Controlled-Release Technology. Pharmaceutical Applications 9780841214132, 9780841211919, 0-8412-1413-1

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Controlled-Releas

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

ACS SYMPOSIUM SERIES 348

Controlled-Release Technology Pharmaceutical Applications Ping I. Lee, EDITOR Ciba-Geigy Corporation

William R. Ciba-Geigy Corporation

Developed from a symposium sponsored by the Division of Industrial and Engineering Chemistry at the 191st Meeting of the American Chemical Society, New York, New York, April 13-18, 1986

American Chemical Society, Washington, DC 1987

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Library of Congress Cataloging-in-Publication Data Controlled-release technology. (ACS symposium series, ISSN 0097-6156; 348) "Developed from a symposium sponsored by the Division of Industrial and Engineering Chemistry at the 191st meeting of the American Chemical Society, New York, New York, A p r i l 13-18, 1986." Includes bibliographies and indexes. 1. Drugs—Controlled release—Congresses 2. Controlled release technology—Congresses I. Lee, Ping I., 1948. II. Good 1940. III. American Chemical Society. Division of Industrial and Engineering Chemistry. IV. American Chemical Society. Meeting (191st: 1986: New York, N.Y) V. Series. RS201.C64C67 1987 ISBN 0-8412-1413-1

615M 91

87-17447

Copyright © 1987 American Chemical Society A l l Rights Reserved. The appearance of the code at the bottom of the first page of each chapter in this volume indicates the copyright owners consent that reprographic copies of the chapter may be made for personal or internal use or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., 27 Congress Street, Salem, M A 01970, for copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright L a w . This consent does not extend to copying or transmission by any means—graphic or electronic—for any other purpose, such as for general distribution, for advertising or promotional purposes, for creating a new collective work, for resale, or for information storage and retrieval systems. The copying fee for each chapter is indicated in the code at the bottom of the first page of the chapter. The citation of trade names and/or names of manufacturers in this publication is not to be construed as an endorsement or as approval by A C S of the commercial products or services referenced herein; nor should the mere reference herein to any drawing, specification, chemical process, or other data be regarded as a license or as a conveyance of any right or permission, to the holder, reader, or any other person or corporation, to manufacture, reproduce, use, or sell any patented invention or copyrighted work that may in any way be related thereto. Registered names, trademarks, etc., used in this publication, even without specific indication thereof, are not to be considered unprotected by law. PRINTED IN T H E UNITED STATES OF A M E R I C A

American Chemical Society Library 1155 16th St., N.W.

In Controlled-Release Technology; Lee, P., et al.; Washington, D.C Society: 20036Washington, DC, 1987. ACS Symposium Series; American Chemical

ACS Symposium Series M. Joan Comstock, Series Editor 1987 Advisory Board Harvey W. Blanch University of California—Berkeley

Vincent D. McGinniss Battelle Columbus Laboratories

Alan Elzerman Clemson University John W. Finley Nabisco Brands, Inc.

James C . Randall Exxon Chemical Company

Marye Anne Fox The University of Texas—Austin

E . Reichmanis AT&T Bell Laboratories

Martin L . Gorbaty Exxon Research and Engineering Co.

C . M . Roland U.S. Naval Research Laboratory

Roland F Hirsch U.S. Department of Energy

W. D. Shults Oak Ridge National Laboratory

G . Wayne Ivie USDA, Agricultural Research Service

Geoffrey K. Smith Rohm & Haas Co.

Rudolph J. Marcus Consultant, Computers & Chemistry Research

Douglas B. Walters National Institute of Environmental Health

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Foreword The ACS S Y M P O S I U M S E R I E S 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 A D V A N C E S IN C H E M I S T R Y SERIES except that, in order to save time, the papers are not typeset but are reproduced as they are submitted by the authors in camera-ready form. Papers are reviewed under the supervision of th Advisory Board and ar symposia; however, verbatim reproductions of previously published papers are not accepted. Both reviews and reports of research are acceptable, because symposia may embrace both types of presentation.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Preface CONTROLLED-RELEASE TECHNOLOGY HAS RAPIDLY EMERGED over the past decade as a new interdisciplinary science that offers novel approaches to the delivery of bioactive agents. These agents include pharmaceutical, agricultural, and veterinary compounds. By achieving predictable and reproducible release rates of bioactive agents, particularly pharmaceuticals, to the target environment for an extended time, controlled-release delivery systems can achieve optimum therapeutic responses, prolonged efficacy, and decreased toxicity. Man oped; some of them have including medicine, agriculture, forestry, and consumer products. However, the pharmaceutical area has gained the most significant growth and rapid advances in recent years, as evidenced by the proliferation of publications, patents, and controlled-release products in this area. This expanding field represents an interdisciplinary effort that requires input from chemistry, materials science, engineering, pharmacology, and other related biological sciences. Controlled release has been the subject of many books. However, most of them are published with a specific group of readers in mind, usually pharmaceutical, agricultural, or biological scientists. Because many of the disciplines needed in the area of controlledrelease research are related to chemistry (including polymer chemistry; polymer physics; organic, medicinal, physical, and analytical chemistry, as well as chemical engineering), this publication, addressed to chemically oriented scientists, is timely. A review of the current status and future prospect of the field is provided. The symposium on which this book is based represented an effort to examine recent advances in the field with particular emphasis on pharmaceutical applications within the context of basic science and engineering. The chapters in this book are selected from the 33 papers presented at the symposium. Each manuscript was thoroughly reviewed by leading experts in the field, edited for content and style, and revised by the authors as needed. The interdisciplinary nature of controlled-release technology is reflected in the diversity of subject areas presented here. To provide focus and cohesiveness, the chapters have been divided into six general areas. In addition, an overview chapter is included to provide perspectives on the current status and future prospects of the pharmaceutical applications of controlled-release technology.

ix

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

The editors thank all contributing authors whose cooperation and effort made this book possible. We also acknowledge support for the symposium from the American Chemical Society's Division of Industrial and Engineering Chemistry. PING I. LEE WILLIAM R. GOOD

Ciba-Geigy Corporation Ardsley, NY 10502 February 19, 1987

x

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Chapter 1

Overview of Controlled-Release Drug Delivery Ping I. Lee and William R. Good Ciba-Geigy Corporation, Ardsley, NY 10502

During the past two decades, significant advances have been made in the area of controlled release as evidenced by an increasing number of patents, publications, as well as commercial controlled-release products for the delivery of a variety of bioactive agents ranging from pharmaceutical to agricultural and veterinary compounds. This proliferation of interes that by achieving predictabl active agents, particularly pharmaceuticals, to the target environ ment for a desired duration, optimum biological responses, prolonged efficacy, decreased toxicity as well as reduction of required dose level as compared to the conventional mode of delivery can be effectively achieved. So far, the controlled-release pharmaceutical area has gained the most significant growth as a result of intense interdisciplinary efforts involving contributions from chemistry, material science, engineering, pharmacology and other related biological sciences. By improving the way in which drugs are delivered to the target organ, a controlled-release drug delivery system is capable of achieving the following benefits: (1) maintenance of optimum therapeutic drug concentration in the blood with minimum fluctuation; (2) predictable and reproducible release rates for extended duration; (3) enhancement of activity duration for short half-life drugs; (4) elimination of side effects, frequent dosing, and waste of drug; and (5) optimized therapy and better patient compliance. A number of controlled-release drug delivery systems have been developed and some are already commercialized. These include, for example, transdermal nitroglycerin delivery systems for the prevention of angina and oral osmotic pump devices for the delivery of a variety of therapeutic agents. The purpose of this overview chapter is to provide perspectives in the current status and future prospects of controlled release drug delivery. This is accomplished by examining various delivery systems from a mechanistic point of view, exploring applications of these systems, and discussing relevant biopharmaceutical parameters. A major section of this book is devoted to fundamental issues and applications of transdermal and transmucosal delivery systems (Chapter 6,8,17-23). Other developing systems of future potential

0097-6156/87/0348-0001$06.00/0 © 1987 American Chemical Society

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

CONTROLLED-RELEASE TECHNOLOGY

2

a r e a d d r e s s e d by v a r i o u s C h a p t e r s o f t h i s book i n v o l v i n g s e l f - r e g u l a t i n g i n s u l i n d e l i v e r y systems (Chapter 13), h y d r o g e l s (Chapters 5,10-12), drug-polymer c o n j u g a t e s (Chapter 14), and b i o d e g r a d a b l e m i c r o s p h e r e s ( C h a p t e r s 15,16). To p r o v i d e a b r o a d e r scope on the p h y s i c o c h e m i c a l b a s i s o f c o n t r o l l e d r e l e a s e , the fundamental a s p e c t s of d i f f u s i o n i n polymers ( C h a p t e r s 2-4), polymer and d e l i v e r y system c h a r a c t e r i z a t i o n ( C h a p t e r s 7,9) as w e l l as o t h e r r e l a t e d a p p l i c a t i o n s o f d e l i v e r y systems ( C h a p t e r s 24,25) a r e a l s o d i s c u s s e d . C l a s s i f i c a t i o n o f C o n t r o l l e d - R e l e a s e Drug D e l i v e r y Systems. An i d e a l drug d e l i v e r y system i s one which p r o v i d e s the drug o n l y when and where i t i s needed, and i n the minimum dose l e v e l r e q u i r e d t o e l i c i t the d e s i r e d t h e r a p e u t i c e f f e c t s . In p r a c t i c e , such a system s h o u l d p r o v i d e a programmmable c o n c e n t r a t i o n - t i m e p r o f i l e t h a t p r o d u c e s optimum t h e r a p e u t i c r e s p o n s e s . T h i s g o a l can o n l y be a c h i e v e d t o a l i m i t e d e x t e n t w i t h c o n v e n t i o n a l dosage forms. Recent developmen t r o l l e d r e l e a s e of t h e r a p e u t i systems not o n l y can improve drug s t a b i l i t y b o t h i n v i t r o and i n v i v o by p r o t e c t i n g l a b i l e drugs from h a r m f u l c o n d i t i o n s i n the body, but a l s o can i n c r e a s e r e s i d e n c e time a t the a p p l i c a t i o n s i t e and enhance the a c t i v i t y d u r a t i o n o f s h o r t h a l f - l i f e d r u g s . Therefore, compounds which o t h e r w i s e would have to be d i s c a r d e d due to s t a b i l i t y and b i o a v a i l a b i l i t y problems may be r e n d e r e d u s e f u l through a p r o p e r c h o i c e o f p o l y m e r i c d e l i v e r y system. A u s e f u l c l a s s i f i c a t i o n o f c o n t r o l l e d - r e l e a s e p o l y m e r i c system based on the mechanism c o n t r o l l i n g the drug r e l e a s e i s as f o l l o w s : A. C h e m i c a l l y - c o n t r o l l e d systems a. B i o e r o d i b l e systems b. Drug-polymer c o n j u g a t e s B. D i f f u s i o n - c o n t r o l l e d systems a. M e m b r a n e - r e s e r v o i r systems - Solution-diffusion - Osmotic pumping b. M a t r i x systems - Matrix d i f f u s i o n - Polymer e r o s i o n - Polymer s w e l l i n g - Geometry - Concentration d i s t r i b u t i o n Most o f the d e l i v e r y systems d e s c r i b e d i n t h i s book can be d e s c r i b e d by one o f the above c l a s s i f i c a t i o n s . Chemically-Controlled

Systems

B i o e r o d i b l e Systems. In t h i s system, the polymer m a t r i x c o n t a i n s h y d r o l y t i c a l l y o r e n z y m a t i c a l l y l a b i l e bonds and u n i f o r m l y d i s s o l v e d or d i s p e r s e d drug. As the polymer erodes by h y d r o l y s i s o r enzymatic c l e a v a g e , the drug i s r e l e a s e d t o the s u r r o u n d i n g environment. One major advantage o f such an approach i s the e l i m i n a t i o n o f the need to s u r g i c a l l y remove the d e v i c e a f t e r a p p l i c a t i o n . However, dependi n g on the s p e c i f i c polymer u s e d , the e r o s i o n / d e g r a d a t i o n p r o d u c t s may have d i f f e r e n t degree o f t o x i c i t y . As a r e s u l t o f r e s e a r c h on improved a b s o r b a b l e s u t u r e s , p o l y ( l a c t i c a c i d ) , p o l y ( g l y c o l i c

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

1. LEE AND GOOD

Overview of Controlled-Release Drug Delivery

3

a c i d ) , and l a c t i c / g l y c o l i c a c i d c o p o l y m e r s , which h y d r o l y z e t o n a t u r a l m e t a b o l i t e s , have been d e v e l o p e d f o r drug d e l i v e r y p u r p o s e s (1_) . O f t e n the terms " b i o e r o d i b l e " and " b i o d e g r a d a b l e " a r e used i n terchangeable. However, " b i o e r o d i b l e " i s u s u a l l y r e s e r v e d f o r s y s tems where the polymer e r o s i o n o c c u r s i n a time s c a l e s i m i l a r t o t h a t o f the drug r e l e a s e . In o t h e r words, the e r o s i o n p r o c e s s has a d i r e c t e f f e c t on the drug r e l e a s e . On the o t h e r hand, " b i o d e g r a d a b l e " polymer i s f o r systems where the polymer d e g r a d a t i o n o c c u r s a f t e r the drug r e l e a s e i s l o n g completed. In t h i s c a s e , the d e g r a d a t i o n p r o c e s s has no d i r e c t e f f e c t on the drug r e l e a s e . As p o i n t e d out by H e l l e r ( 2 ) , polymer e r o s i o n can be c o n t r o l l e d by the f o l l o w i n g t h r e e t y p e s o f mechanisms: (1) w a t e r - s o l u b l e p o l y mers i n s o l u b i l i z e d by h y d r o l y t i c a l l y u n s t a b l e c r o s s - l i n k s ; (2) w a t e r - i n s o l u b l e polymers s o l u b i l i z e d by h y d r o l y s i s , i o n i z a t i o n , o r p r o t o n a t i o n o f pendant groups; (3) h y d r o p h o b i c polymers s o l u b i l i z e d by backbone c l e a v a g e t o s m a l l water s o l u b l e m o l e c u l e s . These mechanisms r e p r e s e n t extrem c o m b i n a t i o n o f mechanisms ( g l y c o l i c a c i d ) , and l a c t i c / g l y c o l i c a c i d c o p o l y m e r s , o t h e r commonly used b i o e r o d i b l e / b i o d e g r a d a b l e polymers i n c l u d e p o l y o r t h o e s t e r s , p o l y c a p r o l a c t o n e , p o l y a m i n o a c i d s , p o l y a n h y d r i d e s , and h a l f e s t e r s of m e t h y l v i n y l e t h e r - m a l e i c a n h y d r i d e copolymers C3). With r e s p e c t t o the mechanism o f drug r e l e a s e , i t i s i m p o r t a n t to d i s t i n g u i s h between two t y p e s o f h y d r o l y t i c e r o s i o n o f w a t e r - i n s o l u b l e polymers. On one hand, homogeneous e r o s i o n o c c u r s by h a v i n g h y d r o l y s i s a t a u n i f o r m r a t e throughout the m a t r i x . T h i s i s o f t e n r e f e r r e d t o as b u l k e r o s i o n which i s c a p a b l e o f i n c r e a s i n g the drug p e r m e a b i l i t y t h r o u g h the polymer as time p r o c e e d s and t h e r e b y p r o d u c i n g an a c c e l e r a t e d r e l e a s e v i a a c o m b i n a t i o n o f d i f f u s i o n and erosion. On the o t h e r hand, heterogeneous e r o s i o n c o n f i n e s the hyd r o l y s i s to the s u r f a c e o f the d e v i c e and t h e r e f o r e commonly r e f e r r e d to as s u r f a c e e r o s i o n . This process i s capable of g i v i n g r i s e t o a z e r o - o r d e r drug r e l e a s e f o r d e v i c e s w i t h c o n s t a n t s u r f a c e a r e a . M a t h e m a t i c a l a n a l y s i s o f s u r f a c e b i o e r o d i b l e systems has been p r e s e n t e d by Lee (4)who r e c e n t l y a l s o i n v e s t i g a t e d the e f f e c t o f n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n on the k i n e t i c s o f drug r e l e a s e from polymer m a t r i c e s o f v a r i o u s g e o m e t r i e s ( 5 ) . Drug-Polymer C o n j u g a t e s . T h i s system i n v o l v e s drug m o l e c u l e s c h e m i c a l l y bounded to a polymer backbone. The drug w i l l be r e l e a s e d t h r o u g h h y d r o l y t i c or enzymatic c l e a v a g e . Such p o l y m e r i c drug c a r r i e r s a r e a l s o r e f e r r e d to as p o l y m e r i c p r o d r u g s . The attachment of drugs to m a c r o m o l e c u l a r c a r r i e r s a l t e r s t h e i r r a t e o f e x c r e t i o n from the body and p r o v i d e s the p o s s i b l i t y f o r c o n t r o l l e d r e l e a s e over a prolonged p e r i o d . F u r t h e r m o r e , i t l i m i t s the uptake o f drug by c e l l s to the p r o c e s s o f e n d o c y t o s i s , thus p r o v i d i n g the o p p o r t u n i t y t o t a r g e t the drug t o the p a r t i c u l a r c e l l - t y p e where i t s a c t i v i t y i s needed ( 6 ) . Both n a t u r a l polymers such as p o l y s a c c h a r i d e s and s y n t h e t i c polymers such as p o l y l y s i n e , p o l y g l u t a m i c a c i d , p o l y p h o s p h a z e n e s , copolymers o f v i n y l p y r r o l i d o n e , copolymers o f 2-hydroxypropylmetha c r y l a m i d e , and e t c . have been used as drug c a r r i e r s . The s t r u c t u r e o f t h e s e polymers can be m o d i f i e d by the i n c o r p o r a t i o n o f h y d r o p h o b i c u n i t s , sugar r e s i d u e s , o r s u l f o n y l groups t o a c h i e v e a s p e c i f i c tissue a f f i n i t y .

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

4

CONTROLLED-RELEASE TECHNOLOGY

The drug-polymer l i n k a g e may be c o v a l e n t , i o n i c , o r through some weaker s e c o n d a r y m o l e c u l a r f o r c e s . The polymer backbone may be e i t h e r biodegradable or non-biodegradable. The drug can be p a r t o f the p o l y m e r i c backbone o r a t t a c h e d t o the s i d e - c h a i n e i t h e r d i r e c t l y or t h r o u g h a s p a c e r group. The s p a c e r group i s g e n e r a l l y s e l e c t e d i n such a way t h a t i t may be h y d r o l y z e d o r degraded e n z y m a t i c a l l y under s p e c i f i c e n v i r o n m e n t a l c o n d i t i o n s . Examples o f such d r u g polymer c o n j u g a t e s i n c l u d e the attachment o f a m p i c i l l i n , 6-aminop e n i c i l l a n i c a c i d , daunomycin, and puromycin to N - ( 2 - h y d r o x y p r o p y l ) m e t h a c r y l a m i d e copolymers (]_>§), m e t h o t r e x a t e to p o l y ( L - l y s i n e ) ( 9 ) , and n o r e t h i n d r o n e t o p o l y ( h y d r o x y a l k y l ) - L - g l u t a m i n e ( 1 0 ) . In a d d i t i o n t o d i f f u s i o n r a t e l i m i t a t i o n s as d e s c r i b e d i n the next s e c t i o n , the drug r e l e a s e r a t e i s p r i m a r i l y governed by the r a t e o f c l e a v a g e o f the drug from the polymer. Diffusion-Controlled

System

Membrane-Reservoir Systems systems a r e f i n d i n g i n c r e a s i n g a p p l i c a t i o n s i n the a r e a o f c o n t r o l l e d r e l e a s e p h a r m a c e u t i c a l s . To a c h i e v e optimum t h e r a p e u t i c e f f e c t s e s p e c i a l l y f o r drugs w i t h s h o r t b i o l o g i c a l h a l f - l i v e s , i t i s o f t e n d e s i r a b l e t o have a z e r o - o r d e r drug r e l e a s e . Membrane-reservoir d e v i c e s , where the drug c o r e i s s u r r o u n d e d by a r a t e - c o n t r o l l i n g membrane, a r e o f t e n employed f o r t h i s p u r p o s e . The p r e s e n c e o f a s a t u r a t e d r e s e r v o i r i n t h i s case i s e s s e n t i a l to m a i n t a i n a constant r a t e o f drug r e l e a s e . The k i n e t i c s o f drug r e l e a s e from such membrane-reservoir systems g e n e r a l l y f o l l o w s e i t h e r a s o l u t i o n - d i f f u s i o n mechanism o r an o s m o t i c pumping mechanism. In the s o l u t i o n - d i f f u s i o n mechanism, the drug t r a n s p o r t o c c u r s by f i r s t d i s s o l v i n g i n the membrane a t one i n t e r f a c e f o l l o w e d by d i f f u s i o n down a c h e m i c a l p o t e n t i a l g r a d i e n t a c r o s s the membrane and e v e n t u a l l y r e l e a s e d from the second i n t e r f a c e i n t o the e x t e r n a l medium. Such s o l u t i o n - d i f f u s i o n mechanism i s t y p i c a l l y o b s e r v e d i n non-porous membranes. A s i m i l a r mechanism i s a l s o r e s p o n s i b l e f o r drug p e r m e a t i o n t h r o u g h s w o l l e n h y d r o g e l membranes as w e l l as porous membranes. In the l a t t e r case the drug p e r m e a t i o n t a k e s p l a c e by d i f f u s i o n through the s o l v e n t f i l l e d porous network. Under s t e a d y s t a t e c o n d i t i o n s , a membrane d e v i c e h a v i n g a s a t u r a t e d drug r e s e r v o i r can m a i n t a i n a c o n s t a n t thermodynamic a c t i v i t y g r a d i e n t a c r o s s the membrane f o r an extended p e r i o d o f t i m e . As a r e s u l t , a c o n s t a n t r a t e o f drug r e l e a s e sometimes r e f e r r e d t o as " z e r o - o r d e r r e l e a s e " o f the d r u g i s e s t a b l i s h e d . The r a t e o f r e l e a s e from such a system i s g e n e r a l l y dependent on the d e v i c e geometry and the n a t u r e , t h i c k n e s s and a r e a o f the membrane, whereas the d u r a t i o n o f the r e l e a s e i s governed by the s i z e o f the drug r e s ervoir. The m a t h e m a t i c a l a n a l y s i s of the k i n e t i c s o f drug r e l e a s e from membrane-reservoir systems has been d i s c u s s e d e x t e n s i v e l y i n the l i t e r a t u r e Q l ,_12) . B e f o r e the e s t a b l i s h m e n t o f a s t e a d y s t a t e , the membrane-reserv o i r d e v i c e w i l l e x h i b i t i n i t i a l r e l e a s e r a t e h i g h e r o r lower t h a n the s t e a d y s t a t e v a l u e , depending on the p r i o r h i s t o r y o f the device. Thus, i m m e d i a t e l y a f t e r f a b r i c a t i o n , a f i n i t e time l a g w i l l be r e q u i r e d t o e s t a b l i s h the s t e a d y - s t a t e c o n c e n t r a t i o n p r o f i l e

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

1.

L E E A N D GOOD

Overview of Controlled-Release Drug Delivery

5

w i t h i n t h e membrane. However, a f t e r t h e d e v i c e i s s t o r e d f o r some time, drug w i l l s a t u r a t e t h e membrane and s u b s e q u e n t l y g i v e r i s e t o an i n i t i a l r e l e a s e r a t e h i g h e r than the s t e a d y s t a t e v a l u e . T h i s i s the s o - c a l l e d b u r s t e f f e c t . The magnitude o f t h e s e t r a n s i e n t e f f e c t s i s r e l a t e d t o t h e drug d i f f u s i o n c o e f f i c i e n t i n t h e membrane and t h e membrane t h i c k n e s s . Membrane-reservoir systems based on s o l u t i o n - d i f f u s i o n mechanism have been u t i l i z e d i n d i f f e r e n t forms f o r the c o n t r o l l e d d e l i v e r y of therapeutic agents. These systems i n c l u d i n g membrane dev i c e s , m i c r o c a p s u l e s , l i p o s o m e s , and h o l l o w f i b r e s have been a p p l i e d to a number o f a r e a s r a n g i n g from b i r t h c o n t r o l , t r a n s d e r m a l d e l i v ery, to cancer therapy. Various polymeric materials i n c l u d i n g s i l i cone r u b b e r , e t h y l e n e v i n y l a c e t a t e copolymers, p o l y u r e t h a n e s , and h y d r o g e l s have been employed i n the f a b r i c a t i o n o f such membraner e s e r v o i r systems ( 1 3 ) . I n a d d i t i o n t o t h e s o l u t i o n - d i f f u s i o n mechanism d i s c u s s e d above, the drug r e l e a s take p l a c e through an o r i f i c mechanism, where a semipermeable membrane such as c e l l u l o s e a c e t a t e i s u t i l i z e d t o r e g u l a t e t h e osmotic p e r m e a t i o n o f water (14) . F o r a system o f c o n s t a n t r e s e r v o i r volume, t h e d e v i c e d e l i v e r s a volume o f drug s o l u t i o n e q u a l t o t h e volume o f o s m o t i c water uptake w i t h i n any g i v e n time i n t e r v a l . The r a t e o f o s m o t i c water i n f l u x and t h e r e f o r e the r a t e o f drug d e l i v e r y by t h e system w i l l be c o n s t a n t as l o n g as a c o n s t a n t thermodynamic a c t i v i t y g r a d i e n t , u s u a l l y d e r i v e d from a s a t u r a t e d r e s e r v o i r w i t h e x c e s s s o l i d , i s m a i n t a i n e d a c r o s s the membrane. However, t h e r a t e d e c l i n e s p a r a b o l i c a l l y once t h e r e s e r v o i r c o n c e n t r a t i o n f a l l s below s a t u r a t i o n . Such an osmotic d e l i v e r y system i s c a p a b l e o f p r o v i d i n g n o t o n l y a p r o l o n g e d z e r o - o r d e r r e l e a s e b u t a l s o a d e l i v e r y r a t e much h i g h e r than t h a t a c h i e v a b l e by the s o l u t i o n - d i f f u s i o n mechanism. The system i s a l s o c a p a b l e o f d e l i v e r i n g drugs w i t h a wide range o f m o l e c u l a r weight and c h e m i c a l c o m p o s i t i o n which a r e n o r m a l l y d i f f i c u l t t o d e l i v e r by the s o l u t i o n - d i f f u s i o n mechanism. The d e l i v e r y r a t e from such d e v i c e s i s g e n e r a l l y r e g u l a t e d by t h e o s m o t i c p r e s s u r e o f the drug c o r e f o r m u l a t i o n and by the water p e r m e a b i l i t y o f the semipermeable membrane. E q u a t i o n s f o r p r e d i c t i n g r e l e a s e r a t e from o s m o t i c pumping d e v i c e s have been d i s c u s s e d by Theeuwes ( 1 5 ) . Matrix

