10.1201 9780429276620 Previewpdf

Medical Applications
of
Controlled Release
Volume II
Applications and Evaluation
Editors
Robert S. Langer, Ph.D.

Dorothy Poitras Associate Professor
Biochemical Engineering
Department of Nutrition and Food Science
Whitaker College of Health Sciences
Massachusetts Institute of Technology
Cambridge, Massachusetts
Children's Hospital Medical Center
Boston, Massachusetts
Donald L. Wise, Ph.D.

Vice President
Dynatech RID Company
Cambridge, Massachusetts
Boca Raton London New York
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PREFACE
The ways in which chemicals or drugs are administered have gained increasing attention
in the past 2 decades. Normally, a chemical is administered in high dose at a given time
only to have to repeat that dose several hours or days later. This often results in damaging
side effects and leads to poor control of drug therapy. As a consequence, increasing attention
has been focused on methods for giving drugs continuously for prolonged time periods and
in a controlled fashion. The primary method of accomplishing this controlled release has
been through incorporating the drugs within polymers.
The purpose of this book is to review controlled release technology as it relates to medical
applications. We should perhaps begin with a definition of what a controlled release system
is, and contrast it to a sustained release system. Ideally, a controlled released system is one
in which the rate of release is largely determined by the design of the device itself (which
could be a polymer system or pump) and is not dependent on environmental conditions (e.g.,
pH of the gastrointestinal tract). In contrast, a sustained release system is one which provides
prolonged action but whose release rate is significantly affected by environmental conditions.
Since there is no perfectly clear-cut distinction between “ controlled” and “ sustained”
release, our intention in this book has been to focus principally on controlled release for-
mulations, but to include sustained release systems on those occasions where it is appropriate
to the completeness of a particular topic.
The goal of this text is threefold. The first volume is intended to be a handbook on the
design, fabrication, methods of controlling release, and theoretical considerations of various
classes of drug delivery systems (matrixes, membrane controlled reservoir systems, bioer-
odible systems, and pendant chain systems). Implantable pumps are also discussed. In
addition, two chapters in this section cover the application of these systems for oral and
transdermal delivery. The information provided in this section is intended to enable those
new to the field to be able to develop a particular kind of drug delivery system and to know
how to appropriately modify it to achieve desired release kinetics. The methods of deter-
mining parameters critical to performance evaluation are discussed in detail.
The first part of the second volume covers different areas of medical usage of controlled
release polymers. Each chapter covers a particular area of interest (e.g., ophthalmology)
and gives a critical analysis of both the advantages and disadvantages of controlled release
systems from such standpoints as expense, comfort, control of the disease, possibility of
side effects, and patient compliance. These chapters review both the successes and failures
of controlled release technology in already conducted studies and clinical evaluations, discuss
ongoing studies, and assess future prospects. The types of drug delivery systems used in
these applications are discussed and the types of constraints one would want to impose on
the design of the systems for a practical clinical application are evaluated. The last two
chapters of the second volume will consider the evaluation of drug delivery systems. Such
topics as mathematical modeling and pharmacokinetic and bioavailability considerations are
discussed.
Each chapter is intended to be a complete treatise on a particular topic. As such, there is
a minor amount of repetition, for example, in the case of discussing diffusion equations
between certain chapters. This was done to provide continuity within each chapter itself and
to facilitate the understanding of individual topics for the researcher.
It is hoped all the chapters of the book will complement the other and that the reader will
have a better understanding of when it would be useful to use a controlled release system
for a particular application, what system to choose, and how to formulate and evaluate that
system so that it has desired characteristics.
THE EDITORS
Robert S. Langer, Ph.D. is the Dorothy Poitras Associate Professor of Biochemical

Engineering at MIT. He is in the MIT Department of Nutrition and Food Science, the
Whitaker College of Health Sciences, Technology, and Management, and the Harvard-MIT
Division of Health, Science, and Technology. Dr. Langer is also Research Associate in the
Department of Surgery at Boston’s Children's Hospital. He received a Bachelor’s Degree
from Cornell University in 1970 and an Sc.D. from MIT in 1974, both in chemical engi-
neering. His research interests include drug delivery systems, microencapsulation, medical
applications of enzyme technology, and tumor vascularization. Dr. Langer is the Editor of
Biomaterials and a member of the editorial board of several other biomedical journals. He
is a member of the American Institute of Chemical Engineers, American Chemical Society,
American Society for Artificial Organs, Biomedical Engineering Society, and the Board of
Governors of the Controlled Release Society. He has written 100 articles, 75 abstracts, 10
patents, given 120 invited lectures, and edited 1 book.
Donald L. Wise, Ph.D., is Vice President, Dynatech R/D Company, Cambridge, Mas-
sachusetts. Dr. Wise received his B.S., M.S., and Ph.D. degrees in chemical engineering
at the University of Pittsburgh. Dr. Wise is a specialist in biotechnology including advanced
biomaterials development. While an Associate Professor of Engineering at Widener Uni-
versity in Chester, Pennsylvania, Dr. Wise carried out research as Principal Investigator for
the National Institute of Health. Dr. Wise was an NIH Special Research Fellow at MIT in
Biochemical Engineering, Department of Nutrition and Food Science. Part of his work there
concerned diffusion studies in microbial systems. Dr. Wise received a Corporate Appoint-
ment to Harvard University as a Research Fellow in the Division of Engineering and Applied
Physics. At Dynatech, Dr. Wise has developed a unique program area in biotechnology.
This work has been in both biomaterials and bioconversion, including specialized work on
enzyme stabilization.
Dr. Wise initiated a project for development of a unique implantable sustained release
contraceptive with The Population Council of the Rockefeller University and has continued
this program with the World Health Organization and the U.S. Agency for International
Development; human testing is now scheduled. Dr. Wise was Principal Investigator on a
program to develop a sustained release implant for the chemotherapeutic treatment of malaria
for the Walter Reed Army Institute of Research and has continued this work with WHO.
He was also Principal Investigator on the program for development of an implantable sus-
tained release drug antagonist for treatment of drug addiction patients with the National
Institute for Drug Abuse; human testing has been carried out. Dr. Wise is working on
biopolymers for selectively binding antigens/antibodies for improved sensitivity of diagnostic
systems. Dr. Wise is working with the U.S. Army Institute of Dental Research on a bio-
polymeric repair material for avulsive combat-type maxillofacial injuries. He has a project
with the U.S. Army Medical R & D Command to synthesize an “ enzyme fragment’’ or
peptide for selectively binding chemical agents. In a related biomaterials area, Dr. Wise
initiated a program with the Office of Naval Research (Naval Medical Research Institute,
Bethesda, Maryland) for development of a biocompatible synthetic polymer for the treatment
of bum patients.
CONTRIBUTORS
James M. Anderson Sung W. Kim

Professor of Pathology, Macromolecular Professor of Pharmaceutics
Science, and Biomedical Engineering Department of Pharmaceutics
Case Western Reserve University University of Utah
Cleveland, Ohio Salt Lake City, Utah
Gilbert S. Banker Fred A. Kind

Professor of Industrial Pharmacy Professor of Biology
Head of Industrial and Physical Pharmacy The College of Staten Island
Department City University of New York
School of Pharmacy and Pharmacal Staten Island, New York
Sciences
Purdue University Robert S. Langer
West Lafayette, Indiana Assistant Professor
Nutritional Biochemistry
Howard Conn Department of Nutrition and Food
Clinical Instructor in Opthalmology Science
School of Medicine Massachusetts Institute of Technology
University of Southern California Cambridge, Massachusetts
Los Angeles, California
Harold A. Nash
Charles D. Ebert Associate Director
Senior Research Scientist Center for Biomedical Research
Ciba-Geigy Corporation The Population Council
Ardsley, New York New York, New York
Julian Frick Lawrence S. Olanoff

Department Chief Research Associate and Drug Science
Urological Department Foundation Scholar
General Hospital Department of Pharmacology
Salzburg Medical University of South Carolina
Austria Charleston, South Carolina
J. Max Goodson Nikolaos A. Peppas

Senior Staff Member Professor
Pharmacology Department Head Department of Chemical Engineering
Forsyth Dental Center Purdue University
Boston, Massachusetts West Lafayette, Indiana
Joseph Gresser Michael Phillips

Dynatech R/D Company Professor of Internal Medicine
Belmont, Massachusetts Pharmacology
Chicago Medical School
John S. Kent Chicago, Illinois
Director
Pharmaceutical Development Donald L. Wise
Institute of Pharmaceutical Sciences Vice President
Syntex Research Dynatech R/D Company
Palo Alto, California Cambridge, Massachusetts
TABLE OF CONTENTS
VOLUME I
Chapter 1
Membrane Controlled Reservoir Drug Delivery Systems................................................... 1
William R. Good and Ping I. Lee
Chapter 2
Matrix Systems..................................................................................................................... 41
John R. Cardinal
Chapter 3
Bioerodible Systems............................................................................................................. 69
Jorge Heller
Chapter 4
Controlled Release from Polymers Containing Pendent
Bioactive Substituents.........................................................................................................103
F. W. Harris
Chapter 5
Implantable Pumps..............................................................................................................129
Michael V. Sefton
Chapter 6
Oral Controlled Release Systems....................................................................................... 159
Kinam Park, Ray Wood, and Joseph Robinson
Chapter 7
Transdermal Controlled Release Systems.......................................................................... 203
Gary W. Cleary
Index....................................................................................................................................253
VOLUME II
APPLICATIONS OF CONTROLLED RELEASE SYSTEMS

Chapter 1
Pharmaceutical Applications of Controlled Release — An
Overview of the Past, Present, and Future......................................................................... 1
Gilbert S. Banker
Chapter 2
Controlled Release Systems for Contraception ...................................................................35
Harold A. Nash
Chapter 3
Ocular Applications of Controlled Release 65
Howard Conn and Robert Langer
Chapter 4
Heparin/Polymers for the Prevention of Surface Thrombosis 77
Charles D. Ebert and Sung W. Kim
Chapter 5
Controlled Release for Use in Treatment of Narcotic Addiction ................................... 107
Donald L. Wise
Chapter 6
Dental Applications...........................................................................................................115
J. Max Goodson
Chapter 7
Applications in Cancer...................................................................................................... 139
Julian Frick and Fred Kind
Chapter 8
Veterinary Applications......................................................................................................149
John S. Kent
Chapter 9
Other Controlled Release Applications.............................................................................. 161
Donald L. Wise, Joseph Gresser, Michael Phillips, and Robert Langer
EVALUATION OF CONTROLLED RELEASE SYSTEMS

Chapter 10
Mathematical Models for Controlled Release Kinetics...................................................... 169
Nickolaos A. Peppas
Chapter 11
Pharmacokinetic Modeling and Bioavailability................................................................. 189
Lawrence Olanoff and James Anderson
INDEX.................................................................................................................................221
Applications of Controlled Release Systems
Volume II 1
Chapter 1
PH ARM ACEUTICAL APPLICATIO NS OF CONTROLLED RELEASE:
AN OVERVIEW OF THE PAST, PRESENT, AN D FUTURE
Gilbert S. Banker
TABLE OF CONTENTS
I. History of Controlled Release.................................................................................2

