K. E. Hellstrom, and I. Hellstrom, Character
izat ion of a human melanoma-associated ganglioside ant
igen defined by a monoclonal an t ibody , 4 .2 , J. Biol.
Chem. 257, 12752 (1982).

102. D. A. Cheresh , R. A. Reisfeld, and A. P. Vark i ,

O-Acetylation of disialoganglioside GD3 by human melanoma
cells c rea tes a unique antigenic de te rminant , Science
225, 846 (1984).
103. J . M. Levine, L. Beasley, and W. B. Stal lcup, The D
. l . l an t igen: A cell surface marker for germinal
cells of the cen t ra l ne rvous sys tem, J. Neurosci. 4,
831 (1984).

104. D. A. Che re sh , A. P. Varki , N. M. Varki , W. B.

Stal lcup, J . Levine, and R. A. Reisfeld, A monoclonal
ant ibody recognizes an O-acylated sialic acid in a human
melanoma-associated ganglioside, J. Biol. Chem. 259, 259
7453 (1984).

105. H. Koprowski, M. Her lyn, Z. Steplewski , and H. F.

Sea r s , Specific ant igen in serum of pa t ien ts with
colon carcinoma, Science 212, 53 (1981).

106. M. Her lyn, M. Blaszczyk, and H. Koprowski,

Immunodiagnosis of human solid t umours , Contr. Oncol.
19, 160 (1984).

107. V. G insbu rg , P. Fredman, and J . L. Magnani,

Cancerassociated ca rbohydra te ant igens detected by
monoclonal an t i bodies , Contr. Oncol. 19, 44 (1984).

108. H. F . Sea r s , D. Heryln , H. Koprowski, and J . Wen

Shen, Immunotherapy of gas t ro in tes t ina l
malignancies with a murine IgG2a an t ibody , Contr.
Oncol. 19, 180 (1984).

109. H. Koprowski, D. Her lyn , M. Lubeck, E. DeFrei tas ,

and H. F . Sea r s , Human ant i id iotype antibodies in
cancer p a t i e n t s : Is the modulation of the immune
response beneficial for the pa t ient? Proc. Natl. Acad.
Set USA 81, 216 (1984).

110. D. G. Gilliland, Z. Steplewski , R. J . Collier, K. F

. Mitchell, T. H. Chang , and H. Koprowski, Ant ibody-di
rec ted cytotoxic agen t s : Use of monoclonal ant ibody
to direct the action of toxin A chains to colorectal
carcinoma cel ls , Proc. Natl. Acad. Sci. USA 77:4539
(1980).

111. G. F. Rowland, C. A . , Axton, R. W. Baldwin, J . P .

Brown, J . R. F. Corvalan, M. J . Embleton, V. A. Gore, I.
Hellstrom, K. E. Hellstrom, E. Jacobs , C. H. Marsden, M.
V. Pimm, R. G. Simmonds, and VV. Smith, Antitumor p roper
t i e s of vindesine-monocolonal ant ibody conjugates
Cancer Immunol. Immunothera., 19, 1 (1985).

112. A. C. Braban , J . F . Williams, and R. D. Cardiff, A

monoclonal ant ibody to a human b reas t tumor protein
released in response to e s t r o g e n , Cancer Res. 44,
2704 (1984).

113. S. B. Baylin, A. F. Gazdar , J . D. Minna, S. D. Berna

l , and J . H. Shaper , A unique cel l-surface protein
phenotype d i s t inguishes human small-cell from
non-small-cell lung cance r , Proc. Natl. Acad. Sci. USA
79, 4650 (1982).

114. L. C. Huang, M. Brockhaus , J . L. Magnani, F . Cu t t

i t t a , S. Rosen, J . D. Minna, and V. Ginsburg , Many
monoclonal antibodies with an apparen t specificity for
cer ta in lung cancers are directed against a suga r
sequence found in lacto-Nfucopentaose III , Arch. Biochem.
Biophys. 220, 318 (1983).

115. S. T. Rosen, J . L. Mulsine, F. Cu t t i t t a , J .

Fedorko, D. N. Carney , A. F. Gazdar , and J . D. Minna,
Analysis of human small cell lung cancer differentiation
ant igens us ing a panel of ra t monoclonal an t ibodies ,
Cancer Res. 44, 2052 (1984).

116. M. M. Varki , R. A. Reisfeld, and L. E. Walker,

Antigens associated with a human lung adenocarcinoma
defined by monoclonal an t ibodies , Cancer Res. 44, 681
(1984).

117a. I. Hellstrom, D. Horn, P . l i n s l e y , J . P.

Brown, V. Brankovan , and K. E. Hellstrom, Monoclonal mouse
atibodies raised against human lung carcinoma, Cancer
Res., 46, 3917 (1986).

117b. I . Hellstrom, P. L. Beaumier, and K. E. Hellstrom,

Antitumor effects of L6, an IgG2a ant ibody reac t ing
with most human c a r cinomas, Proc . Natl. Acad. Sci. USA,
83, 7059 (1986).

118. G. J . Todaro , H. Marquard t , D. R. Twardzik , P .

A. Johnson , C. M. Fry l ing , and J . E. DeLarco,
Transforming growth factors p roduced by tumor cel ls . In
, Tumor Cell Heterogeneity, Origins and Implications, Vol.
4, Academic P r e s s , New York, 1982, p . 205.

119. L. Sachs , Control of growth and normal

differentiation in leukemic cel ls : Regulation of the
developmental program and res tora t ion of the normal
phenotype in myeloid leukemia, J. Cell. Physiol. Suppl. 1,
151 (1982).
120. I. J . Fidler and G. Pos te , Macrophage-mediated des
t ruc t ion of malignant tumor cells and new s t ra teg
ies for the t he r apy of metastatic d i seases , Springer
Emin. Immunopathol. 5, 161 (1982).