Systems

Matrix Diffusion. H i s t o r i c a l l y , t h e most p o p u l a r d i f f u s i o n - c o n t r o l l e d d e l i v e r y system has been t h e m a t r i x system, such as t a b l e t and g r a n u l e s , where t h e drug i s u n i f o r m l y d i s s o l v e d o r d i s p e r s e d , because o f i t s low c o s t and ease o f f a b r i c a t i o n . However, t h e i n h e r e n t drawback o f t h e m a t r i x system i s i t s f i r s t - o r d e r r e l e a s e behavior with continuously diminishing release rate. This i s a r e s u l t o f t h e i n c r e a s i n g d i f f u s i o n a l r e s i s t a n c e and d e c r e a s i n g a r e a a t t h e p e n e t r a t i n g d i f f u s i o n f r o n t as m a t r i x d i f f u s i o n p r o c e e d s . The k i n e t i c s o f drug r e l e a s e from m a t r i x d e v i c e s c o n t a i n i n g u n i f o r m l y d i s s o l v e d o r d i s p e r s e d drug a r e w e l l documented. In a f l a t s h e e t geometry, where t h e s u r f a c e a r e a i s r e l a t i v e l y c o n s t a n t ,

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

CONTROLLED-RELEASE TECHNOLOGY

6

the amount o f drug r e l e a s e f o l l o w s a s q u a r e - r o o t - o f - t i m e r e l a t i o n ship. F o r systems c o n t a i n i n g d i s s o l v e d d r u g , the f r a c t i o n a l drug r e l e a s e M/M^ can be e x p r e s s e d as (11) M/M^

= (4/A) [ D t / i r ] *

(1)

where M i s the amount o f drug r e l e a s e d a t time t , the t o t a l amount o f drug r e l e a s e d , I the t h i c k n e s s o f the s h e e t , and D the drug d i f f u s i o n c o e f f i c i e n t i n t h e m a t r i x . E q u a t i o n (1) i s a c c u r a t e t o w i t h i n 1% f o r up t o a p p r o x i m a t e l y 60% o f the t o t a l amount r e leased. F o r systems c o n t a i n i n g d i s p e r s e d d r u g , where the drug l o a d i n g per u n i t volume, A, i s g r e a t e r than t h e drug s o l u b i l i t y i n the m a t r i x , C , the drug r e l e a s e k i n e t i c s can be a n a l y z e d by the f a m i l i a r Higucfii equation (16) : M - [C (2As However, because o f t h e pseudosteady s t a t e assumptions i n v o l v e d , H i g u c h i s e q u a t i o n i s o n l y v a l i d when the drug l o a d i n g i s i n e x c e s s o f t h e drug s o l u b i l i t y ( A » C ) . At the l i m i t of A+C , H i g u c h i s e q u a t i o n g i v e s a r e s u l t 11.31 s m a l l e r than t h e e x a c t s o l u t i o n . Lee ( 4 ) r e c e n t l y p r e s e n t e d a s i m p l e a n a l y t i c a l s o l u t i o n f o r t h i s problem which i s u n i f o r m l y v a l i d o v e r a l l A / C v a l u e s : f

1

S

g

M = C (l+H)[Dt/3H] s

i

(3)

where 1

2

H = C ' [5A+(A -C s s

V]-4

When E q u a t i o n (3) i s a p p l i e d t o drug r e l e a s e , the d e v i a t i o n s from the e x a c t r e s u l t s a r e c o n s i s t e n t l y one o r d e r o f magnitude s m a l l e r than those o f H i g u c h i ' s e q u a t i o n . As A/C >1.04, E q u a t i o n (3) has an a c c u r a c y w i t h i n 1% o f the e x a c t s o l u t i o n . T h e r e f o r e , E q u a t i o n (3) i s much more a c c u r a t e than E q u a t i o n ( 2 ) , p a r t i c u l a r l y a t low A/C values. The l a t t e r case o c c u r s q u i t e o f t e n i n d e l i v e r y systems i n v o l v i n g h y d r o p h i l i c polymers and drugs o f h i g h water s o l u b i l i t y . In c a s e s where w e l l - d e f i n e d p o r e s r a n g i n g i n s i z e s from a few hundredths t o s e v e r a l hundred m i c r o n s e x i s t throughout t h e m a t r i x , the k i n e t i c s o f drug r e l e a s e can s t i l l be d e s c r i b e d by E q u a t i o n s (l)-(3) p r o v i d e d t h a t an e f f e c t i v e d i f f u s i o n c o e f f i c i e n t i s u s e d . When the drug d i f f u s i o n o n l y t a k e s p l a c e t h r o u g h the s o l v e n t f i l l e d porous network, the e f f e c t i v e d i f f u s i o n c o e f f i c i e n t i s f u r t h e r r e l a t e d t o the m a t r i x s t r u c t u r e by: D e eff

T

where e i s the p o r o s i t y e x p r e s s e d as the volume f r a c t i o n o f the v o i d space i n the m a t r i x , T the t o r t u o s i t y f a c t o r e x p r e s s e d as the r a t i o of t h e e f f e c t i v e average b a t h l e n g t h i n t h e porous medium t o t h e s h o r t e s t d i s t a n c e measured a l o n g the d i r e c t i o n o f mass f l o w , and D

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

1. LEE AND GOOD

Overview of Controlled-Release Drug Delivery

1

the d i f f u s i o n c o e f f i c i e n t o f the drug i n the pore s o l v e n t . Since the r a t i o e/x i s e q u i v a l e n t t o the f r a c t i o n a l a r e a a v a i l a b l e f o r drug r e l e a s e , an i n c r e a s e i n p o r o s i t y o r a d e c r e a s e i n t o r t u o s i t y w i l l c e r t a i n l y i n c r e a s e the amount of drug r e l e a s e d a t any g i v e n time. Polymer E r o s i o n . The r e l e a s e o f a d i s s o l v e d o r d i s p e r s e d drug from an e r o d i b l e polymer m a t r i x can be c o n t r o l l e d by a v a r i e t y of mechanisms r a n g i n g from h y d r o l y s i s / e n z y m a t i c c l e a v a g e as d i s c u s s e d i n the p r e v i o u s s e c t i o n t o s w e l l i n g and d i s s o l u t i o n . The s i t u a t i o n where polymer e r o d e s by a p u r e l y h e t e r o g e n e o u s p r o c e s s , namely s u r f a c e e r o s i o n , i s o f s p e c i a l i n t e r e s t because the drug r e l e a s e from such d e v i c e s h a v i n g c o n s t a n t geometry (sheet geometry) w i l l be o f c o n s t a n t r a t e ( 2 ) . U n f o r t u n a t e l y , the c o r r e s p o n d i n g r e l e a s e s from b o t h the c y l i n d r i c a l and s p h e r i c a l g e o m e t r i e s a l l e x h i b i t d e c r e a s i n g r a t e s w i t h time ( 1 7 ) . In c a s e s where th t i o n to s u r f a c e e r o s i o n sheet geometry g e n e r a l l y s t a r t s w i t h t y p i c a l f i r s t o r d e r k i n e t i c s then s h i f t s toward z e r o - o r d e r k i n e t i c s . Apparently, a synchronizat i o n o f b o t h the d i f f u s i o n and e r o s i o n f r o n t v e l o c i t i e s a t l a r g e time g i v e s r i s e t o the o b s e r v e d c o n s t a n t r a t e of drug r e l e a s e . Rec e n t l y , Lee (5)has shown t h a t by b u i l d i n g i n a n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n , a v a r i e t y of r e l e a s e p r o f i l e s r a n g i n g from z e r o - o r d e r to p u l s a t i l e d e l i v e r y can be a c h i e v e d from s u r face erosion c o n t r o l l e d matrices i n various geometries. Geometry F a c t o r s . To overcome the i n h e r e n t f i r s t - o r d e r r e l e a s e b e h a v i o r w i t h c o n t i n u o u s l y d i m i n i s h i n g r e l e a s e r a t e from m a t r i x s y s tems, geometry f a c t o r s have been u t i l i z e d to compensate f o r the i n c r e a s i n g d i f f u s i o n a l d i s t a n c e and d e c r e a s i n g a r e a a t the p e n e t r a t i n g d i f f u s i o n f r o n t g e n e r a l l y e n c o u n t e r e d i n m a t r i x systems. A h e m i s p h e r i c a l polymer m a t r i x t h a t i s c o a t e d on a l l s u r f a c e s w i t h an impermeable c o a t i n g e x c e p t f o r an a p e r t u r e i n the c e n t e r f a c e has been demonstrated t o p r o v i d e near c o n s t a n t r a t e r e l e a s e p r o f i l e s (18). A n o t h e r approach c o n s i s t s o f a c y l i n d e r w i t h impermeable w a l l and a c a v i t y h a v i n g a c i r c u l a r s e c t o r c r o s s s e c t i o n . The c e n t e r o f the c i r c u l a r s e c t o r l i e s o u t s i d e the c y l i n d e r , t h e r e b y p r o d u c i n g a s l i t f o r d r u g r e l e a s e from the drug c o n t a i n i n g m a t r i x i n the c a v i t y . The r e l e a s e p r o f i l e s from t h i s system a l s o show a subs t a n t i a l c o n s t a n t r a t e r e g i o n (19,20). I t i s c l e a r that, i n both systems, the i n c r e a s e i n d i f f u s i o n a l d i s t a n c e and c o n s e q u e n t l y the d e c r e a s e i n d i f f u s i o n r a t e have been b a l a n c e d by the i n c r e a s e i n a r e a a t the d i f f u s i o n f r o n t t h e r e b y g i v i n g r i s e t o a near c o n s t a n t rate region. Polymer S w e l l i n g . S w e l l i n g phenomena are g e n e r a l l y e n c o u n t e r e d i n b o t h the h y d r o p h i l i c and h y d r o p h o b i c polymer m a t r i c e s d u r i n g the r e l e a s e of e n t r a p p e d water s o l u b l e drug i n an aqueous environment. I f the polymer i s c r o s s l i n k e d e i t h e r c h e m i c a l l y t h r o u g h c o v a l e n t b o n d i n g or p h y s i c a l l y t h r o u g h e x t e n s i v e entanglement or c r y s t a l l i t e f o r m a t i o n , the s w e l l i n g w i l l c o n t i n u e to some e q u i l i b r i u m s t a t e a t which the e l a s t i c and s w e l l i n g (or o s m o t i c ) f o r c e s b a l a n c e each other.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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CONTROLLED-RELEASE

TECHNOLOGY

Depending on the r e l a t i v e magnitude o f the r a t e o f polymer s w e l l i n g t o the r a t e o f drug d i f f u s i o n , v a r i o u s r e l e a s e p r o f i l e s may be p o s s i b l e . The s i t u a t i o n where the polymer s t r u c t u r a l r e a r r a n g e ment t a k e s p l a c e r a p i d l y i n r e s p o n s e to the s w e l l i n g s o l v e n t as compared to drug d i f f u s i o n g e n e r a l l y l e a d s to t y p i c a l F i c k i a n d i f f u s i o n c h a r a c t e r i s t i c s and the s o - c a l l e d f i r s t - o r d e r r e l e a s e behavior. The case of p a r t i c u l a r i n t e r e s t i s the g l a s s y h y d r o g e l system where, upon water p e n e t r a t i o n , a slow m a c r o m o l e c u l a r r e l a x a t i o n p r o c e s s a t the g l a s s / r u b b e r y s w e l l i n g f r o n t i n a d d i t i o n to d i f f u s i o n p r o v i d e s an a d d i t i o n a l mechanism to a l t e r the r e l e a s e k i n e t i c s from the i n h e r e n t f i r s t - o r d e r b e h a v i o r . The p r o s p e c t o f h a v i n g z e r o o r d e r r e l e a s e k i n e t i c s from g l a s s y polymer m a t r i c e s v i a such a s w e l l i n g c o n t r o l l e d mechanism has s t i m u l a t e d an i n c r e a s i n g number of r e s e a r c h s t u d i e s , p u b l i c a t i o n s and p a t e n t s i n t h i s a r e a i n v o l v i n g the c o n t r o l l e d - r e l e a s e of b o t h s m a l l m o l e c u l a r weight and macrom o l e c u l a r b i o a c t i v e compounds (21-28). Mechanistically, a c o n t a i n i n g d i s s o l v e d or g l a s s t r a n s i t i o n temperature i s l o w e r e d , and the d i s s o l v e d drug d i f f u s e s through the s w o l l e n r u b b e r y phase i n t o the e x t e r n a l r e l e a s i n g medium. At the same t i m e , a sharp p e n e t r a t i n g s o l v e n t f r o n t s e p a r a t i n g the g l a s s y from the r u b b e r y phase i n a d d i t i o n t o volume s w e l l i n g i s o b s e r v e d d u r i n g the i n i t i a l s t a g e of the dynamic s w e l l ing process. Depending on the r e l a t i v e magnitude o f the r a t e of polymer r e l a x a t i o n a t the p e n e t r a t i n g s o l v e n t f r o n t and the r a t e of d i f f u s i o n o f the d i s s o l v e d d r u g , the drug r e l e a s e b e h a v i o r may range from f i r s t to z e r o - o r d e r (21). V a r i o u s a n a l y s e s and c r i t e r i a have been r e p o r t e d i n the l i t e r a t u r e f o r p r e d i c t i n g whether drug r e l e a s e from s w e l l i n g - c o n t r o l l e d polymer m a t r i c e s w i l l be f i r s t o r z e r o - o r d e r ( d i f f u s i o n o r r e l a x a t i o n - c o n t r o l l e d ) (29). However, they have been s u c c e s s f u l o n l y f o r l i m i t e d s i t u a t i o n s o f v e r y low drug l o a d i n g . In g e n e r a l , the drug l o a d i n g l e v e l has a d e f i n i t i v e e f f e c t on the r e l e a s e k i n e t i c s from s w e l l i n g - c o n t r o l l e d polymer m a t r i c e s . E x p e r i m e n t a l e v i d e n c e s have shown t h a t the p r e s e n c e of an a d d i t i o n a l component, namely the water s o l u b l e d r u g , a l t e r s b o t h the s w e l l i n g o s m o t i c p r e s s u r e and the a s s o c i a t e d time-dependent r e l a x a t i o n o f the h y d r o g e l network d u r i n g the s i m u l t a n e o u s a b s o r p t i o n o f water and d e s o r p t i o n o f drug ( 2 5 ) . As a r e s u l t , the drug r e l e a s e and s o l v e n t f r o n t p e n e t r a t i o n a r e o b s e r v e d t o behave more F i c k i a n as drug l o a d i n g l e v e l i n c r e a s e s . Such t r a n s i t i o n can be c o n s i d e r e d as a change of r e l a t i v e importance o f the d i f f u s i o n p r o c e s s v e r s u s the polymer r e l a x a t i o n as a f u n c t i o n of drug l o a d i n g . C o n c e n t r a t i o n D i s t r i b u t i o n . D e s p i t e the t h e o r e t i c a l p r o s p e c t o f having a t o t a l l y r e l a x a t i o n - c o n t r o l l e d s i t u a t i o n thereby achieving z e r o - o r d e r r e l e a s e from a g l a s s y polymer m a t r i x , h y d r o g e l s w i t h pure r e l a x a t i o n - c o n t r o l l e d (Case I I ) s w e l l i n g k i n e t i c s a r e y e t to be demonstrated experimentally. In a d d i t i o n , the i n e v i t a b l e geometry l i m i t a t i o n s and d e v i a t i o n s from r e l a x a t i o n - c o n t r o l l e d k i n e t i c s a t h i g h e r drug l o a d i n g l e v e l s f u r t h e r i m p a i r the f l e x i b i l i t y i n a l t e r ing the r e l e a s e k i n e t i c s i n such systems. T h i s d i f f i c u l t y can be overcome by a r e c e n t l y r e p o r t e d , n o v e l approach t o c o n s t a n t r a t e of drug r e l e a s e from g l a s s y h y d r o g e l m a t r i c e s v i a an immobolized

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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n o n - u n i f o r m drug c o n c e n t r a t i o n d i s t r i b u t i o n (30>3^) · Hydrogel polymers a r e p a r t i c u l a r l y s u i t a b l e f o r t h i s a p p l i c a t i o n because they are g l a s s y i n the d e h y d r a t e d s t a t e c a p a b l e o f i m m o b o l i z i n g any n o n - u n i f o r m drug d i s t r i b u t i o n i n t r o d u c e d p r i o r t o t h e d e h y d r a t i o n step. The drug r e l e a s e w i l l n o t o c c u r u n t i l t h e h y d r o g e l i s s w o l l e n by water a t the time o f u s e . As a r e s u l t o f t h i s s t u d y , the e f f e c t o f n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n on t h e k i n e t i c s o f drug r e l e a s e from polymer m a t r i c e s o f d i f f e r e n t g e o m e t r i e s has been a n a l y z e d i n d e t a i l (5). Concentration p r o f i l e s capable of generating zero-order r e l e a s e c h a r a c t e r i s t i c s have a l s o been i d e n t i f i e d . The impact o f t h i s approach i s r e a l l y p r o f o u n d s i n c e t h e concept o f u t i l i z i n g n o n - u n i f o r m i n i t i a l drug c o n c e n t r a t i o n d i s t r i b u t i o n as a mechanism f o r r e g u l a t i n g drug r e l e a s e from b o t h d i f f u s i o n - c o n t r o l l e d and s u r f a c e e r o s i o n - c o n t r o l l e d polymer m a t r i c e s o f f e r s a unique o p p o r t u n i t y t o a c h i e v e programmable ( i n c l u d i n g z e r o - o r d e r and p u l s a t i l e ) drug d e l i v e r requirement. This i s p a r t i c u l a r l e x p e r i m e n t a l f l e x i b i l i t y i n a c h i e v i n g e s s e n t i a l l y an u n l i m i t e d number o f n o n - u n i f o r m d r u g c o n c e n t r a t i o n d i s t r i b u t i o n i n polymer systems. U n l i k e membrane-reservoir systems, t h e c o n c e n t r a t i o n d i s t r i b u t i o n approach does n o t r e q u i r e a s a t u r a t e d r e s e r v o i r and a r a t e - c o n t r o l l i n g membrane t o a c h i e v e a c o n s t a n t r a t e o f d r u g r e l e a s e . I n a d d i t i o n , t h e o n s e t o f c o n s t a n t - r a t e r e l e a s e i n t h e p r e s e n t approach can be almost i n s t a n t a n e o u s and the c o n s t a n t - r a t e r e l e a s i n g p e r i o d can be r e l a t i v e l y s h o r t . These a r e d i f f i c u l t t o a c h i e v e i n convent i o n a l membrane-reservoir systems. Biopharmaceutical Considerations The most i m p o r t a n t a t t r i b u t e o f a c o n t r o l l e d r e l e a s e drug d e l i v e r y system i s i t s c a p a b i l i t y t o m a i n t a i n a t h e r a p e u t i c a l l y e f f e c t i v e r a t e o f drug d e l i v e r y over a r e a s o n a b l y l o n g p e r i o d o f time. The d u r a t i o n o f such c o n t r o l l e d d e l i v e r y must be c o m p a t i b l e w i t h p h y s i o l o g i c a l c o n s t r a i n t s and the r o u t e o f a d m i n i s t r a t i o n . F o r example, w h i l e a d u r a t i o n o f s e v e r a l months may be a p p r o p r i a t e f o r a polymer i m p l a n t , i t i s much t o o l o n g a time frame t o c o n s i d e r f o r an o r a l dosage form. S i m i l a r l y , a c o n s t a n t r a t e o f drug d e l i v e r y may p r o v i d e l i t t l e r e a l advantage over w e l l c o n t r o l l e d f i r s t - o r d e r r e l e a s e under c e r t a i n b i o p h a r m a c e u t i c c o n d i t i o n s , e s p e c i a l l y when the b i o l o g i c a l h a l f - l i f e o f t h e drug i s l o n g . I n some s i t u a t i o n s , an o s c i l l a t o r y o r p u l s a t i l e drug r e l e a s e may be needed i n o r d e r t o simulate i n v i v o s e c r e t o r y p a t t e r n s or to avoid t a c h y p h y l a x i s . In the f o l l o w i n g s e c t i o n s , c r i t e r i a f o r system s e l e c t i o n and r e l e v a n t b i o p h a r m a c e u t i c a l c o n s i d e r a t i o n s w i l l be b r i e f l y d i s c u s s e d w i t h i n the r e a l m o f o r a l and t r a n s d e r m a l d e l i v e r y systems. Similar conside r a t i o n s can c e r t a i n l y be extended t o o t h e r t y p e s o f d e l i v e r y systems. O r a l D e l i v e r y Systems. The o r a l r o u t e o f drug a d m i n i s t r a t i o n has been t h e most p o p u l a r one, however, i t i s n o t w i t h o u t problems and constrains. F i r s t o f a l l , t h e t o t a l g a s t r o i n t e s t i n a l r e s i d e n c e time l i m i t s t h e time frame o r "window" f o r o r a l a b s o r p t i o n . The

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s i t u a t i o n can become more c o m p l i c a t e d i f the drug i n q u e s t i o n i s o n l y absorbed i n c e r t a i n segments of the GI t r a c t ( 3 2 ) . Realizing the p o t e n t i a l i n t e r - s u b j e c t v a r i a b i l i t y and the e f f e c t of food on GI r e s i d e n c e time and m o b i l i t y p a t t e r n s (33,34), a r e a s o n a b l e d u r a t i o n c o n s t r a i n i n the GI t r a c t i s a p p r o x i m a t e l y 24 hours t a k i n g i n t o c o n s i d e r a t i o n the g a s t r i c emptying mechanism and i t s d u r a t i o n as w e l l as s m a l l and l a r g e i n t e s t i n a l t r a n s i t t i m e s . A n o t h e r time c o n s t r a i n i s a s s o c i a t e d w i t h drug a b s o r p t i o n t h r o u g h the GI mucosa i n t o the g e n e r a l h e p a t i c c i r c u l a t i o n . In o r d e r to c o n t r o l the del i v e r y of drug t o the u l t i m a t e t a r g e t o r g a n v i a the g e n e r a l c i r c u l a t i o n , i t i s e s s e n t i a l t o have the system r e l e a s i n g i t s c o n t e n t a t a s l o w e r r a t e than the p h y s i o l o g i c a l a b s o r p t i o n r a t e . In a d d i t i o n , when the gut w a l l and f i r s t pass l i v e r m e t a b o l i s m a r e s i g n i f i c a n t , the r a t e of drug d e l i v e r y to the GI t r a c t may have p r o f o u n d e f f e c t s on the amount o f unchanged drug which r e a c h e s the p e r i p h e r a l c i r c u l a t i o n and the r a t e which m e t a b o l i s m t a k e s p l a c e . Understandably, the e x c r e t i o n r a t e o r c l e a r a n c l a t i o n and/or any t i s s u and d e s i g n of the drug d e l i v e r y system. For the r a t i o n a l d e s i g n o f a c o n t r o l l e d - r e l e a s e o r a l d e l i v e r y system, one o b v i o u s l y would have t o take i n t o c o n s i d e r a t i o n pharmac o k i n e t i c r a t e p a r a m e t e r s f o r the a b s o r p t i o n , d i s t r i b u t i o n , and e l i m i n a t i o n o f a s p e c i f i c drug i n q u e s t i o n as w e l l as the drug del i v e r y r a t e p r o f i l e from the d e l i v e r y system. In the l a t t e r c a s e , p r a c t i c a l l i m i t a t i o n s i n d e l i v e r y system d e s i g n such as f i n i t e t o t a l dose, d e c r e a s i n g r e s e r v o i r c o n c e n t r a t i o n s , and/or i n c r e a s i n g d i f f u s i o n a l r e s i s t a n c e would have t o be t a k e n i n t o a c c o u n t . Such an approach has r e c e n t l y been a p p l i e d to the d e s i g n o f c o n t r o l l e d - r e l e a s e o r a l d e l i v e r y systems (11,35) . E x c e l l e n t agreement has been demonstrated between e x p e r i m e n t a l d a t a and p r e d i c t e d performance b o t h i n v i t r o and i n v i v o . T r a n s d e r m a l D e l i v e r y Systems. T r a n s d e r m a l d e l i v e r y of drugs over extended p e r i o d s of time f o r s y s t e m i c t h e r a p y has r e c e i v e d significant attention. The importance and f u t u r e p r o s p e c t s o f t h i s f i e l d are f u r t h e r r e f l e c t e d i n the s e c t i o n on T r a n s d e r m a l and T r a n s m u c o s a l D e l i v e r y Systems ( C h a p t e r s 17-23). I n t a c t human s k i n , once thought t o be an impermeable b a r r i e r , was r e a l i z e d as a p o t e n t i a l p o r t a l o f e n t r y f o r s y s t e m i c drug t h e r a p y o n l y r e c e n t l y . U n l i k e the GI t r a c t , the p e r f u s i o n o f s k i n s t r u c t u r e s i s s u p p l i e d by post-hepatic blood flow. T h e r e f o r e , drugs absorbed through the s k i n do not undergo e x t e n s i v e f i r s t pass m e t a b o l i s m . A l t h o u g h p r o t e i n b i n d i n g of drugs (36) as w e l l as a c t i v e m e t a b o l i s m i n s k i n (37) have been r e p o r t e d , they are g e n e r a l l y minor i n e f f e c t s compared t o t h a t due t o l i v e r m e t a b o l i s m . A d d i t i o n a l advantages to t r a n s d e r m a l d e l i v e r y can be r e a l i z e d from i t s i n h e r e n t n o n - i n v a s i v e c h a r a c t e r as w e l l as the a b i l i t y t o r a p i d l y remove the dosage form a t any t i m e , a s i g n i f i c a n t s a f e t y f e a t u r e not a v a i l a b l e i n o r a l o r p a r e n t e r a l routes of a d m i n i s t r a t i o n . The upper l a y e r s of e p i d e r m i s , the s t r a t u m corneum, i s a p r i n c i p a l b a r r i e r to t r a n s d e r m a l drug d e l i v e r y . I t c o n s i s t s of a h e t e r o g e n e o u s s t r u c t u r e made up o f k e r a t i n i z e d c e l l s and l i p i d s . Drug p e r m e a t i o n i s b e l i e v e d t o o c c u r by e i t h e r p o l a r o r l i p o p h i l i c pathways depending on the h y d r o p h i l i c i t y o r l i p o p h i l i c i t y of the

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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drug (38). The fundamental q u e s t i o n t o be answered b e f o r e d e s i g n i n g a t r a n s d e r m a l system i s whether d e l i v e r y - r a t e c o n t r o l must be p a r t of t h e system o r whether i t i s more d e s i r a b l e s i m p l y t o a l l o w t h e s k i n t o s e r v e as t h e p r i n c i p l e b a r r i e r t o t r a n s p o r t . In e i t h e r c a s e , r a t e o f drug a b s o r p t i o n i s dependent on b o t h s k i n permeability and t h e p h y s i c o - c h e m i c a l p r o p e r t i e s o f t h e system. The degree o f c o n t r o l d e s i r e d i s d i c t a t e d by t h e p h a r m a c o l o g i c a l p r o f i l e o f t h e drug. A good comparison can be i l l u s t r a t e d by t h e d i f f e r e n c e i n d e s i g n c o n s i d e r a t i o n s between t r a n s d e r m a l s c o p o l a m i n e and t r a n s dermal n i t r o g l y c e r i n systems (11,39). Scopolamine i s a p o t e n t drug w i t h modest s k i n p e r m e a b i l i t y and a wide range o f s i d e e f f e c t s associated with i n c r e a s i n g blood l e v e l s . Therefore, i n order to t r e a t motion s i c k n e s s without producing s i d e e f f e c t s , i t i s n e c e s s a r y t o produce t h e r a p e u t i c a l l y e f f e c t i v e i n p u t r a t e by p r e c i s e l y c o n t r o l l i n g t h e r a t e a t which i t i s t r a n s p o r t e d from t h e system t o t h e s k i n . I t h e r a p e u t i c i n d e x , and v a r i a b i l i t y among i n d i v i d u a l s . Given n i t r o g l y c e r i n ' s short h a l f l i f e , i t s i n p u t r a t e s h o u l d be m a i n t a i n e d a t a r e a s o n a b l y h i g h l e v e l i n order t o m a i n t a i n e f f i c a c y . T h e r e f o r e , the c o n t r o l of n i t r o g l y c e r i n d e l i v e r y r a t e i s m e r e l y t o ensure an upper bound b e i n g s e t by the system f o r i n d i v i d u a l s even w i t h extreme s k i n permeability. Such d e s i g n c r i t e r i a have been s u c c e s s f u l l y u t i l i z e d i n c o m m e r c i a l l y a v a i l a b l e m e m b r a n e - r e s e r v o i r type o f t r a n s d e r m a l d e l i v e r y systems f o r s c o p o l a m i n e , n i t r o g l y c e r i n , and more r e c e n t l y , e s t r a d i o l (40,41).