II. Controlled Release of Effectors.............................................................................. 2
A. Terms and Concepts in the Field................................................................2
B. Purposes for the Design of Controlled Release Effector Products........ 5
C. The Ideal Attributes of EffectorControlled Delivery Systems................ 6
D. The Concept of the OptimizedDrug orChemical Effector System........ 7
III. Safety Enhancement as a Primary Objective of Controlled Release Product
Design.........................................................................................................................9
IV. Reliability Enhancement as an Objective of Controlled Release Product
Design....................................................................................................................... 13
V. Effectiveness Enhancement as an Objective of Controlled Release Product
Design....................................................................................................................... 13
VI. Considerations in the Selection of Candidate Drugs and Chemical Effectors
for Incorporation in Controlled Release Systems............................................... 16
A. Physical-Chemical Properties of Drugs Influencing their Viability as
Candidates for Sustained and Controlled Release Systems................... 16
1. Aqueous Solubility and Solubility R a te ....................................... 16
2. Drug Stability and pKa ................................................................... 17
3. Molecular Size and Partition Coefficient.....................................19
B. Biological and Pharmacological Properties of Drugs Influencing
their Viability as Candidates for Sustained and Controlled Release
Systems..........................................................................................................20
1. Size of Dose and Biological Half-Life and Maximum Feasible
Duration ofEffect.......................................................................... 20
2. Absorption Properties.................................................................... 21
3. Distribution and M etabolism ........................................................ 22
4. Safety Margin and Side Effects of the Drug................................ 22
5. Therapeutic Goal, Disease State, and Route of
A dm inistration................................................................................ 23
VII. Regulatory Considerations in Developing Controlled Release Drug
P ro d u cts...................................................................................................................25
A. In Vivo Bioavailability D a ta .....................................................................25
B. In Vitro Drug Release D a ta ...................................................................... 26
VIII. Regulatory Considerations in the Verification of Effectiveness of Controlled
Release Products......................................................................................................27
IX. Significance and Importance of Designing Optimized Effector Controlled
Release Products......................................................................................................29
References............................................................................................................................ 30
2 Medical Applications o f Controlled Release
I. HISTORY OF CONTROLLED RELEASE
The original controlled release pharmaceuticals were coated pills, and they date back
over 1000 years to Greco-Roman antiquity. The first coating of pills is recorded in the
drug literature of early Islam. Rhazes (850 to 923), recommended mucilage coating of
pills using an extract of psyllium seeds while Avicenna (980 to 1037) suggested the
silvering and gilding of pills.1These coating techniques, and many other Islamic devel-
opments in pharmacy and medicine, were adopted in Europe beginning from the 10th
century. Thus many of the nobility of Europe, or other persons of wealth, took some
of their pills in glittering silver- or gold-coated form. These products were not metallic-
coated to provide controlled release, but to mask bitter-tasting agents, to promote
swallowing ease, and for appearance sake. These products did, however, undoubtedly
alter the release of the “ drugs” they contained, as did the “ pearl coating” technique
which soon followed, where pills were coated with a talc-mucilage composition, pro-
ducing coated pills resembling pearls. These “ pearls” and gold- and silver-coated pills
continued to be used through colonial times and into the 19th century, and “ pearls”
even into the 20th century. You may recall seeing such coated pills in restorations of
early American pharmacies or displays of colonial memorabilia. Since talc is not only
water insoluble, but is also water repellent, and since gold and silver resist dissolution
even in aqua regia, most such products undoubtedly exited the gastrointestinal tracts
of their users in substantially the same form in which they were administered, i.e.
intact. Considering the crude and impure form, uncertain safety, and questionable
efficacy of most drugs of that day, these early coatings may at least have served one
use — consumer protection.
Coating technology advanced in the mid to late 1800s, with the following pill coating
advances being reported: first gelatin coatings,2 first sugar-coated pills made in Europe
and used in the U.S.,3 first coated pills made in the U.S.,4 and first enteric-coated pills.5
The natural gum exudate, shellac, was one of the first enteric coating materials.
Various sugar- and enteric-coating techniques were advanced and production tech-
niques developed in the first half of the 20th century. Among the sugar-coating tech-
niques developed was the sealing of the core tablet with an enteric or barrier material,
followed by addition of a second drug dose in sugar-coating layer. The result was a
repeat action or two-step releasing tablet, with one drug dose being released in the
stomach from the sugar coating, and the second dose being released after the barrier-
coated core left the stomach. A major development in coating technology was the
concept of coating a plurality of drug containing beads with combinations of fats and
waxes. This approach was first reported by Blythe6 and was the basis for the first
significant commercially marketed sustained release products in this country. Since the
mid 1900s, hundreds of reports of papers, and nearly a thousand patents have ap-
peared on various approaches to delayed, prolonged, sustained, and most recently,
controlled release. The science and modern technology of sustained and controlled
release is less than 35 years old.
II. CONTROLLED RELEASE OF EFFECTORS
A. Terms and Concepts in the Field

In the late 1940s and early 1950s, the first so-called sustained release products ap-
peared as a major new class of pharmaceutical products in which product design was
intended to modify and improve drug performance by increasing the duration of drug
action and reducing the required frequency of dosing. Some of the first such products
were actually repeat action forms (Curve B of Figure 1). These products were typically
coated tablets, in which the coating contained the initial dose of drug, and was de-
Volume II 3
signed for immediate release in the stomach. The tablet core was designed not to release
in the stomach, but to release later during its passage along the intestinal tract. Curve
B of Figure 1 depicts the idealized profile of such a repeat action form. Unfortunately,
such products tended to be sensitive to physiological variables such as gastric emptying,
and the two releases could occur virtually one on top of the other. Furthermore, they
did not produce smooth drug concentration or activity time profiles, but produced
profiles with peaks and valleys (Figure 1).
The Spansule®, which was probably the first true prolonged release system, mar-
keted by Smith, Kline, and French Labs of Philadelphia, was comprised of populations
of small coated beads, which were in turn placed in a capsule.6 The 50 to 100 or more
beads per capsule were comprised of several bead populations, each designed to release
at a different rate. A major advantage of the bead approach is that the beads are
gradually metered from the stomach, rather than dumped out at any single time as
with a tablet, thereby circumventing the major physiologic variable of gastric empty-
ing, and producing a built-in prolonged release effect. Curve C of Figure 1 illustrates
the type of rate profile seen from such sustained release products. A large number of
the currently marketed prolonged release products use the coated bead (tiny time cap-
sule) approach. The definition of a prolonged release product is inherent in Curve C
of Figure 1. Such dosage forms initially make the drug available to the body in an
amount adequate to produce the desired drug concentration or activity response. How-
ever, a portion of the active ingredient which they contain is not immediately available,
but only becomes available with time as this retarded fraction slowly dissolves at a rate
which extends the length of time over which the blood or tissue level or response is
maintained when compared to the usual, single, unrestricted dose of the drug. Such
products do not produce a long-lasting, constant plateau level, but greatly smooth the
shape of the drug concentration or activity time profile.
Curve A of Figure 1 describes the sharp peak-shaped curve seen with most immediate
release drug products. Curve D illustrates the idealized type curve which would follow
administration of a precision controlled release, sustained release product, capable of
producing virtually constant concentration or activity levels. To achieve the constant
concentration or activity levels depicted by Curve D, a sustained release product must
rapidly release some predetermined fraction of the total dose for immediate absorption
(the loading dose) followed by the controlled release of the primary drug dose fraction
(the maintenance dose), which is released at a constant rate to maintain the maximum
concentration or activity level depicted in Figure 1. The rate of release for absorption
of the maintenance dose must thus equal the rate of agent removal from the body by
all of the metabolism, elimination, or other processes over the time period for which
the constant effect is designed or required. The most common method of achieving
such sustained and constant effects currently in medical use, especially in critical care
situations, is the use of the i.v. infusion. This, however, does not represent the use of
controlled drug delivery to achieve such true sustained release effects. There are cur-
rently very few sustained release products in the marketplace in accordance with the
definitions given here and those depicted in Figure 1. For many years pharmaceutical
companies have advertised sustained release products when in actuality their products
are prolonged release dosage forms.
In the mid to late 1960s, the term controlled drug delivery came into being to de-
scribe new concepts of dosage form design, which also usually involved controlling and
retarding drug dissolution from the dosage form, but with additional or alternative
objectives to sustained drug action (improving safety, enhancing bioavailability, effi-
ciency, or reliability, or other beneficial effects). As will be noted later in this chapter,
a primary objective of a controlled release system may be to enhance the safety of a
product rather than to extend its duration of action. Furthermore, we have controlled
FIGURE 1. Relationship between drug concentration or activity and

tim e for p ro d u cts possessing various release profiles; A-
curve=immediate release; B-curve=repeat action; C-curve=prolonged
release, D-curve=controlled, sustained release.
release systems today which are designed to enhance drug dissolution and increase
dissolution rates to produce more reliable absorption of drugs or other agents and to
improve their bioavailability and efficiency of delivery from the product, respectively.
One such illustration of a controlled release product designed to enhance solubility,
absorption rates, and bioavailability is the molecular dispersion of the antifungal drug
griseofulvin. Dorsey7 markets a product known as Gris-Peg, which is a molecular dis-
persion or solid solution of griseofulvin in polyethylene glycol. This molecular disper-
sion has such enhanced solubility properties that the dose can be reduced by 50®7o over
previously existing micronized powder forms of the drug. And, due to the higher blood
levels produced, less frequent dosing of the drug is also possible. An even newer con-
cept of controlled release is that of site-specific release. Very new technology is being
developed which utilizes drug delivery systems capable of prolonged retention in the
stomach or other body cavities, using bioadhesion and other principles to control not
only rates of release but also sites of release. Most recently, in the 1970s, yet another
term and concept of drug product design and administration has appeared: the thera-
peutic system. The objective of the therapeutic system is to optimize drug therapy by
the design of a product which incorporates an advanced engineering systems-control
approach. Three types of therapeutic systems have been proposed, the first of which is
already in use: (1) the “ passive preprogramed” therapeutic system which contains a
controlling “ logic element” such as a membrane or series of plastic laminates, which
preprograms at the time of fabrication or assembly a predetermined delivery pattern
(usually constant zero-order release), that is ideally independent of all in vivo physical,
chemical, and biological processes; (2) the “ active, externally programed or con-
trolled” therapeutic system wherein the logic element is capable of receiving and con-
verting a signal (such as an electromagnetic signal) sent from a source external to the
body, to control and properly modulate drug release from the device within the body;
and (3) the “ active, selfprogramed” therapeutic system contains a sensing element
which responds to the biological environment (such as blood sugar concentration in
diabetes) to modulate drug delivery in response to that information. Prior to the sus-
tained release concepts of the 1940s and 1950s, which also included depot forms of
parenteral products, no significant new oral drug delivery concepts had occurred in the
preceding 75 years (since the enteric coating concept).
Volume II 5
A great deal of confusion has existed in the controlled release area over the years
based on the fact that no standard nomenclature has been developed to describe the
various terms used in the field. The terms sustained release and prolonged release are
often used interchangeably. The fact that standard terminology does not exist also
makes it difficult for scientists working in the field to survey and review the literature.
Ballard8 has illustrated this confusion by reporting on the wide range of dosage form
names which can be found by a cursory examination of the literature as follows: con-
tinuous release,9 10 controlled release,11 13 delayed absorption,1415 delayed action,16 de-
layed release,17 20 depot,21 25 extended action,26 27 gradual release,26 long-acting,28 32
long-lasting,33 34 long-term release,35 programmed release,36 prolonged action,37 39 pro-
longed release,40 41 protracted release,26 repository,42 44 retard,23 45 slowly acting,46 slow
release,47 51 spaced release,52 sustained action,53 54 sustained release,55 61 time coat,62
timed disintegration,63 and timed release.64 70
Until sharper definitions are employed to define the terms in the field of controlled
release the scientist has little recourse than to employ a large number of terms in con-
ducting either a manual or computer search for topics in this field. At least six different
topic headings must be employed to even follow the patent literature using the Official
Gazette (listings of all U.S. patents as published).
B. Purposes for the Design of Controlled Release Effector Products

The purposes behind controlling the release of herbicides, insecticides, and parasiti-
cides are often the same as the purposes for controlling drug release. Indeed, major
pharmaceutical texts treat parasiticides and insecticides just as they do drugs. Thus,
the term “ effector” has now been coined to describe chemicals which can affect any
life process.71 According to this definition, effectors would include all human and vet-
erinary drugs, all insecticides, herbicides, plant growth stimulants and regulators, an-
tiparasite agents, etc. Common principles are involved in the design of all controlled
release effector products. Table 1 lists the primary objectives of designing controlled
release systems for chemical effectors. Polymeric controlled delivery systems are the
usual mechanism by which these objectives are achieved.
Safety maximizing the duration of effectiveness (Table 1) is usually the primary ob-
jective in effector controlled release product design. However, controlling the specific
duration of effectiveness can also be important, and might, for example, be the goal
for a product which is to be applied to a crop shortly before it is harvested in order to
control a specific insect pest, but then allow workers to safely enter the field to harvest
a crop at some time thereafter. Controlling the site of release of an agent, especially
after oral administration to an animal or man, is a relatively new concept in controlled
delivery. The oldest such products were the enteric-coated pharmaceuticals which were
designed to remain intact while they passed through the stomach and thereafter quickly
release in the upper small intestine. More recently, systems have been designed and
reported which are intended to be retained in a body cavity at a particular absorption
site or site of action such as the stomach, rectum, vagina, or along a particular region
of the intestinal tract. While being retained at a particular site the products are also
designed to release the chemical agent at a controlled rate. Yet another recent objective
of effector controlled delivery (Table 1) is to target the effector to a particular organ.
Liposomes are one such class of products which are selectively removed from the blood
stream in the liver or in various regions of the reticuloedothelium system, to target
drugs at these sites. Where molecular dispersion of a potent chemical effector can be
achieved in a polymeric carrier it may be possible not only to facilitate dispersion and
spreading of the agent to improve uniformity of dosing or application, but to also
control release rates or protect the agent from the environment. This too is a new
concept in controlled release, and provides the ultimate in dispension and content uni-
formity, and in some cases the maximum potential effectiveness and reliability.
Table 1
PRIMARY OBJECTIVES IN THE DESIGN OF EFFECTOR CONTROLLED
RELEASE SYSTEMS
Objective Example or application
Maximize duration of effectiveness All effectors