121. J . Gutterman and J . Quesda, Clinical invest igat ion

of part ial ly p u r e and recombinant DNA derived
leukocyte in ter feron in human cance r , Tex. Rep. Biol.
Med. 41, 626 (1981-1982).

122. F. L. Meyskens, J r . , E. Gilmartin, D. S. A lbe r t

s , N. S. Levine, R. Brooks , S. E. Salmon, and E. A.
Surwit , Activity of isoretinoin against squamous cell
cancers and pre-neoplas t ic les ions , Cancer Treat. Rep.
66, 1315 (1982).

123. G. E. Goodman, D. S. A lbe r t s , D. L. E rnes t ,

and F . L. Meys k e n s , Trial of ret inol in cancer p a t
i e n t s , J. Clin. Oncol. 1, 394 (1983).

124. R. Arnon and E. Hurwitz , Ant ibody-and po lymer -drug

con

, j u g a t e s , In , Durable Resistance in Crops ( F .

Lamberti , J . M. Waller, and N. A. Van der Graff, E d s .
) , Plenum P r e s s , New York, 1983, p . 23.

125. M. Sela, E. Hurwitz , and R. Maron, Use of antibodies

for del ivery of chemotherapeut ic d r u g s . In ,
Non-specific Immunity in the Prevention and Treatment of
Cancer, Vol. 43, Pontificia Academia Scientiarvm, 1979, p
. 481.

126. B. A. Chabner and C. E. Myers. In , Cancer, Principles

and Practice of Oncology (V. T. DeVita and R. S. Hellman,
E d s . ) , J . B . Lippincott & C o . , Philadelphia,
1982, p . 156.

127. S. E. Salmon, A. W. Hamberger , B. Soehlen, G. G. Dur

ie , D. S. Alber t s , and T. E. Moon, Quantitation of
differential sensi t iv i ty of human tumor stem cells to
an t i -cancer d r u g s , N. Engl. J. Med. 298, 1321
(1978).

12 8. L. Foulds , The experimental s t u d y of tumor p

rogress ion : A review, Cancer Res. 14, 327 (1954).

129. I. R. Hart and I. J . Fidler , The implications of

tumor h e t e r geneity for s tudies on the biology of
cancer metas tas is , Biochim. Biphys. Acta 651, 37 (1981).
130. G. L. Nicolson and G. Poste , Tumor cell d ivers i ty
and host r e sponses in cancer metas tas is . Par t I.
Proper t ies of metastatic cel ls , Curr. Probl. Cancer 7,
1 (1982).

131. M-Y. Yeh, I. Hellstrom, and K. E. Hellstrom, Clonal

variat ion in express ion of a human melanoma antigen
defined by a monoclonal an t ibody , J. Immunol. 126, 1312
(1981).

132. K. Albino, O. Lloyd, A. N. Houghton, H. F. Oet tgen ,

and L. J . Old, Heterogenei ty in surface ant igen and
glycoprotein express ion of cell lines der ived from
different melanoma metastases of the same pa t i en t .
Implications for the s t u d y of tumor an t igens , J.
Exp. Med. 154, 1764 (1981).

133. T. Ghose and A. H. Blair , Antibody-limited cytotoxic

agents in the t rea tment of c ance r , J. Natl. Cancer
Inst. 61, 657 (1978).

134. J . D. Everal l , P . Dowd, D. A. L. Davies , G. J .

O'Neill, and G. F. Rowland, Treatment of melanoma by pass
ive humoral immunotherapy us ing ant ibody d r u g synerg
i sm, Lancet 1, 1105 (1977).

135. I. Tsukada , W. K. Bishop, N. Hibe, H. Hirai , E.

Hurwitz , and M. Sela, Effect of conjugates of daunomycin
and antibodies to ra t a lphafe topro te in-producing
tumor cel ls , Proc. Natl. Acad. Sci. USA 79, 621 (1982).

136. G. F. Rowland, R. G. Simmonds, J . R. F. Corvalan, R.

W. Baldwin, J . P . Brown, M. J . Embleton, C. H. J . Ford
, K. E. Hellstrom, I . Hellstrom, J . T . Kerns head , C.
E. Newman, and C. S. Woodhouse, Monoclonal antibodies for
t a rge t ed t he rapy with v indes ine . In , Protides of
the Biological Fluids, Proceedings of Colloquium 30 (H. P e
e t e r s , E d . ) , Pergamon P r e s s , New York, 1983,
p p . 375-379.

137. M. J . Embleton, G. F. Rowland, R. G. Simmonds, E. J

acobs , C. H. Marsden, and R. W. Baldwin, Selective
cytotoxici ty against human tumour cells by a
vindesine-monoclonal ant ibody conjugate , Br. J. Cancer
47, 43 (1983).

138. G. F. Rowland and R. G. Simmonds, Effects of

monoclonal an t ibod ies -d rug conjugates on human tumour
cell cu l tu res and xenogra f t s . In , Monoclonal
Antibodies for Cancer Detection and Therapy (R. W.
Baldwin, E d . ) , Academic P r e s s , New York 1985, p .
345,

139. E. Klein, Tumors of the skin X. Immunotherapy of

cutaneous and mucosal neoplasms, NY State J. Med. 68, 900
(1968).

140. J. J . Mule 1 , S. Shu , S. L. Schwartz , and S. A.

Rosenberg , Adoptive immunotherapy of es tabl ished
pulmonary metastases with LAK cells and recombinant In te
r l euk in -2 , Science 225, 1487 (1984).