Controlled Release: A Quantitative Treatment PDF
Preview Controlled Release: A Quantitative Treatment
Polymers 13 Properties and Applications Editorial Board: Prof. Hans-Joachim Cantow Institut fUr Makromolekulare Chemie der Universitiit Stefan-Meier-StraBe 31, 7800 Freiburg/Federal Republic of Germany Prof. H. James Harwood Institute of Polymer Science, The University of Akron Akron, OH 44325/USA Prof. Joseph P. Kennedy Institute of Polymer Science, The University of Akron Akron, OH 44325/USA Prof. Anthony Ledwith Pilkington Brothers pic., R&D Laboratories Lathom Ormskirk Lancashire UO 5UF/UK Prof. Joachim MeifJner Eidgentissische Technische Hochschule Zurich Institut fUr Polymere, ETH-Zentrum CH-8092 Zurich Prof. Seizo Okamura No. 24 Minami-Goshomachi Okazaki Sakyo-ku, 606 Kyoto, Japan Dr. G. Henrici-Olivet Prof. S. OIM 1332 Neal Road Cantonment, FL 32533/USA L. T. Fan, S. K. Singh Controlled Release A Quantitative Treatment With 81 Figures Springer-Verlag Berlin Heidelberg NewY ork London Paris Tokyo Hong Kong Professor Liang-tseng Fan Department of Chemical Engineering Kansas State University Durland Hall Manhattan, KS 66506jUSA Dr. Sat ish Kumar Singh Kabi Pharma Giirdsvagen 6 Box 1828 S-171 26 Solna, Sweden ISBN-13: 978-3-642-74509-6 e-ISBN-13: 978-3-642-74507-2 DOl: 10.1007/978-3-642-74507-2 Library of Congress Cataloging-in-Publication Data Fan, L. T. (Liang-tseng), 1929 Controlled release: a quantitative treatment 1 L. T. Fan, S. K. Singh, p. cm. - (Polymers, properties and applications; 13) Includes index. 1. Controlled release technology. 1. Singh, S. K. II. Title. III. Series. TP 156.C64F36 1989 660.2 -dc 19 89-4323 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provi sions of the German Copyright Law of September 9,1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag, Berlin Heidelberg 1989 Solkover reprint of the hardcover 1st edition 1989 The use of registered names, trademarks, etc. in this publication does not imply, even in tbe absence of a specific state ment, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. 2152/3020-543210 To the Memory of Professor Takeru Higuchi Father of Modem Controlled-Release Technology Preface The concept of controlled release has attracted increasing attention over the last two decades, with the applications of this technology proliferating in diverse fields in cluding medicine, agriculture and biotechnology. Research and developmental efforts related to controlled release are multiplying in both industry and academia. The reason for this phenomenal growth is obvious. The use of a variety of biologically active agents, such as drugs, fertilizers and pesticides, has become an integral part of modern society. Along with the use of these reagents has evolved an awareness that their uncontrolled application almost inevitably induces harmful effects on the health of humans and their surrounding environments. To eliminate or minimize these harmful effects necessitates the controlled release of these chemicals. Moreover, the controlled release of substances, not usually considered toxic or hazardous, e.g., some catalysts and nutrients, can enhance their effectiveness. The number and variety of controlled release systems, differing in their physical and chemical makeup, are increasing rapidly. Proliferation almost always demands correlation, generalization and unification; it requires both the development of underlying theories of their behavior and the mechanistic interpretation of their performance. This, in turn, requires a statistical and mathematical (quantitative) treatment of the scientific information and technical data pertaining to them. A quantitative treatment can also facilitate the formulation of procedures for computer-aided design of these systems through a priori prediction of their per formance for a variety of design parameters. Various controlled release systems are treated in this monograph; these systems are classified on the basis of the release mechanisms. A discussion is given of the release mechanisms and of the factors governing the release profile. This is followed by a review of major mathematical models that are .applicable to the systems. These mathematical models are classified on the basis of the assumptions involved. The majority of the models are of the deterministic type; however, the hetero geneous or meso scopic nature of some of the systems requires that a stochastic approach be employed. Thus a fairly extensive treatment of this approach to the modeling of diffusion is included at the end. Acknowledgement The authors' research, supported for several years by the Kansas Agricultural Experiment Station, Kansas State University, has culminated in the present mono- VII Preface graph. The manuscript was ably typed mainly by Janet Vinduska and Peggy Hanes. The first author (LTF) also wishes to acknowledge the aid of his wife, Eva, in preparing the manuscript. March 1989 L. T. Fan S. K. Singh VIII Table of Contents 1 Introduction . . . . . . . . . . I 1.1 Diffusion-Controlled Systems . 3 1.1.1 Reservoir Devices . . . 3 1.1.2 Monolithic Devices. . . 4 1.2 Erosion or Chemical Reaction Controlled Systems 5 1.2.1 Erosion-Controlled Devices . . . . . 5 1.2.2 Chemical Reaction Controlled Devices 6 1.3 Swelling-Controlled Release Systems. 6 1.4 Osmotic Pumping Systems 6 References. . . . . . . . 7 2 Diffusion-Controlled Release 9 2.1 Diffusion in Polymers . II 2.1.1 Estimation of Diffusion Coefficients 14 2.1.2 Factors Influencing Diffusional Release. 20 2.2 Models for Diffusion-Controlled Release Systems . 44 2.2.1 Reservoir Devices . 49 2.2.2 Monolithic Devices. 61 2.2.3 Porous Devices 79 References. . . . . . . 83 3 Chemical Reaction Controlled Release . . . . . . 89 3.1 Physically Immobilized Active Agent Systems . 90 3.2 Chemically Immobilized Active Agent Systems 94 3.3 Models for Physically Immobilized Erosion-Activated Systems 102 References. . . . . . . . 107 4 Swelling-Controlled Release . 110 4.1 Penetrant Transport and the Polymer Relaxation Phenomena 111 4.1.1 Transport of Penetrants in Polymers . . . . . . . . . 