Control specific duration of effectiveness Controlled short acting insecticides
Control site of release in the organism Enteric release drug systems, controlled gastric re-
tention
Target effector in the organism Liposomes, drug targeting to specific tissues
Facilitate dispersion, spreading, and uniformity of All potent, low dose effectors
dose or application
Reduce toxicity and improve safety Drugs and insecticides in particular
Reduce undesirable side effects of effectors Drugs, herbicides, and insecticides
Improve effector reliability All effectors
Increase chemical and physical stability of effectors All effectors with chemical lability, high volatility,
in exposure environment etc.
Increase effector selectivity Desirable for all effectors
Prevention or reduction of effector mismanagement Desirable for all effectors
or abuse
Optimization of total effector action and perform- Ultimate goal with all effectors
ance
While Table 1 describes the common purposes and objectives behind the design of
any controlled release effector product, this section would be incomplete without de-
scribing some of the specific purposes which have been reported for the design of
controlled release drug products. The objectives have historically been to reduce the
frequency of dosing and to permit a dosage regimen which would allow the patient to
sleep through the night without being disturbed to take a required medication dosage.41
Reducing dosing frequency is especially important with psychiatric patients72 but is also
very important in treating hospitalized patients since such products reduce nursing time
and reportedly also reduce the incidence of therapeutic errors.73 75 Where drugs are
given by injection, reducing frequency of dosing cannot only have a substantial influ-
ence on savings of nursing time but also strongly relates to patient comfort and con-
venience. Patient acceptability is reportedly better with prolonged-action products in
general.10 In veterinary applications, injectable products which can produce their in-
tended effect with a single injection have great total cost advantages over products
which require mutiple injections. The ability to increase the safety and reduce the side
effects of many drugs through controlled release has been reported,73 76 78 and will be
further described in a later section, with examples.
C. The Ideal Attributes of Effector Controlled Delivery Systems

The ideal attributes of effector controlled release systems are shown in Table 2. A
primary attribute is that the systems not be highly sensitive to environmental factors.
For drugs this means the physiological factors noted in Table 2. For herbicides it means
the environmental factors noted in the table. For insecticides, both physiological fac-
tors of the insects themselves and environmental factors of the exposed substrate to
which the insecticide was applied are involved.
The second attribute (Table 2), is that each particular controlled delivery system is
predicated on physicochemical principles such as controlled precipitation or coprecip-
itation, complexation, or other chemical reactions, etc. rather than on pharmaceutical
art or other imprecise and high skill requirement techniques. The importance of this
attribute relates to the ability to precisely design, manufacture, reproduce, and control
the release of the controlled release systems.
Volume II 1
Table 2
THE IDEAL ATTRIBUTES OF EFFECTOR CONTROLLED DELIVERY
SYSTEMS
1. Not highly sensitive to environmental factors

Drug effectors — (physiological factors affecting oral administration)
Gastric motility and emptying
pH of the gut (especially acidity of the duodenal contents)
Type of food present and temperature of the meal
State of fasting
Fluid volume, composition, and viscosity
Physical position and activity of the subject
Excitation and/or mental state of the subject
Age
Individual variability
Disease state or pathological condition(s)
Distention of the stomach
Herbicides and some insecticides (environmental factors)
Temperature
Temperature cycling
Sunlight exposure
Water and moisture exposure
Physiochemical properties of soil substrates
2. Predicated on physicochemical principles
3. Functions by several mechanisms or not be keyed to any single item no. 1 above
4. High order of effector dispersion
5. Flexible: capable of handling a wide variety of agents and dosage levels. Applicable to many agents,
regardless of ionic form, physical properties such as solubility, and capable of achieving a wide range
of latitude in controllable delivery rates.
6. Maintenance or enhancement of physical and chemical stability. Capable of controlling volatility or
other physical stability problems and of maintaining or enhancing chemical integrity.
7. Serve as an optimized controlled delivery system for the effector.
The third attribute states that any system should function by several release mecha-
nisms rather than keying on any single environmental factor such as with physiological
factors, pH effects, or the presence or concentration of enzymes. The purpose of this
attribute is to reduce the sensitivity of a controlled release product to physiologic or
environmental factors, thereby increasing product reliability. This leads to another
important concept. All controlled release systems require some driving force to affect
release of the active agent. Each and every effector controlled release product should
be designed with a driving force in mind which will be most consistent in the environ-
ment in which the product is to be placed (e.g., exposure to moisture in the GI tract of
an animal or man if a drug, and diffusional release from a polymer matrix or through
a film independent of moisture levels if an herbicide or insecticide).
The fourth attribute suggests a high order of effector dispersion, since this promotes
accuracy of dosing for drugs and uniformity of spreading and application for herbi-
cides and insecticides. The highest order of dispersion possible is molecular scale,
wherein the number of “ particles” distributed is the number of molecules or active
moiety ions per mole (6 x 1023). This level of entrapment is possible if the effector can
be entrapped from solution. Methods of molecular scale entrapment of effectors for
the purpose of controlled release have been reported.71 79 84
The fifth and sixth attributes of Table 2, while self-explanatory, are often over-
looked in the initial design of controlled release products.
D. The Concept of the Optimized Drug or Chemical Effector System

Increasingly an objective of effector controlled delivery is not only to specifically
maximize duration of action, but also to reduce toxicity and improve safety. Another
primary objective in the design of many effectors is the goal of maximizing their reli-
ability. This is especially true for products that are exposed to a wide range of environ-
ments or types of exposures. This leads to the concept of the optimized drug or other
effector product as depicted in Figure 2. Some pharmaceutical scientists are now re-
cognizing the increasing importance of controlled delivery approaches to optimize a
product’s safety or reliability, and either of these goals maybecome the primary objec-
tive over the effectiveness objective. Depending on the properties of a drug or other
effector, the purpose for which the product is being designed, the various physiologic
or environmental factors which will influence the action of the agent, and the toxicity
or safety margin of the agent, primary product goals other than effectiveness may enter
the picture. As examples, several drug companies are now marketing controlled release
barbiturate products which are designed not to prolong the effectiveness period, but to
make the products safer when they are purposefully or accidently overdosed, combined
with other depressant drugs (including alcohol) or otherwise abused.
It should be noted that the three basic quality features of Figure 2 are connected by
doubleheaded arrows. Thus, as the formulator modifies the design of a drug or other
effector product, or its method of manufacture, in order to improve one quality fea-
ture or one physicochemical property related primarily to one quality feature, the other
properties or quality features may be and usually are altered. As an example, it may
be our goal to increase the hardness of a tablet by formulation (adding more binder)
and processing (compressing harder) in order to improve tablet gloss and appearance
and/or to reduce tablet friability (powdering and chipping in the bottle), and thus
enhance physical stability. This is a worthy objective, but it may also reduce the rate
and extent of drug dissolution from the tablet. This, in turn, could reduce the reliability
of drug absorption and drug performance from patient to patient, or influence transit
rate and drug dissolution along the GI tract within a given patient, or even reduce
effectiveness if the dissolution rate now limits or reduces bioavailability. In this exam-
ple, maximizing tablet hardness and appearance is a “ competing objective” to maxi-
mizing drug dissolution and bioavailability.
In Figure 2 we can visualize the definition of the optimized drug or effector product
as a delivery system which balances all these factors against each other, to produce the
maximum possible effectiveness as the primary objective, while producing the best
possible simultaneous safety and reliability as secondary objectives, with mathematical
certainty. An alternative optimization approach would be to produce the maximum
possible (optimized) product safety as the primary objective while producing the best
effectiveness and reliability as the secondary objectives. Yet a third approach would be
to optimize safety and effectiveness as equally weighted primary objectives while max-
imizing reliability as the secondary objective.
Mathematical-statistical optimization treats the manner in which experiments must
be designed to establish the necessary factors and relationships between factors (inde-
pendent and controllable processing, formulation, and other variables) as these influ-
ence one another and the product quality features (dependent or response variables).
Optimization methods then treat this data base to design and manufacture the best
possible product from an overall standpoint, considering quality features which may
be competing (i.e., as you improve one feature, another degrades), taking into account
primary vs. secondary features and numerous possible trade-off decisions. While it is
true that the vast majority of drug products that are on the market today are reasona-
bly safe and effective, it is also true that very few products have been designed as
optimized systems. Indeed, until about a decade ago, formal optimization methods
were unknown in the pharmaceutical and most other industries. The significance of
drug products not being optimum systems varies with drug product class. For drugs
and drug product classes with a high therapeutic index (ratio of LDS0 :ED50), maximiz-
9
FIGURE 2. The concept of the optimized drug or effector product.
ing safety is of less concern, and if the drug is well absorbed, a good, stable, pure, and
potent drug product that is reasonably reliable may be nearly optimum. For drugs that
have less of a safety margin, it may be argued that the conventional, rapidly releasing,
effective, stable, and reliable product which is currently typically marketed is not op-
timum.
Increasingly the use of controlled release systems to prevent or reduce mismanage-
ment or abuse of various chemical effectors has become a goal of product design. In
some cases, pharmaceutical manufacturers have found it necessary to formulate drug
products in which an abuse agent could not readily be separated from the other com-
ponents of a pharmaceutical tablet or capsule. In all cases, as noted at the bottom of
Tables 1 and 2 and in Figure 2, optimization of total effector action and performance
is the ultimate goal and objective in product design, and is a goal which can usually
only be achieved by appropriate controlled release in a system which is based on phys-
ical chemical principles, and is accordingly highly reproducible.
Mathematical and statistical techniques for optimizing effectors through product
design have been described, particularly in the pharmaceutical field.85 91
III. SAFETY ENHANCEM ENT AS A PRIMARY OBJECTIVE OF