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12

10. Petersen, R.V.; Anderson, J.H.; Fang, S.M.; Feijen, J . ; Gregonis, D.E.; Kim, S.W. Polym. Prepr. 1979, 20, 20. 11. Good, W.R.; Lee, P.I. In "Medical Applications of Sustained Release" Langer, R.S.; Wise, D.L., Eds.; CRC Press:Boca Raton, FL, 1984; pp. 1. '

12. Baker, R.W.; Lonsdale, H.K. In "Controlled Release of Biologically Active Agents"' Tanquary, A.C.; Lacey, R.E., Eds.; ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY SERIES NO. 47; Plenum:New York, NY, 1974; pp.15. 13. Kim, S.W.; Petersen, R.; Feijen, J. Drug Design 1980, 10, 193. 14. Theeuwes, F. In "Controlled Release Technologies:Methods, Theory and Applications", Kydonieus, A.F., Ed.; CRC Press:Boca Raton, FL, 1980; pp 15. Theeuwes, F. J. Pharm. Sci. 1975, 64, 1987. 16. Higuchi, T. J. Pharm. Sci. 1961, 50, 874. 17. Hopfenberg, H.B. In "Controlled Release Polymeric Formulations"; Paul, D.R.; Harris, F.W., Eds.; ACS SYMPOSIUM SERIES NO. 33; American Chemical Society:Washington, D.C., 1976; pp. 26. 18. Hsieh, D.S.T.; Rhine, W.D.; Langer, R. J. Pharm. Sci. 1983, 72, 17. 19. Brooke, D.; Washkuhn, R.I. J. Pharm. Sci. 1977, 66, 159. 20. Lipper, R.A.; Higuchi, W.I. J. Pharm. Sci. 1977, 66, 163. 21. Lee, P.I. J. Controlled Release 1985, 2, 277. 22. Pedley, D.G.; Skelly, P.J.; Tighe, B.J. Br. Polym. J. 1980, 12, 99. 23.

Speiser, P. U.S. Patent 3,390,050, 1968.

24. Mueller, K.F.; Heiber, S.J.; Plankl, W.L. U.S. Patent 4,244,427, 1980. 25. Lee, P.I. Polym. Commun. 1983, 24, 45. 26. Good, W.R.; Mueller, K.F. In "Controlled Release of Bioactive Materials"' Baker, R., Ed.; Academic:New York, NY, 1980; pp. 155. 27. Mueller, K.F.; Good, W.R. U.S. Patent 4,177,056, 1979. 28. Peppas, N.A. "Hydrogels in Medicine and Pharmacy"; CRC Press: Boca Raton, Fl, 1987; Vol. I-III.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

1.

LEE AND GOOD

Overview of Controlled-Release Drug Delivery

29. Korsmeyer, R.W.; Peppas, N.A. In "Controlled Release Delivery Systems"; Roseman, T.J.; Mansdorf, S.Z., Eds.; Marcel Dekker, NY, 1983; pp. 77. 30. Lee, P.I. Polymer 1984, 25, 973. 31. Lee, P.I.

J. Pharm. Sci.

1984, 73, 1344.

32. Morrison, A.B.; Perusse, C.B.; Campbell, J.A. New Engl. J. Med. 1960, 263, 115. 33.

Cortot, Α.; Colombel, J.F. Int. J. Pharm. 1984, 22, 321.

34.

Spiller, R.C. Gut 1986, 27, 879.

35. Good, W.R.; Leeson, L.J.; Zak, S.L.; Wagner, W.E.; Meeker, J.B.; Arnold, J.D 36.

Chandrasekaran, S.K.; Bayne, W.; Shaw, J. J. Pharm. Sci. 1978, 67, 1370.

37. Ando, H.Y.; Ho, N.F.; Higuchi, W.I. J. Pharm. Sci. 1977, 66, 1525. 38. Knutson, K.; Krill, S.L.; Lambert, W.J.; Higuchi, W.I. Proc. 13th Int. Symp. Cont. Rel. Bioac. Mater., 1986, p. 199. 39.

Shaw, J.E.; Chandrasekaran, S.K. Drug Metab. Rev. 1978, 8, 223.

40. Good, W.R.; Powers, M.S.; Campbell, P.; Schenkel, L. trolled Release 1985, 2, 89. 41.

J. Con

Schenkel, L.; Barlier, D.; Riera, M.; Barner, A. J. Controlled Release 1986, 4, 195.

RECEIVED May 18, 1987

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

13

Chapter 2

Microstructural Models for Diffusive Transport in Porous Polymers 1,3

2,4

W. Mark Saltzman , Stephen H. Pasternak , and Robert Langer

2

1

2

Division of Health Sciences and Technology, Harvard University/Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Applied Biological Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Room E25-342, Cambridge, MA 02139

The controlled releas erodible, hydrophobi modelled as a discrete diffusion process with the release of solute occuring through distinct pores in the polymer which are formed as solid particles of molecule dissolve. In order to formulate predictive models of the release behavior of these devices, quantitative information on the microgeometry of the system is required. We present a computer-based system for obtaining estimates of the system porosity, isotropy, particle shape, and particle size distribution from observations on two-dimensional sections from the polymer matrix. Our algorithms were verified by analyzing images from computer generated three-dimensional structures. Problems o f t r a n s p o r t t h r o u g h heterogeneous media o c c u r i n many disciplines. The movement o f f l u i d t h r o u g h porous g e o l o g i c a l m a t e r i a l (1) and t h e d i f f u s i o n o f gases i n t o c a t a l y s t p e l l e t s (2.) have been s t u d i e d b y p h y s i c i s t s and e n g i n e e r s f o r many y e a r s . Many problems o f p h y s i o l o g i c a l i n t e r e s t a l s o i n v o l v e c o n d u c t i o n i n heterogeneous e n v i r o n m e n t s : f o r example, t h e c o n d u c t i o n o f e l e c t r i c a l i m p u l s e s t h r o u g h c a r d i a c t i s s u e o r t h e movement o f heat o r s o l u t e s t h r o u g h d e n s e l y packed c e l l u l a r m a t e r i a l . Current b i o m e d i c a l t e c h n o l o g y , which employs n a t u r a l and a r t i f i c i a l p o l y m e r i c membranes f o r a h o s t o f a p p l i c a t i o n s , p r e s e n t s a n o t h e r example o f t h i s fundamental problem. In many a p p l i c a t i o n s o f p o l y m e r i c membrane t e c h n o l o g y , movement o f s o l u t e t h r o u g h t h e porous membrane environment r e p r e s e n t s t h e r a t e - l i m i t i n g s t e p i n t h e process. C l e a r d e s c r i p t i o n s o f t h e dynamics o f s o l u t e movement t h r o u g h c o m p l i c a t e d g e o m e t r i e s s h o u l d p r o v i d e t h e key t o u n d e r s t a n d i n g and e x p l o i t i n g t h e s e membrane phenomena. ^Current address: Department of Chemical Engineering, Maryland Hall, Johns Hopkins University, Baltimore, MD 21218 'Current address: 1882 Clarance Street, Sarnia, Ontario N7T 7H6, Canada 0097-6156/87/0348-0016$06.00/0 © 1987 American Chemical Society

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

2.

S A L T Z M A N ET A L .

Modeh for Diffusive Transport in Porous Polymers

17

An i m p o r t a n t example o f t h e s e p r o c e s s e s i s t h e c o n t r o l l e d r e l e a s e o f b i o a c t i v e m o l e c u l e s from p o l y m e r i c membranes. Many p h a r m a c e u t i c a l l y a c t i v e a g e n t s have been r e l e a s e d a t c o n t r o l l e d r a t e s from h y d r o p h o b i c polymer c a r r i e r s . These f o r m u l a t i o n s p r o v i d e a means f o r r e l e a s i n g s m a l l q u a n t i t i e s o f d r u g d i r e c t l y i n t o t h e body a t a c o n s t a n t r a t e f o r a l o n g p e r i o d o f t i m e . In 197 6 i t was d e m o n s t r a t e d t h a t h y d r o p h o b i c polymers, i n p a r t i c u l a r e t h y l e n e - v i n y l a c e t a t e copolymer (EVAc), c o u l d be u s e d t o r e l e a s e m o l e c u l e s w i t h m o l e c u l a r w e i g h t s g r e a t e r t h a n 1000 (3.) · Many new b i o a c t i v e a g e n t s a r e now b e i n g p r o d u c e d by g e n e t i c e n g i n e e r i n g ; t h e s e agents a r e commonly p o l y p e p t i d e s and a r e q u i c k l y consumed by t h e body's m e t a b o l i c p r o c e s s e s i f a d m i n i s t e r e d by c o n v e n t i o n a l methods (A)· By e n c a p s u l a t i n g t h e s e l a b i l e drugs i n h y d r o p h o b i c c o n t r o l l e d r e l e a s e systems: i ) t h e drugs a r e r e l e a s e d c o n s t a n t l y f o r s e v e r a l months and i i ) t h e u n r e l e a s e d drugs a r e p r o t e c t e d from t h e body's c a t a b o l i c enzymes.. Without a d r u g d e l i v e r y system, many o f t h e n o v e l compounds now b e i n g p r o d u c e utility. While many d i f f e r e n range o f p h y s i c a l p r o p e r t i e s , have been r e p r o d u c i b l y r e l e a s e d from EVAc m a t r i c e s , t h e e x i s t a n c e o f a p r e d i c t i v e model o f t h e r e l e a s e b e h a v i o r would g r e a t l y f a c i l i t a t e t h e f u r t h e r development o f t h e s e systems. T h i s r e p o r t b r i e f l y r e v i e w s p r e v i o u s attempts t o model t h i s p r o c e s s and d i s c u s s e s t h e i r i n a b i l i t y t o e x p l i c i t l y e v a l u a t e t h e complex environment t h r o u g h which r e l e a s e must o c c u r . Our h y p o t h e s i s f o r t h e mechanism o f r e l e a s e o f l a r g e m o l e c u l a r weight drugs from h y d r o p h o b i c m a t r i c e s i s t h e n p r e s e n t e d ; t h i s h y p o t h e s i s s u g g e s t s t h a t t h e heterogeneous geometry o f t h e d r u g d e l i v e r y systems i s an i m p o r t a n t f a c t o r i n i n f l u e n c i n g r e l e a s e r a t e s . As e n c o u n t e r e d i n o t h e r problems o f t r a n s p o r t i n porous systems (5.) , q u a n t i t a t i v e d e s c r i p t i o n o f t h e microgeometry i s an e s s e n t i a l i n g r e d i e n t f o r complete model development. A computer-based a p p r o a c h f o r i d e n t i f y i n g i m p o r t a n t f e a t u r e s o f t h e complex geometry i s p r e s e n t e d . T h i s q u a n t i t a t i v e approach w i l l p e r m i t t h e development o f models o f t h e d i f f u s i v e r e l e a s e o f macromolecules from n o n - e r o d i b l e polymer m a t r i c e s : models which w i l l be a p p l i c a b l e t o a g e n e r a l c l a s s o f water s o l u b l e d r u g s . While we demonstrate our t e c h n i q u e s by c o n s i d e r i n g n o v e l d r u g d e l i v e r y d e v i c e s , t h i s q u a n t i t a t i v e approach f o r e x a m i n i n g t h e complex geometry o f p o l y m e r i c membrane systems may have a p p l i c a t i o n i n a number o f evolving disciplines. Theory P r e v i o u s models o f r e l e a s e b e h a v i o r . The r e l e a s e o f l a r g e m o l e c u l a r weight drugs from i n e r t , h y d r o p h o b i c polymer v e h i c l e s o c c u r s i n s p i t e o f two o b s e r v a t i o n s : i ) l a r g e m o l e c u l a r weight drugs do n o t permeate t h r o u g h t h e pure polymer phase Q ) and i i ) water does n o t e n t e r t h e polymer phase ( £ ) . P r e v i o u s d e s c r i p t i o n s o f t h e r e l e a s e o f macromolecules from n o n - e r o d i b l e h y d r o p h o b i c m a t r i c e s assume t h a t t h e continuum d i f f u s i o n e q u a t i o n a p p l i e s a t e v e r y p o i n t i n t h e m a t r i x (7-8). C o n s i d e r , f o r example, a t y p i c a l d r u g d e l i v e r y system, f a b r i c a t e d as a t h i n s l a b . Since the depth o f the s l a b i s

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

CONTROLLED-RELEASE

18

TECHNOLOGY

s m a l l i n comparison t o i t s d i a m e t e r , r e l e a s e of m a c r o m o l e c u l e s o c c u r s p r i m a r i l y t h r o u g h the t o p and bottom f a c e s o f t h e s l a b . Assuming F i c k ' s law of d i f f u s i o n y i e l d s :

2c

a =

2

c (i)

D

3t

eff

3 x

2

where χ i s t h e d i r e c t i o n normal t o t h e t o p and bottom f a c e o f t h e s l a b , t i s time s i n c e i n i t i a t i o n of r e l e a s e , C i s t h e c o n c e n t r a t i o n at p o s i t i o n χ and time t , and D t h e e f f e c t i v e d i f f u s i v i t y of the drug i n the s l a b . Boundary and i n i t i a l c o n d i t i o n s f o r t h i s geometry are : e f f

C = C

Q

;

C=0

0 < χ < ;

x = 0 , L

L

t = 0

(2

)

t > 0

where C i s the i n i t i a c o n d i t i o n s h o l d at t h e d i f f u s i v i t y i s r e l a t e d to the m o l e c u l a r d i f f u s i o n c o e f f i c i e n t d r u g by: Q

D

eff

=

D

o

/ *

of

the


1, n o n - F i c k i a n (anomalous) d i f f u s i o n i n c l u d i n g the s p e c i a l case of Case I I t r a n s p o r t can be e x p e c t e d depending on whether the r a t e o f rearrangement o f polymer m o l e c u l e s i s comparable t o o r s m a l l e r than the d i f f u s i o n r a t e . On the o t h e r hand c l a s s i c a l F i c k i a n d i f f u s i o n i n e i t h e r the r u b b e r y o r g l a s s y s t a t e can be e x p e c t e d i n the l i m i t o f e i t h e r v e r y s m a l l or v e r y l a r g e Deborah numbers, i . e . (DEB) « 1 or ( ϋ Ε Β ) >> 1. Most o f the e x i s t i n g t h e o r i e s on d i f f u s i o n i n g l a s s y polymers c o n s i d e r the t r a n s p o r t o f a s i n g l e p e n e t r a n t , namely the s o l v e n t . The i n t e r p r e t a t i o n of v a r i o u s o b s e r v e d anomalous s o r p t i o n k i n e t i c s i s g e n e r a l l y based on one o f the f o l l o w i n g t h r e e approaches (a) D i f f u s i o n w i t h c o n v e c t i o n model; where a c o n s t a n t s w e l l i n g f r o n t v e l o c i t y due t o Case I I d i f f u s i o n i s i n c o r p o r a t e d e i t h e r i n t o the boundary c o n d i t i o n o r i n t o the d i f f u s i o n e q u a t i o n as a c o n v e c t i v e term (10-11); (b) D i f f e r e n t i a l s w e l l i n g s t r e s s model; where the v e l o c i t y o f the s w e l l i n g f r o n t i s r e l a t e d to the s w e l l i n g s t r e s s e x e r t e d by the p e n e t r a t i n g s o l v e n t on the g l a s s y m a t r i x a t the moving f r o n t (12-13); and (c) M o l e c u l a r r e l a x a t i o n model; where the r e l a t i v e l y slow p e n e t r a n t - i n d u c e d polymer m o l e c u l a r r e l a x a t i o n p r o c e s s i s t a k e n i n t o a c c o u n t t h r o u g h the use of a v a r i a b l e s u r f a c e c o n c e n t r a t i o n , a time-dependent d i f f u s i o n c o e f f i c i e n t , o r a t i m e dependent s o l u b i l i t y c o e f f i c i e n t (14-17). In the case o f a d r u g - l o a d e d h y d r o g e l m a t r i x , the r e l e a s e k i n e t i c s and s w e l l i n g b e h a v i o r are f u r t h e r c o m p l i c a t e d by the p r e s e n c e o f a t h i r d component, namely the drug ( 5 ) . U n l i k e the s i t u a t i o n w i t h a s i n g l e p e n e t r a n t , the p r e s e n c e o f the water s o l u b l e drug a l t e r s b o t h the s w e l l i n g o s m o t i c p r e s s u r e and the a s s o c i a t e d time-dependent r e l a x a t i o n o f the polymer network d u r i n g the s i m u l ­ taneous a b s o r p t i o n o f water and r e l e a s e of d r u g . Only few a t t e m p t s have been made to model such s w e l l i n g - c o n t r o l l e d r e l e a s e systems with l i m i t e d success. For example, Good (4) employed a t i m e dependent d i f f u s i o n c o e f f i c i e n t w h i c h was s e t t o be p r o p o r t i o n a l t o β

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

74

CONTROLLED-RELEASE TECHNOLOGY

the f r a c t i o n a l s o l v e n t a b s o r p t i o n . The r e s u l t s were used t o f i t drug r e l e a s e data from i n i t i a l l y d r y h y d r o g e l s . Lee (18-19) ana­ l y z e d drug r e l e a s e from polymer m a t r i c e s i n v o l v i n g moving b o u n d a r i e s g e n e r a t e d by b o t h the polymer s w e l l i n g and e r o s i o n . Accurate approximate a n a l y t i c a l s o l u t i o n s f o r v a r i o u s g e o m e t r i e s were p r e ­ sented. Korsmeyer and Peppas (20) d e v e l o p e d m a t h e m a t i c a l models based on a drug d i f f u s i o n c o e f f i c i e n t which depends on the concen­ t r a t i o n o f absorbed s o l v e n t i n a f u n c t i o n a l form c o n s i s t e n t w i t h the free-volume theory. A l t h o u g h the importance o f polymer r e l a x a t i o n on drug r e l e a s e from s w e l l i n g - c o n t r o l l e d h y d r o g e l s has been r e c o g n i z e d f o r some t i m e , i t has not been t a k e n i n t o account a p p r o p r i a t e l y i n the g o v e r n i n g d i f f u s i o n e q u a t i o n s . To i n t e r p r e t o b s e r v e d anomalous s o r p t i o n k i n e t i c s o f p e n e t r a n t i n p o l y m e r s , Crank (14) f i r s t i n t r o d u c e d a time-dependent ( o r h i s t o r y - d e p e n d e n t ) d i f f u s i o n c o e f f i c i e n t , which i s a f f e c t e d p a r t l y by an i n s t a n t a n e o u s r e s p o n s e a t t r i b u t a b l e to f a s t l o c a or s m a l l segments o f c h a i n r e s u l t e d from the r e l a t i v e l y slow u n c o i l i n g and rearrangement o f l a r g e segments o f the polymer c h a i n s . Good agreement between the model and e x p e r i m e n t a l r e s u l t s was then demonstrated f o r a s i n g l e p e n e t r a n t system. By a d o p t i n g a s i m i l a r time-dependent d i f f u s i o n c o e f f i c i e n t ( 8 ) , we w i l l demonstrate i n the f o l l o w i n g s e c t i o n t h a t v a r i o u s drug r e l e a s e b e h a v i o r s from g l a s s y h y d r o g e l s can a l s o be c o n s i s t e n t l y described. The r a t i o n a l e o f employing a time-dependent d i f f u s i o n c o e f f i c i e n t i s q u i t e e v i d e n t i n t h a t the v a r i o u s o b s e r v e d anomalous d i f f u s i o n b e h a v i o r s a l l share a common p h y s i c a l o r i g i n , namely, the slow p e n e t r a n t - i n d u c e d polymers m o l e c u l a r r e l a x a t i o n . In a d d i t i o n , i t can be shown t h a t the drug d i f f u s i o n c o e f f i c i e n t d e f i n e d i n a p o l y m e r - f i x e d frame o f r e f e r e n c e which i s e n c o u n t e r e d i n d e s c r i b i n g a system w i t h c o n s i d e r a b l e volume s w e l l i n g i s p r o p o r t i o n a l t o the square o f the polymer volume f r a c t i o n . S i n c e the polymer volume f r a c t i o n i s a s t r o n g f u n c t i o n o f time d u r i n g the s w e l l i n g p r o c e s s , one can e x p e c t a s i g n i f i c a n t c o n t r i b u t i o n from i t t o the o v e r a l l time dependence o f the drug d i f f u s i o n c o e f f i c i e n t . Theory To examine the e f f e c t o f time-dependent d i f f u s i o n c o e f f i c i e n t on the r e l e a s e b e h a v i o r from a s w e l l a b l e polymer system c o n t a i n i n g d i s s o l v ­ ed o r d i s p e r s e d d r u g , we c o n s i d e r a polymer s h e e t w i t h h a l f t h i c k ­ ness £, an i n i t i a l drug l o a d i n g A, a drug s o l u b i l i t y i n the polymer m a t r i x C , and a time-dependent drug d i f f u s i o n c o e f f i c i e n t o f the f o l l o w i n g form: D ( t ) - D.

1

+ (D - D . ) ( l - e x p ( - k t ) ) 00

(1)

ι

which t a k e s i n t o a c c o u n t the time-dependent, p e n e t r a n t - i n d u c e d p o l y ­ mer r e l a x a t i o n , where D i s the i n s t a n t a n e o u s p a r t o f the drug diffusion coefficient, the drug d i f f u s i o n c o e f f i c i e n t a t s w e l l i n g e q u i l i b r i u m , and k the average r e l a x a t i o n c o n s t a n t c o n t r o l l i n g the

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

5.

Drug-Release Kinetics from Hydrogel Matrices

LEE

75

approach to e q u i l i b r i u m c h a r a c t e r i s t i c to the s p e c i f i c polymer-drugsolvent combination. E q u a t i o n 1 i s e q u i v a l e n t to the h i s t o r y de­ pendent d i f f u s i o n c o e f f i c i e n t i n t r o d u c e d by Crnk [Eqn. (11.6) o f Ref. 14], however the c o n c e n t r a t i o n dependence i s n e g l e c t e d f o r the sake o f s i m p l i c i t y . By d e f i n i n g a new time v a r i a b l e dT =

D(t)dt

D

where

i 1 - (1- ]£) £ ( l - e x p ( - kt))]

Τ = D^t

(2)

the t r a n s i e n t d i f f u s i o n e q u a t i o n r e d u c e s t o a form s i m i l a r to t h a t f o r a constant d i f f u s i o n c o e f f i c i e n t . T h i s can r e a d i l y be s o l v e d a n a l y t i c a l l y f o r b o t h the d i s s o l v e d and d i s p e r s e d systems i n terms o f f r a c t i o n a l drug r e l e a s e as a f u n c t i o n o f t i m e . Dissolved

Systems

(AC

00

œ

)

By s o l v i n g the moving boundary problem a s s o c i a t e d w i t h a s w e l l a b l e d i s p e r s e d system, the f o l l o w i n g a n a l y t i c a l s o l u t i o n r e s u l t s :

M M" »

W

i

t

h

=

1

2

7Â~r~77T

Τ

(^-)erf(n) s

π

,.

r [ Τ

"

( 1

V

" D"

oo

77

}

oo

2

D

k [

1

"

E

X

P(- —

i

2

Τ

I ^

(5)

oo

k£/

2

Aexp(n )erf(n) = ^ -

(6) S

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

76

CONTROLLED-RELEASE TECHNOLOGY

The r e l a t i v e p e n e t r a t i o n o f the d i f f u s i o n f r o n t which s e p a r a t e s the d i s s o l v e d r e g i o n from the u n d i s s o l v e d c o r e i s e x p r e s s e d a s :

f

= 2η[τ-(1- ^ )

—j

[ l - e x p ( - ψ-

τ)]]

2

Where ξ i s the p e n e t r a t i o n d i s t a n c e and η i s e v a l u a t e d e q u a t i o n 6.

