Polymeric Drugs and Drug Delivery Systems

310 Pages·1991·5.336 MB·English

by  Richard L. Dunn and Raphael M. Ottenbrite (Eds.)

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ACS SYMPOSIUM SERIES 469
Polymeric Drugs and Drug
Delivery Systems
Richard L. Dunn, EDITOR
Atrix Laboratories, Inc.
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9.fw Raphael M. Ottenbrite, EDITOR
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4 Virginia Commonwealth University
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0. Developed from a symposium sponsored
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American Chemical Society, Washington, DC 1991
Library of Congress Cataloging-in-Publication Data
American Chemical Society. Meeting. (200th: 1990: Washington, D.C.)
Polymeric drugs and drug delivery systems / Richard L. Dunn,
editor, Raphael M. Ottenbrite, editor; developed from a symposium
sponsored by the Division of Polymeric Chemistry, Inc. at the 200th
National Meeting of the American Chemical Society, Washington, D.C.,
August 26-31, 1990.
p. cm.—(ACS symposium series, ISSN 0097-6156; 469)
Includes bibliographical references and indexes.
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0 ISBN 0-8412-2105-7
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69.f 1. Polymeric drugs—Congresses. 2. Polymeric drug delivery
04 systems—Congresses.
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9 I. Dunn, Richard L. II. Ottenbrite, Raphael M. III. American
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k- Chemical Society. Division of Polymer Chemistry. IV. Title. V. Series.
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21/ RS201.P65A44 1991
10 615'.—dc20 91-23423
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Foreword
THE ACS SYMPOSIUM SERIES was founded in 1974 to provide
a medium for publishing symposia quickly in book form. The
format of the Series parallels that of the continuing ADVANCES
IN CHEMISTRY SERIES except that, in order to save time, the
papers are not typeset, but are reproduced as they are submit
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Preface
DELIVERY OF DRUGS by means of controlled-release technology began
in the 1970s and has continued to expand so rapidly that there are now
numerous products both on the market and in development. These
controlled-release drug-delivery products have given new life to old phar
maceuticals that either were no longer patented or had properties that
prevented them from being used effectively to treat various diseases. In
1 addition to stimulating use of these older drug products, controlled-
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pr release technology is now being directed toward the newer biopharma-
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6 ceuticals produced by genetic research. It is with biopharmaceuticals that
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1- controlled-release technology may find its most important applications in
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19 medicine.
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b Polymers have played a major role in the development of controlled-
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2 release systems and, as expected, the earlier polymeric drug-delivery sys
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0. tems incorporated polymers that were commercially available and
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oi: approved by the U.S. Food and Drug Administration. There are many
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1 | polymers that meet this need, and they have been successfully incor
99 porated into commercial products for oral, injectable, implantable, topi
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5, cal, and transdermal administration. The mechanisms by which drugs are
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st released from these polymers and the processes for fabricating such
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ug controlled-drug-delivery devices have been well reviewed in the literature.
A
e: Extensive research efforts are being made to improve both the polymers
Dat and the processes, as well as to apply them to the controlled release of a
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o wide variety of pharmaceutical products. However, with the continued
cati development of controlled-release technology, the need has arisen for
ubli materials with more specific drug-delivery properties. These materials
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include new biodegradable polymers, polymers with both hydrophilic and
hydrophobic characteristics, and hydrogels that respond to temperature or
pH changes. In addition, methods to overcome some of the barriers asso
ciated with current drug-delivery systems are necessary. Finally, polymers
that may not only be used to deliver drugs, but that may themselves elicit
biological responses are needed.
This book is divided into four sections that cover the main topics in the
field of drug delivery. The first section gives an overview of the polymers
and materials currently being used in drug delivery and some of the prob
lems with and opportunities for polymeric drug delivery. The overview
chapters are followed by a section on polymeric drugs and polymer-drug
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conjugates. This section describes novel polymers that function as drugs
themselves or that are covalently attached to drugs. This field of research
offers tremendous possibilities for new materials that can be made either
synthetically or by genetic engineering. The third section of the book
deals with new polymers that can be used as matrices for drug delivery.
Polymers described in this section are not covalently bound to a drug but
rather are physically mixed or blended with the drug. Polymer-drug mix
tures are currently the most widely used drug-delivery systems, and the
chapters included here describe new materials that may be useful in the
future. The final section covers new developments in the area of drug
delivery with liposomes. This area has intrigued researchers for years, and
with the development of new materials to target the liposomes, this field
of research should remain prominent for the next several years.
1 As editors, we hope that this book will alert researchers to the prob