CONTROLLED RELEASE PRODUCT DESIGN
With some drugs and effectors, safety enhancement may be accomplished by con-
trolling the rate of agent release from the product and the corresponding rate of ab-
sorption and appearance of the compound in the tissues of animals and man. Most
drug and effector products do not control the release rates of their agents. As a result
(e.g., with drugs) the shape of the blood or tissue level time profiles typically show a
rapid rise, a sharp peak, and a fairly rapid decline, typical of Curve A in Figure 1.
Curves A and B of Figure 3 illustrate the type of blood level profiles that are seen
on single or repetitive dosing, respectively, of a drug from conventional drug products,
whether given by oral, certain parenteral, or other routes, when the products provide
no reservoir or controlled release effects. In such systems the drug product is making
the drug immediately available for dissolution in the stomach contents, body fluids, or
tissues for subsequent absorption. The shape of the blood level time profile is com-
pletely dependent on the body’s ability to absorb the drug depending on the route of
administration used. These products are basically “ dump” systems that quickly release
drug in an uncontrolled fashion in the stomach or tissue for rapid dissolution and
absorption. As different single doses of drug are given we see the curves identified with
the A designation. Assuming the drug has linear pharmacokinetics, then with increas-
FIGURE 3. Typical blood or tissue level time profiles following the

administration of four different single doses (A-curve profiles) and
following repetitive dosing every 6 hr (B-curve).
ing dose, the maximum peak height will increase, time from dosing to maximum peak
height will be the same, the rate of decline from maximum peak height will be the
same, and the time required to go from the maximum peak height to any given lower
value will increase. The difficulty of simply increasing drug dosage to increase duration
of effectiveness can be seen from the spectrum of A-curves. Prolonged effectiveness
can be achieved (e.g., the largest dose produces a 12-hr effect) but only by dosing into
the toxic range.
Curve B of Figure 2 describes the type of blood level time profile that might be seen
with repetitive dosing, where perhaps one third the dose used as the maximum dose in
the A-curve series is given every 6 hr. It is now easier to remain within the desirable
therapeutic blood level range, but a sawtooth curve profile, with a series of peaks and
valleys nonetheless occurs. It is not until the third dose that the minimum tissue con-
centration clearly remains in the effectiveness or therapeutic range. Furthermore, the
maximum peak height seen on each subsequent dose tends to rise as each new tissue
concentration builds on the residual concentration present, toward the toxic levels.
Although a steady-state condition will eventually be reached where the peaks no longer
climb, achieving accurate drug or tissue concentrations within the therapeutic range,
especially where the range is narrow, is difficult using conventional drug products.
The two families of curves shown in Figure 4 typify blood level time profiles for 4
doses of a drug from a conventional drug product and for the same 4 doses from a
controlled, prolonged release product. As noted, in the controlled release product it is
not the body’s inherent ability to absorb the drug at some rate that describes the shape
of the curves; it is the controlled rate of release of the drug from the dosage form that
is now the rate-limiting factor. Peak heights seen from each controlled release product
will tend to be lower than those seen from each corresponding dose of the immediate
release, conventional product. To achieve the same peak height as that produced by
the highest dose, immediate release product (Figure 4) might require a 50% or larger
drug dose from the controlled release product.
Figures 3 and 4 also illustrate the point that drugs have two types of safety charac-
teristics. These are acute and chronic safety, and relate in turn to the relative safety
following administration of a single dose or following repetitive dosing. Both types of
Volume II lì
Time (hr)
FIGURE 4. Blood level time profile from a dump system (solid
lines) and from a controlled release system (dashed lines) following
the administration of four equivalent doses.
safety can be altered and enhanced by appropriate controlled delivery product design.
Table 3 defines the methods by which acute and chronic safety may be assessed for
drug products. On an acute or absolute single-dose basis, the safety of a drug product
may be determined as the therapeutic index, which is the ratio of the lethal dose in a
test group (e.g., animals or humans) 50% of the time to the effective dose in 50% of
the subjects. If the dose response of a drug is similar in one or more animal species and
in humans, it may be reasonable to calculate therapeutic index values in humans from
animal data. The larger the number from this ratio, the safer the drug or drug product.
Some dangerous and depressant drugs have ratios of 10:20 or less, which represents a
narrow safety margin. As noted in Figure 4 and as previously discussed, a controlled
release system typically removes the sharp spike of the blood or tissue concentration
time profile, which is basically wasteful of drug, producing a more rounded curve. It
is for this reason that controlled release products can be produced which have thera-
peutic index values that are two to three times higher than those for the same drug
product from a conventional dosage form.
Chronic safety considerations for drugs are related to repeated dosage, days or
weeks on end, and to the appearance of side effects and toxicity manifestations as
blood and tissue concentrations of drug climb or as drug accumulates in the body. The
manner in which blood or tissue concentrations rise on repeated dosing was depicted
in Figure 3. As has also been previously discussed, controlled release systems can be
readily designed which minimize, but do not necessarily prevent, such increases toward
toxic levels.
Controlled release can improve the safety and effectiveness of agricultural chemicals
as well as drugs. Figure 5 illustrates the relationship between the level of use of another
type of product (an herbicide), and its duration of action, from a conventional product
and from a controlled release product.92 As the application rate is increased to produce
peak values above this effective level, an increase in dose does produce an increase in
duration of effectiveness (as shown by the curves designated A). The 2,4-D herbicide
has a half-life of about 30 days and must maintain a surface soil concentration above
about 0.2 kg/acre to be effective and above 4 kg/acre for optimum action. Using a
conventional system, this would require application at a level of at least 12 kg or over
26 lb/acre to provide protection over 40 days. Protection over 100 days would require
40 kg or nearly 90 lb/acre (top A-curve). Even this high level of application would be
Table 3
ACUTE AND CHRONIC SAFETY ASSESSMENT OF DRUG PRODUCTS
Acute safety quantification

Therapeutic index = LD50/EDso
Chronic safety considerations
Onset of side effects
Accumulations effects
Nature of side effects-----Severity
^^Reversibility
Frequency of side effects
Drug interactions
Idiosyncratic responses
Anaphylaxis
Tolerance
Addiction
Stability considerations
Chemical stability
Toxicity of breakdown products
Physical stability
Effects on dose precision
Microbiological stability
FIGURE 5. Relationship between the level of use for an herbicide

and duration of effector action relative to ineffective, optimum, or
toxic levels following various single application rates of a conven-
tional product (A-curves) and from a controlled release product (B-
curve).
inadequate to cover the growing season for most weeds and it represents an application
of 100 to 200 times the minimum effective level. Another difficulty with such massive
applications is, of course, that desirable plants will be destroyed, and we have a situa-
tion that becomes hazardous to the environment and to the animal or human life in
that environment.
An idealized controlled release profile for this herbicide is also shown in Figure 5.
Such controlled release products may serve three important roles for agricultural chem-
icals: prolonging effectiveness through gradual controlled release, protecting the agent
from the environment to enhance chemical stability, and protection of the environment
from excessive or inefficient use of the agent. The stabilization effect may be as im-
Volume II 13
portant as controlling the release rate in achieving the required efficiency necessary for
such long-acting products. If the entrapment or encapsulation of the herbicide or other
agent can promote stability, great efficiencies in controlled release may be achieved,
and a single application of material may provide protection for an entire 120- to 180-
day growing season.
IV. RELIABILITY ENHANCEM ENT AS AN OBJECTIVE OF

The reliability of a drug product may be influenced by chemical, physical, biovaila-

bility, and microbiological stability, unit dose precision, patient acceptance, dosage
regimen compliance, reproducible presentation for absorption, and a high percentage
and uniformity of bioavailability. A loss of drug due to chemical instability results in
a reduction of the drug dose and hence reduced reliability. A product which exists as a
dispersed system, such as a suspension or emulsion, and which has poor or uncertain
physical stability, will deliver an uncertain drug dose to the patient and thus have poor
reliability.
A third type of stability that was completely unrecognized only a few years ago is
bioavailability stability. The bioavailability of drug products (the fraction of the ad-
ministered dose that is absorbed) may change dramatically as a product changes on
aging; especially as physical properties such as crystal or polymorph form, tablet hard-
ness, moisture content, porosity, or density change. With such physical changes, a
product’s bioavailability profile may change, usually declining with time. The reliabil-
ity of a drug product is also affected by patient acceptance and patient dosage regimen
compliance, which in turn are influenced by product elegance, product convenience of
use, and even the recommended dosage regimen (e.g., whether every 3 or 4 hr or only
1 or 2 times a day). Patient compliance may be much better with prolonged controlled
release products given only once or twice a day.
A product that has a high percentage bioavailability (e.g., 80 to 100% of the admin-
istered dose with little patient-to-patient variability) would be a reliable product in
comparison to a product with 60 to 80% bioavailability and a twofold or greater pa-
tient-to-patient variability.
Controlled release products which have the ability to control not only the rate of
release in the body, but also the site of release (e.g., GI tract), could greatly enhance
the reliability of future drug products. By holding a drug at or above its site of absorp-
tion in the GI tract (e.g., the stomach) and releasing it there to solution, and subse-
quent effective absorption in the upper intestinal tract (where most absorption takes
place), physiological variables such as gastric contents, motility, gastric emptying, etc.
are largely overcome. The result is greatly improved product reliability of perform-
ance.
V. EFFECTIVENESS ENHANCEM ENT AS AN OBJECTIVE OF

Drug and drug product effectiveness may most meaningfully be assessed by deter-
mining how well the product relieves the disease or condition for which the drug is
intended (i.e., clinical effectiveness). Unfortunately, clinical endpoints are often un-
clear. Such studies are thus more subjective, may require large numbers of patients,
and may raise ethical questions over routine product testing with sick patients. Accord-
ingly, most studies of the probable effectiveness of sustained release products are based
on blood level determinations, urinary elimination studies, or evaluation of pharma-
cological responses. Blood level determinations of the amount of drug reaching the
systemic circulation over time are usually the preferred method of determining the
effectiveness of sustained release products. Historically, sustained release products of
a drug have been introduced years after the initial marketing of the drug. Blood level
time profiles at various oral dosing levels from conventional fast release products are
known by then, and often desirable blood level ranges are known, below which activity
will not be seen and above which toxic symptoms occur. The drug’s pharmacokinetics
will also be known, further providing a basis for the design of the sustained release
product.
Urinary excretion is the second method of measuring the performance of sustained
release products and of estimating the absolute bioavailability of such products. This
method has the advantage of being a noninvasive method in comparison to blood level
determinations. It is a less accurate procedure, however, and is basically limited to
relatively few drugs which are quantitatively eliminated unchanged in the urine (e.g.,
phenylpropanolamine), or are primarily eliminated unchanged. Where urinary elimi-
nation is employed to evaluate drug product performance, urine samples are collected
at frequent time points, such as hourly, at least through the first 4 to 8 hr postdosing
over which the absorption phase is occurring, and then at longer time intervals of every
2 to 3 hr thereafter, until essentially all of the drug and metabolites have been re-
covered. The rate of drug elimination is determined by assaying each of the urine
specimens collected and multiplying the concentration of drug in each specimen by its
volume to determine the amount eliminated in that time interval. From a previously
established relationship between urinary elimination rates and the blood level concen-
trations generating those elimination rates, blood level time relationships may be con-
structed. The midpoint of the collection period is usually employed as the time point
for the blood level concentration which generated the particular urinary elimination
rate over that interval. Based on total drug collected in the urine samples of the sus-
tained release and of a standard, conventional, oral product, bioavailability compari-
sons may also be made. This method generally requires the following assumptions to
exist:
1. A one-compartment open model (the blood and other fluids of distribution act
as a single compartment with respect to both the drug and the metabolite).
2. Equilibrium between drug and metabolite in blood and other fluids of distribu-
tion is maintained at all times.
3. The elimination rate constants for the drug and metabolites are all constant dur-
ing the interval over which elimination is being followed.
4. The compound measured in the plasma for purposes of correlation is either the
unmetabolized intact drug or is a metabolite formed directly from the drug by a
process which obeys first-order kinetics.
5. A single dose of the drug has been administered in each case.
6. Urinary excretion of both the drug and its metabolite, if a metabolite is also
involved, obey first-order kinetics.
Currently, the manufacturer of any sustained release drug product may expect to be
required by the Federal Food and Drug Administration (FDA) to conduct an appro-
priate in vivo evaluation of any candidate sustained release product, with such evalu-
ation representing a clinical trial of the availability and performance of the product.
As noted previously, that study may take the form of a blood level study as opposed
to one involving the measurement of actual clinical performance. A major considera-
tion in the determination of which drug or drugs to place in a sustained release dosage
form will be the availability of a definitive in vivo test, which may be undertaken in a
statistically meaningful fashion with a reasonable number of test subjects, so as to
Volume II 15
clearly demonstrate the performance of such a product to the satisfaction of the FDA.
For example, drugs which cannot be accurately measured in the blood and which lack
definitive clinical response measurements might be poor candidates or very costly can-
didates for the required in vivo or clinical proofs. The manner in which the in vivo
study is undertaken should receive the same care and attention with regard to experi-
mental design as is given any clinical test procedure. The FDA has recently published
some general guidelines describing test procedures and requirements for assessment of
sustained release pharmaceutical products (refer to regulatory considerations section
of this chapter). Unless a manufacturer has previous knowledge of the in vivo proce-
dures used for approval of a prior sustained release product of a particular drug, it
may be advisable to confer with the Biopharmaceutics Division of the FDA prior to
undertaking the clinical trial to verify that the appropriate test procedures are being
undertaken. In developing the in vivo test to determine the effectiveness of the sus-
tained release product, the first part of the experimental design should be the identifi-
cation of the questions to be answered. Among these questions will certainly be the
identification of the absorption rate, characterization of the time to peak activity or
blood level, the time over which the peak activity or blood level is maintained, and the
rate at which the activity or blood levels decline. Verification that adequate activity or
blood levels are achieved and maintained will also be a critical question together with
the possible adjustments that may be required in the release rate of the drug from the
dosage form to maintain constant activity at peak level. The second question in the
construction of the in vivo study to establish effectiveness will be the actual design of
the experiment, and this design will be predicated at least in part on the questions that
are to be answered, together with other good clinical testing procedures (use of cross-
over designs and double-blind procedures, especially if clinical endpoints are being
employed as opposed to chemical analytical tests, and utilization of the appropriate
number of test subjects to achieve statistically valid data depending on the variability
expected in the test results, etc.). The third part of the in vivo test procedure will be
the actual experimentation followed by the fourth part which is the evaluation of the
results.
As noted previously, a controlled release system may be intended to achieve other
goals rather than to simply extend the duration of action or blood level time peak of
the drug. These other goals may be to enhance the safety of a product by diminishing
the sharp spike of the normal blood level time profile or to reduce the difference be-
tween the peaks and valleys of maximum and minimum blood level concentrations on
repeated dosing. Depending on the particular objective for the product, different tech-
niques may be required to assess the effectiveness of the product in achieving its in-
tended goals. Where the minimum effective blood concentration is known, the ability
to exceed this concentration and remain above the concentration for a prolonged pe-
riod may be a primary indication of effectiveness. Achieving the peak level for the
controlled release system as quickly as is done with a conventional fast releasing drug
product may not be of significance, especially for chronically administered drugs. Fre-
quently, controlled release systems achieve their peak values or minimum effective
concentration levels somewhat more slowly than do fast releasing systems. Since con-
trolled release systems are not typically used for emergency drug therapy, and where
such products are used for chronic types of drug administration, a delay of 30 min or
more may not be of consequence. The total bioavailability of the sustained release
product will almost certainly be of interest to the FDA on review of the data, both
from the standpoint of average bioavailability and variability between subjects. A sus-
tained release system should not reduce the bioavailability of the drug in comparison
to that of the standard innovator or originally marketed product. Likewise, the sus-
tained release product should not have greater variability in bioavailability from sub-
ject to subject than does the conventional drug product. If it does, this may indicate
that the slow release of drug along the gastrointestinal (GI) tract is leading to greater
variability of absorption, and the product is not a good candidate for sustained release
drug therapy. Ballard93 has tabulated over 50 drugs which have been employed in clin-
ical trials in the form of prolonged action formulations together with the pertinent
references.
VI. CONSIDERATIONS IN THE SELECTION OF CANDIDATE DRUGS