(7)

from

R e s u l t s and D i s c u s s i o n U s i n g e q u a t i o n s 3-7, i t i s p o s s i b l e t o d e s c r i b e v a r i o u s o b s e r v e d r e l e a s e b e h a v i o r i n g l a s s y h y d r o g e l s based on the Deborah number concept d i s c u s s e d e a r l i e r . Parameter D /ki u t i l i z e d i n equations 3-7 i s e s s e n t i a l l y the Deborah number f o r t h e r e l e a s e systems which d e s c r i b e s the r e l a t i v e the c h a r a c t e r i s t i c d i f f u s i o o f r e l e a s e b e h a v i o r on Deborah number as summarized i n T a b l e I can be r e a l i z e d from the c o r r e s p o n d i n g time dependence o f the d i f f u s i o n c o e f f i c i e n t d e f i n e d i n e q u a t i o n 1. As i l l u s t r a t e d q u a l i t a t i v e l y i n F i g u r e 2, when the Deborah number i s v e r y s m a l l , the d i f f u s i o n c o e f f i c i e n t D q u i c k l y a p p r o a c h e s the c o n s t a n t e q u i l i b r i u m d i f f u s i o n c o e f f i c i e n t D^, g i v i n g r i s e t o a F i c k i a n d i f f u s i o n b e h a v i o r . At the o t h e r extreme, when t h e Deborah number i s v e r y l a r g e , t h e d i f f u s i o n c o e f f i c i e n t remains t o be e s s e n t i a l l y the c o n s t a n t i n s t a n t a n e o u s p o r t i o n o f the d i f f u s i o n c o e f f i c i e n t D , and a s l o w e r F i c k i a n d i f f u s i o n w i l l occur. In the i n t e r m e d i a t e range o f Deborah number, the d i f f u s i o n c o e f f i c i e n t r e q u i r e s a f i n i t e amount o f time t o a p p r o a c h i t s e q u i l i b r i u m v a l u e r e s u l t i n g i n a time-dependent anomalous d i f f u s i o n b e h a v i o r . In f a c t , the s m a l l e r the Deborah number, t h e f a s t e r i t w i l l a p p r o a c h the c o n s t a n t e q u i l i b r i u m d i f f u s i o n c o e f f i c i e n t and t h e r e f o r e the e a r l i e r i t w i l l e x h i b i t Fickian d i f f u s i o n behavior. 2

The f r a c t i o n a l r e l e a s e s as p r e d i c t e d from e q u a t i o n 3-7 a r e p l o t t e d i n F i g u r e s 3 and 4 as a f u n c t i o n o f the square r o o t o f t h e reduced time v a r i a b l e . I t c a n be seen t h a t f o r b o t h t h e d i s s o l v e d and d i s p e r s e d systems, the r e l e a s e b e h a v i o r e x h i b i t s the so c a l l e d r u b b e r y - s t a t e F i c k i a n f o r D / k i , = 0 as c h a r c t e r i z e d by the l i n e a r dependence i n the s q u a r e - r o o t - o f - t i m e p l o t , where t h e polymer m o l e c u l a r r e l a x a t i o n p r o c e s s i s f a s t compared t o t h e d i f f u s i v e transport. F o r D / k i , - l o r >1 t h e r e l e a s e b e h a v i o r s h i f t s t o anomalous d i f f u s i o n ( i n c l u d i n g Case I I ) ; where t h e m o l e c u l a r r e l a x a t i o n p r o c e s s o c c u r s i n a comparable o r s l i g h t l y s l o w e r time s c a l e than t h a t o f the d i f f u s i v e t r a n s p o r t p r o c e s s . When D / k £ » l , t h e r e i s e f f e c t i v e l y no time v a r i a t i o n o f t h e polymer s t r u c t u r e d u r i n g t h e d i f f u s i o n p r o c e s s and the r e l e a s e b e h a v i o r approached t h e s o - c a l l e d g l a s s y - s t a t e F i c k i a n d i f f u s i o n as c h a r a c t e r i z e d a g a i n by the l i n e a r dependence i n the s q u a r e - r o o t - o f - t i m e p l o t . As p o i n t e d out p r e v i o u s l y , t h i s g l a s s y - s t a t e F i c k i a n d i f f u s i o n i s governed by the c o n s t a n t i n s t a n t a n e o u s p o r t i o n o f t h e d i f f u s i o n c o e f f i c i e n t , D^. T h i s a l s o i m p l i e s that a non-zero instantaneous d i f f u s i o n c o e f f i c i e n t i s a p r e r e q u i s i t e f o r the g l a s s y - s t a t e F i c k i a n 2

2

œ

2

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

LEE

Drug-Release Kinetics from Hydrogel Matrices

0.8

A

A

0.7 0.6 0.5 M M»

0.4

Jy

0.3 0.2 0.1 ο

1.26.06% 2.17.91% 3. 9.21%

1.5

1

0.5

0

>it(hr°- ) s

F i g u r e 1. E f f e c t of l o a d i n g on the f r a c t i o n a l r e l e a s e ^ f t h i a ­ mine HC1 from i n i t i a l l y d e h y d r a t e d PHEMA s h e e t s a t 37.5 C.

D(t)=D +(D«-D )[1-exp(-^?r)] l

l

where r - d t / l

2

(DEB)D«^ 1

where k": characteristic relaxation time I V D L * characteristic diffusion time

F i g u r e 2. E f f e c t o f Deborah number (DEB)D on the C h a r a c t e r i s t i c time-dependent d i f f u s i o n c o e f f i c i e n t .

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

CONTROLLED-RELEASE TECHNOLOGY

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

5. L E E

79

Drug-Release Kinetics from Hydrogel Matrices

diffusion. These p r e d i c i t i o n s a r e c e r t a i n l y c o n s i s t e n t w i t h p h y s i c a l o b s e r v a t i o n s r e p o r t e d i n the l i t e r a t u r e ( 9 - 1 3 ) . The magnitude o f D. i n r e l a t i o n t o D a l s o has a p r o f o u n d i co e f f e c t on the o v e r a l l r e l e a s e b e h a v i o r . As shown i n F i g u r e s 5 and 6, where the time dependence o f f r a c t i o n a l r e l e a s e i s p l o t t e d as a f u n c t i o n o f Ώ^/Ό^ f o r b o t h the d i s s o l v e d and d i s p e r s e d systems a t D / k £ = 10, as D./D +1 the r e l e a s e b e h a v i o r becomes more F i c k i a n 2

co

ι

*

oo

and as D^/D^-K) the r e l e a s e b e h a v i o r becomes more z e r o - o r d e r (or Case II). S i n c e most r e p o r t e d d a t a on drug r e l e a s e from s w e l l i n g c o n t r o l l e d systems show i n t e r m e d i a t e r e l e a s e b e h a v i o r (20,21), i t i s r e a s o n a b l e t o b e l i e v e t h a t the i n s t a n t a n e o u s p a r t o f the d i f f u s i o n c o e f f i c i e n t , D^, e x i s t s and p l a y s an i m p o r t a n t r o l e i n d e t e r m i n i n g the o b s e r v e d drug r e l e a s e b e h a v i o r . A n o t h e r i n t e r e s t i n g o b s e r v a t i o n i s from F i g u r e 7, where the f r a c t i o n a l r e l e a s e fro dispersed i plotted functio of the drug l o a d i n g to m a i n t a i n e d a t 1. The r e l e a s l o a d i n g (A/C = 1) as one would expect from the Deborah number and i s seen t o a p p r o a c h F i c k i a n b e h a v i o r ( w i t h more c u r v a t u r e ) as the drug l o a d i n g l e v e l i n c r e a s e s . T h i s i s c o n s i s t e n t w i t h our p r e v i o u s e x p e r i m e n t a l f i n d i n g s (5) t h a t the r e l e a s e o f t h i a m i n e HC1 from an i n i t i a l l y d e h y d r a t e d poly-HEMA h y d r o g e l becomes more F i c k i a n as the l o a d i n g l e v e l o f t h i a m i n e HC1 i s i n c r e a s e d . As a r e s u l t o f t r e a t i n g the d i s p e r s e d system as a moving boundary p r o b l e m , the r e l a t i v e p e n e t r a t i o n o f the d i f f u s i o n f r o n t i s o b t a i n e d and shown i n F i g u r e 8 f o r the case o f D. = 0 . F o r the f i r s t t i m e , a f u l l spectrum o f p e n e t r a t i o n b e h a v i o r r a n g i n g from F i c k i a n a t D / k £ = 0 t o Case I I ( c o n s t a n t - r a t e ) a t D / k £ > l i s 2

2

X

OO

00

o b t a i n e d from the s o l u t i o n t o F i c k ' s second law u s i n g the g e n e r a l time-dependent d i f f u s i o n c o e f f i c i e n t d e f i n e d by e q u a t i o n 1. Again the dependence on D ^ / k i , , the Deborah number f o r the r e l e a s e system, i s c o n s i s t e n t w i t h the d i f f u s i o n c h a r a c t e r i s t i c s d e s c r i b e d i n T a b l e I. P r e v i o u s l y , the d e r i v a t i o n o f Case I I p e n e t r a t i o n b e h a v i o r from F i c k i a n d i f f u s i o n was r e g a r d e d as not p o s s i b l e because o f i t s inherent l a c k of a r e l a x a t i o n c o n t r i b u t i o n . Approaches i n the l i t e r a t u r e have been l i m i t e d t o s i m p l y assuming a c o n s t a n t f r o n t v e l o c i t y as i n the d i f f u s i o n and c o n v e c t i o n model d e s c r i b e d e a r l i e r . To f u r t h e r i l l u s t r a t e the u t i l i t y o f the p r e s e n t time-dependent d i f f u s i o n c o e f f i c i e n t a p p r o a c h , d a t a from R e f e r e n c e 21 f o r the t h i a m i n e HC1 r e l e a s e from i n i t i a l l y d e h y d r a t e d poly-HEMA s h e e t s w i t h d i f f e r e n t l o a d i n g l e v e l s a r e a n a l y z e d w i t h e q u a t i o n s 3-7. The r e s u l t s a r e shown i n F i g u r e 9 and T a b l e I I . I t has t o be emphasized T A B L E I . G e n e r a l Dépendance o f R e l e a s e B e h a v i o r o n D e b o r a h Number 2

(DEB)D «

1:

^

+0

2

(DEB)D

=: 1 o r > 1 :

(DEB)

»

, D^D

W

Fickian

Diffusion

Anomalous D i f f u s i o n ( i n c l u d i n g Case I I )

Deo D

2

1: kl

+ °°, D - * i

Fickian (Glassy

Diffusion State)

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

80

CONTROLLED-RELEASE TECHNOLOGY

F i g u r e 6. Time dependence o f f r a c t i o n a l r e l e a s e as a f u n c t i o n o f D-L/DQO f o r a s w e l l a b l e polymer s h e e t c o n t a i n i n g d i s p e r s e d drug; ψ : s o l v e n t f r o n t s meet.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

LEE

Drug-Release Kinetics from Hydrogel Matrices 1.0

y /\5

or

0.8 0.6 04

V/

/

0.2

ι

ι

F i g u r e 7. Time dependence o f f r a c t i o n a l r e l e a s e as a f u n c t i o n o f A/C f o r a s w e l l a b l e polymer s h e e t w i t h Doc/k£ = 1 and D^/Doo = 0 2

s

0.8-

0.60.4

A . =

5

0.2

F i g u r e 8. Time dependence o f r e l a t i v e p e n e t r a t i o n o f t h e d i f ­ f u s i o n f r o n t as a f u n c t i o n o f r e l e a s e Deborah number, Doo/k£ , f o r a s w e l l a b l e polymer s h e e t c o n t a i n i n g d i s p e r s e d d r u g . 2

t(hr) F i g u r e 9. E f f e c t o f l o a d i n g on the f r a c t i o n a l r e l e a s e o f t h i a ­ mine HC1 from i n i t i a l l y d e h y d r a t e d PHEMA s h e e t s a t 37.5°C. Data p o i n t s c a l c u l a t e d from e q u a t i o n s 3-6.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

82

CONTROLLED-RELEASE TECHNOLOGY

t h a t t h i s a n a l y s i s i s not a pure c u r v e - f i t t i n g e x e r c i s e . Rather, the e q u i l i b r i u m d i f f u s i o n c o e f f i c i e n t , D , i s f i r s t c a l c u l a t e d from the l a t t e r p a r t o f the e x p e r i m e n t a l r e l e a s e curve u s i n g the l a r g e - t i m e a p p r o x i m a t i o n t o the s o l u t i o n t o the F i c k i a n d i f f u s i o n equation. T h i s i s a r e a s o n a b l e approach, s i n c e a t l a r g e time the h y d r o g e l m a t r i x i s a l r e a d y f u l l y s w o l l e n by the s o l v e n t w h i l e t h e d i f f u s i o n o f the drug i s s t i l l t a k i n g p l a c e . The o b t a i n e d e x p e r i m e n t a l D i s then used i n c o n j u n c t i o n w i t h e q u a t i o n s 3-6, the A/C v a l u e , and the e x p e r i m e n t a l r e l e a s e c u r v e t o c a l c u l a t e the c o r r e s p o n d i n g D^/ki, and k v a l u e s . Indeed, as shown i n T a b l e I I , the average polymer r e l a x a t i o n c o n s t a n t , k, so o b t a i n e d i n c r e a s e s w i t h t h e drug l o a d i n g l e v e l i n d i c a t i n g t h a t F i c k i a n d i f f u s i o n w i l l be t h e r a t e l i m i t e d s t e p under h i g h drug l o a d i n g s i t u a t i o n . Again t h i s i s i n agreement w i t h o u r p r e v i o u s e x p e r i m e n t a l f i n d i n g s t h a t the r e l e a s e o f t h i a m i n e HC1 from an i n i t i a l l y d e h y d r a t e d poly-HEMA h y d r o g e l bead becomes more F i c k i a n as t h e l o a d i n g l e v e l o f t h i a m i n e HC1 i s i n c r e a s e d ( 5 ) . 2

TABLE

II.

C h a r a c t e r i s t i c s o f T h i a m i n e HC1 R e l e a s e poly-HEMA S h e e t s

from

A Cs

D [10

7

œ

2.13 3.84 5.55

1 1.17 1.70

1 = 0 . 0 5 1 6 c m , IT 2

7

1

2

cm /sec]

2

kl

0.33 0.20 0.17

k[10 "sec ] 2.40 7.21 12.51

= 0.01

^oo

Literature Cited 1. Ratner, B.D., Hoffman, A.S. In "Hydrogels for Medical and Related Applications"; Andrade, J.D., Ed.; ACS SYMPOSIUM SERIES No. 31, American Chemical Society: Washington, D.C., 1976; pp. 1-36. 2. Graham, N.B.; McNeill, M.E. Biomaterials 1984, 5, 27. 3. Law, T.K.; Whateley, T.L.; Florence, A.T. Br. Polym. J. 1986, 18, 34. 4. Good, W.R. In "Polymeric Delivery Systems"; Kostelnik, R., Ed.; Gordon and Breach; New York, NY, 1976; pp. 139-153. 5. Lee, P.I. Polymer Commun. 1983, 24, 45. 6. Lee, P.I. J. Pharm. Sci. 1984, 73, 1344. 7. Lee. P.I. Polymer 1984, 25, 973. 8. Lee, P.I. J. Controlled Release 1985, 2, 277. 9. Vrentas, J.S.; Jarzebski, C.M.; Duda, J.L. AIChE J. 1975, 21, 894. 10. Wang, T.T.; Kwei, T.K.; Frish, H.L. J. Polym. Sci. A-2 1969, 7, 2019. 11. Peterlin, A. Makromol. Chem. 1969, 124, 136. 12. Thomas, N.L.; Windle, A.H. Polymer 1982, 23, 529. 13. Gostoli, C.; Sarti, G.C. Chem. Eng. Commun. 1983, 21, 67.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

5. LEE 14. 15. 16. 17. 18. 19. 20. 21.

Drug-Release Kinetics from Hydrogel Matrices

Crank, J. J. Polym. Sci. 1953, 11, 151. Long, F.A.; Richman, D. J. Amer. Chem. Soc. 1960, 82, 513. Petropoulos, J.H.; Roussis, P.P. J. Membrane Sci. 1978, 3, 343. Petropoulos, J.H. J. Polym. Sci. Polym. Phys. Ed. 1984, 22, 1885. Lee, P.I. J. Membrane Sci. 1980, 7, 255. Lee, P.I. In "Controlled Release of Pesticides and Pharmaceuticals"; Lewis, D.H., Ed.; Plenum: New York, NY, 1981; pp. 39-48. Korsmeyer, R.W.; Peppas, N.A. Proc. 10th Int. Symp. Cont. Rel. Bioac. Mater., 1983, p. 141. Lee, P.I. Proc. 9th Int. Symp. Cont. Rel. Bioac. Mater., 1982, p. 54.

RECEIVED February

16, 1987

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Chapter 6

Physicochemical Models for Percutaneous Absorption 1

2

J. Hadgraft and Richard H. Guy 1

Welsh School of Pharmacy, UWIST, P.O. Box 13, Cardiff, CF1 3XF, United Kingdom School of Pharmacy, University of California, San Francisco, CA 94143 2

A mathematical model which predicts the process of percutaneous absorption based on the physicochemical properties of the permeant is described. Its relevance in predictin assessed using nitroglyceri has the flexibility to allow for drug loss by processes such as volatilisation, microbial degradation, enzyme metabolism. The kinetic steps involved in skin penetration are modified by the presence of penetration enhancers. The model allows a mechanistic interpretation of the potential role of such percutaneous promoters in transdermal drug delivery. The modelling can also be modified to describe dermal absorption in the neonate where it has been used successfully to predict the transdermal delivery of theophylline.

M a t e r i a l s have been a p p l i e d t o t h e s k i n f o r many y e a r s t o o b t a i n medical b e n e f i t . There a r e r e p o r t s t h a t t h e E g y p t i a n s a p p l i e d o i n t m e n t s t o t h e s k i n but i t took u n t i l t h e l a t e n i n e t e e n t h c e n t u r y t o e s t a b l i s h t h a t compounds such as s a l i c y l i c a c i d c o u l d be absorbed p e r c u t a n e o u s l y and t h a t t o x i c e f f e c t s c o u l d be produced from a g e n t s s u p p l i e d t o t h e s k i n s u r f a c e [J_][2]. Throughout t h e f i r s t h a l f o f the t w e n t i e t h c e n t u r y many advances were made w i t h r e g a r d t o an u n d e r s t a n d i n g o f t o p i c a l drug d e l i v e r y f o r l o c a l e f f e c t but i t has o n l y been i n t h e l a s t decade t h a t drug d e l i v e r y t h r o u g h t h e s k i n f o r systemic effect has been seriously considered. In order t o understand t h e advantages and d i s a d v a n t a g e s o f t r a n s d e r m a l drug d e l i v e r y i t i s i m p o r t a n t t o have a thorough comprehension o f t h e p h y s i c o c h e m i c a l parameters which c o n t r o l p e r c u t a n e o u s a b s o r p t i o n . I t i s t h e s e f a c t o r s and how they may be m o d e l l e d which t h i s c h a p t e r addresses.

0097-6156/87/0348-0084$06.00/0 © 1987 American Chemical Society

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

6.

HADGRAFT AND GUY

Route o f

Percutaneous Absorption

85

penetration

I n d e f i n i n g a model f o r p e r c u t a n e o u s a b s o r p t i o n i t i s n e c e s s a r y to i d e n t i f y the r o u t e by which a drug m o l e c u l e c r o s s e s the s k i n . For a l l but the most l i p o p h i l i c m a t e r i a l s , the p r i n c i p a l b a r r i e r to p e n e t r a t i o n i s the s t r a t u m corneum. There a r e , however, a number o f routes a diffusing drug m o l e c u l e can take in traversing this outermost l a y e r o f the e p i d e r m i s . These a r e d e p i c t e d s c h e m a t i c a l l y i n F i g u r e 1. The l a y e r o f sebum on the s k i n s u r f a c e does not a c t as a barrier and can largely be ignored for assessing percutaneous absorption. Shunt diffusion through the appendages has been s u g g e s t e d as b e i n g s i g n i f i c a n t , p a r t i c u l a r l y d u r i n g the p e r i o d i m m e d i a t e l y a f t e r drug a p p l i c a t i o n . However the s m a l l s u r f a c e a r e a a v a i l a b l e f o r d i f f u s i o n i n d i c a t e s t h a t l a r g e c o n c e n t r a t i o n s o f drug are not transported via this route. The e c c r i n e glands are c e r t a i n l y o f no s i g n i f i c a n c e i n which the p i l o s e b a c e o u formulation contains high concentrations of surfactant [k]. The p r i n c i p a l r o u t e s o f p e n e t r a t i o n are thus t r a n s c e l l u l a r and intercellular. C u r r e n t l y t h e r e i s c o n s i d e r a b l e debate as t o which o f t h e s e p r e d o m i n a t e s . Work w i t h e s t e r s o f n i c o t i n i c a c i d has shown t h a t the i n t e r c e l l u l a r c h a n n e l s a r e s i g n i f i c a n t [5.] and c o n s i d e r a b l e e f f o r t i s b e i n g conducted t o i d e n t i f y t h e i r e x a c t n a t u r e and r o l e . M i c r o s c o p i c e x a m i n a t i o n shows t h a t they c o n t a i n s t r u c t u r e d l i p i d s the c h e m i c a l n a t u r e o f which i s complex [ 6 ] . Cholesterol esters, cerebrosides and sphingomyelins are present i n a s s o c i a t i o n with o t h e r l i p i d s i n s m a l l e r c o n c e n t r a t i o n s . I t i s l i k e l y t h a t the main b a r r i e r to s k i n p e n e t r a t i o n r e s i d e s i n the c h a n n e l s and that a d i f f u s i n g drug m o l e c u l e e x p e r i e n c e s a l i p i d environment which has considerable structure. Penetration enhancers may act by t e m p o r a r i l y a l t e r i n g the n a t u r e o f the s t r u c t u r e d l i p i d s , perhaps by lowering t h e i r normal phase t r a n s i t i o n temperature which occurs around 38°C. When a drug has d i f f u s e d through the s t r a t u m corneum i t must p a r t i t i o n from a p r i m a r i l y l i p i d r i c h environment t o one which i s p r e d o m i n a n t l y aqueous i n n a t u r e , the v i a b l e e p i d e r m i s . It i s p o s s i b l e that t h i s p a r t i t i o n i n g process can c o n t r o l the overall t r a n s f e r o f a drug to the s y s t e m i c c i r c u l a t i o n . C o n s e q u e n t l y any assessment of the physicochemical parameters which influence p e r c u t a n e o u s a b s o r p t i o n must a l s o take i n t o a c c o u n t the p a r t i t i o n i n g c h a r a c t e r i s t i c s o f the d r u g . I t i s also feasible that penetration enhancers may a c t , not o n l y by a f f e c t i n g the s t r u c t u r e d lipid b a r r i e r , but a l s o i n a i d i n g p a r t i t i o n i n g a t the s t r a t u m corneum -viable tissue interface. K i n e t i c d e s c r i p t i o n of percutaneous

absorption

The d i f f e r e n t s t e p s i n v o l v e d i n drug t r a n s f e r from a d e l i v e r y system t o the cutaneous c i r c u l a t i o n a r e shown i n F i g u r e 2 [ 7 - 1 0 ] , Drugs d i f f u s i n g t h r o u g h the s k i n may be s u b j e c t t o v a r i o u s l o s s p r o c e s s e s which a r e d i f f i c u l t to q u a n t i f y but w i l l be d i s c u s s e d . The first s t e p i n the t o t a l t r a n s f e r p r o c e s s i s d i f f u s i o n from the d e v i c e . In i t s s i m p l e s t form, the ' d e v i c e c o u l d be an ointment base which w i l l 1

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

CONTROLLED-RELEASE TECHNOLOGY

sebum epidermal

append ageal

inter intra cellular

eccrine

follicular

viable epidermis

Figure

1.

Potentia

Location

loss

formulation

evaporation

processes

microbial transformation

Stratum corneum

binding skin

metabolism

viable epidermis

dermis' k

4

drug removal circulation

F i g u r e 2. Schematic k i n e t i c r e p r e s e n t a t i o n o f drug a c r o s s t h e s k i n and a s s o c i a t e d l o s s p r o c e s s e s .

into

transfer

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

6.

HADGRAFT AND

87

Percutaneous Absorpnon

GUY

r e l e a s e drug t o the s k i n s u r f a c e w i t h f i r s t o r d e r k i n e t i c s ( k ) . In a membrane moderated t r a n s d e r m a l system t h e r e w i l l be two i n p u t functions describing drug delivery t o the skin. The contact a d h e s i v e which c o n t a i n s a l o a d i n g dose o f the drug w i l l r e l e a s e i t s payload with f i r s t order k i n e t i c s ( k ) , i n a s i m i l a r f a s h i o n to a c o n v e n t i o n a l t o p i c a l dose. The membrane moderation w i l l a l s o ensure t h a t drug i s r e l e a s e d f o r a p r o l o n g e d p e r i o d o f time w i t h z e r o o r d e r kinetics ( k ) . The t o t a l amount a r r i v i n g at the s k i n s u r f a c e w i l l be the sum o f t h e two. A t h i r d t y p e o f d e v i c e r e l e a s e s drug w i t h 'square r o o t o f t i m e k i n e t i c s and c o n s t a n t b l o o d l e v e l s o f the drug a r e r e l i a n t on the s k i n i t s e l f b e i n g the r a t e d e t e r m i n i n g s t e p i n d e l i v e r y t o the s y s t e m i c c i r c u l a t i o n . At the j u n c t i o n between the d e v i c e and the s k i n s u r f a c e t h e drug w i l l e x p e r i e n c e a phase change and hence a p a r t i t i o n i n g s t e p . The d e s i g n o f p o l y m e r i c and a d h e s i v e systems i n t r a n s d e r m a l drug delivery should ensure that this step is thermodynamically f a v o u r a b l e , i . e . the dru lipids. Once i n t o the s t r a t u rate. T r a n s f e r t h r o u g h the s k i n i s s l o w e s t i n t h i s r e g i o n and a f i r s t o r d e r c o n s t a n t , k-|, can be w r i t t e n t o d e s c r i b e t h i s i n terms o f the d i f f u s i o n c o e f f i c i e n t o f the drug D and the d i f f u s i o n a l path length l . a

a

0

1

s c

s

k

1

c

2

= Dsc/l sc

(1)

D i f f u s i o n then continues through the v i a b l e t i s s u e at a f a s t e r r a t e and a second r a t e c o n s t a n t , k2, can be w r i t t e n i n a s i m i l a r manner

k

2

= D

v e

/l2

y e

(2)

where the s u b s c r i p t s now r e f e r t o the v i a b l e e p i d e r m i s . In p r e v i o u s work i t has been shown t h a t t h e s e r a t e c o n s t a n t s a r e r e l a t e d t o the m o l e c u l a r s i z e and hence m o l e c u l a r weight (M) o f the d i f f u s a n t [ 1 1 ] . The r a t e c o n s t a n t s can be p r e d i c t e d based on p r e v i o u s d a t a f o r b e n z o i c a c i d and f o r s u b s t a n c e s w i t h m o l e c u l a r weights o f l e s s than 500 Da,

1

k^n" ) =

0.91M-1/3

(3)

k ( h - ) = 14.36M-1/3

(4)

1

2

From F i g u r e 2, i t i s a p p a r e n t t h a t t h e r e i s a l s o a p a r t i t i o n i n g s t e p as the drug d i f f u s e s from the s t r a t u m corneum t o the v i a b l e t i s s u e , t h i s can be d e s c r i b e d by a backward r a t e c o n s t a n t , kg. Empirically it has been shown t h a t the r a t i o kg/k2 can be r e l a t e d t o the o c t a n o l - w a t e r (pH 7.4) p a r t i t i o n c o e f f i c i e n t o f t h e drug d i v i d e d by

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

88

CONTROLLED-RELEASE TECHNOLOGY

5 [ 1 1 ] . Thus drugs which a r e v e r y l i p o p h i l i c may be h e l d back i n the s t r a t u m corneum. T r a n s f e r a c r o s s both l a y e r s o f s k i n w i l l be f a c i l i t a t e d f o r drugs which have b a l a n c e d p a r t i t i o n i n g b e h a v i o u r and r e a s o n a b l e s o l u b i l i t y i n both o i l and water phases. When t h e drug arrives a t t h e cutaneous vasculature i t e q u i l i b r a t e s r a p i d l y i n t o the systemic c i r c u l a t i o n which has a volume o f d i s t r i b u t i o n , V. E l i m i n a t i o n from t h i s compartment i s d e s c r i b e d by a n o t h e r f i r s t o r d e r r a t e c o n s t a n t ki| ( a l t h o u g h t h i s c o u l d be made more complex) which i s t h e c l a s s i c pharmacokinetic rate of elimination. Using t h e above rate constants i t i s p o s s i b l e to write e q u a t i o n s d e s c r i b i n g t h e plasma c o n c e n t r a t i o n ( C p ) , time ( t ) c o u r s e of a t r a n s d e r m a l l y a p p l i e d drug [9.][V2][J_3]. A simple a n a l y t i c s o l u t i o n i s p o s s i b l e i n t h e case o f t h e z e r o and f i r s t o r d e r r e l e a s e which i s : -

C

f(k )

= Mk k k

a

a

= f (k

p

1

(

2

a

exp(-qt)

exp(-pt)

\(β-α)(α-ω)( •ω) (α-μ)

f(k )

ω

exp(-q)t )

exp(-||t)

(α-ω) (ω-β)(ω-μ)

(οτμ) (μ-β) ( μ - ω ^

( _ 1 _

= Akok^

0

(α-β)(β- )(β-μ)

-

(6)

expiât)

\ αβε

"

exp(-Rt)

exp(-

(

(7)

Where Μ i s t h e amount o f drug of t h e d e v i c e , k

k

=

ωμ

= a 1î

(ω+μ)

αβ

= k k4;

ε

= k-i+k

2

k

a

+ k

r

i n the adhesive,

+ k

A i s the surface area

1

(α+β) = k + k + k 4 2

3

r

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

6.