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pr lems associated with drug delivery and the opportunities for fiiture
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6 developments. If the material presented here can stimulate new ideas and
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1- concepts for polymeric drugs and polymeric drug-delivery systems, then
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9 our efforts will have been worthwhile. We wish to thank the Division of
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bk- Polymer Science, Inc., for sponsoring the symposium that served as the
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2 basis for this book, and Glaxo, Inc., Lilly Research Laboratories, and
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0. Atrix Laboratories, Inc., for providing partial funding. We also want to
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oi: thank each of the authors for their participation and cooperation.
1 | d Without them, this book would not have been possible. We gratefully ack
9 nowledge the staff of Atrix Laboratories and, specifically, Karen Miller
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5, and Sisca Wolff, for their assistance in the editing and production aspects
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st of the book. Most of all, we want to thank Carol Dunn for her efforts in
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cati Atrix Laboratories, Inc.
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Fort Collins, CO 80525
RAPHAEL M. OTTENBRITE
Virginia Commonwealth University
Richmond, VA 23284
March 15, 1991
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Chapter 1
Biologically Active Polymers
Raphael M. Ottenbrite
Department of Chemistry, High Technology Materials Center, Virginia
Commonwealth University, Richmond, VA 23284
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99 This paper provides an introduction to these types of materials and a
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1 Drug delivery systems are ideally devised to disseminate a drug when and
15, where it is needed and at minimum dose levels. Polymeric drugs and delivery
ust systems provide that possibility through several different approaches. Polymeric
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e: bioerodible matrices, diffusion through membranes or from monolithic devices, and
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Polymeric Drugs.
Polymeric drugs are macromolecules that elicit biological activity (1). Many
synthetic polymers are biologically inert. However, some exhibit toxicity, while
others exhibit a wide range of therapeutic activities. There are three kinds of
polymer drugs: polycations, polyanions, and polynucleotides.
Polycationic polymers. These are macromolecules that have electropositive groups
attached to the polymer chain or pendant to the chain. These materials are active
against a number of bacteria and fungi. However, due to their inherent toxicity to
animal species through their destructive interaction with cell membranes they are
0097-6156/91/0469-0003$06.00/0
© 1991 American Chemical Society
4 POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS
only used topically (2). Recent reports indicate that they can enhance cellular
antigen uptake and exhibit antitumor activity against Ehrlich carcinoma.
Polyanionic polymers. Polyelectrolytes with negative charges on the polymer can
also function as drugs. These polymers are much less toxic. Both natural
polyanions, such as heparin and heparinoids, and synthetic polyanions such as,
poly(acrylic acid), exhibit a variety of biological activity (5). For example,
poly(divinyl ether-co-maleic anhydride) exhibits antiviral, antimicrobial and
antifungal activity. It is best known for activity against a number of animal tumor
models most notable Lewis lung carcinoma, Ehrlich carcinoma, and Friend
leukemia. One mechanism of activity is the activation of macrophages and
augmentation of natural killer cell activity.
1 Other polycarboxylates, such as Carbetimer, poly(maleic anhydride-co-
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h cyclohexyl-l,6-dioxepin) and poly(maleic anhydride-co-4-methylpentenane), elicit a
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99 throughout the host and they behave similar to proteins, glycoproteins and
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1 reticuloendothelial system (RES) macrophages.
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1 The synthetic polymer which has received the most interest is divinyl ether-
doi: maleic anhydride copolymer, commonly referred to as pyran copolymer due to the
1 | tetrahydropyran ring which forms during polymerizaton. In the literature it is also
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1 referred to by the acronym DIVEMA (divinyl ether-maleic anhydride copolymer)
5,
1 and, more recently, as MVE (maleic anhydride-vinyl ether copolymer). Pyran was
ust first reported by Butler in 1960 and submitted to the NIH screen (4). Pyran showed
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e: Institute. It has been under investigation for use in cancer chemotherapy and has
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blic including Friend leukemia, Rauscher leukemia, Maloney sarcoma, polyoma,
Pu vesicular stomatitis, Mengo and encephalomyo-carditis.

A number of investigations have clearly demonstrated that the structure and
molecular weight of synthetic polyanions are directly related to biological activity
and toxicity. Breslow showed that the acute toxicity caused by pyran in mice
increased with increased molecular weight (5). Biological activity data of pyran
fractions (2,500-32,000) indicated that molecular weights up to 15,000 stimulated
RES whereas higher molecular weight fractions suppressed RES, resulting in
biphasic response. It was found that the level of serum glutamic pyruvate
transaminase, which is a measure of liver damage, also increased with molecular
weight, as did inhibition of drug metabolism and sensitization to endotoxin.
However, the activities against Lewis lung and Ehrlich ascites tumor were shown to
be independent of molecular weight.
Recently, considerable evidence has emerged that implicates the macrophage as
a major effector of tumor cytotoxicity and/or cytostasis. Both synthetic