A N D CHEM ICAL EFFECTORS FOR INCORPORATION IN
CONTROLLED RELEASE SYSTEMS
The previous section indicated some of the major considerations which should be
taken into account when evaluating various drugs or other chemical effectors as can-
didates for incorporation into controlled release systems. Foremost among these con-
siderations is the ability to appropriately test the product to demonstrate effectiveness
of action from the controlled or sustained release product. There are other considera-
tions, however, related to the physical-chemical properties of the drug or chemical
effector and to its biological or pharmacological properties. In the section which fol-
lows, these considerations are treated separately or as combined factors. Often it is
necessary to consider various properties together (as will be noted) in order to deter-
mine the viability of a candidate drug for a sustained release product.
A. Physical-Chemical Properties of Drugs Influencing their Viability as Candidates for

Sustained and Controlled Release Systems
1. Aqueous Solubility and Solubility Rate
The aqueous solubility of a drug or chemical effector may, by itself, dictate whether
or not a controlled release system is feasible. Drugs which possess a very low aqueous
solubility pose problems in the design of controlled release dosage forms from two
standpoints. On the one hand, they often have bioavailability problems from immedi-
ately releasing systems or they may suffer somewhat erratic drug absorption based on
difficulty in achieving adequate solubility at or above their primary absorption sites
along the GI tract. A second problem is that aqueous solubility is usually involved as
a driving force in bringing about the gradual dissolution and controlled release of the
drug or effector from the product, in its environment, especially along the GI tract of
animals or man. With drugs with very low aqueous solubility, the problem with im-
mediately releasing products is to promote the solubility rate to such an extent that
consistent drug absorption may be achieved. Such drug products which have their oral
absorption limited by their dissolution rate may be very poor candidates for sustained
release products in conventional systems. They may be good candidates for controlled
release products where the purpose of the controlled release is to optimize the dissolu-
tion rate. As a rule of thumb, Fincher94 has indicated that drugs with a water solubility
of less than 0.1 m g/m i are likely to have reduced physiologic ability from conventional
dosage forms. Aguiar95 considers drugs with an aqueous solubility of less than 0.01
m g/m i to be relatively insoluble and to be in a class which will demonstrate dissolu-
tion-limited bioavailability, which in and of itself may provide an inherent sustained
action. Some investigators have discussed the approach of preparing slightly soluble
forms and derivatives of drugs as one method of producing prolonged-action dosage
forms. To take this approach in controlled release dosage form design, however, is
viewed as walking a tightrope. Prolonged drug effects may be achieved, but at the
expense of inconsistent and incomplete bioavailability.
A second difficulty that can exist with the aqueous solubility of a drug or chemical
effector being considered for a controlled sustained release system is to have a com-
pound whose solubility is too great. Drugs which have a very high aqueous solubility,
Volume II 17
such as greater than 1 g/10 m i, may prove very difficult to effectively retard in a
controlled release system. Difficulties in effectively controlling the release of such com-
pounds over a prolonged period will depend on the dosage from approach taken. For
example, when such drugs are incorporated in matrix systems, a high ratio of insoluble
matrix to drug may be required to produce the necessary retardation and controlled
release. On the other hand, such drugs may be effectively incorporated in diffusional
controlled film-membrane types of systems.
The equilibrium aqueous solubility of a drug can mislead a pharmaceutical devel-
opment scientist into thinking no problem exists where a major solubility problem may
in fact exist. This is the case for drugs which have reasonably good to excellent equilib-
rium solubility in aqueous media but which have very slow solubility rates. Some an-
tibiotics and high molecular weight drugs have such solubility properties. While their
equilibrium aqueous solubility places them in a category which would not produce
expected bioavailability problems, based on the fact that they dissolve very slowly, via
production of hydrated layers at the surface of the dissolving particle from which drug
diffusion is very slow under the low agitation intensity of the GI tract, dissolution-
limited drug absorption may occur. Such drugs, with diffusion-limited solubility from
pure drug or crystal surfaces may have very slow release from a viscous, hydrating
surface of a polymer-containing particle being employed for controlled release pur-
poses. Banker et al.96-97 have published on the influence of the hydrated layer of poly-
mers and on the steps in formation of this hydrated layer formation and on polymer
dissolution rates with application to selection of polymers for coatings and sustained
release systems. Some investigators may not appreciate the fact that certain high mo-
lecular weight drugs, including certain penicillin and cephalosporin derivatives whose
absorption occurs most completely in the upper GI tract, may have such diffusion
controlled, slow dissolution release properties as well. Under conditions of high mixing
intensity, drug molecules may be effectively released from the hydrated layer at the
surface of the particle, while under low mixing intensity similar to that of the GI tract,
very slow drug diffusion from the hydrated layer into the bulk phase occurs. Careful
attention must therefore be given to the solubility rate under conditions of low agita-
tion intensity of such compounds. Controlled release systems of such compounds must
be formulated, possibly utilizing erosion-type systems, to accommodate the slow solu-
bility rates of these chemicals.
Yet another factor in aqueous solubility is that of pH-dependent solubility. Drugs
with a very strong, pH-dependent solubility profile over the physiologic pH range of
the GI tract may be poor candidates for oral sustained release products. This is espe-
cially the case for drugs which are highly soluble in the stomach at perhaps a pH of 1
to 3, but which have a greatly diminished solubility at pH 5 or more, which may cor-
respond to the pH of the environment of primary absorption. Unless the sustained
release dosage form has the capability of retaining the drug in the stomach and grad-
ually releasing it there, to be metered past its absorption site in solution, such drugs
may be very poor candidates for more conventional sustained release systems.
2. Drug Stability and pKa
The stability of a drug or chemical effector in the environment to which it must be
exposed is another critical physical-chemical factor to be considered in determining the
feasibility of preparing such a product in a sustained release system, or in considering
approaches by which such systems might be designed. In the case of drugs, those which
are degraded by the pH, ionic environment, or enzymes of the small intestine, would
be of questionable viability in sustained release systems. This is the case since most
drugs are substantially absorbed in the small intestine and the controlled, gradual re-
lease will usually occur there. By slowly releasing the drug to solution in an environ-
ment in which it is unstable will simply serve to effectively destroy virtually all of the
drug. The optimum way to deliver such a drug might be to quickly release it to solution
in the stomach for quick metering (fasted stomach) from the stomach to the upper
small intestine for rapid and hopefully effective absorption there, with minimal decom-
position. For drugs which may be unstable in the stomach but are absorbable in the
intestinal tract, sustained or delayed release may be the only viable oral dosage-form
option. Coatings and other protective measures may be employed which protect the
drug from contact with gastric acid or enzymes but which provide an immediate release
fraction in the upper small intestine, as well possibly as controlled release along the
intestinal tract.
The influence of enzymes on drug decomposition must also be considered. Drugs
such as chlorpromazine, which reportedly undergo considerable metabolism along the
intestinal tract and possibly in the gut wall, may be poor candidates for sustained
release systems. Once again, gradually releasing such drugs in low concentration as
they pass along the small intestine will only serve to increase the fraction of the drug
that is metabolized.
The pKa of a drug is an important physical-chemical consideration as it indicates the
fraction of the drug which will be ionized and/or un-ionized at various pH values.
Since it is generally accepted that most drugs are preferentially absorbed in their un-
charged form, acidic drugs with low pKa values will have a higher fraction of un-
charged species at the low pH of the stomach and first region of the small intestine.
They may be virtually completely ionized in the mid to lower small intestine where the
pH increases to 7 and above. Basic drug moieties which have higher pKa values, will
on the other hand usually be more soluble in the lower pH of the stomach, but may be
essentially completely in their charged species form under the conditions of the lower
pH of the stomach and upper small intestine. The pKfl of a drug may thus provide a
relatively good indication of the site of absorption of the drug along the GI tract as
well as indicate possible problems with regional absorbability. Fairly strongly acidic
drugs which will have less than 1 molecular species in 1000 or in 10,000 in un-ionized
form at pH greater than 3 or 4, may be poor candidates for a sustained release system
which will be liberating drug all along the small intestine where the drug is no longer
effectively absorbed. Although the pKa of the drug is not the only factor to be consid-
ered in this matter of bioavailability, it may be a useful value to consider, especially
for acidic drug moieties.
Many drugs are Bronsted acid or bases which may be described by the following
relation:
Acids HA H+ -I- A
Bases RNH-f RNH2 + H +
In this relation, the dissociation of either an acid or a base is illustrated by the loss
of a proton, permitting a single form of the Henderson-Hasselbalch equation to be
applied.
Protonated
pH = pKa
Unprotonated
Recognizing the acidic forms as HA and RNH3+, it is obvious that by decreasing the
pH of a solution (increasing the concentration of H+), the above reactions would be
shifted to the left, increasing the concentration of HA and RNH3+. This would thus
increase the concentration of the protonated (neutral and absorbable) species of the
weak acid and unprotonated (charged and nonabsorbable) species of the weak base.
The above equation permits rapid approximations of the ratio of protonated to unpro-
tonated species for a Bronsted acid or base at any pH, by remembering that the log of
10 is 1, the log of 100 is 2, etc. The ratio of protonated to unprotonated species may
thus be estimated in terms of pH units that are equal to the pKa, or that differ from
the pKa by units of 1, 2, etc., as summarized below.
Volume II 19
PH = Ratio of (Protonated/
pK„ -3 1000
pK„ -2 100
pK„ - 1 10
pK. 1
pKa +l 0.1
pKa +2 0.01
pKa +3 0.001
3. Molecular Size and Partition Coefficient