The

HADGRAFT A N D G U Y

loss

89

Percutaneous Absorption

processes

F i g u r e 2 a l s o shows t h a t v a r i o u s l o s s p r o c e s s e s a r e a l s o p o s s i b l e . From the s u r f a c e o f the s k i n t h e r e a r e two p o t e n t i a l methods by which a drug can be l o s t . I f i t i s not c o v e r e d , i t may d i s a p p e a r as a r e s u l t o f s u r f a c e a b r a s i o n , on t o , f o r example c l o t h i n g . Volatile m a t e r i a l s may e v a p o r a t e and t h i s p r o c e s s i s not e a s i l y q u a n t i f i e d . I t i s apparent t h a t e i t h e r z e r o o r d e r , f i r s t o r d e r o r a c o m b i n a t i o n o f both may o c c u r i n the v o l a t i l i s a t i o n o f an a c t i v e i n g r e d i e n t . The r a t e s have not been q u a n t i f i e d i n many i n s t a n c e s and w i l l be s u b j e c t t o a l a r g e number o f v a r i a b l e s . A l t h o u g h e q u a t i o n s can be d e r i v e d to p r e d i c t the s i g n i f i c a n c e o f t h e s e l o s s p r o c e s s e s t h e y a r e d i f f i c u l t t o j u s t i f y i n l i g h t o f the c u r r e n t p a u c i t y o f e x p e r i m e n t a l data [ J I 4 ] Q 5 ] . A f u r t h e r p o t e n t i a l l o s s p r o c e s s i n v o l v e s metabolism o f the drug by m i c r o - o r g a n i s m s on the s k i n s u r f a c e . H e a l t h y s k i n s u p p o r t s a wide range o f micro organisms Staphylococcus epidermidis m e t a b o l i s i n g drugs such as s t e r o i d e s t e r s [±6] and nitroglycerin (GTN) [J7.]. Thus drugs i n t e n d e d f o r both l o c a l and s y s t e m i c e f f e c t may be d e a c t i v a t e d b e f o r e they even p a r t i t i o n i n t o t h e o u t e r l a y e r s o f the s k i n . T h i s e f f e c t can be q u a n t i f i e d and t h e o r e t i c a l r e s u l t s indicate that blood levels of topically applied GTN can be s i g n i f i c a n t l y reduced [ 1 8 ] . W i t h i n the s t r a t u m corneum drug l o s s can o c c u r by b i n d i n g to components o f the s k i n . L i t t l e work has a s s e s s e d t h e magnitude o f such e f f e c t s but some i n v e s t i g a t i o n s have a t t r i b u t e d the f o r m a t i o n o f s t e r o i d r e s e r v o i r s t o b i n d i n g phenomena. B i n d i n g may o c c u r as a r e s u l t o f van der Waals i n t e r a c t i o n s or hydrogen bonding. Another i m p o r t a n t l o s s p r o c e s s i s t h a t o f metabolism by enzymes w i t h i n the s k i n . Many non s p e c i f i c enzymes have been shown to be present i n the skin. These i n c l u d e esterases, oxidases and r e d u c t a s e s [J_9][20]. Thus t h e r e a r e a number o f p o t e n t i a l p r o c e s s e s which may d e a c t i v a t e the drug as i t d i f f u s e s . T h i s d e a c t i v a t i o n can be q u a n t i f i e d but a g a i n t h e r e i s l a c k o f s p e c i f i c d a t a [21 ] [ 2 2 ] , F u r t h e r work i s r e q u i r e d t o monitor the l o c a t i o n and c o n c e n t r a t i o n o f the enzymes p r e s e n t and t o p r o v i d e g u i d e l i n e s about the e x a c t k i n e t i c s o f the m e t a b o l i c p r o c e s s e s . T h i s s t e p i s not n e c e s s a r i l y disadvantageous s i n c e f o r some drugs i t i s p o s s i b l e t o s y n t h e s i s e prodrugs. These p o s s e s s the c o r r e c t p h y s i c o c h e m i c a l p r o p e r t i e s t o o p t i m i s e s k i n p e n e t r a t i o n and d u r i n g the d i f f u s i o n p r o c e s s they a r e m e t a b o l i c a l l y c l e a v e d t o produce t h e a c t i v e drug a t the s i t e a t which i t i s r e q u i r e d [24-26]. Transdermal

d e l i v e r y of

nitroglycerin

S i n c e n i t r o g l y c e r i n has been one o f the most w i d e l y s t u d i e d drugs which have been d e l i v e r e d by the t r a n s d e r m a l r o u t e , the u t i l i t y o f the model w i l l be i l l u s t r a t e d f o r t h i s compound. One membrane moderated d e v i c e r e l e a s e s drug w i t h w e l l d e f i n e d c h a r a c t e r i s t i c s t h a t have been measured i n v i t r o [ 2 7 ] . There i s an i n i t i a l first o r d e r r e l e a s e o f GTN (2mg) from the a d h e s i v e w i t h an e s t i m a t e d rate c o n s t a n t o f 1.3 h " over a s u r f a c e a r e a 10 cm . The z e r o o r d e r r e l e a s e from t h i s d e v i c e has been determined as 36yg/cm /h. The 1

2

2

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

90

CONTROLLED-RELEASE TECHNOLOGY

d e s i g n o f t h i s system i s such t h a t GTN p a r t i t i o n s f a v o u r a b l y from the a d h e s i v e i n t o the s t r a t u m corneum. Consequently a s m a l l value of k has been chosen ( l O ' ^ h ) such t h a t p a r t i t i o n i n g does not i n f l u e n c e the r e l e a s e c h a r a c t e r i s t i c s o f t h e d e v i c e . E s t i m a t e s o f k-|. k2 and k3 have been a s s e s s e d from the p h y s i c o c h e m i c a l p r o p e r t i e s o f GTN u s i n g e q u a t i o n s (3) and ( 4 ) . They a r e , r e s p e c t i v e l y , 0.15, 2.36 and 53 h " . The r a t e o f e l i m i n a t i o n o f GTN from the s y s t e m i c circulation, i s 18.2h" w i t h a volume o f d i s t r i b u t i o n o f 231 1 [ 12]. U s i n g these parameters and e q u a t i o n s (6) and (7) g i v e s the theoretical profile shown i n F i g u r e 3. This i l l u s t r a t e s the r e l a t i v e importance o f the f i r s t and z e r o o r d e r p r o c e s s e s . Also i n c l u d e d on t h e graph a r e e x p e r i m e n t a l d a t a showing plasma l e v e l s o f GTN f o l l o w i n g transdermal drug delivery [28]. There i s good agreement between the t h e o r e t i c a l c a l c u l a t i o n s and t h e e x p e r i m e n t a l data. In o t h e r membrane moderated systems f o r the d e l i v e r y o f c l o n i d i n e [JJJ and e s t r a d i o l [ 2 9 ] , e q u a l l y good agreement can be obtained by estimatin p r o p e r t i e s o f the drug - 1

r

1

1

Other transdermal systems g i v e r a t e s o f r e l e a s e which are p r o p o r t i o n a l t o the square r o o t o f t i m e . In o r d e r t o model t h i s behaviour i t i s p o s s i b l e to w r i t e a s e r i e s of l i n e a r d i f f e r e n t i a l e q u a t i o n s t o d e s c r i b e t r a n s f e r from the d e v i c e and a c r o s s the s k i n . However u n l i k e the c a s e s o f f i r s t and z e r o o r d e r i n p u t , t / i n p u t does not produce a s i m p l e a n a l y t i c a l s o l u t i o n o f the type g i v e n i n e q u a t i o n ( 5 ) . Plasma l e v e l s have t h e r e f o r e been c a l c u l a t e d u s i n g a numerical approach and by solving the equations using the Runge-Kutta method. F o r GTN d e l i v e r y , i d e n t i c a l r a t e c o n s t a n t s t o t h o s e d e s c r i b e d above have been used f o r k-j, k2, k3 and kjj w i t h an i n p u t c o n s t a n t o f 500 y g / c m / h ° * 5 over a s u r f a c e a r e a o f 8 cm . The drug r e s e r v o i r c o n t a i n s 16 mg o f GTN. The p r e d i c t e d p r o f i l e i s reproduced i n F i g u r e 4. The plasma l e v e l s a r e not as c o n s t a n t as i n the z e r o o r d e r case but t h e r e i s s t i l l r e a s o n a b l e agreement between the t h e o r e t i c a l p r o f i l e and p u b l i s h e d d a t a [30]» T h i s k i n e t i c a p p r o a c h t o d e s c r i b e t r a n s d e r m a l drug d e l i v e r y f o r a range o f i n p u t f u n c t i o n s can be u s e f u l l y employed and, i n view o f the good c o r r e l a t i o n s w i t h i n v i v o d a t a , can be used p r e d i c t i v e l y . 1

2

Physicochemical requirements

2

2

f o r transdermal

delivery

The s t r a t u m corneum forms an e x c e l l e n t b a r r i e r t o p e n e t r a t i o n and thus t r a n s d e r m a l d e l i v e r y i s o n l y f e a s i b l e f o r drugs where the t o t a l d a i l y dose i s l e s s t h a n one o r two m i l l i g r a m s . T h i s c o r r e s p o n d s t o plasma c o n c e n t r a t i o n s o f the o r d e r o f nanograms per milliliter. There i s t h u s a r e s t r i c t i o n t h a t t h e drug must be v e r y p o t e n t . U s i n g the above model i t i s p o s s i b l e t o i d e n t i f y f u r t h e r c o n s t r a i n t s which a r e based on the p h y s i c o c h e m i c a l p r o p e r t i e s o f t h e d r u g . F i r s t l y the drug must p a r t i t i o n i n t o the l i p i d s o f the s t r a t u m corneum. Thus i o n i c compounds w i l l not be s u c c e s s f u l u n l e s s t h e y can be f o r m u l a t e d as i o n p a i r s . I t i s important, t h e r e f o r e , to c o n s i d e r o n l y drugs o r t h e i r complexes which have a p p r o p r i a t e physicochemical properties for partitioning from the topical formulation into the skin lipids. Assuming this process is favourable are there any further constraints? These can be i d e n t i f i e d by c o n s i d e r i n g two drugs which a r e p o t e n t i a l c a n d i d a t e s

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

HADGRAFT AND GUY

Percutaneous Absorption

plasma cone (ng/ml) 0.2

0.1

.01

24

12 time

(hours)

F i g u r e 3 · P r e d i c t i o n o f GTN plasma c o n c e n t r a t i o n f o l l o w i n g t r a n s d e r m a l d e l i v e r y from a membrane moderated system. Curve F r e p r e s e n t s t h e c o n t r i b u t i o n from the l o a d i n g dose i n t h e a d h e s i v e , c u r v e Z, t h e z e r o o r d e r d e l i v e r y and c u r v e Τ t h e sum o f t h e two. C o r r e s p o n d i n g i n v i v o d a t a were o b t a i n e d ( s o l i d c i r c l e s ) from r e f . [28]. plasma cone, (ng/ml) 0.4

0.2

time

(hours)

F i g u r e 4. P r e d i c t i o n o f GTN plasma c o n c e n t r a t i o n f o l l o w i n g t r a n s d e r m a l d e l i v e r y from a system which r e l e a s e s w i t h t / k i n e t i c s . C o r r e s p o n d i n g i n v i v o d a t a were o b t a i n e d ( s o l i d c i r c l e s ) from r e f . [28]. 1

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

2

92

CONTROLLED-RELEASE TECHNOLOGY

f o r transdermal d e l i v e r y , p r o p r a n o l o l and c h l o r d i a z e p o x i d e . The r e l e v a n t k i n e t i c parameters [J_0] f o r these a r e g i v e n i n T a b l e 1 ·

Kinetic and chlordiazepoxide

Table 1 parameters

biological

propranolol m o l e c u l a r weight log octanol-water partition coefficient t a r g e t plasma cone,(ng/ml) k (ug cm~ h- ) k (h-1) k (h-1) k! (h-1) k (h-1) k (h-1) k (h-1) V (1) A (cm ) M (mg) 2

1

Q

a

r

for

propranolol

and

chlordiazepoxide

259

300

1.17 20 35

2.5 700 30

1

1

3

· .

3

· .

ίο- * 0.143

ίο- * 0.136

0.18

0.07 21 50 100

2

2

2

3

4

2

273 30 30

F i g u r e s (5) and (6) show r e s p e c t i v e l y t h e p r e d i c t e d p r o f i l e s f o r p r o p r a n o l o l and c h l o r d i a z e p o x i d e . I t i s immediately apparent t h a t p r o p r a n o l o l i s a drug c a n d i d a t e which c o u l d be c o n s i d e r e d f o r d e l i v e r y using t h i s route of administration. The d e l i v e r y o f chlordiazepoxide i s , however, u n l i k e l y t o s u c c e e d . The p r i m a r y r e a s o n f o r t h i s i s t h e l a r g e v a l u e o f k such t h a t drug t r a n s f e r o u t of the stratum corneum i s slow. Thus drugs which a r e v e r y l i p o p h i l i c i n n a t u r e can p a r t i t i o n w e l l i n t o the s t r a t u m corneum but t r a n s f e r out o f t h i s r e g i o n impedes t h e a r r i v a l o f t h e drug a t t h e cutaneous v a s c u l a t u r e . The o n l y method of circumventing this problem i s by t h e use o f a p e n e t r a t i o n enhancer which w i l l m o d i f y the partitioning characteristics a t t h e stratum corneum-viable epidermis i n t e r f a c e . 3

Penetration

enhancers

In o r d e r t o i n c r e a s e the number o f drugs which can be a d m i n i s t e r e d t r a n s d e r m a l l y , t h e b a r r i e r f u n c t i o n o f t h e s k i n must be r e d u c e d . The k i n e t i c model can be used t o a s s e s s t h e r o l e o f a p e n e t r a t i o n enhancer as a f u n c t i o n o f t h e p h y s i c o c h e m i c a l properties o f the drug. In i t s s i m p l e s t form a p e n e t r a t i o n enhancer may be c o n s i d e r e d t o a c t i n one o f two ways. F i r s t l y i t may i n c r e a s e t h e p e r m e a b i l i t y of the s k i n and, s e c o n d l y , i t may additionally modify t h e p a r t i t i o n i n g c h a r a c t e r i s t i c s a t the stratum corneum-viable t i s s u e interface. F o r i l l u s t r a t i o n , two enhancers have been a r b i t r a r i l y chosen, t h e f i r s t PE1 i n c r e a s e s t h e p e r m e a b i l i t y by a f a c t o r o f 10, i . e . k 1987 American Chemical Society

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

140

CONTROLLED-RELEASE TECHNOLOGY

The i n i t i a l r a t e of drug r e l e a s e from polymer m o n o l i t h s can be slowed down by s u r f a c e e x t r a c t i o n and s e v e r a l such methods have been described (3,4). A c o n t r o l l e d s u r f a c e - e x t r a c t i o n p r o c e s s l e a d i n g to a s i g m o i d a l d r u g d i s t r i b u t i o n and t h e r e b y a c h i e v i n g n e a r l y c o n s t a n t r e l e a s e of v e r y water s o l u b l e drugs has been d e s c r i b e d by Lee (5, 6, 7). P h a s e - s e p a r a t e d h y d r o g e l c o m p o s i t i o n s w i t h water s w e l l i n g below 25% (8) were found to g i v e p r a c t i c a l r e l e a s e r a t e s f o r drugs w i t h medium water s o l u b i l i t y (= 2%) , but had the s h o r t c o m i n g of r e l a t i v e l y low s w e l l i n g i n o r g a n i c s o l v e n t s . S i n c e d u r i n g the c y c l e of d r u g l o a d i n g and drug r e l e a s e the l o a d i n g s t e p and the a t t a i n a b l e l o a d i n g l e v e l depends on the polymer's degree of s w e l l i n g i n the l o a d i n g s o l v e n t - u s u a l l y a lower a l c o h o l - whereas the r e l e a s e depends i n v e r s e l y on the water u p t a k e , we d e c i d e d to p r e p a r e beads which combined a h i g h e t h a n o l s w e l l i n g c a p a c i t y and t h e r e f o r e h i g h d r u g l o a d a b i l i t y w i t h a w a t e r - s w e l l i n g c a p a c i t y as low as p r a c t i c a l . In t h i s paper we d e s c r i b e th c a r r i e r s f o r v e r y wate Experimental Materials. A l l monomers used f o r s y n t h e s i s were f r e e of i n h i b i t o r s and f r e s h l y d i s t i l l e d : 2 - h y d r o x y e t h y l m e t h a c r y l a t e (HEMA); d i m e t h y l a c r y l a m i d e (DMA); N - v i n y l p y r r o l i d o n e (NPV); m e t h y l m e t h a c r y l a t e (MMA); 2 - e t h y l h e x y l a c r y l a t e (ERA); i s o p r o p y l m e t h a c r y l a t e (IPMA); n - b u t y l a c r y l a t e (BA); e t h y l e n e g l y c o l - d i m e t h a c r y l a t e (EGDMA); d i m e t h a c r y l a t e macromer o b t a i n e d by r e a c t i o n of 1 mol p o l y t e t r a r a e t h y l e n e o x i d e d i o l (MW: 2000) w i t h 2 mol 2 , 4 , 4 - t r i m e t h y l - l , 6 - d i i s o c y a n a t o h e x a n e and 2 mol HEMA (PX). A c t i v e i n g r e d i e n t s : O x p r e n o l o l - H C l ; (OX) MW 290; MP: 107°C; 77% s o l u b l e i n water. Diclofenac-Na (DCL); MW: 323; MP: 268°C; 2.65% s o l u b l e i n water a t 25°C; b o t h s u p p l i e d by CIBA-GEIGY. Methods : The polymer beads were s y n t h e s i z e d by s u s p e n s i o n polymer­ i z a t i o n i n c o n c e n t r a t e d aqueous NaCl s o l u t i o n u s i n g 0.1% (of mono­ mers) AIBN as i n i t i a t o r , a monomer/aqueous phase r a t i o of 2/5 and f r e s h l y p r e c i p i t a t e d M g ( 0 H ) as s u s p e n d i n g agent ( 9 ) . The beads were S o x h l e t e x t r a c t e d w i t h e t h a n o l f o r 24 hours and a f t e r d r y i n g c l a s s i f i e d i n t o mesh s i z e s . The 30 mesh (0.59-0.70 mm φ ) and 18 mesh (1.00-1.19 mm φ ) f r a c t i o n s were used f o r r e l e a s e e x p e r i m e n t s (30 mesh f o r DC1; 18 mesh f o r OX). 2

40% m e t h a n o l i c s o l u t i o n s of DC1 and OX were used to l o a d beads to e q u i l i b r i u m , f o l l o w e d by f i l t r a t i o n , r i n s e and d r y i n g v a c u o . Drug c o n c e n t r a t i o n was determined g r a v i m e t r i c a l l y and t o t a l methanol e x t r a c t i o n u s i n g an U V - s p e c t r o p h o t o m e t e r . Drug l e a s e was measured a t 37.5°C i n b u f f e r e d s a l i n e s o l u t i o n (pH = c i r c u l a t i n g through an UV-spectrophotometer c e l l .

the in by re­ 7)

F o l l o w i n g the p r o c e s s d e s c r i b e d i n r e f e r e n c e s 5,6 and 7 ex­ t r a c t i o n was done a t ambient temperature w i t h d i s t i l l e d water or a c e t o n e by s t i r r i n g the m o n o l i t h i c a l l y l o a d e d beads i n e x c e s s s o l ­ v e n t f o r a g i v e n time, f o l l o w e d by f i l t r a t i o n and f r e e z e - d r y i n g . O p t i c a l m i c r o s c o p y to o b s e r v e volume changes was done w i t h a Z e i s s s t e r e o m i c r o s c o p e , u s i n g a 3 mm h i g h round sample c e l l . E t h a n o l and water s w e l l i n g (% E t h , % H 0) as w e l l as d r u g 2

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

11.

MUELLER

Release of Water-Soluble Drugs from Polymer Beads

141

l o a d i n g a r e e x p r e s s e d as weight p e r c e n t o f s w o l l e n o r drug l o a d e d polymer. The polymer c o m p o s i t i o n s , t h e i r r e l e v a n t p h y s i c a l p r o p e r t i e s , t h e i r l o a d i n g s w i t h DC1 and OX t o g e t h e r w i t h t (time t o 50% r e l e a s e ) a r e shown i n T a b l e I . 5

Polymer

Q

Compositions

In s e p a r a t e experiments we had determined t h a t m o d i f i c a t i o n o f a c r y l i c h y d r o g e l c o m p o s i t i o n s based on HEMA o r DMA w i t h a l k y l a c r y l a t e s and t o a l e s s e r e x t e n t , m e t h a c r y l a t e s w i t h from f o u r t o ten c a r b o n atoms i n the e s t e r group r e s u l t s not o n l y i n lower w a t e r , but s h a r p l y i n c r e a s e d e t h a n o l s w e l l i n g f o r a g i v e n c r o s s l i n k d e n s i t y and h y d r o p h o b i c comonomer c o n t e n t ( 1 0 ) . The maximum degree o f s w e l l i n g i s u s u a l l y 5 t o 10% h i g h e r than e t h a n o l s w e l l i n g and o c c u r s i n e t h a n o l - w a t e r m i x t u r e s w i t h ^ 10% w a t e r , c o r r e s p o n d i n g t o a s o l u b i l i t y parameter o n l y s l i g h t l y h i g h e r than t h a t o f e t h a n o l . As shown i n T a b l e I , the comonomer EH t e n t o f 21% and 10% HEM i n g the OH-groups from water i n t e r a c t i o n s ; i n c o n t r a s t , the water c o n t e n t o f the 10% HEMA/89% MMA copolymer No. 13 i s , as e x p e c t e d , c l o s e t o one t e n t h t h a t o f poly-HEMA ( T a b l e I , P o l . 3 ) . We chose EHA f o r i t s h i g h h y d r o p h o b i c i t y as main h y d r o p h o b i c comonomer, and MMA t o g e t h e r w i t h 1% EGDMA c r o s s l i n k e r as components to p r e v e n t a g l o m e r a t i o n d u r i n g s u s p e n s i o n p o l y m e r i z a t i o n and t o r e d u c e s u r f a c e t a c k i n e s s . T h e r e i s c o n s i d e r a b l e room f o r i m p r o v i n g e t h a n o l s w e l l i n g by r e d u c i n g c r o s s l i n k - d e n s i t y o r v a r y i n g comonomers. In T a b l e I h i g h water c o n t e n t (^ 20%) h y d r o g e l s a r e grouped i n the f i r s t s e t , P o l . 1 t o 5; a l l have h i g h g l a s s - t r a n s i t i o n tempera t u r e s ( T g ) . The low water c o n t e n t polymers a r e d i v i d e d i n t o mediumlow (7-10%, P o l . 6-8), low (^ 4%, P o l . 9) and v e r y - l o w ( 4 2-3%, P o l . 10-13) water c o n t e n t beads. The medium-low and v e r y - l o w groups a r e o r d e r e d by i n c r e a s i n g Tg, w h i c h p a r a l l e l s polymer p o l a r i t y , water c o n t e n t and, o f c o u r s e , EHA-content. Drug R e l e a s e from M o n o l i t h s R e l e a s e Rates and Volume E x p a n s i o n . The r e l e a s e o f d i c l o f e n a c - N a and o x p r e n o l o l - H C l f o l l o w s a f i r s t o r d e r p a t t e r n t y p i c a l f o r h y d r o g e l m o n o l i t h i c s p h e r e s w i t h a f a s t r e l e a s e phase up t o 70-80% c u m u l a t i v e r e l e a s e , f o l l o w e d by a phase of slow r e l e a s e , o f t e n c a l l e d ' t a i l i n g ( F i g u r e s 1 and 2 ) . The t time - a t w h i c h h a l f o f the l o a d e d drug i s r e l e a s e d - i s i n t h e s e c a s e s a good measure f o r the speed o f the i n i t i a l , o s m o t i c a l l y d r i v e n r e l e a s e phase; i t i s i n v e r s e l y p r o p o r t i o n a l t o t h e polymer's e q u i l i b r i u m water c o n t e n t ( F i g u r e 3 ) , even i f one t a k e s t h e d i f f e r e n c e s i n drug l o a d i n g s i n t o account ( T a b l e 1 ) . P h a s e - s e p a r a t e d P o l . 2 and 4 a l s o show s l o w e r r e l e a s e than p r e d i c t e d by t h e i r water c o n t e n t . Below ^ 4% water c o n t e n t the r e l e a s e becomes i n c r e a s i n g l y i n f l u e n c e d by the polymers g l a s s t r a n s i t i o n temperature; a f t e r an i n i t i a l b u r s t n e i t h e r DC1 nor OX i s r e l e a s e d from P o l . 10 beads, whose Tg i s below t h e r e l e a s e t e m p e r a t u r e , w h i l e P o l . 11 and 12, w h i c h a l s o have v e r y low water c o n t e n t but h i g h e r Tg, show a normal, o s m o t i c a l l y d r i v e n r e l e a s e phase ( F i g u r e 4). S i m i l a r t o the o b s e r v a t i o n s by Lee (11,12), the beads undergo g r e a t volume e x p a n s i o n d u r i n g the i n i t i a l r e l e a s e phase even w i t h p o o r l y s o l u b l e DC1 as a r e s u l t o f the o s m o t i c d r i v i n g f o r c e . The 1

5

Q

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

-

-

-

-

-

-

-

-

-

-

-

Polymer

Compositions:

2

114 111 115 110 77 80%) prepared by t h i s process were l e s s than 150 ym i n diameter, making them

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

16.

FONG ET AL.