Molecular size and partition coefficient are important characteristics of drugs which
influence the viability of drugs as candidates for controlled release applications from
the same cause and effect standpoint — the influence of these properties on the ability
of drugs to diffuse through and penetrate membranes. Membrane penetrability is in
turn important from two standpoints in reviewing the viability of any drug as a candi-
date for controlled release: (1) as it relates to the absorbability of the drug across
biological membranes, and (2) as it relates to controlled drug diffusion across or
through a rate controlling membrane in the controlled release device or product itself.
Drugs which have such large molecular dimensions or unfavorable partition coeffi-
cients so as to produce unreliable absorption of the drug by a particular route will
probably make that route unreliable and unattractive for the design of a controlled
release product for that drug. Conversely, drugs with molecular dimensions and par-
tition coefficients which allow them to readily penetrate through or diffuse from mem-
branes, allow a membrane or diffusion controlled system to be considered as the rate
controlling mechanism for the controlled release system. This may be a very desirable
circumstance because such systems permit the design of products which release drug at
a constant, unvarying rate over most of their release profile, while being relatively
insensitive to the physiological variables impacting the system. Furthermore, diffusion
control can be a purely physicochemical approach, which is highly predictable, often
highly controllable, and lends itself to all types of controlled release dosage forms. It
may be the only viable approach to the design of longer-acting dosage forms intended
to release product constantly over periods longer than 6 to 12 hr.
Molecular size is related to diffusivity through membranes by the following equa-
tions:
log D = - sv log V + kv
where D is diffusivity, V is molecular volume, and sv and kv are constants related to

the volume term, or
log D = sm log M + km
where M is molecular weight, D is as above, and sm and kmare constants related to the
molecular weight term.
The partition coefficient of a drug describes the dynamic equilibrium ratio of drug
in solution between two immiscible solvents, usually expressed as concentration in oil
or water immiscible nonpolar solvent/concentration in water. A parabolic relation is
generally found between partition coefficient values and rates of penetration of drugs
through membranes.98 At low partition coefficients the drug is too insoluble in the
lipoidal membrane to readily penetrate it. At high partition coefficients, while the drug
can readily penetrate the membrane, it will tend to remain in the lipid phase rather
than to move into the aqueous circulation, provided there is adequate aqueous solubil-
ity to even establish a flux into and through the membrane in the first place. An “ in-
termediate” partition coefficient, reflecting a balance of solubility in both aqueous and
nonpolar solvents, is necessary to establish the optimum penetration through biological
membranes in drug absorption, and likewise is important in designing controlled re-
lease products which will have adequate release rates through or from polymeric mem-
branes. It has been reported that the approximate optimum partition coefficient, (n-
octanol/water), for maximum flux across many tissues and membranes, is 1000/1.98 99
Flynn100 101 has written a review and book chapter which provides detailed discus-
sions of membrane permeability and diffusion, including the influences of partition
coefficient, molecular weight, and other factors. For drugs of intermediate molecular
weight (up to about 400), diffusion coefficients through flexible polymer membranes
will be in the order of 10~8 cm2 sec-1, while through a hydrated or high water content
membrane this value may increase to the order of 10"6 cm2 sec'1, which approximates
the diffusion coefficient of a drug in water. As the molecular weight exceeds 400, and
certainly 500, the diffusion coefficients through polymeric membranes decrease rap-
idly, while at molecular weights of 600 to 700 and above the diffusion coefficient values
are not only useless, they are virtually immeasurable.
B. Biological and Pharmacological Properties of Drugs Influencing their Viability as

Candidates for Sustained and Controlled Release Systems
1. Size o f Dose and Biological Half-Life and Maximum Feasible Duration o f Effect
The size of a drug dose is the first obvious factor influencing the viability of a can-
didate drug for a controlled release dosage form. In such viability determinations,
dosage size is also related to the biologic or pharmacologic property of half-life for
elimination, which is the time required for a drug to decline from any particular con-
centration in the body to one half that concentration following completion of the ab-
sorption phase. Drugs with a short biologic half-life which have the goal of being
sustained for three or four times their half-life may require a maintenance or sustaining
dose many times the conventional single dose. If that usual single dose is relatively
large the total dosage for the sustained release product (initial plus sustaining fractions)
may exceed that which can be conveniently swallowed in a single or perhaps even sev-
eral solid dosage forms. Even where the sustaining dose is only equal to that of the
“ initial” dose, it may be difficult to produce a single sustained release dosage form
which can be readily swallowed if that initial dose exceeds 0.5 g. Depending on the
amount of retarding polymer or other material which must be used to control drug
release, and whether or not the initial dose is to be coupled with the sustaining dose,
even a 0.3-g dose may be excessively large. It is not uncommon for matrix drug delivery
systems to require an amount of retarding polymer or other material which equals or
exceeds the mass of the drug dosage being retarded. Thus, in this case, even a 0.3-g
drug dose may require a tablet weighing over 0.6 g without considering the loading
dose or total drug quantity needed for the intended durational effect.
Another factor related to the maximum dose size which can be accommodated in a
sustained release system is that of the mechanism by which the sustaining action is to
be achieved. The most efficient method of sustaining drug release from a weight addi-
tion standpoint is the use of the diffusion controlling film. A film coating which hy-
drates or otherwise performs to provide a controlled diffusional releasing barrier may
add as little as 20 or 30 mg to the total weight of a 500 to 800 mg tablet. Such systems,
however, require a drug which possesses some appreciable aqueous solubility in order
to function by diffusional release or osmotic effects. The size of the single drug dose
together with the biological half-life of the drug may also dictate the maximum reason-
able duration of prolongation which may be achieved, based simply on the amount of
active agent that can be incorporated in a single dosage form.
Volume II 21
Drugs with short biological half-lives which require frequent dosing to provide con-
sistent and satisfactory therapy are usually the best candidates for design into sustained
release systems. Indeed, sustained controlled release systems may be the most ideal
dosage forms for such drugs. However, for drugs with very short half-lives there are
several primary challenges which must be faced: adding sufficient drug to the dosage
form to achieve the desired duration of effect, achieving a sufficiently rapid controlled
rate of release in a reliable manner (diffusion controlled release may not provide an
adequate release rate unless through a hydrated film membrane), and developing a
“ fail-safe” dosage form which will not permit dumping of all the doses in the product
at one time through failure of the product or through exposure to some “ quirk” of
combination of physiological variables.
Table 4 shows the problem of working with drugs with short (2 hr) to very short (1
hr or less) half-lives. With a t 1/2 of 1 hr, the ratio of sustaining dose to immediate
release dose is 4.6 to achieve only a 6-hr duration of action. Thus 5.6 times the normal
dose must be placed in the dosage form. As shown in Table 4 this jumps to 6.5 and 9.3
times the normal single dose, as the total dose to be incorporated (5.5 + 1 and 8.3 +
1), to achieve an 8-hr and a 12-hr duration, respectively. Such doses are impractical
from a safety as well as from a total manageable dosage size standpoint for most drugs.
Table 4 and the discussion given immediately above explain why drugs with interme-
diate to short, but not very short t 1/2 values, provide the best candidates for sustained
controlled release products.
In looking to the desired duration of action for an oral sustained release dosage form
one must consider the normal transit time of materials through the GI tract, from
entrance into the stomach, to and along the small intestine, as well as where the drug
is absorbable. For strongly acidic drug moities, the absorbable region may only include
the stomach and upper small intestine, with the stomach being a marginal absorption
region. Unless the dosage form can be retained in the stomach by some technique, the
duration of time over which the drug is in an absorbable region may be only a few
hours. For basic drug moieties, the stomach is not an absorption region, but may
provide some hold-up and metering of the dosage form. While gastric emptying and
intestinal motility vary widely, it may be unrealistic to count on a conventional oral
sustained release product being in a region of effective absorption, for any drug, for a
period longer than 8 to 12 hr.
2. Absorption Properties
As noted in other sections of this chapter (including the regulatory considerations
section), drugs to be considered for oral conventional controlled sustained release ap-
plications should have consistent, complete, nonerratic, and reliable absorption along
the small intestine. Such drugs will be substantially completely bioavailable from con-
ventional oral drug products. The only situation under which an incompletely or errat-
ically absorbed compound should be considered for a sustained release product is in
the case that the cause of the incomplete or erratic absorption is clearly known, and
the proposed dosage form has the capability of overcoming the causal factor. As an
example of such a situation, drugs which are absorbed by specialized transport proc-
esses, or at limited regional sites along the GI tract, are generally very poor candidates
for controlled release applications. While riboflavin falls in this category, being ab-
sorbed by an active, saturable transport process, Banker103 demonstrated that a gastric
retention, diffusion controlled dosage form not only effectively prolonged the release
of this compound, but also enhanced its bioavailability. This occurred because the drug
is only effectively absorbed in the upper GI tract, and the unique dosage form could
retain the dosage form above that site while gradually releasing the drug to solution.
Table 4
RATIO OF SUSTAINING
DOSE TO IMMEDIATELY
RELEASING (INITIAL
LOADING) DOSE AS A
FUNCTION OF
BIOLOGICAL HALF-LIFE
AND INTENDED
DURATION OF EFFECT“
Intended duration of
effect (hr)
Half-life (hr) 6 8 12
1 4.60 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
° Based on drugs having a one -com-

partment open model.
From Lee, V. H. and Robinson, J. L.,

S u sta in e d a n d C o n tr o lle d R e le a se D ru g
D e l i v e r y S y s te m s , Robinson, J. R., Ed.,
Marcell Dekker, N.Y., 1978. With per-
mission.
3. Distribution and Metabolism

The distribution and binding of drugs to various tissues and to proteins of the blood
can influence the inherent duration of action of a drug given by any route. The fraction
of drug and/or active metabolite(s) that is bound at any time is usually considered to
be inactive, and unable to cross further membranes to sites of action. The extent and
rate at which the active moiety or moieties are bound, and the subsequent rate at which
they are unbound and released, can influence the duration of drug action, even though
the rate of elimination of the unbound fraction is relatively rapid. Where the binding
level and affinity is high, a compound may exhibit an inherent, depot-type, prolonged
action, to which a sustained release drug product will contribute nothing in providing
further prolongation. Drug binding to plasma proteins has been more extensively stud-
ied than tissue binding due to the relative accessibility of blood. Several references and
reviews have focused on the influence of this factor on duration of drug action.104105
Compounds which exist as charged species in the blood have a greater affinity for
protein binding than do essentially uncharged molecules, and the presence of a hydro-
phobic chain on such compounds appears to stabilize the binding.
4. Safety Margin and Side Effects of the Drug

The therapeutic index has previously been defined to describe the acute safety mar-
gin of a drug. It was also noted that this value can be increased to enhance safety on
purposeful or accidental overdosing by proper controlled release product design. At
Volume II 23
one time it was thought, and reported in the literature on sustained release, that only
compounds which had a large safety margin should be considered as candidates for
sustained release products. The fear was that some failure of the product would lead
to dumping of several doses of drug at one time with serious consequences. Today,
however, as earlier described, drugs such as barbiturates, with relatively low therapeu-
tic indexes have been formulated into controlled release products and are being mar-
keted for the very purpose of safety enhancement by eliminating the sharp peak of
their usual blood level time profiles. In such cases, however, careful thought must be
given to the design of the controlled release product, to produce a more nearly fail-
safe system. Diffusion or osmotically controlled membrane or film barrier systems
which require intact, undamaged coatings, might be less fail-safe than solid erosion
controlled or matrix systems, or systems combining a matrix with a constant rate re-
leasing barrier. A further complicating factor however, is that such products should
not only be reasonably fail-safe, they should also provide precise and reproducible
control of release rate, which is not sensitive to the physiological variables encoun-
tered, while being physically and chemically very stable.
In Figure 4 and the discussion which accompanied it, it was noted that the side
effects of some drugs may be related to their plasma (and tissue) concentrations. Sev-
eral clinical studies have been reported in which reduced side effects have occurred as
a result of controlled release product design.105 107
The utilization of controlled release to reduce the incidence of GI side effects, in-
cluding irritation, nausea and vomiting, bleeding, and ulceration, by totally protecting
the stomach from contact with irritating acidic compounds or strong electrolytes, or
by reducing that rate of release and consequent irritancy along the GI tract, is widely re-
ported. Examples include aspirin,108 109 potassium chloride,110 112 ferrous sulfate,113 115
and aminophylline.116 Once again, depending on the cause of the irritancy effect, the
design of the dosage form can be critical relative to its capacity and rationale for ov-
ercoming the problem.
5. Therapeutic Goal, Disease State, and Route o f Administration

The therapeutic goal should be analyzed in examining whether a controlled, sus-
tained release product is really rational or desirable for a particular drug. Oral, sus-
tained release forms of many antibiotics are not rational, for example, since high spike
blood levels are desirable on repeated dosing, as they are related to antibiotic effective-
ness. Another situation in which the sustained, controlled release product would be
contraindicated, is where a fast onset of action is indicated, to meet some type of
medical emergency (such as shock, onset of an asthmatic attack, onset of an angina
attack, a cardiac emergency, etc.). On the other hand, controlled release products may
be the products of choice in preventing or controlling some of these ailments (asthma
and angina for example).
A number of biological processes and certain disease states are known to follow
circadian rhythms, reaching peak (or valley) effects at certain times of the day. Among
biological processes, liver enyme activity,117 intraocular pressure,118 and even blood
pressure119 120 are known to undergo diurnal circadian rhythms. Certain disease crises
appear to have their own rhythms and times during the day. Asthma attacks and acute
myocardial insufficiency episodes reportedly occur most often in the middle of the
night (around 4 a.m .),121 while epileptic seizures in the epileptic and high blood-glucose
levels in the diabetic occur most often in the morning.122 123 When conventional ther-
apy is being employed, these are the times when prophylactic protective drug levels
may be at their lowest points in the body, leaving the patient least protected during the
most critical period. Sustained release products could play a greater role here.
Diseases which require maintenance of some prophylactic blood or tissue level to
control the symptoms of the disease, especially pain, respiratory difficulties, or dis-
comfort may be best treated by utilizing controlled release systems which can better
assure maintenance of those tissue levels. Cases in point might be the diseases of angina
pectoris, rheumatoid arthritis, peptic ulcer, allergies, and asthma. Certain forms of
cancer are another example, although here the direct control of pain, rather than con-
trol of the process causing the pain, may be the goal. Recognizing the therapeutic merit
of providing constant or prophylactically effective prolonged blood levels of angina
drugs, especially organic nitrates, a number of long-acting topical, transdermal oint-
ment and device systems are now commercially available. Drugs which can better con-
trol gastric pH in the treatment of peptic ulcers have long been sought. This objective
is being met by the development of long-acting histamine H2 receptor antagonist drugs.
Nevertheless, long-acting, locally acting drugs such as antacids, which resist gastric
emptying and are capable of neutralizing gastric acid on demand, would still be of use
in treating peptic ulcer, and are under development.
Aspirin is still the most widely used drug in the treatment and control of rheumatoid
arthritis. Several companies have marketed sustained release forms of aspirin over the
past decade, largely in the hope of providing better aspirin therapy for this market.
Such sustained release forms of aspirin have not, however, been greatly successful, and
this fact illustrates again the importance of carefully considering the various biological
and medical elements prior to developing a particular drug into a sustained release
form for a given therapeutic indication. The problems with sustained release aspirin in
general are twofold; the drug (with a pKa of 3.5) may not be well absorbed in the lower
small intestine, and controlled release systems which remain in one location on a GI
mucosal site may lead to greater gastric bleeding124 (although other reports with differ-
ent sustained release products reported less bleeding in comparison to conventional
aspirin). 125 126 The medical problem with sustained release aspirin for use in arthritis is
that aspirin (acetysalicyclic acid) is rapidly metabolized to salicylic acid, which is some-
what less effective as an anti-inflammatory agent. Slow releasing forms of aspirin pro-
duce lower levels of the parent drug than do immediate release tablets.
The oral route of administration is the preferred route when systemic drug effects
are sought since seif-administration is facilitated, it is usually the lowest cost, and it is
typically the most reliable and safest method of self-medication. Thus, when sustained
release drug products are being considered, an oral product is usually the goal. A recent
review article details the physiological and pharmacokinetic factors effecting perform-
ance of sustained release dosage forms given by the oral route.127 As noted previously
in this section however, new topical transdermal drug products are appearing, and this
route will soon expand from nitroglycerin and scopolamine (motion sickness) marketed
products to other drugs and drug classes (notably steroids). Advantages of the trans-
dermal route are that it overcomes many of the disadvantages of the oral route (expo-
sure to unfavorable acidic pH's, enzymes, etc., first-pass effects through the liver, a
limited GI transit time, and many physiological variables). The primary disadvantage
of the transdermal route is overcoming the skin barrier to systemic absorption.
The parenteral route offers challenges as well as opportunities for sustained, con-
trolled release. The two primary challenges are that the systems (usually as dispersions
or implants) must be sterile, and they must also be biocompatible and safe. As will be
noted in other chapters of this book these are formidable but not insurmountable chal-
lenges. New parenteral controlled release dosage forms, including multiple emulsions,
liposomes, and colloidal dispersions of biodegradable polymers will greatly expand this
route for controlled release systems in the next several decades.
Volume II 25
V II. R E G U L A TO R Y C O N SID ER A TIO N S IN D E V ELO PIN G

C O N T R O L L E D RELEA SE DRUG PR O D U C TS
Regulatory considerations related to the effectiveness of controlled release drug

products are described in the section on effectiveness enhancement as an objective of
controlled release product design. There are other regulatory considerations that
should be taken into account in the process of developing controlled release products,
which have been reported by Cabana,128 130 and which will be further defined here.
A. In Vivo Bioavailability Data

These requirements are discussed in the next section on regulatory considerations in
the verification of effectiveness of controlled release products, but it should be noted
that the FDA will be specifically looking for data in three areas:
1. Pharmacokinetic profiles
2. Bioavailability data
a. A comparison with a conventional drug product(s) employing a multidose,
steady-state study
b. A comparison demonstrating equivalence with a reference controlled re-
lease (C.R.) dosage form, wherein the same labeling for dosage, indica-
tions, and side effects can be justified
c. A comparison demonstrating nonequivalence with a reference dosage form,
with demonstration of safety and efficacy, and justification for appropriate
but different labeling
3. Reproducibility of in vivo performance
In viewing this bioavailability data the FDA will be looking especially hard at two
points:
1. Does the controlled release product allow for complete bioavailability, or for the
maximum possible percentage of the total dose of the C.R. formulation to be
absorbed (possibly in comparison to a standard conventional product)?
2. Does the controlled release product minimize subject to subject variations in
bioavailability (again possibly in comparison to standard reference conventional
product)?
If the answer to either of these questions is no, and the difference is significant, some
other very major advantage of the controlled release product would need to be demon-
strable in order to hope to obtain regulatory approval.
A third biopharmaceutic aspect that the FDA will certainly scrutinize is whether or
not the drug selected for the controlled release product is a rational choice. Factors
considered here are detailed in this chapter in the section on considerations in the
selection of candidate drugs for incorporation in controlled release systems. If the drug
is somewhat questionable as a controlled release candidate, whether because it has a
long biological half-life, a low therapeutic index, or an established, substantial, first-
pass effect, the agency will look very hard for proof of any enhancement in product
advantage to the patient, whether it is convenience of dosing, better patient compli-
ance, reduction in unwanted side effects related to peaking from conventional repeated
single doses, etc. Drugs with known or strongly suspected ‘‘first-pass metabolism” ,
whether hepatic, gut wall, or both, will not be favorably received by the agency, unless
it can be shown that the metabolite(s) is active, or that in the case of gut wall metabo-
lism perhaps, that the controlled release product releases the drug in a manner that
enhances absorption of the intact drug (as might be feasible with a controlled release,
gastric-retention product).
B. In Vitro Drug Release Data

An appropriate in vitro dissolution, drug release test will be required as a condition
of the approval of any application for a controlled release product. If at all possible,
one of the USP dissolution test methods should be employed. If not, a basic USP
method should be modified such that another testing laboratory could reasonably eas-
ily undertake the test. The purpose for the in vitro test method is to provide a mean-
ingful quality control procedure for the product capable of assuring the suitability of
the controlled rate of release for each manufactured lot of product. Therefore, the in
vitro drug dissolution, release rate method should be sufficiently accurate, sensitive,
and discriminating that it will detect any differences in raw materials, processing vari-
ables, or interactions of these effects, as they may impact on drug dissolution release
rate in any significant manner. Ideally, in the process of developing the controlled
release product, such a dissolution release test will have been developed which corre-
lates with in vivo performance. Unfortunately, yet today, to develop such correlation
requires testing at least three release profiles in vivo, perhaps one being poor (much
too slow), one fair (still too slow), and one about right (the aproxímate correct rate).
Alternatively, an immediate release product may provide one rate (too fast) vs. or
along with two slow release products having substantially different slow controlled
rates. Some companies are now attempting to validate and are successfully validating
their controlled release products. This can be done at reasonable cost and without
additional clinical or bioavailability testing, provided a statistically valid correlation
has been established between the in vitro test and the in vivo data. In this author’s
opinion all controlled release products should be subjected to validation procedures.
One difficulty is that the manufacturing procedures and formulations of some sus-
tained release products are so complex, contain so many variables, and have so many
interaction effects, that mathematical/statistical validation procedures are very diffi-
cult, and the processes themselves may involve so many variables and interactions as
to defy validation, and permit only final product “ go/no-go” approval.
The critical components of any in vitro dissolution test are the following:
1. The dissolution medium

2. The volume of the dissolution medium (and sink conditions)
3. The dissolution apparatus and geometry of the components in the apparatus
4. Agitation mechanism, intensity, and hydrodynamics
5. Temperature
6. The method of mounting, locating, or positioning the dosage form in the disso-
lution cell
7. Other possible components of the dissolution apparatus, such as a dialysis mem-
brane
The dissolution medium should reflect the medium at the site of absorption or above
it in the GI tract. For example, acidic drugs should be tested in simulated gastric fluid
or in an acidic medium since, for best absorption, they must dissolve in the stomach
or upper small intestine. Dissolution testing of such drugs in simulated intestinal fluid
at pH 7.4 would likely serve little purpose. The volume of the dissolution medium
should be more than adequate to dissolve all the drug in the dosage form, even if
several liters of fluid are required. By exceeding the minimum volume of dissolution
fluid required for complete drug dissolution by a factor of at least five, assurance of
sink conditions can usually be achieved. If drug solubility is so low that this is impract-
Volume II 21
ical, a miscible organic solvent (e.g., alcohol) may be added to the medium, or a more
elaborate dissolution cell employing a membrane system or a water-immiscible organic
solvent layer may be used to provide a reservoir. A membrane, providing a dialysis
step, may also be useful if there is a likelihood that bound drug is being released,
perhaps in the form of a polymer drug complex. However, complicated dissolution
cells which attempt to simulate human physiology by means of elaborate glassware or
animal membranes, do not typically give any better correlations with in vivo release
than are obtained with simpler, well-designed systems.
The method of mounting the dosage form in the dissolution apparatus should be
precisely reproducible for all solid dosage forms including coated and uncoated tablets
as well as capsules. The dissolution apparatus should have a widely variable but highly
controllable range of agitation intensities. Where possible, one of the U.S.P. dissolu-
tion test procedures should be employed.
V III. R E G U L A T O R Y C O N SID E R A T IO N S IN T H E V E R IFIC A T IO N OF