Enhancing Drug Release from Polylactide Microspheres

s u i t a b l e f o r i n j e c t a b l e pharmaceutical a p p l i c a t i o n s (20 ga. n e e d l e ) . No s i g n i f i c a n t d i f f e r e n c e was observed i n the r e l e a s e p a t t e r n s o f a batch o f microspheres which was s i e v e d i n t o d i f f e r e n t s i z e f r a c t i o n s . It is b e l i e v e d t h a t the high drug l o a d i n g (50%) may have a g r e a t e r i n f l u e n c e on drug r e l e a s e than the d i f f e r e n c e s i n t h e s i z e d i s t r i b u t i o n o f these microspheres. Therefore, t h e i n c l u s i o n o f the s i z e d i s t r i b u t i o n data i n the c a p t i o n s o f t h e f i g u r e s i n t h i s paper i s f o r the purpose o f completeness r a t h e r than f o r any comparison to drug r e l e a s e . In the previous paper (1), an i n - v i t r o d i s s o l u t i o n study demonstrated t h a t the f i r s t 70% o f drug was r e l e a s e d i n a r e p r o d u c i b l e manner from four separate batches o f microspheres which were prepared under i d e n t i c a l conditions. Drug r e l e a s e ma parameters such as weight, polymer composition, i n i t i a l c o n c e n t r a t i o n of the polymer i n the organic phase o f the emulsion, amount of e m u l s i f i e r , s t i r r i n g speed, vacuum pressure, s o l v e n t evaporation time and temperature. These parameters were kept constant and only the amount o f NaOH was v a r i e d . Therefore, changes i n the i n v i t r o r e l e a s e curves should r e f l e c t only the e f f e c t o f NaOH i n v a r i o u s concentrations. Another c o n t r i b u t i o n t o drug r e l e a s e was i n d i c a t e d i n a previous paper (5) which r e p o r t e d on the h y d r o l y s i s of p o l y e s t e r s c a t a l y z e d by encapsulated amine drug such as t h i o r i d a z i n e . The microsphere batches prepared f o r t h i s i n v e s t i g a t i o n have i d e n t i c a l drug l o a d i n g s . Theref o r e , any c o n t r i b u t i o n due t o the amine drug should be equal f o r a l l the samples being compared. The e f f e c t o f NaOH on drug r e l e a s e was examined with microspheres prepared with t h i o r i d a z i n e and two biodegradable polymers. The w a l l - f o r m i n g polymers were p o l y ( D L - l a c t i d e ) and p o l y ( L - l a c t i d e ) . Sodium o l e a t e was used as the e m u l s i f i e r , with the exception o f one s e t o f experiments where the emulsions were s t a b i l i z e d with polyvinyl alcohol. Figure 1 d e p i c t s the e f f e c t o f NaOH on t h i o r i d a z i n e r e l e a s e from p o l y ( D L - l a c t i d e ) microspheres. The amount of NaOH i n d i c a t e d i n the c a p t i o n r e f e r s t o the amount added t o the aqueous phase o f the emulsion p r i o r t o the s o l v e n t evaporation step. These r e s u l t s suggest t h a t the amount o f drug r e l e a s e as a f u n c t i o n o f time i s dependent on the amount o f NaOH added t o t h e emulsion. For t h i o r i d a z i n e microspheres prepared without NaOH, 50% of t h e drug r e l e a s e occurred i n 11 days. When t h e microspheres were prepared i n the presence o f 0.045 mole NaOH/mole l a c t i c a c i d , the time f o r 50% drug r e l e a s e was somewhat shortened t o 9 days. I n c r e a s i n g t h e l e v e l o f base t o 0.14 mole NaOH/mole l a c t i c a c i d decreased s i g n i f i c a n t l y the time f o r 50% drug r e l e a s e t o 4 days.

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

217

CONTROLLED-RELEASE TECHNOLOGY

218

0

4

8

12

16

20

24

28

Days

Figure 1. E f f e c t o f NaOH on t h i o r i d a z i n e r e l e a s e from p o l y ( D L - l a c t i d e ) microspheres. Key: ( O ) no NaOH, 15-85 ym; ( A ) 0.045 mole NaOH/mole l a c t i c a c i d , 10-75 ym; (•) 0.14 mole NaOH/mole l a c t i c a c i d , 10-75 ym. Drug loading, 43%. E m u l s i f i e r , sodium o l e a t e .

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

16.

FONG ET AL.

Enhancing Drug Release from Polylactide Microspheres

The e f f e c t o f NaOH on drug r e l e a s e was a l s o observed with p o l y ( L - l a c t i d e ) microspheres, as shown i n F i g u r e 2. For the microspheres prepared without NaOH, 50% o f the drug was r e l e a s e d i n 2 days. When the microspheres were prepared with 0.14 mole NaOH/mole l a c t i c a c i d , 50% o f t h e drug was r e l e a s e d i n 2 hours. The i n i t i a l drug r e l e a s e was so enhanced by t h e NaOH t h a t i t was comparable t o the f r e e drug, which was 60% d i s s o l v e d i n 2 hours. One may question whether t h i s high i n i t i a l r e l e a s e i s due t o the e f f e c t o f NaOH o r t o nonencapsulated drug. I f i t was due t o the l a t t e r case, i t would mean t h a t about h a l f o f the drug p a r t i c l e s were not encapsulated. However, f r e e drug p a r t i c l e s were not detected when the microsphere samples were examined with the microscope. In order t o determine whether the e f f e c t o f NaOH was s p e c i f i c t o th e m u l s i f i e r , microsphere v i n y l a l c o h o l t o s t a b i l i z e the emulsion. F i g u r e 3 i n d i c a t e s t h a t there was only a moderate i n c r e a s e i n drug r e l e a s e by the a d d i t i o n o f NaOH t o t h e emulsion. The time f o r 50% r e l e a s e was 8 days f o r the 50% t h i o r i d a z i n e - l o a d e d microspheres prepared without NaOH. I t was decreased t o 5 days f o r those prepared with NaOH. The e f f e c t o f NaOH was more pronounced when the drug l o a d i n g was increased t o 58%, as shown i n F i g u r e 4. The time f o r 50% r e l e a s e was s i g n i f i c a n t l y reduced from 7 days (without NaOH) t o 1 day (with NaOH). To r e c a p i t u l a t e , t h i o r i d a z i n e r e l e a s e from microspheres was enhanced when NaOH was added t o the emulsion p r i o r t o the s o l v e n t evaporation step. T h i s was observed f o r both p o l y ( D L - l a c t i d e ) and p o l y ( L - l a c t i d e ) and a l s o f o r two e m u l s i f i e r systems, sodium o l e a t e and polyvinyl alcohol. I t should be p o i n t e d out t h a t NaOH i s added only t o the aqueous phase o f t h e emulsion. I t i s not incorporated i n t o the microspheres by t h i s process. Two experiments were conducted i n an attempt t o understand why drug r e l e a s e was enhanced by t h e a d d i t i o n of NaOH. The f i r s t experiment i n v o l v e d the p r e p a r a t i o n of microspheres u s i n g polymer which was p r e t r e a t e d with NaOH. The second experiment i s concerned with p o s t t r e a t i n g t h e microspheres with NaOH. These p o l y l a c t i d e s a r e known t o degrade by h y d r o l y s i s (4). Therefore, the most obvious e x p l a n a t i o n i s t h a t the molecular weight o f the polymer i s decreased by t h e NaOH. I t has been r e p o r t e d (6) t h a t drug r e l e a s e i s increased when the polymer molecular weight i s lowered. T h i s would then account f o r the enhanced drug r e l e a s e observed. The f i r s t experiment c o n s i s t e d of two steps. In the f i r s t step the polymer i s p r e t r e a t e d with NaOH. T h i s i s done by p r e p a r i n g polymer microspheres (without drug) i n the presence o f 0.14 mole NaOH/mole l a c t i c a c i d . The l e v e l of NaOH i s the same as t h a t used f o r

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Figure 2. E f f e c t o f NaOH on t h i o r i d a z i n e from poly ( L - l a c t i d e ) microspheres. Key: NaOH, 15-100 ym; ( • ) 0.14 mole NaOH/mole a c i d , 10-90 ym; ( À ) nonencapsulated drug. l o a d i n g , 58%. E m u l s i f i e r , sodium o l e a t e .

release ( o ) no lactic Drug

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F i g u r e 3. E f f e c t of NaOH on t h i o r i d a z i n e r e l e a s e from p o l y (DL-lactide) microspheres. Key: (o) no NaOH, 15-85 ym; (#) 0.14 mole NaOH/mole l a c t i c a c i d , 10-85 ym. Drug loading, 50%. Emulsifier, polyvinyl alcohol.

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F i g u r e 4. E f f e c t o f NaOH on t h i o r i d a z i n e r e l e a s e from p o l y (DL-lactide) microspheres. Key: ( o ) no NaOH, 20-85 ym; ( • ) 0.14 mole NaOH/mole l a c t i c a c i d , 15-75 ym. Drug loading, 58%. E m u l s i f i e r , polyvinyl alcohol.

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studying t h e e f f e c t o f NaOH i n t h i s i n v e s t i g a t i o n . The r a t i o n a l e f o r t h i s experiment i s t h a t any e f f e c t o f NaOH, e.g. lowering o f the molecular weight, would be imparted i n t o these polymer microspheres i n the same manner as f o r the drug-loaded microspheres. The polymer microspheres p r e t r e a t e d with NaOH i n t h i s manner were d i s s o l v e d and used i n a second step. Drug-loaded microspheres were then prepared with the NaOH-pretreated polymer, but without adding NaOH i n t h i s second step. To r e i t e r a t e t h i s p o i n t , NaOH was used only t o p r e t r e a t the polymer i n the f i r s t step. I t was not added t o the aqueous phase i n the second step f o r p r e p a r i n g t h e drugloaded microspheres. The r e l e a s e p r o f i l e o f a batch o f microspheres prepared with NaOH-pretreated polymer i s shown i n F i g u r e 5. For comparison, r e l e a s e curves f o r microspheres prepared i n the usua also included i n t h i a c t i o n between the polymer and NaOH, one would expect t h a t the r e l e a s e c h a r a c t e r i s t i c s o f t h i s batch o f microspheres would be s i m i l a r t o those prepared i n the u s u a l manner with NaOH, as represented by t h e d o t t e d l i n e . Instead, the r e l e a s e p a t t e r n o f the microspheres prepared with the NaOH-pretreated polymer, represented by t h e s o l i d c i r c l e s , almost c o i n c i d e s with the s o l i d l i n e , which corresponds t o microspheres prepared without NaOH. T h i s i n d i c a t e s t h a t drug r e l e a s e was not enhanced by p r e t r e a t i n g the polymer with NaOH p r i o r t o p r e p a r i n g the drug-loaded microspheres. In the second experiment, t h e drug-loaded microspheres were p o s t t r e a t e d with NaOH. The purpose o f t h i s experiment was t o determine whether t h e s u r f a c e o f the microspheres can be a l t e r e d by NaOH. Any such m o d i f i c a t i o n o f the polymeric surface would i n c r e a s e i t s permeability. T h i s would then account f o r t h e enhanced drug release effect. For t h i s experiment, a sample o f drugloaded microspheres was prepared without NaOH i n t h e usual manner. I t was then p o s t t r e a t e d with 0.14 mole NaOH/mole l a c t i c a c i d . The c o n d i t i o n s f o r t h e p o s t treatment were the same as f o r t h e s o l v e n t evaporation step. F i g u r e 6 compares the r e l e a s e p r o f i l e s o f a batch of microspheres before and a f t e r NaOH posttreatment. The r e l e a s e data f o r the p o s t t r e a t e d microspheres f o l l o w c l o s e l y the s o l i d l i n e which represents t h e o r i g i n a l microspheres prepared without NaOH. The data f o r the p o s t t r e a t e d microspheres d i f f e r s i g n i f i c a n t l y from those f o r microspheres prepared i n the u s u a l manner with NaOH. I f t h e r e was any i n t e r a c t i o n between NaOH and the drugloaded microspheres, i t was not s u f f i c i e n t t o cause any measurable i n c r e a s e i n drug r e l e a s e . T h i s i n d i c a t e s t h a t the e f f e c t o f NaOH occurred p r i o r t o completion o f s o l v e n t evaporation. I t was not caused by any subsequent i n t e r a c t i o n between the drug-loaded microspheres and NaOH.

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F i g u r e 5. E f f e c t of NaOH pretreatment on t h i o r i d a z i n e r e l e a s e from p o l y ( D L - l a c t i d e ) microspheres. Key: ( O ) prepared i n usual manner with no NaOH, 15-85 ym; ( # ) polymer p r e t r e a t e d with 0.14 mole NaOH/mole l a c t i c a c i d , 15-55 ym; ( • ) prepared i n u s u a l manner with 0.14 mole NaOH/mole l a c t i c a c i d , 10-75 ym. Drug l o a d i n g , 46%. E m u l s i f i e r , sodium o l e a t e .

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F i g u r e 6. E f f e c t of NaOH posttreatment on t h i o r i d a z i n e r e l e a s e from p o l y ( D L - l a c t i d e ) microspheres. Key: (o) before NaOH posttreatment, 15-90 ym; ( # ) p o s t t r e a t e d with 0.14 mole NaOH/mole l a c t i c a c i d , 15-90 ym; ( • ) prepared i n u s u a l manner with 0.14 mole NaOH/mole l a c t i c a c i d , 10-75 ym. Drug l o a d i n g , 43%. E m u l s i f i e r , sodium o l e a t e .

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The r e s u l t s o f these two experiments i n d i c a t e t h a t i f t h e r e was any a l t e r a t i o n o f the polymer by NaOH, i t was not t r a n s l a t e d i n t o an i n c r e a s e i n drug r e l e a s e . The data a l s o suggest t h a t the e f f e c t o f NaOH occurred d u r i n g the s o l v e n t evaporation step, r a t h e r than before or a f t e r t h i s step. Two p o i n t s should be mentioned. One i s t h a t the two c o n t r o l s without NaOH treatment i n F i g u r e s 5 and 6 were prepared under d i f f e r e n t process c o n d i t i o n s . Therefore, the r e l e a s e p r o f i l e s f o r these two d i f f e r e n t c o n t r o l s should not be compared t o each other. The second p o i n t i s t h a t t h e S-shapes o f many o f the r e l e a s e curves i n t h i s study i n d i c a t e a b i p h a s i c p a t t e r n o f drug r e l e a s e . T h i s was a l s o observed by Wakiyama e t a l ( 7 - 9 ) , who used scanning e l e c t r o n microscopy t o demonstrate t h a t the second r i s e i n the r e l e a s e r a t e was du p o l y l a c t i d e microspheres A p l a u s i b l e e x p l a n a t i o n f o r the e f f e c t o f NaOH i s provided by examination o f scanning e l e c t r o n micrographs of t h e drug-loaded microspheres. The microspheres i n F i g u r e 7 were f r a c t u r e d t o expose t h e i r i n t e r n a l morphology, r e v e a l i n g a porous s t r u c t u r e . The m a g n i f i c a t i o n o f these micrographs i s about 2 0 0 0 X . The pores i n F i g u r e s 7 C and 7D (higher l e v e l s o f NaOH) are s m a l l e r and more numerous than those i n F i g u r e s 7 A (no NaOH) and 7B (low NaOH l e v e l ) . Therefore, the i n t e r n a l s u r f a c e area i n these microspheres prepared with base i s g r e a t e r than those prepared with no NaOH. The i n c r e a s e d i n t e r n a l s u r f a c e area may account f o r t h e f a s t e r r e l e a s e of drug from microspheres prepared with NaOH. T h i s phenomenon may be r e l a t e d t o the i n c r e a s e d p e r m e a b i l i t y observed i n p o l y l a c t i d e f i l m which was found t o have a h i g h l y porous s t r u c t u r e by scanning e l e c t r o n microscopy (10).

I t i s i n t e r e s t i n g t o note t h a t d u r i n g biodégradat i o n o f s i m i l a r microspheres, i t was the i n t e r n a l matrix which e x h i b i t e d extensive d e t e r i o r a t i o n w e l l before t h e e x t e r n a l s u r f a c e was a f f e c t e d . T h i s was observed with biodegradable, p e p t i d e - c o n t a i n i n g microspheres which were i n j e c t e d i n t r a m u s c u l a r l y i n t o r a t s ( 1 1 , 1 2 ) . The p o r o s i t y o f the microspheres i s apparently r e l a t e d t o the formation o f a m u l t i p l e emulsion when sodium o l e a t e was used as the e m u l s i f i e r . M i c r o s c o p i c examination o f the emulsion p r i o r t o s o l v e n t evaporation i n d i c a t e d t h a t the o i l d r o p l e t s prepared i n the presence of NaOH were comprised o f numerous but very small dropl e t s w i t h i n the l a r g e r d r o p l e t s which serve as p r e c u r sors f o r the f i n a l microspheres. In c o n t r a s t , o i l d r o p l e t s prepared i n the absence o f NaOH contained fewer but l a r g e r i n t e r n a l d r o p l e t s . The pores w i t h i n the f i n a l microspheres appeared t o be generated by evaporat i o n o f the s o l v e n t from these i n t e r n a l d r o p l e t s . The formation o f the f i n e r pore s t r u c t u r e of the

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microspheres prepared i n the presence o f NaOH seems t o i n v o l v e more than the e f f e c t o f e l e c t r o l y t e on the e m u l s i f i e r . When the microspheres were prepared i n the presence o f e q u i v a l e n t amounts o f NaCl, the pore s t r u c t u r e was s i m i l a r t o microspheres prepared without NaOH. The increased pore s t r u c t u r e o f the microspheres due t o NaOH may be explained by c o n s i d e r i n g t h e following equilibrium: C H COONa 17

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The formation o f o l e i c a c i d due t o h y d r o l y s i s o f the o l e a t e i o n would r e s u l t i n a lowering o f t h e o l e a t e i o n c o n c e n t r a t i o n and a r e d u c t i o n i n i t s e m u l s i f y i n g effectiveness. O would s h i f t the e q u i l i b r i u higher l e v e l o f sodium o l e a t e i n t h e system. The r e s u l t i n g h i g h e r e f f e c t i v e n e s s o f t h e e m u l s i f i e r would s t a b i l i z e a g r e a t e r number o f t h e s m a l l e r i n t e r n a l dropl e t s from c o a l e s c i n g i n t o l a r g e r d r o p l e t s . Evaporation of s o l v e n t from these i n t e r n a l d r o p l e t s would account f o r the h i g h e r p o r o s i t y (hence h i g h e r drug r e l e a s e ) o f microspheres prepared i n the presence o f NaOH. Although there may be other c o n t r i b u t i n g mechanisms of drug r e l e a s e , t h e scanning e l e c t r o n microscopy study does i n d i c a t e t h a t the h i g h l y porous s t r u c t u r e may have a major i n f l u e n c e on drug r e l e a s e from microspheres prepared i n t h i s study. Conclusions Drug r e l e a s e o f t h i o r i d a z i n e was enhanced when t h e microspheres were prepared i n the presence o f base. The e f f e c t was dependent on the amount o f NaOH added t o the aqueous phase o f the emulsion p r i o r t o t h e s o l v e n t evaporation step. The p o l y l a c t i d e s employed t o form t h e matrices o f these microspheres a r e known t o be s u s c e p t i b l e t o a l k a l i n e h y d r o l y s i s . However, any a l t e r a t i o n o f the polymer by NaOH was not t r a n s l a t e d i n t o any i n c r e a s e i n drug r e l e a s e a t the l e v e l s o f base used i n t h i s i n v e s t i gation. Scanning e l e c t r o n micrographs o f f r a c t u r e d microspheres r e v e a l t h a t the pores i n the polymeric matrix became s m a l l e r and more numerous when t h e l e v e l o f NaOH was increased. The increased s u r f a c e area generated by these pores may account f o r t h e enhanced drug r e l e a s e observed with microspheres prepared i n t h e presence o f base.

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F i g u r e 7. Scanning e l e c t r o n m i c r o g r a p h s of t h i o r i d a z i n e m i c r o s p h e r e s p r e p a r e d w i t h mole NaOH/mole l a c t i c a c i d : (A) no NaOH and (B) 0.045. Drug l o a d i n g , 43%. E m u l s i f i e r , sodium o l e a t e . C o n t i n u e d on next page.

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F i g u r e 7. C o n t i n u e d . Scanning e l e c t r o n m i c r o g r a p h s o f t h i o r i d a z i n e m i c r o s p h e r e s p r e p a r e d w i t h mole NaOH/mole l a c t i c a c i d : (C) 0.09 and (D) 0.14. Drug l o a d i n g , 43%. E m u l s i f i e r , sodium o l e a t e .

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Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Fong, J . W.; Nazareno, J . P.; Pearson, J . E.; Maulding, H.V. J . Controlled Release 1986, 3, 119-130. Fong, J . W. U.S. Patent 4 384 975, 1983. Fong, J . W. U.S. Patent 4 479 911, 1984. Pitt, C. G.; Schindler, A. In "Controlled Drug Delivery, Volume I, Basic Concepts"; Bruck, S. D., Ed.; CRC Press: Boca Raton, 1983; pp. 53-80. Maulding, H. V . ; Tice, T. R.; Cowsar, D. R.; Fong, J . W.; Pearson, J.E.; Nazareno, J . P. J . Controlled Release 1986, 3, 103-117. Suzuki, R.; Price, J . C. J . Pharm. Sci. 1985, 74, 21-24. Wakiyama, Ν., Juni, Κ., and Nakano, M. Chem. Pharm. Bull. 1981, 29 Wakiyama, Ν., Bull. 1982, 30, 2621-2628. Wakiyama, Ν., Juni, Κ., and Nakano, M. Chem. Pharm. Bull. 1982, 30, 3719-3727. Pitt, C. G.; Jeffcoat, A. R.; Zweidinger, R. A . ; Schindler, A. J . Biomed. Mater. Res. 1979, 13, 497-507. Visscher, G. E.; Robison, R. L.; Maulding, H. V . ; Fong, J . W.; Pearson, J . E.; Argentieri, G. J . J . Biomed. Mater. Res. 1985, 19, 349-365. Visscher, G. E.; Robison, R. L.; Maulding, H. V . ; Fong, J . W.; Pearson, J . E.; Argentieri, G. J . J . Biomed. Mater. Res. 1986, 20, 667-676.

RECEIVED October 10,

1986

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Chapter 17

Effects of Ethanol on the Transport of β-Estradiol in Hairless Mouse Skin Comparison of Experimental Data with a New Theoretical Model 1

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University of Utah, Salt Lake City, UT 84112 Basic Pharmaceutics Research, Ciba-Geigy Corporation, Ardsley, NY 10502

2

This paper describe th strikin effect f ethanol the transport of Three sets of two-chambe experiment were conducted: 1) ethanol/saline in the donor chamber and saline in the receiver chamber, 2) saline in the donor and ethanol/saline in the receiver chamber, and 3) with ethanol/saline in both chambers. The results were shown to deviate enormously from the classical lipid barrier model. A new model, based on diffusion across a binary solvent mixture, was used to analyze the data. A good agreement was observed between experimental data and theoretical results. I t had p r e v i o u s l y been t h o u g h t (1,2) t h a t most o r g a n i c s o l v e n t s had o n l y m o d e r a t e e f f e c t s upon t h e i n t r i n s i c p e r m e a b i l i t y o f t h e s t r a t u m corneum. T h e r e f o r e i t had been assumed t h a t t h e t h e r m o d y n a m i c a c t i v i ­ t y o f t h e permeant i n t h e donor phase and t h e s t r a t u m corneum/donor p h a s e p a r t i t i o n c o e f f i c i e n t s h o u l d be t h e p r i m a r y d e t e r m i n a n t s f o r t h e t r a n s p o r t o f m o s t l o w t o medium m o l e c u l a r w e i g h t s o l u t e s . Such t h i n k i n g i sthe basis f o r p r e d i c t i v e r e l a t i o n s h i p s which c o r r e l a t e maximum f l u x e s t o t h e w a t e r s o l u b i l i t i e s o f t h e p e r m e a n t a n d t h e l i p i d p a r t i t i o n i n g t e n d e n c i e s o f t h e permeant ( 3 ) . Recent l i t e r a t u r e r e s u l t s i n d i c a t e t h a t s o l v e n t s s u c h a s p r o p y l e n e g l y c o l may d i r e c t l y a f f e c t t h e i n t r i n s i c b a r r i e r p r o p e r t i e s o f t h e s t r a t u m corneum ( 4 - 7 ) . F o r e x a m p l e , J o n e s a n d R a y k a r h a v e shown ( 8 ) t h a t 1 ) t h e r e i s s i g n i f i c a n t s o l v e n t u p t a k e by s t r a t u m corneum from p r o p y l e n e g l y c o l w a t e r s o l u t i o n s , 2 ) t h e r e may be a n a s s o c i a t e d i n c r e a s e i n p e r m e a n t u p t a k e b y t h e s t r a t u m c o r n e u m i n s u c h c a s e s , a n d 3 ) t h i s may be a c c o m p a n i e d by a s u b s t a n t i a l i n c r e a s e i n t h e p e r m e a n t f l u x . They h a v e c o i n e d a term, "sponge e f f e c t " , t o d e s c r i b e t h e s e r e s u l t s . The p u r p o s e o f t h i s r e p o r t i s t o p r e s e n t r e s u l t s o n ( a ) t h e e f f e c t o f e t h a n o l o n t h e t r a n s p o r t o f β-estradiol a c r o s s h a i r l e s s mouse s k i n a n d ( b ) t h e e f f e c t u p o n t h e e f f e c t i v e p e r m e a b i l i t y c o e f f i c i e n t as solvent compositions a r e independently varied i n the donor and r e c e i v e r chambers. A l s o , since there i sevidence f o r pore f o r m a t i o n , a t l e a s t a t t h e h i g h e s t e t h a n o l l e v e l s , a n o v e l pore model 0097-6156/87/0348-0232$06.00/0

© 1987 American Chemical Society

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

17.

for

HIGUCHI ET

AL.

Transport of β-Estradiol

in Hairless Mouse Skin

233

3 - e s t r a d i o l t r a n s p o r t i s p r e s e n t e d and compared w i t h t h e

experimental

data.