E FF E C T IV E N E SS O F C O N T R O L L E D RELEA SE PR O D U C TS
Currently, the manufacturer of any sustained release drug product may expect to be
required by the FDA to conduct an appropriate in vivo evaluation of any candidate
sustained release product, with such evaluation representing a clinical trial of the avail-
ability and performance of the product. The manner in which the in vivo study is
undertaken should receive the same care and attention with regard to experimental
design as is given any clinical test procedure. In developing the in vivo test to determine
the effectiveness of the sustained release product, the first part of the experimental
design should be the identification of the questions to be answered. Among these ques-
tions will certainly be the identification of the absorption rate, characterization of the
time to peak activity or blood level, the time over which the peak activity or blood level
is maintained, and the rate at which the activity or blood levels decline. Verification
that adequate activity or blood levels are achieved and maintained will also be a critical
question together with the possible adjustments that may be required in the release rate
of the drug from the dosage form to maintain constant activity at peak level. The
second question in the construction of the in vivo study to establish effectiveness will
be the actual design of the experiment, and this design will be predicated at least in
part on the questions that are to be answered, together with other good clinical testing
procedures (use of cross-over designs and double-blind procedures, especially if clinical
end points are being employed as opposed to chemical analytical tests, utilization of
the appropriate number of test subjects to achieve statistically valid data depending on
the variability expected in the test results, etc.). The third part of the in vivo test pro-
cedure will be the actual experimentation, followed by the fourth part, which is the
evaluation of the results.
As noted previously, a controlled release system may be intended to achieve other
goals than to simply extend the duration of action or blood level time profile of the
drug. These other goals may be to enhance the safety of a product by diminishing the
sharp spike of the normal blood level time profile or to reduce the values between the
peaks and valleys of maximum and minimum blood level concentrations on repeated
dosing. Depending on the particular objective for the product, different techniques
may be required to assess the effectiveness of the product in achieving its intended
goals. Where the minimum effective blood concentration is known, the ability to ex-
ceed this concentration and remain above it for a prolonged period may be a primary
indication of effectiveness. Achieving the peak level for the controlled release system
as quickly as is done with a conventional fast releasing drug product may not be of
significance. Frequently, controlled release systems achieve their peak values or mini-
mum effective concentration levels somewhat more slowly than do fast releasing sys-
tems. Since controlled release systems are not typically used for emergency drug ther-
apy, and where such products are used for chronic types of drug administration, a
delay of 30 min or more may not be of consequence. The total bioavailability of the
sustained release product will almost certainly be of interest to the FDA on review of
the data, both from the standpoint of average bioavailability, and variability between
subjects. A sustained release system should not reduce the bioavailability of the drug
in comparison to that of the standard innovator or originally marketed product. Like-
wise, the sustained release product should not have greater variability in bioavailability
from subject to subject than does the conventional drug product. If it does, this may
indicate that the slow release of drug along the GI tract is leading to greater variability
of absorption, and the product is not a good candidate for sustained release drug
therapy.
Drug products which are designed to release medication to patients from a controlled
release formulation over a prolonged period are regarded as new drugs under Section
201 (p) of the Code of Federal Regulations. Therefore, the same regulatory approval
is required as for any new drug, including submission of scientific data and documen-
tation to substantiate the safety and efficacy of the controlled release product, together
with demonstration of its controlled release characteristics. The requirements to dem-
onstrate safety and effectiveness are basically the following:128
1. For drugs which have been published in the Federal Register as safe and effective
in conventional dosage forms:
a. Controlled clinical studies may be required to demonstrate the safety and
efficacy of the drugs in the controlled release formulations.
b. Bioavailability data of the drugs delivered in the controlled release formu-
lations are also required and may be acceptable in lieu of clinical trials.
2. For drugs which have been published in the Federal Register as safe and effective
in controlled release dosage forms:
a. Bioavailability data are required and acceptable when comparable to an
approved controlled release drug product.
b. The labeling must be identical to the reference standard with regard to ef-
fectiveness and side effects. Without appropriate clinical studies the label-
ing cannot be modified to make any different claims in clinical effectiveness
and side effects.
c. Bioavailability studies, which have been performed under steady-state con-
ditions to demonstrate comparability to an approved immediate release
drug product, are acceptable for supporting a labeling for dosage adminis-
tration.
Where bioavailability studies are employed in the submission of the new drug appli-
cation, the “ Bioavailability Requirements for Controlled Release Formulations”
should be followed as described in the Federal Register, CFR 320.25 (f). These bioa-
vailability regulations require the following types of information for controlled release
products:
1. The drug product meets the controlled release claims made for it.
2. The bioavailability profile established for the drug product rules out the occur-
rence of any dose dumping.
3. The drug product’s steady-state performance is equivalent to a currently mar-
keted noncontrolled 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.
Volume II 29
4. The drug product’s formulation provides consistent pharmacokinetic perform-

ance between individual dosage units.
The reference standard for comparative studies should usually be
1. Either a solution or suspension of the same active drug ingredient or therapeutic

moiety.
2. A currently marketed, approved, noncontrolled release drug product containing
the same active drug ingredient or therapeutic moiety.
3. A currently marketed, controlled release drug product subject to an approved
full new drug application containing the same active drug ingredient or therapeu-
tic moiety.
In summary then, blood level and/or urinary elimination rate profiles performed
under steady-state conditions may be acceptable in place of clinical trials, provided it
can be demonstrated that these parameters are comparable to the values from multiple-
dose studies of the same drug from conventional dosage forms (for drugs listed in the
Federal Register as safe and effective from conventional dosage forms). In the case of
drugs listed in the Federal Register as safe and effective in controlled release dosage
forms it may be sufficient to demonstrate that single-dose blood level and/or urinary
elimination rate profiles are equivalent to an appropriate reference product. However,
in this case, the product labeling must clearly state the dosage regimen, claims of effec-
tiveness, and side effects in a manner identical to the controlled release reference prod-
uct. As noted above, when a controlled release product is being developed for a drug
which has not previously existed in controlled release form, a multiple-dose, steady-
state study may be required, not only to establish comparability to more frequent mul-
tiple dosing from the convention dosage form, but also to provide a basis of support
for the labeling of the new product. In any controlled release product, any labeling
claims indicating a clinical advantage such as greater effectiveness or reduced incidence
of side effects must be substantiated by the appropriate controlled clinical studies.
IX. S IG N IF IC A N C E A N D IM PO R T A N C E O F D E SIG N IN G O P T IM IZ E D
E F F E C T O R C O N T R O L L E D RELEA SE PR O D U C TS
It is well known that drugs are the number one method of treating disease today,
whether measured from the standpoint of the frequency of use of the chemotherapy
approach, or whether based on treatments of choice for various disease states. Great
advancements have been made in chemotherapy, particularly over the last 4 decades.
The fact remains however, that many drug products that are currently marketed are
not optimum systems as far as drug delivery is concerned. They have not been designed
to maximize their reliability of absorption while considering the many variables influ-
encing such absorption, particularly by the oral route, nor have they been formulated
to produce the safest possible blood level or tissue concentration profiles when consid-
ering the accidental or purposeful overdosing which may occur with many drugs. In-
deed, as noted earlier, the vast majority of drug products today could be described as
dump systems. Optimization of drug action by utilization of controlled delivery sys-
tems to achieve precise control of the release of the drug, possibly not only from a rate
standpoint but also at a particular site, is a worthy goal for drugs which are extremely
potent, which treat life-threatening ailments, which require careful dose titration to
produce the desired effect, which have a narrow margin of safety between the effective
dose and toxic dosage levels, or which are frequently abused. Drug products as a class
are not routine consumer products, since they deal directly with the life and well-being
of the user. The extra effort to produce a product which has been optimized so as to
be as simultaneously safe, effective, and reliable as possible, with mathematical cer-
tainty, is increasingly being recognized as a worthy goal. In nondrug chemical effector

fields, the additional concepts of maximizing safety to the user and minimizing envi-
ronmental impacts while achieving effectiveness, convenience of use, and reliability,
regardless of environmental variables to which such products might be exposed, is a
recent dimension of insecticide and herbicide product design.
Table 1 and the discussion which has focused on Table 1 indicated the common
product objectives for all classes of effectors. However, many persons do not recognize
that nondrug effectors can have as great an influence on the health and well-being of
entire populations as do drugs, and this too makes a simultaneous treatment of these
compounds for controlled delivery purposes appropriate and meaningful. Between one
third and one half of the population of the world is underfed. Improved animal and
plant growth stimulants and regulators will continue to play an important role in com-
bating this problem. However, also related to this problem is the fact that insects have
been making major gains in recent years in their quests to expand their populations
and areas of infestation around the globe.131 Problems with the Medfly in the U.S. are
just one case in point. The increasing problems seen with insect infestations may be
traced to at least three factors: (1) increased government controls such as those of the
U.S. Environmental Protection Agency (EPA), which have banned or restricted the
use of some of the most effective insecticides; (2) development of resistance to existing
insecticides by many insect species; and (3) misuse of insecticides and other insect con-
trol methods, especially in areas of the world where such methods are relatively new.
Not only do insects continue to threaten our food supply but they are a major cause of
disease, especially in underdeveloped and tropical countries. The fact that the least
developed countries around the globe tend to be in the tropics is probably not totally
coincidental but may be related in part to insect problems. Malaria, which was once
coming under world-wide control, has increased as a major disease in recent years. It
now victimizes 100 million people a year in Africa alone, killing about 800,000/year.
Most victims are children under five.131 In the Volta River Basin, a species of blackfly
afflicts a million Africans annually with river blindness, leaving the majority sightless.
The tsetse fly, a carrier of sleeping sickness, dominates most of that continent. In the
U.S., where the control of agricultural pests is among the best in the world, insects still
destroy about 10% of all crops grown and represent a loss of $5 to 6 billion an-
nually.131 132 In the least developed and Third World nations of the world the average
crop losses due to insects are closer to 50%, where such crop losses can least be af-
forded. The need for more effective agents to control insects which are disease vectors,
and which have yet today a very adverse effect on crop production, as well as to en-
hance the effectiveness of animal and plant growth stimulants, is an increasingly im-
portant area of work in light of the continuing rapid growth in populations world-
wide.
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Medical Applications

Robert S. Langer, Ph.D.

Donald L. Wise, Ph.D.

Boca Raton London New York

CRC Press is an imprint of the

Reissued 2019 by CRC Press

© 1984 by Taylor & Francis Group, LLC

No claim to original U.S. Government works

A Library of Congress record exists under LC control number:

ISBN 13: 978-0-367-22729-6 (hbk)

Robert S. Langer, Ph.D. is the Dorothy Poitras Associate Professor of Biochemical

James M. Anderson Sung W. Kim

Gilbert S. Banker Fred A. Kind

Julian Frick Lawrence S. Olanoff

J. Max Goodson Nikolaos A. Peppas

Joseph Gresser Michael Phillips

APPLICATIONS OF CONTROLLED RELEASE SYSTEMS

EVALUATION OF CONTROLLED RELEASE SYSTEMS

I. History of Controlled Release.................................................................................2

I. HISTORY OF CONTROLLED RELEASE

II. CONTROLLED RELEASE OF EFFECTORS

A. Terms and Concepts in the Field

FIGURE 1. Relationship between drug concentration or activity and

B. Purposes for the Design of Controlled Release Effector Products

Objective Example or application

Maximize duration of effectiveness All effectors

C. The Ideal Attributes of Effector Controlled Delivery Systems

1. Not highly sensitive to environmental factors

D. The Concept of the Optimized Drug or Chemical Effector System

FIGURE 2. The concept of the optimized drug or effector product.

III. SAFETY ENHANCEM ENT AS A PRIMARY OBJECTIVE OF

FIGURE 3. Typical blood or tissue level time profiles following the

Acute safety quantification

FIGURE 5. Relationship between the level of use for an herbicide

IV. RELIABILITY ENHANCEM ENT AS AN OBJECTIVE OF

The reliability of a drug product may be influenced by chemical, physical, biovaila-

V. EFFECTIVENESS ENHANCEM ENT AS AN OBJECTIVE OF

VI. CONSIDERATIONS IN THE SELECTION OF CANDIDATE DRUGS

A. Physical-Chemical Properties of Drugs Influencing their Viability as Candidates for

3. Molecular Size and Partition Coefficient

where D is diffusivity, V is molecular volume, and sv and kv are constants related to

B. Biological and Pharmacological Properties of Drugs Influencing their Viability as

1 4.60 5.54 8.32

° Based on drugs having a one -com-

From Lee, V. H. and Robinson, J. L.,

3. Distribution and Metabolism

4. Safety Margin and Side Effects of the Drug

5. Therapeutic Goal, Disease State, and Route o f Administration

V II. R E G U L A TO R Y C O N SID ER A TIO N S IN D E V ELO PIN G

Regulatory considerations related to the effectiveness of controlled release drug

A. In Vivo Bioavailability Data

B. In Vitro Drug Release Data

1. The dissolution medium

V III. R E G U L A T O R Y C O N SID E R A T IO N S IN T H E V E R IFIC A T IO N OF

4. The drug product’s formulation provides consistent pharmacokinetic perform-

1. Either a solution or suspension of the same active drug ingredient or therapeutic

tainty, is increasingly being recognized as a worthy goal. In nondrug chemical effector

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