Experimental Materials. [ 3 H ] - 3 - e s t r a d i o l (New E n g l a n d N u c l e a r , B o s t o n , MA) was u s e d a f t e r t h e p u r i t y was c h e c k e d by T L C . T h e l i q u i d scintillation c o u n t e r c o c k t a i l ( A q u a s o l , New E n g l a n d N u c l e a r , B o s t o n , MA) was s t o r e d i n t h e d a r k a n d 10 m l w a s t r a n s f e r r e d by a p i p e t i n t o e a c h v i a l f o r s c i n t i l l a t i o n c o u n t i n g . F u l l - t h i c k n e s s s k i n from male h a i r l e s s m i c e ( S K H 1 , T e m p l e U n i v e r s i t y , P h i l a d e l p h i a , P A ) , 8-12 w e e k s o l d w e r e u s e d . N o r m a l s a l i n e ( S o d i u m C h l o r i d e , USP, McGaw, I r v i n e , C A ) a n d e t h a n o l ( D e h y d r a t e d A l c o h o l , USP P i n c t i l l i a n s , US I n d u s t r i a l C h e m i c a l Co., T u s c o l a , I L ) were used t o p r e p a r e s o l v e n t m i x t u r e s f o r a l l the experiments. Diffusion Cells. T h e tw by a No. 18 s p r i n g c l a m b e t w e e n . T h e v o l u m e o f e a c h h a l f c e l l w a s 2.0 cm , An 8 mm s t i r r e r made o f s t a i n l e s s s t e e l a n d e q u i p p e d w i t h a s m a l l t e f l o n p r o p e l l e r was d r i v e n by a 150 rpm c o n s t a n t s p e e d m o t o r ( H u r s t , P r i n c e t o n , I N ) was u t i l i z e d f o r s t i r r i n g . T h e a s s e m b l e d c e l l was t h e n i m m e r s e d i n a 37°C h e a t e d w a t e r b a t h ( H a a k e , K a r l s r u h e , W. G e r m a n y ) , s o t h a t t h e s t i r r i n g and s a m p l i n g p o r t s were t h e o n l y components above t h e water s u r f a c e . T h e d i f f u s i o n c e l l w a s k e p t f o r 10 m i n u t e s i n t h e w a t e r b a t h to a l l o w t e m p e r a t u r e e q u i l i b r i u m p r i o r t o any e x p e r i m e n t . Then e t h a n o l / s a l i n e m i x t u r e s p r e h e a t e d t o 37°C w e r e p i p e t t e d i n t o t h e c e l l to s t a r t an experiment. Procedure For Skin Preparations. A m a l e h a i r l e s s m o u s e , 8-12 w e e k s o f a g e , was s a c r i f i c e d by c e r v i c a l c l e a v a g e o f t h e s p i n a l c o r d . A s q u a r e s e c t i o n o f t h e a b d o m i n a l s k i n , 3 cm i n e a c h d i m e n s i o n , was e x c i s e d from the animal w i t h a s u r g i c a l s c i s s o r . After the incision was made, t h e s k i n was l i f t e d a n d t h e a d h e r i n g f a t a n d o t h e r v i s c e r a l d e b r i s were removed c a r e f u l l y from t h e under s u r f a c e . A f t e r t h e s k i n was m o u n t e d b e t w e e n h a l f c e l l s a n d c l a m p e d , e x c e s s s k i n was t r i m m e d . Permeability Experiments. Three s e t s o f i n - v i t r o d i f f u s i o n e x p e r i ­ ments were c o n d u c t e d : 1) i d e n t i c a l e t h a n o l / s a l i n e c o m p o s i t i o n i n b o t h d i f f u s i o n chambers, 2) e t h a n o l / s a l i n e i n t h e donor chamber and s a l i n e i n t h e r e c e i v e r , and 3) s a l i n e i n t h e donor and e t h a n o l / s a l i n e i n t h e r e c e i v e r chamber. T r i t i u m l a b e l e d 3 - e s t r a d i o l was added t o t h e donor s i d e and samples were t a k e n from b o t h compartments a t p r e d e t e r ­ mined t i m e s and r e a d i n a s c i n t i l l a t i o n c o u n t e r (Beckman I n s t . , San Ramon, C A ) . E f f e c t i v e p e r m e a b i l i t y c o e f f i c i e n t s w e r e t h e n c a l c u l a t e d a f t e r s t e a d y s t a t e was r e a c h e d u s i n g t h e f o l l o w i n g e q u a t i o n : ρ

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α =

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i s combined w i t h E q u a t i o n s 2 and 3. J i s the f l u x , A i s the area, and D i s t h e d i f f u s i v i t y . This r e s u l t s i n a release rate R at r = a of

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CONTROLLED-RELEASE TECHNOLOGY

346

h e p a r i n s o l u t i o n (260 IU/ml) and p l a c e d i n t h e i n f u s i o n d e v i c e as d e s c r i b e d above. A f t e r 3 days d u r i n g which t h e a n i m a l became accustomed t o t h e h a r n e s s and t h e wounds were h e a l e d , t h e p i n c h e d s e c t i o n on t h e c a t h e t e r was r e l e a s e d t o a l l o w i n f u s i o n t o begin. A t d a i l y i n t e r v a l s , t h e a n i m a l was b l e d by t h e t a i l and 50 μ ΐ o f b l o o d was c o l l e c t e d i n t o a l o n g stemmed P a s t e u r pipet. The a n t i - c o a g u l a t i o n was d e t e r m i n e d as t h e d e l a y i n c l o t t i n g t i m e by t h e Lee-White t e s t ( 5 ) o n l y , because o f t h e s m a l l amount o f b l o o d t h a t c o u l d be c o l l e c t e d . Results The Flow M o d e r a t o r s . The a l i g n e d n y l o n f i b r e f l o w moderator can p r o v i d e a f l o w r a t e o f about 60 mL p e r hour a t a d r i v i n g p r e s s u r e o f 48 kPa. When two such moderators a r e c o n n e c t e d i n s e r i e s , t h e flow r a t e about 11 mL/hr c a n be kPa ( T a b l e I ) d r i v i n g p r e s s u r e . This i s the pressure g e n e r a t e d by an e q u a l volume a d m i x t u r e o f F r e o n 11 and F r e o n 114 which c a n be u s e d a s a p r o p e l l a n t f o r t h e i n f u s i o n d e v i c e . T h e r e f o r e , by removing o r b y - p a s s i n g t h e s e r i a l l y c o n n e c t e d m o d e r a t o r s , f l o w r a t e s may be i n c r e a s e d from 11 mL/hr t o 60 mL/hr i n one s t e p . L i k e w i s e , by r e c o n n e c t i n g o r c l o s i n g t h e b y - p a s s , i t i s p o s s i b l e t o r e d u c e t h e f l o w r a t e from 60 mL/hr t o 22 mL/hr o r 11 mL/hr.

Table

I.

Flow Rate o f A l i g n e d F i b r e M o d e r a t o r s

No. o f M o d e r a t o r s Connected i n S e r i e s

ϊ

Time (min)

15 30 45

S a l i n e Volume C o l l e c t e d (mL)

Flow Rate (mL/hr)

Ï477Ô 30.40 44.70

58.80 60.80 59.60 Average: 59.73

2

15 30 45

5.80 11.20 16.20

23.20 22.40 21.60 Average: 22.40

3

15 30 45

3.20 6.70 10.30

12.80 13.40 13.70 Average

4

15 30 45

2.70 4.80 7.60

13.30

10.80 9.60 10.10 Average: 10.20

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

25. WANG ET AL.

Disposable Controlled-Release Device for Drug Infusion 347

G l a s s h o l l o w f i b r e s o f i n t e r n a l d i a m e t e r v a r y i n g from 5 t o 60 m i c r o n s were p r e p a r e d t o e v a l u a t e t h e e f f e c t o f t h e i r i n t e r n a l d i a m e t e r on f l o w r a t e . However, no c l e a r c o r r e l a t i o n was o b s e r v e d , and t h e f l o w r a t e c o u l d n o t be p r e d i c t e d from the f i b r e i n t e r n a l diameter. Close examination o f the g l a s s h o l l o w f i b r e sideways under t h e m i c r o s c o p e showed t h a t t h e drawing o f t h e g l a s s c a p i l l a r y by hand produced w i d e l y d i f f e r e n t degrees o f t a p e r i n g a l o n g t h e f i b r e stem. The i n t e r n a l d i a m e t e r measured as d e s c r i b e d was j u s t t h e a n n u l a r s i z e o f the hollow f i b r e t i p . T h e r e f o r e each g l a s s hollow f i b r e f l o w moderator must be c a l i b r a t e d t o o b t a i n t h e f l o w r a t e f o r micro-volume d e l i v e r y . To a v o i d f l o w decay, t h e i n c l u s i o n o f a 0.22-micron p o r o s i t y f i l t e r u n i t ( d i a m e t e r : 2.5 cm) between t h e e x i t p o r t o f t h e drug s o l u t i o n bag and t h e f l o w moderator may h e l p t o e l i m i n a t e any i n v i s i b l e s u s p e n s i o n i n t h e s o l u t i o n which c a n c l o g the f i n e channel I n f u s i o n D e v i c e Flow Rate. The example g i v e n i n T a b l e I I shows t h a t t h e f l o w r a t e w i t h 4 a l i g n e d n y l o n f i b r e f l o w moderators i n s e r i e s i s e s s e n t i a l l y c o n s t a n t up t o 200 mL o f

Table I I .

Time(hr) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

D e l i v e r y R a t e from a 250-mL C a p a c i t y S o l u t i o n C o n t a i n e r by t h e Compression D e v i c e Flow Rate(mL/hr)

T o t a l Volume

Delivered(mL)

11.30 22.80 33.80 45.00 56.90 68.10 79.10 90.10 101.30 112.30 123.10 134.20 145.70 156.80 167.60 178.60 189.50 200.30 209.20 215.50 219.60 220.80 221.10 221.10 221.10

11.30 11.50 11.00 11.20 10.90 11.20 11.00 11.00 11.20 11.00 10.80 11.10 11.50 11.10 10.80 11.00 10.90 10.80 8.90 6.30 4.10 1.2 0.3 0.0 0.0

American Chemical Society Library 1155 16th St., N.W.

In Controlled-Release Technology; Lee, P., et al.; Washington, 20036 ACS Symposium Series; American ChemicalD.C. Society: Washington, DC, 1987.

CONTROLLED-RELEASE TECHNOLOGY

348

t h e 250 mL s o l u t i o n f i l l i n g t h e f l e x i b l e V i a f l e x container, i . e . , a v o i d i n g e f f i c i e n c y o f 80% a t t h e c o n s t a n t f l o w r a t e e x p e c t e d w i t h o u t t h e need f o r any i n t e r m i t t a n t a d j u s t m e n t . The t o t a l volume d e l i v e r e d u n t i l f l o w c e a s e s i s 89% o f t h e 250 mL p u t i n t h e f l e x i b l e s o l u t i o n c o n t a i n e r . Also the flow r a t e of the i n f u s i o n device i s not a f f e c t e d by o v e r f i l l i n g o r u n d e r f i l l i n g t h e bags w i t h s o l u t i o n s , because t h e o v e r s i z e d p o l y e t h y l e n e s a c s c a n a d j u s t t o t h e v a r i o u s s i z e s o f t h e drug c o n t a i n e r . Because t h e p r e s s u r e o f t h e gas remains e s s e n t i a l l y c o n s t a n t even when t h e r e i s s l i g h t f l u c t u a t i o n i n ambient t e m p e r a t u r e , t h e c o m p r e s s i o n e x e r t e d on t h e f l e x i b l e s o l u t i o n c o n t a i n e r p o s i t i o n e d in-between t h e two i n f l a t e d s a c s changes l i t t l e as w e l l . Consequently, a c o n s t a n t f l o w r a t e o f t h e s o l u t i o n d i s c h a r g i n g from t h e container i s realized. However, i f one o f t h e i n f l a t a b l e s a c s i s o m i t t e d , t h e f l o w r a t e o f s o l u t i o n from t h e f l e x i b l e c o n t a i n e r w i l l decay p r o g r e s s i v e l i n s i d e the remaining i n f l a t a b l III).

Table

Time(hr) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

III.

Decay o f Volume D e l i v e r e d from a 150-ml Capacity S o l u t i o n Container

Flow Rate(mL/hr) 21.70 18.10 13.70 10.30 8.90 7.20 5.00 4.60 2.90 1.20 0.30 0.00 0.20 0.00 0.00 0.00

T o t a l Volume D e l i v e r e d ( m L ) 21.70 39.80 53.50 63.80 72.20 79.90 84.90 89.50 92.40 93.60 93.90 93.90 94.10 94.10 94.10 94.10

In V i v o T e s t o f t h e I n f u s i o n D e v i c e . Before the i n f u s i o n d e v i c e was u s e d t o d e l i v e r micro-volume o f a h e p a r i n s o l u t i o n , t h e amount o f t h e a n t i c o a g u l a n t r e q u i r e d t o d e l a y t h e normal c l o t t i n g time from 1.02 min t o > 15 min was d e t e r m i n e d . An i n t r a p e r i t o n e a l s i l i c o n e c a t h e t e r was i n s e r t e d by way o f a t r o c a r n e e d l e i n t o an a n e s t h e t i z e d W i s t a r r a t , and t h e e x t e r n a l c a t h e t e r end was c o n n e c t e d t o t h e f l o w r a t e t e s t i n g assembly. W i t h a g l a s s h o l l o w f i b r e f l o w moderator h a v i n g a f l o w r a t e o f 50 u l i t r e / h r a t 48 kPa d r i v i n g p r e s s u r e , i t was found t o r e q u i r e about 25 IU/kg/hr t o o b t a i n a Lee-White

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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Disposable Controlled-Release Device for Drug Infusion 349

c l o t t i n g time o f about 20 min f o r venous b l o o d drawn i n t o a l o n g stem P a s t e u r p i p e t by t a i l c l i p p i n g . The i n f u s i o n d e v i c e was then t e s t e d on a group o f 3 W i s t a r r a t s u s i n g t h e same g l a s s h o l l o w f i b r e f l o w moderator and h e p a r i n s o l u t i o n . The Lee-White c l o t t i n g time was d e t e r m i n e d d a i l y by o b s e r v i n g t h e t i m e t a k e n when a c l o t c o u l d be p u l l e d from t h e lumen o f t h e c a p i l l a r y stem s e c t i o n o f a P a s t e u r p i p e t which was snapped i n 0.5 cm segments e v e r y 5 min. The i n c r e a s e i n c l o t t i n g t i m e was m a i n t a i n e d as a r e s u l t o f c o n t r o l l e d r e l e a s e o f h e p a r i n s o l u t i o n by t h e e x t e r n a l i n f u s i o n device, while the e f f e c t of a bolus i n j e c t i o n of the same d a i l y dose o f 300 IU i n t r a p e r i t o n e a l l y a t once o r a s i n g l e i n j e c t i o n o f 300 IU s u b c u t a n e o u l s y were d i s t i n c t l y different. As w e l l , t h e d e l i v e r y r a t e , o b s e r v e d d a i l y by i n t e r r u p t i n g t h e f l o w t o l e t i n an a i r b u b b l e t o a i d v i s u a l t r a c k i n g , was 5 0 + 6 μΐ/hr over t h e 6-day p e r i o d . D u r i n g t h i s t i m e , about 8 o f t h c o n t a i n e r was d e l i v e r e d a t t h i s t i m e because i n f e c t i o n u s u a l l y began t o d e v e l o p a t t h e catheter e x i t s i t e . Discussion I n drug d e l i v e r y , i n f u s i o n pumps have a c h i e v e d r e m a r k a b l e success i n recent years. As o f 1983, t h e r e were 18 d i f f e r e n t models o f e x t e r n a l pumps a v a i l a b l e ( 6 ) . These b a t t e r y - p o w e r e d p o r t a b l e pumps a r e u s e d t o i n f u s e i n s u l i n i n t o d i a b e t i c patients. Although capable o f v a r i a b l e d e l i v e r y r a t e s , they have a r e s e r v o i r volume o f l e s s t h a n 6 m l , w h i c h i s u n s u i t a b l e f o r f l u i d replenishment. Further, the cost of these small pumps i s v e r y h i g h w h i c h l i m i t s t h e a f f o r d a b i l i t y t o a few selected individuals. T h e i r pumping mechanism i s t h e r o l l e r p e r i s t a l t i c a c t i o n which i s a l s o u s e d f o r f l o w c o n t r o l . But t h e power consumption i s h i g h and t h e b a t t e r y i n some o f t h e s e pumps needs t o be r e p l a c e d p r a c t i c a l l y e v e r y day ( 6 ) . The c l i n i c a l i n f u s i o n d e v i c e s a f o r e m e n t i o n e d a r e much t o o e x p e n s i v e f o r r e s e a r c h p u r p o s e s i n l a b o r a t o r y a n i m a l s , which a r e used because t h e i r i n b r e e d i n g h e l p s t o a v o i d v a r i a t i o n s i n p h a r m a c o l o g i c a l a c t i o n due t o g e n e t i c f a c t o r s . Thus, t h e r e i s a need t o d e v i s e a s i m p l e and low c o s t i n f u s i o n pump t h a t can r e a d i l y be m o d i f i e d i n s i z e o r f l o w r a t e t o accommodate d i f f e r e n t research requirements. The i n f u s i o n d e v i c e d e s c r i b e d i n t h i s r e p o r t c a n be f a b r i c a t e d i n a few h o u r s w i t h m a t e r i a l s u s u a l l y a v a i l a b l e i n a l a b o r a t o r y . For high flow, the a l i g n e d nylon f i b r e flow moderator can be u s e d . When microvolume d e l i v e r y i s r e q u i r e d , t h e u s e o f t h e h o l l o w f i b r e f l o w moderator can be c o n s i d e r e d . As f o r t h e i n f u s i o n e n c l o s u r e s , t h e t r a n s p a r e n t m a t e r i a l was s p e c i a l l y chosen t o a l l o w v i s u a l i z a t i o n o f t h e i n t e r n a l c o n t e n t s o f t h e drug s o l u t i o n bag, w h i c h i s always i n s p e c t e d a t r e g u a l r i n t e r v a l s d u r i n g use f o r t h e p r e s e n c e o f p a r t i c u l a t e s u s p e n s i o n o r a i r bubbles t h a t may d e v e l o p and be harmful.

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The main c o n c e p t o f t h e box d e s i g n i s t o maximize t h e a r e a o f c o n s t a n t p r e s s u r e , which i s e x e r t e d by t h e p o l y e t h y l e n e bag, i n o r d e r t o p r o v i d e a r e a s o n a b l e z e r o - s l o p e flow rate. C o n s e q u e n t l y , a r e c t a n g u l a r box e n c l o s u r e was u s e d , because t h e f o r c e s would be t r a n s f e r r e d p e r p e n d i c u l a r l y t o most o f t h e s u r f a c e o f t h e drug bag. T h i s a l s o e x p l a i n s why two bags were used i n s t e a d o f one. The s t e a d y f l o w r a t e o b s e r v e d i n t h e h e p a r i n i n f u s i o n study w i t h t h e corresponding delay i n c l o t t i n g time i n d i c a t e s t h a t t h e i n f u s i o n d e v i c e can p r o v i d e dependable c o n t r o l l e d release. S i n c e t h e s e r v i c e l i f e , s i z e and f l o w r a t e o f t h e d e v i c e may be v a r i e d depending on t h e r e q u i r e m e n t s o f an e x p e r i m e n t , t h e s e f e a t u r e s s h o u l d make i t r e a d i l y a d a p t a b l e t o t h e i n f u s i o n o f many o t h e r drugs. Acknowledgments We thank t h e M e d i c a l t h e Department o f H e a l t h & W e l f a r e

Canada f o r a c o n t r a c t .

Literature Cited 1. Heller, J. In "Recent Advances in Drug Delivery Systems"; Anderson, James M. and Kim, Sung Wan, Ed.; Plenum: New York, 1984; pp. 101-102. 2. Wang, P.Y. Proc. 12th International Symposium on Controlled Release of Bioactive Materials, 1985, pp. 235-236. 3. Wang, P.Y.; Evans, D.W.; Samji, N.; Llewellyn-Thomas, E. J. Surg. Res. 1980, 28, 182-187. 4. Wittgenstein, E.; Rowe, K.W. Lab. Animal Care. 1965, 15, 375-378. 5. Lee, R.I.; White, P.D. Amer. J. Med. Sci. 1913, 145, 195-503. 6. "Data on Insulin Infusion Pumps per Sept. 1983", compiled and published by Novo Industri A/S, Denmark. RECEIVED

January 21, 1987

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

Author Index Andrady, A. L., 49 Attwood, D., 128 Bao, Y. T., 49 Beall, P. T., 310 Bennett, R. ML, 324 Berner, Bret, 34 Borsadia, S., 232 Brown, Α., 100 Brown, L. R , 113 Burgess, D., Burton, S. Α. Chien, Yie W., 281 Cline, J. F., 113 Collett, J. H., 128 Cooper, Eugene R., 34 Davies, M . C , 100 Davis, S. S., 201 Duncan, Ruth, 188 Ebert, C. D., 310 Fong, Jones W., 214 Fox, J. L., 232 Gebelein, Charles G., 120 Ghanem, A. H., 232 Gibson, Richard E., 301 Good, William R , 1,232 Graham, Neil B., 158 Guy, Richard H., 84,267 Hadgraft, J., 84 Hartsough, Robert R., 120 Heller J., 172 Henry, M . B., 113 Higuchi, W. I., 232,241 Hinz, Robert S., 267 Ilium, L., 201 Ishikura, Toyoaki, 273 John, V. Α., 310 Keister, J. C , 34 Knepp, Victoria M , 267

Knutson, K., 241 Krill, S. L., 241 Lambert, W. J., 241 Langer, Robert, 16 Lee, Chia-Shun, 281 Lee, Mary C. Y., 341 Lee, Ping I., 1,71 Liu, P., 232 Mahmoud, H., 232

, , Mirza, Tahseen, 120 Mueller, Karl F., 139 Nagai, Tsuneji, 273 Nazareno, Josephine P., 214 Nelson, K . G., 324 Olanoflf, Lawrence S., 301 Pangburn, S. H., 172 Pasternak, Stephen H., 16 Pearson, Jane E., 214 Penhale, D. W. H., 172 Pitt, C. G., 49 Raleigh, C. L., 113 RatclifTe, J., 201 Rohr, U . D., 232 Rosenzweig, Κ. Α., 310 Saltzman, W. Mark, 16 Samuel, Ν. K . P., 49 Schacht, Etienne, 188 Smith, May S. M., 341 Smith, S. J., 324 Szoka, Francis C , Jr., 267 Tait, C. J., 128 Vandoorne, Filip, 188 Vermeersch, Joan, 188 Visscher, George E., 214 Wang, Paul Y., 341

Affiliation Index Hoshi University, 273 Massachusetts Institute of Technology, 16 Moleculon, 113 Research Triangle Institute, 49

Ciba-Geigy Corporation, 1,34,71, 139,232,310 Harvard University, 16 Health and Welfare Canada, 341

352

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INDEX Royal Danish School of Pharmacy, 201 Rutgers—The State University of New Jersey, 281 SRI International, 172 Sandoz Research Institute, 214 State University of Ghent, 188 UMIST, 100 University of California—San Francisco, 84,267

University of Keele, 188 University of Manchester, 128 University of Nottingham, 100,201 University of Strathclyde, 158 University of Toronto, 341 University of Utah, 232,241 Upjohn Company, 301,324 Welsh School of Pharmacy, 84 Youngstown State University, 120

Subject Index A Absorption enhancement strategies, peptides and proteins, 303-305 ionizable drugs from topical dosage form, 273-279 transbuccal, diclofenac sodium in a dog model, 310-321 Activation, dextran and inulin, 189-195 Activation energy of diffusion, 50-52 Additives, effect on percutaneous absorption of drugs in rabbits, 275 Agarose gel, use in liposomal drug delivery system, 267-270 Albumin microspheres intramuscular and intraarticular drug delivery, 204,206,211 preparation, 204,207/ Aldehydes, introduction in polysaccharides, 189-190 Aligned fiber moderators, flow rate, 346/ Amine functions, effect on pH sensitivity of poly(ortho esters), 176-178 Aminobenzoate esters, correlations of partition coefficients for solvent pairs, 62,63/

Β Barrier function, stratum corneum general discussion, 241-242 ways to decrease for enhanced drug delivery, 283 Base, use in microencapsulation process, 214-229 Basket technique, controlled release of bioactive agents, 121,124,125/ Binary image, drug delivery system, 24/ Bioadhesive agents, use to enhance intranasal absorption of peptides and proteins, 304

Bioadhesiv properties microspheres

i

Bioerodible drug delivery systems, 2-3 Bioerodible polymers, use in self-regulated drug delivery systems, 172-186 Biopharmaceutical considerations, controlled-release drug delivery, 9-11 Block copolymer, gelation characteristics after exposure to irradiation, 128-138 Buccal administration of drugs, advantages, 310 Buccal mucosa histology, 311-315 Burst period, frustum array drug delivery device, 332 Butanol, permeability coefficients in hairless mouse skin, 246,247/ C Capric acid effect on progesterone skin permeation, 292,296-299 use to enhance skin permeation of progesterone, 289/ Carbamate content, activation of dextran with 4-nitrophenyl chloroformate, 193,194/ Carbamate derivatives of dextran, preparation, 196 Carboxylic groups, introduction in polysaccharides, 190-191,192/ Carboxymethylcellulose effect on nasal blood flow response, 306-308 use to enhance intranasal absorption of peptides and proteins, 305 Chemically controlled drug delivery systems, 2-4 Chitin hydrogels, partially deacetylated, degradation, 182-184 Chloroformâtes, reaction with polysaccharides, 191,193-195

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INDEX Royal Danish School of Pharmacy, 201 Rutgers—The State University of New Jersey, 281 SRI International, 172 Sandoz Research Institute, 214 State University of Ghent, 188 UMIST, 100 University of California—San Francisco, 84,267

University of Keele, 188 University of Manchester, 128 University of Nottingham, 100,201 University of Strathclyde, 158 University of Toronto, 341 University of Utah, 232,241 Upjohn Company, 301,324 Welsh School of Pharmacy, 84 Youngstown State University, 120

Subject Index A Absorption enhancement strategies, peptides and proteins, 303-305 ionizable drugs from topical dosage form, 273-279 transbuccal, diclofenac sodium in a dog model, 310-321 Activation, dextran and inulin, 189-195 Activation energy of diffusion, 50-52 Additives, effect on percutaneous absorption of drugs in rabbits, 275 Agarose gel, use in liposomal drug delivery system, 267-270 Albumin microspheres intramuscular and intraarticular drug delivery, 204,206,211 preparation, 204,207/ Aldehydes, introduction in polysaccharides, 189-190 Aligned fiber moderators, flow rate, 346/ Amine functions, effect on pH sensitivity of poly(ortho esters), 176-178 Aminobenzoate esters, correlations of partition coefficients for solvent pairs, 62,63/

Β Barrier function, stratum corneum general discussion, 241-242 ways to decrease for enhanced drug delivery, 283 Base, use in microencapsulation process, 214-229 Basket technique, controlled release of bioactive agents, 121,124,125/ Binary image, drug delivery system, 24/ Bioadhesive agents, use to enhance intranasal absorption of peptides and proteins, 304

Bioadhesiv properties microspheres

i

Bioerodible drug delivery systems, 2-3 Bioerodible polymers, use in self-regulated drug delivery systems, 172-186 Biopharmaceutical considerations, controlled-release drug delivery, 9-11 Block copolymer, gelation characteristics after exposure to irradiation, 128-138 Buccal administration of drugs, advantages, 310 Buccal mucosa histology, 311-315 Burst period, frustum array drug delivery device, 332 Butanol, permeability coefficients in hairless mouse skin, 246,247/ C Capric acid effect on progesterone skin permeation, 292,296-299 use to enhance skin permeation of progesterone, 289/ Carbamate content, activation of dextran with 4-nitrophenyl chloroformate, 193,194/ Carbamate derivatives of dextran, preparation, 196 Carboxylic groups, introduction in polysaccharides, 190-191,192/ Carboxymethylcellulose effect on nasal blood flow response, 306-308 use to enhance intranasal absorption of peptides and proteins, 305 Chemically controlled drug delivery systems, 2-4 Chitin hydrogels, partially deacetylated, degradation, 182-184 Chloroformâtes, reaction with polysaccharides, 191,193-195

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Clinical results, morphine hydrogel suppositories, 166-169 Computer-generated images application to drug delivery systems, 27,29/,30 obtained from random structures, 23 verification of methods, 25-27,28/ Concentration determination, drug delivery systems, 18 distribution, matrix drug delivery system, 8-9 gradients, drug release from polymer beads, 151-154 profiles oil-water multilaminate, 38/ steady-state diffusion process, 43/ solutions effect on light-scattering ratio, 131,135 effect on micellar diffusion coefficient, 130-131,134 effect on viscosity, 131-132,135-136 steady-state diffusion process, 42 Conformational alterations, keratinized protein components of hairless mouse skin, 263 Constant-release configurations, drug dispersed in a permeable matrix, 326 Constant-release diffusion systems, rate control by means of geometric configuration, 324-340 Controlled-release device description, 267 disposable, use for drug infusion, 341-350 preparation, 268 Controlled-release drug delivery benefits, 1 classification, 2 frustum array device, 326-340 overview, 1-11 parenteral and nasal drug administration, 201-212 theory, 17-22 use of liposomal delivery system, 267-272 See also Drug delivery systems Controlled-release kinetics of 5-fluorouracil from copolymer system, measurement, 120-125 Copolymer, block, gelation characteristics after exposure to irradiation, 128-138 Copolymer systems, measurement of controlled-release kinetics of 5-fluorouracil, 120-125 Corner flow function, steady-state diffusion process, 42 Crystallinity of polymers, relation to drug release from hydrogels, 162,164 Cylindrical design, comparison with slab design for hydrogels, 164

D Decylmethyl sulfoxide, effect on progesterone skin permeation, 292,296-299 Degradation of dextran derivatives by dextranases, 196-199 Delipidization of skin, effect on progesterone permeation, 292,294-299 Desmopressin, effect on nasal blood flow response, 306-308 Desorption from oil-water multilaminates, 39-40,41/ Dextran, activation, 189-195 Dextran derivatives biodégradation, 196 degradation by dextranases, 196-199 Dialdehyd derivative f dextran

absorption from hydrogel discs, 320 characterization of the buccal permeability, 311 comparison with oxprenolol hydrochloride, 153-156 disposition kinetics in dogs, 312-313 in vitro delivery from a transbuccal drug delivery device, 314,316/ in vivo absorption studies, 314-321 partial extraction and release from polymer beads, 145-156 release as a function of water content of drug-free polymer, 141,143/ release from beads of very low water content, 141,144/ Differential scanning calorimetry (DSC) hairless mouse skin and components, 245-246,247/ use to study thermal transitions of stratum corneum, 242 Diffusion comparison of theoretical results with experimental electrical values, 46,47/ drugs in polymers, estimation of rates, 49-69 drugs through human skin, measurement, 113-119 heterogeneous media, 34-47 steady-state, in a hollow sphere, theory, 328-331 water-filled phase, effect on drug release, 30 Diffusion cells comparison of variability, 117 flow-through, description, 114-115,116/ study of ^-estradiol transport in hairless mouse skin, 233 use to monitor controlled release of progesterone, 268

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INDEX

Diffusion coefficients drug delivery systems, 18 hydrogels, 162 matrix drug delivery systems, 6 methods of estimation, 50 micellar, effect of radiation dose, 130-131,134 Diffusion-controlled drug delivery system, 4-5 Diffusion kinetics, absorption of drugs through human skin, 115,116/ Diffusion systems, rate control by means of geometric configuration, 324-340 Diffusive transport in porous polymers, 16-32 Digital images, drug delivery system, 21/ Diltiazem hydrochloride, percutaneous absorption from polymeric film bases, 273-279 Discontinuous surface coatings, steady-stat permeation, 40-47 Discrete models of release behavior, drug delivery systems, 18-19,21/ Disodium cromoglycate, percutaneous absorption from polymeric film bases, 273-279 Disposable controlled-release device for drug infusion, 341-350 Dissolution rate of a solid, influence of geometry, 325 Dissolution test procedure, enhanced drug release from microspheres, 215-216 Dog, buccal mucosa, 314,315/ Drug(s) advantages of intranasal delivery, 301-302 ionizable, enhanced absorption from topical dosage form, 273-279 transdermal delivery, chemical structure and skin permeation rate, 284/ transport across biological membranes, factors affecting, 311 Drug carriers, activation procedures and biodégradation studies, 188-199 Drug delivery, controlled-release—See Controlled-release drug delivery Drug delivery systems liposomal, use of controlled drug release, 267-272 pH-sensitive, 172-179,180/ schematic, 21/ self-regulated, use of bioerodible polymers, 172-186 surface chemical analysis, 100-111 transbuccal, preparation, 312 transdermal, with enhanced skin permeability, 281-299 Drug delivery systems—See also Controlled-release drug delivery

Drug diffusion in polymers, estimation of rates, 49-69 through human skin, measurement, 113-119 Drug dispersed in a permeable matrix, constant-release configurations, 326 Drug infusion disposable controlled-release device, 341-350 in vivo test of device, 348-349 Drug loading percentage of microspheres, effect on drug release, 217,219,222/ Drug-polymer conjugates, controlled-release drug delivery, 3-4 Drug release by partial extraction, 145-156 enhanced, polylactide microspheres, 214-229

Drug solubilities in polymers determination using partition coefficients, 61-68 estimation, 57-61

Ε Egg phosphatidylcholine liposomes, multi­ lamellar, associated with progesterone, effect on controlled drug release, 268-272 Electrolytes combined with nonelectrolytes, effect on percutaneous absorption of drugs in rabbits, 275,278 weak, solubilities, 64,67/ Emulsifiers, effect on thioridazine release from microspheres, 219,221/ Emulsion characteristics, effect on porosity of thioridazine microspheres, 226-227 Enhanced absorption of ionizable drugs from topical dosage form, 273-279 Enhanced drug release from polylactide microspheres, 214-229 Enhanced intranasal peptide delivery, 301-308 Enhanced skin permeability, transdermal drug delivery, 281-299 Enhancement factor enhanced permeation of progesterone across various skin structures, 297-299 skin permeation of progesterone, factors affecting, 285,290/ Enzymatic degradation, dextran and derivatives, 196-199 Enzyme-degradable hydrogel, triggered drug delivery system, 182-184 Enzyme-substrate reactions, effect on drug delivery systems, 172-179,180/

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Enzyme-triggered drug delivery system, reversibly inactivated, 182,184-186 Erosion matrix drug delivery systems, 7 modulated drug delivery systems, 172-179,180/ ^-Estradiol effects of ethanol on transport in hairless mouse skin, 232-240 enhancement of skin permeability by different enhancers, 285,291/ solubility in various ethanol-water solutions, 234-235,236/ transport across skin, 234,236/ Ethanol concentration-distance profile, 234 effects on the transport of ^-estradiol in hairless mouse skin, 232-240 swelling of polymers for drug release, 141,142/ l-(N-2-Ethylmethacrylcarbamoyl)5-fluorouracil (EMCF), controlled release of 5-fluorouracil, 120-125 Extent of orientation, particle, drug delivery systems, 20 Extraction lipids from hairless mouse skin, 243-244 mechanism, drug release from polymer beads, 151-153,154/

F Fabrication, drug delivery systems, 22 Fatty acids, use to enhance skin permeation of progesterone, 285,290/ Fatty matrix pathway, contribution to enhancement of progesterone skin permeation, 297-299 Fiber flow moderator, aligned, preparation, 342 Fick's first law, determination of diffusion rates, 50 Fick's second law, solute concentration, 35 Film continuity, role in steady-state diffusion processes, 46 Flow diagram, steady-state diffusion process, 45/ Flow moderators, disposable controlled-release device for drug infusion, 346-347 Flow rate aligned fiber moderators, 346/ infusion devices, assembly for testing, 343 Flow-through diffusion cells, description, 114-115,116/ 5-Fluorouracil, measurement of controlled-release kinetics from copolymer systems, 120-125

Flux membrane-dispersed monolith, 317 permeants through hairless mouse skin, thermal dependence, 258 solute across a membrane or stratum corneum, 238 Fourier transform IR spectroscopy (FTIR), hairless mouse skin and components, 245-246,248-261 Fractional drug release, matrix drug delivery systems, 6 Frustum array device application of hollow sphere concept of diffusion, 329-331 construction, 331 controlled drug release, 326-340 schematic, 327/ zero-orde releas phase 329

G Gas dispersion tube, use to study controlled release of 5-fluorouracil from copolymer systems, 121-125 Gastrointestinal residence time, effect on oral drug delivery, 9-10 Gel permeation chromatograms, dextran derivatives, 197/ Gelation characteristics, block copolymer after exposure to irradiation, 128-138 Geometric configuration, use for rate control of drug release, 324-340 Geometric considerations, drug delivery systems, 7,30 Glass hollow fibers effect of internal diameter on flow rate, 347-348 flow moderation, 342-343 Glass transition temperature copolymer system, effect on release rate of a bioactive agent, 124 guidelines for predicting changes, 52,57 Glucose-glucose oxidase modulated drug delivery, 174-179,180/ Glutaraldehyde stabilization, albumin microspheres, 206,208/

H Heat stabilization, albumin microspheres, 204-208 Hemispheric configuration, drug release system, 326 Heparin infusion device, in vivo test, 348-349 microvolume infusion of rodents, 344,346

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INDEX

Heterogeneous media, diffusion, 34-47 High-performance liquid chromatography, rabbit plasma after administration of diltiazem hydrochloride, 278-279 Higuchi equation, drug release kinetics, 6 Histamine effect on nasal blood flow response, 306-308 intranasal administration, 301-308 Histology, buccal mucosa, 311-315 Homogeneous enzyme immunoassay, principle, 184/ Human beings, measurement of in vitro drug diffusion, 113-119 Human oral mucosa, description, 320 Hydration, micellar effect of radiation dose, 132 effect of temperature, 136 Hydrocortisone effect of urea concentration on rate, 174,175/ enhancement of skin permeability by different enhancers, 285,291/ permeability coefficients in hairless mouse skin, 246,247/ Hydrogel(s) description, 159-160 enzyme-degradable, 182-184 for sustained drug release, cross sections of different designs, 160,161/ Hydrogel beads, advantages for oral drug delivery, 139 Hydrogel discs, absorption of diclofenac sodium, 320 Hydrogel suppositories, morphine device design, scale-up, and evaluation, 158-170 photograph, 169/ Hydrogel systems, properties affecting the mechanism of drug release, 159 Hydrolysis studies, controlled release of 5-fluorouracil from copolymer systems, 121-125 Hydrophobic polymers, controlled-release drug delivery, 17 Hydroxypropylcellulose, SSIMS spectra, 103,104/ Hydroxypropylmethylcellulose, SSIMS spectra, 103,105/

Image processing, drug delivery systems, 22-23 Images obtained from computer-generated random structures, estimation of three-dimensional properties, 23 Immunoassay, homogeneous enzyme, 184/

Immunogenic effects, microspheres, 203 In vitro delivery of diclofenac sodium from a transbuccal drug delivery device, 314,316/ In vitro diffusion of drugs through human skin, measurement, 113-119 In vitro drug release from transbuccal disc devices, determination, 312 / In vivo absorption studies, diclofenac sodium, 314-321 In vivo test, drug infusion device, 348-349 Indomethacin enhancement of skin permeability by different enhancers, 285,291/ permeability enhancement by a combination of enhancers, 293/ SSIMS spectra, 106,107/

Infusion drugs, use of a disposable controlled-release device, 341-350 heparin in rodents, 344,346 Infusion device for controlled drug release fabrication, 343-344 factors affecting flow rate, 347-348 flow-rate testing, 343 preparation and running, 344,345/ Insulin delivery system, schematic, 175/ enhancement of intranasal delivery, 304 release rate, modulation in response to glucose concentration, 174-179,180/ Intraarticular delivery of drugs, use of albumin microspheres, 204,206-211 Intramuscular delivery of drugs, use of albumin microspheres, 204,206-211 Intranasal delivery of drugs, advantages, 301-302 Intranasal peptide delivery, enhancement, 301-308 Intravenous delivery of drugs advantages, 281-299 use of microspheres, 203-204,205/ Inulin activation, 189-195 succinoylation, 190-191,192/ Ion-exchange microspheres, uptake in the lung region, 203,205/ Ionizable drugs, enhanced absorption from topical dosage form, 273-279 Irradiation, effect on gelation characteristics of a block copolymer, 128-138 Κ Keratinized protein components of hairless mouse skin, C - H stretching vibration, 262-263

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Keratinized striated epithelia, inner cheek of rodents, 313-314,315/ Kinetics of diffusion, absorption of drugs through human skin, 115,116/

L Lag time, oil-water multilaminate, 39 Laplace's equation, steady-state diffusion process, 40 Laser Doppler flow probe, measurement of nasal blood flow, 305 Laurocapram, effect on progesterone skin permeation, 292,296-299 Light-scattering ratio, solutions exposed to radiation, 131,135 Linked suppositories, release profil f morphine hydrochloride, 166,167 Lipids barrier model, permeability coefficient, 235 extraction from hairless mouse skin, 243-244, 262 mobility within the stratum corneum, correlation to enhanced permeability, 262 mouse stratum corneum, DSC and FTIR studies, 245-261 removal from skin, effect on progesterone permeation, 292-299 stratum corneum, thermal transitions, 242 Lipophilic molecules, enhancement of permeability through hairless mouse skin, 258 Liposomal delivery system for controlled drug release, 267-272 Lung retention, microspheres after intravenous administration, 203 Lysozyme-catalyzed degradation, hydrogels, 182-184 Lysozyme-morphine conjugation scheme, 185/

Membrane-reservoir drug delivery systems, 4-5 Membranization, drug release from polymer beads, 145,146/, 148/ Metabolism of diltiazem hydrochloride by rabbits effect of delivery route, 278-279 study methods, 274 Methanol extraction, effect on FTIR spectra of hairless mouse skin, 256/,260-261/ Micellar properties, effect of temperature, 134-138 Microencapsulation process, use of base, 214-229 Microscopic sample preparation, drug delivery systems, 22 Microspheres controlled-releas fo

drug delivery systems limitations, 202 possible materials, 202 requirements, 202 polylactide, enhanced drug release, 214-229 use in nasal administration of drugs, 209,212 use in parenteral administration of drugs, 203-211 Microstructural models for diffusive transport in porous polymers, 16-32 Modifications, hydrogel suppository, 166-168 Modulated drug delivery systems, 172-179,180/ Molar water solubilities, correlations to partition coefficients, 64 Mole fraction solubility of a drug, relation to melting point, 58-61 Molecular weight, relation to diffusion coefficient, 52,56/ Monosuccinate ester of dextran, preparation, 196 Morphine antibodies added to a M lysozyme-morphine conjugate, effect on glucose oxidase release, 186/ Morphine hydrochloride release from hydrogel slabs into Mass conductance, drug delivery systems, 19 Mathematical simulations, experimental water, 160,161/ studies of constant-release diffusion release from outer surface of dispersions in hollow cylindrical systems, 322,337,339/ hydrogels, 162,163/ Matrix drug delivery systems, 5-9 Morphine hydrogel suppositories, device Matrix inversion algorithm, use to predict design, scale-up, and particle size distributions, 27 evaluation, 158-170 Mechanisms, skin permeation Morphine impregnation in hydrogels, 160-166 enhancement, 292-299 Morphine-lysozyme conjugation scheme, 185/ Melting point of a drug, relation to Mouse skin, hairless solubility, 58 Membrane function, drug release from polymei effect of ethanol on the transport of ^-estradiol, 232-240 beads, 156

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

359

INDEX

Mouse skin, hairless—Continued probing the structure on the molecular level, 241-264 transdermal delivery rate of progesterone, 270-272 Mucosa, human oral, description, 320 Mucosal membrane, nasal, description, 302-303 Multilamellar egg phosphatidylcholine liposomes, associated with progesterone, effect on controlled drug release, 268-272

Ν Naltrexone delivery system, schematic, 180 solubility, 68/ Nasal administration of drugs, us microsphere systems, 201-212 Nasal blood flow, measurement, 305 Nasal mucosal membrane, description, 302-30 Nasal peptide absorption, factors affecting, 303 Negative-ion SSIMS spectra, hydroxypropylcellulose, 103,104/ Nitrocellulose acetate membrane plug, ethanol-water concentration-distance profile, 238,239/ Nitrogen bases, correlations between partition coefficients and solubilities, 64-66 Nitroglycerin, transdermal delivery, 11 4-Nitrophenyl chloroformate activation, dextran, 191,193-195 Nonelectrolytes, solubilities, 64,67/ Non-steady-state permeation through oil-water multilaminates, 35-39

Ο Octanol, permeability coefficients in hairless mouse skin, 246,247/ Oil-water multilaminates desorption, 39-40,41/ non-steady-state permeation, 35-39 Oleic acid, effect on progesterone skin permeation, 292,296-299 Opiate addiction, application of triggered drug delivery systems, 179-186 Optimal transport, oil-water multilaminate, 36,38/,39 Oral administration of diltiazem hydrochloride, comparison with percutaneous administration, 278-279 Oral delivery systems, controlled-release drug delivery, 9-10

Organic solvents, effects on the intrinsic permeability of the stratum corneum, 232 Osmotic pumping mechanism, drug-release from reservoir systems, 4-5 Oxprenolol hydrochloride comparison with diclofenac sodium, 153-156 partial extraction and release from polymer beads, 145-156 release as a function of water content of drug-free polymer, 141,143/

Paracetamol-loaded polymer beads, SIMS image, 109,110/ Parenteral administration of drugs, use of

polyme , Particle size distributions, obtained from computer-generated images, 26/,29/ Partition coefficients correlations for solvent pairs, 62-64 permeability coefficient, 235 use to determine drug solubilities in polymers, 61-68 Peptide drugs advantages of intranasal delivery, 301-302 intranasal delivery, enhancement, 301-308 Percolation theory, evaluation of transport phenomena in heterogeneous environments, 32 Percutaneous absorption of drugs in rabbits, intact versus stripped skin, 275-277 Percutaneous administration of diltiazem hydrochloride, comparison with oral administration, 278-279 Periodate oxidation, dextran, 189-190 Permeability, enhanced skin, transdermal drug delivery, 281-299 Permeability coefficients calculation, 233 determination, 245 lipid barrier model, 235 solute across a membrane or stratum corneum, 235 Permeability studies, hairless mouse skin, 233,244-246,247/ Permeation through discontinuous surface coatings, 40-47 through oil-water multilaminates, 35-39 pH-sensitive polymers, drug delivery systems, 172-182 Pharmaceutical compounds, diffusion through human skin, variability, 118

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

360

CONTROLLED-RELEASE TECHNOLOGY

Pharmacokinetic model, analysis of plasma concentration-time profiles after intravenous dosing, 313 Photomicrographs, drug-loaded beads during extraction, 150/ Physiological modifying agents, use to enhance intranasal absorption of peptides and proteins, 304 Plasma concentration profiles, transbuccal administration of diclofenac sodium, 316/,318/ Plasma levels, drugs after application on stripped rabbit skin, 275-277 Poloxamer, gelation characteristics after exposure to irradiation, 128-138 Polyacrylic acid gel, effect on intranasal absorption of insulin, 307 Polydispersity of micellar sizes poloxamer solutions effect of radiation dose, 133 effect of temperature, 137 Polylactide microspheres, enhanced drug release, 214-229 Polymer(s) beads low water swelling, 139-156 synthesis, 140 erosion, mechanisms of control, 3 estimation of drug diffusion rates, 49-69 estimation of drug solubility, 57-61 for drug release, composition, swelling, and release data, 142/ matrices, advantages as drug delivery systems, 341 monoliths, slowing the initial rate of drug release, 140 porous, diffusive transport, 16-32 solubility parameters, 65/ swelling, matrix drug delivery system, 7-8 Polymer-drug conjugates, controlled-release drug delivery, 3-4 Polymeric drug delivery systems, surface chemical analysis, 100-111 Poly(ortho esters) effect of pH on erosion rate, 177-178/, 180/ use in modulated drug delivery systems, 174-179,180/ Poly(oxyethylene)-poly(oxypropylene) block copolymer, gelation characteristics, 128-138 Polypropylene molds, use to make suppositories, 164 Polysaccharides as drug carriers, 188-199 introduction of aldehydes, 189-190 introduction of carboxylic groups, 190-191,192/ reaction with chloroformâtes, 191,193-195

Porosity estimates, obtained from computer-generated images, 26/,29/ hairless mouse skin, effect of ethanol, 235-240 particle, drug delivery systems, 20 Porous network, drug delivery systems, 19 Porous polymers, diffusive transport, 16-32 Positive-ion SSIMS spectra hydroxypropylcellulose, 103,104/ hydroxypropylmethylcellulose, 103,105/ indomethacin, 106,107 indomethacin-loaded polymer beads, 106,108/ Posttreatment of polylactide microspheres with NaOH, effect on drug release, 223,225/

polylactid microsphere NaOH, effect on drug release, 219,223,224/ Progesterone effect of enhancers on permeation rate across various skin structures, 292,296-299 enhancement of skin permeability by different enhancers, 285,291/ permeability enhancement, effect of location of enhancer, 291/ permeation across a delipidized skin, 292,294-299 permeation across a stripped skin, 292,295-299 release kinetics from controlled-release device, 268-271 solubilities, 68/ transdermal delivery rate across hairless mouse skin, 270-272 use of capric acid to enhance skin permeation, 289/ use of fatty acids to enhance skin permeation, 290/ Prostaglandin, diffusion coefficients, 54-55/ Protein components, keratinized, hairless mouse skin, C - H stretching vibration, 262-263 Protein gel pathway, contribution to enhancement of progesterone skin permeation, 297-299 Protein residue sheets extraction from hairless mouse skin, 244 mouse stratum corneum, DSC and FTIR studies, 245-261 Pumping mechanism, infusion pumps, 349 R Rabbit skin, enhanced absorption of ionizable drugs, 273-279

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

INDEX

361

Skin—Continued Radiation dose, effect on micellar permeation enhancement properties, 130-133 mechanisms, 292-299 Rats transdermal drug delivery, 281-299 buccal mucosa, 313-314,315/ permeation enhancers, examples, 286 use to test heparin infusion device, 349 rabbit, enhanced absorption of ionizable Rectal administration of drugs, advantages drugs, 273-279 and disadvantages, 159 Skin-permeation-enhancing transdermal drug Release kinetics, zero-order, frustum delivery system array drug delivery device, 332-340 Release mechanism, drug release from polymer development, 283-292 structural components, 286/ beads, 145,146/, 148/ Slab design for hydrogels, comparison with Release profiles microspheres prepared with cylindrical design, 164 NaOH-posttreated polymers, 223,225/ Sodium hydroxide, effect on drug release microspheres prepared with NaOH-pretreated from polylactide microspheres, 214-229 polymers, 223 Solid dissolution rate, influence of morphine hydrochloride from geometry, 325 hydrogels, 160-166,167/ Release rates, drugs from polyme beads, 141-145,146/ Reservoir-membrane drug delivery ^-estradiol, 234-235,236/ systems, 4-5 Solubility parameters, polymers, 65/ Reticuloendothelial system, removal of Solution-diffusion mechanism, drug release microspheres, 203 from membrane-reservoir systems, 4-5 Reversibility of erosion rates, poly(ortho Sphere, hollow, theory of steady-state esters), 176,180/ diffusion, 328-331 Reversibly inactivated enzyme, triggered Spring-type diffusion cell, variability, 117 drug delivery system, 182,184-186 Static secondary ion mass spectrometry Rodents, microvolume infusion of description, 101-102 heparin, 344,346 surface analysis of polymers, 101 Rose bengal surface chemical analysis of polymeric clearance from normal and arthritic rabbit drug delivery systems, 100-111 knee joints, 209,210/ Steady-state diffusion in a hollow sphere, release from the lung region of a theory, 328-331 rabbit, 203,204,205/ Steady-state permeation through discontinuous surface coatings, 40-47 Stereological analysis of three-dimensional Sample size, effect on controlled release of materials, 20-22 5-fluorouracil from E M C F Steroids monomer, 122,123/ correlations of solubilities with Scanning electron microscopy partition coefficients, 62,63/ microspheres, 216 diffusion coefficients, 54,55/ thioridazine microspheres, 228-229/ relation of melting point to Scopolamine, transdermal delivery, 11 solubility, 58-61 Screw-type diffusion cell, variability, 117 use of compounds to enhance skin Secondary ion mass spectrometric imaging permeation, 285,291/ description, 102 use of microspheres for controlled surface chemical analysis of polymeric release, 204,206,207/ drug delivery systems, 100-111 Stratum corneum Self-regulated drug delivery systems, use effect of removal on progesterone permeation, 292,295-299 of bioerodible polymers, 172-186 effect on transdermal drug delivery, 10-11 Size distribution of microspheres, effect on hypothesized structure, 258 drug release, 217 modeling as a hydrophilic protein gel Skin dispersing in a continuous lipid hairless mouse, effect of ethanol on the matrix, 292,293/ transport of ^-estradiol, 232-240 mouse human, measurement of in vitro drug DSC and FTIR studies, 245-261 diffusion, 113-119 permeability studies, 244-246,247/ permeation cell, hydrodynamically separation from the epidermis, 243 calibrated, 288/

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

362

CONTROLLED-RELEASE TECHNOLOGY

Stratum corneum—Continued probing the structure on the molecular level, 241-264 thermal transitions, 242 Succinic anhydride activation, inulin, 190-191,192/ Suppositories clinical evaluation, preparation, 164,166 composition, 160 joining with a hydrogel rod, 166,167/ morphine hydrogel, device design, scale-up, and evaluation, 158-170 Surface area, effect on solid dissolution rate, 325 Surface chemical analysis, polymeric drug delivery systems, 100-111 Surface coatings, discontinuous, permeation, 40-47 Surface distribution of drugs, polymeri drug delivery systems, 106-10 Surface-to-volume ratio of drug particles, 20 Surfactant agents, use to enhance intranasal absorption of peptides and proteins, 304 Swelling ethanol and water, polymers for drug release, 141,142/ keratinized protein components of hairless mouse skin, 263 matrix drug delivery systems, 7

Transbuccal drug delivery device general discussion, 314,316/ modeling of drug release, 317 preparation, 312 Transdermal drug delivery rate, progesterone across hairless mouse skin, 270-272 Transdermal drug delivery systems benefits, 282 controlled-release drug delivery, 10-11 potential, 283 uses, 282 with enhanced skin permeability, 281-299 Transmission FTIR spectra, hairless mouse skin and components, 246-261 Transport ^-estradiol in hairless mouse skin, effects of ethanol, 232-240

Τ

intraarticular administration, 209,211/ release from an intramuscular site, 206,208/ U Urea-urease modulated drug delivery system, 173-174,175/ V Viscosity, solutions exposed to radiation, 131-132,135-136 Volume expansion, drug release from polymer beads, 141-145,146/ W

Temperature effects barrier function of stratum corneum, 242 FTIR spectra of hairless mouse skin and components, 246-261 micellar properties, 134-138 Theophylline, structure, 109 Theophylline bead, polymer-coated, SIMS image, 109,110-111/ Thermal dependence, flux of permeants through hairless mouse skin, 258 Thermal transitions, stratum corneum, 242 Thermograms, DSC, hairless mouse skin and components, 246,247/ Thioridazine microspheres preparation, 215 scanning electron micrographs, 228-229/ Thioridazine release from polylactide microspheres, effect of NaOH, 217-229 Three-dimensional materials, stereological analysis, 20-22 Topical dosage form of ionizable drugs, enhanced absorption, 273-279 Tortuosity, drug delivery systems, 18 Transbuccal absorption of diclofenac sodium in a dog model, 310-321

Water diffusion rates across a sealed hollow hydrogel, 162 Water-oil multilaminates, desorption, 39-40,41/ non-steady-state permeation, 35-39 Water solubilities, correlations to partition coefficients, 64 Water-soluble drugs, release from polymer beads with low swelling, 139-156 Wavenumber versus temperature plots C - H stretching band of hairless mouse skin and components, 252/,255/,257/ N - H stretching and bending bands of hairless mouse skin, 255/,259/ Weak electrolytes, solubilities, 64,67/ X X-ray photoelectron spectroscopy, surface analysis of polymers, 100-101

Ζ Zero-order release kinetics, frustum array drug delivery device, 332-340

In Controlled-Release Technology; Lee, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.