112 4.1.2 Models for Transport of Penetrants in Glassy Polymers . 120 IX Table of Contents 4.2 Active Agent Release from Swell able Polymers 125 4.3 Models for Swelling-Controlled Release Systems. 130 4.3.1 One-Region Models 131 4.3.2 Two-Region Models 136 References. . . . . . . . . 152 5 Special Controlled-Release Systems 157 5.1 Osmotic Pumping Devices . . 157 5.2 Osmotically Activated Monolithic Devices 162 5.3 Externally Modulated Devices 164 References. . . . . . . . . . . 166 6 Stochastic Model for Diffusion in Porous or Heterogeneous Polymer Matrix. . . 167 6.1 Derivation . . . . . . . . . . . . . 170 6.1.1 Statistical Model for the Porous! Heterogeneous-Polymer Matrix. . 170 6.1.2 State of the Diffusing Molecule and State Transitions. 172 6.1.3 Derivation of the Master Equation . . . . . 175 6.1.4 Recovery of the Diffusion Equation 177 6.2 Transport Coefficients from the Diffusion Equation 184 6.2.1 Mean or Effective Diffusion Coefficient . 185 6.2.2 Drift or Convective Velocity. . . . 187 6.3 Transport Coefficients in Specific Systems . . 188 6.3.1 Mean or Effective Diffusion Coefficient. 188 6.3.2 Drift or Convective Velocity. . . . . . 191 6.4 Monte Carlo Simulations of Transport in Porous Media 192 6.4.1 Procedure. . . 193 6.4.2 Results . . . . 195 6.5 Concluding Remarks. 197 References. . . . . . . 200 Appendix 6A. Conversion of Probability to Number Concentration 202 Appendix 6B. Derivation of Equation (6.39) from Equation (6.37). 204 Appendix 6C. Algorithm and FORTRAN Code for Monte Carlo Simulation of Transport in Porous Networks 206 7 Epilogue. . 225 References . 226 Author Index . 227 Subject Index . 231 x 1. Introduction In the search for safe, economical, and efficient means of providing for the health and well-being of mankind, modern science has produced numerous active agents that manipulate the biological environment around and within us. Never theless, the use of these active agents is fraught with inefficiencies stemming from an inability to deliver these agents to their targets at the right time and in the right amounts. This results in their loss and in undesirable side effects and leads to a regimen requiring repeated treatment to produce and sustain the desired effect. With drugs, periodic dosage produces peaks and valleys in the concentration of the drug in the blood stream, possibly between harmful and ineffective levels (see Fig. 1.1). Agricultural chemicals such as pesticides, fertilizers, herbicides, and fumigants create the same problems when applied directly. To counter these problems, scientists have conventionally looked to altering the persistency and effectiveness of the reagents through modification of the reagents themselves. However, this approach tends to be difficult, time consuming, and expensive. -c o o ..c c: c: -o t----;;P-'\~--....!.lo;:------------- Tox i c I eve I -o L. c: '" --.... , (dl uco: "\ u \ 0> \ :L:::J. t'fI-:f-----T---4~------.....:\. .......- Mi n i mum effect i ve Cl \ level \ Time Fig. 1.1. Typical drug level in blood vs. time profiles for various modes of delivery. a standard oral dose, b oral overdose, c intraveneous injection, d controlled release dose 1 Introduction In recent years, increasing attention has been given to methods by which active reagents or chemicals are administered, giving rise to the field of controlled release. Controlled release may be defined as a technique by which active chemicals are made available to a target at a rate and duration so as to produce a desired effect. The objective of the technique is the maintenance of this desired rate or concentration level (Kydonieus, 1980). Among the advantages of this technique are more efficient utilization of the active agent, possibility of targeting, less frequent administration, and reduction in side effects. These advantages can sometimes make an otherwise unsuitable active agent attractive. This is especially true in pharmaceutics. New and powerful macromolecular drugs are being discovered or "engineered" at a rapid rate. Nevertheless, these drugs can be cumbersome to administer and often produce side effects. Controlled release can alleviate these difficulties. In medicine, the approach of sustained-release has been utilized for a long time. This approach comprises the formulation of drug complexes, enteric formula tions, suspensions, emulsions, and compressed tablets, to retard the drug's rate of availability to the body. The formulations, however, are strongly influenced by the environmental conditions and are not true controlled-release systems. Controlled release implies a predictible and reproducible release profile relatively independent of environment; this gives rise to a higher degree of control than achieved in sustained release formulations. The basic controlled-release formulation consists of an active agent (the drug, fertilizer etc.) and a carrier (commonly a polymeric material) arranged so as to allow the active agent to be released at the target over a period of time at a controlled rate. Numerous design variations towards this objective have been proposed. Some of the common ones are (see, e.g., Cowsar, 1974; Kydonieus, 1980) : 1. A capsule of polymeric material filled with the active agent in either the solid, liquid or solution form, release being controlled by diffusion through the capsule wall (reservoir deviCes). 2. A heterogeneous dispersion or homogeneous solution of the active agent in a polymeric matrix, release being controlled by diffusion through and/or erosion of the polymer (monolithic devices). 3. A laminate of the active agent and polymer forming a "sandwich", release being controlled by diffusion, erosion or both. 4. A swellable polymeric matrix with the active agent dispersed and/or dissolved in the polymer, release occurring as a result of swelling (or gelatinization) of the polymer in the environmental fluid and the consequent diffusion of the active agent. 5. Liquid-liquid encapsulation of the active agent in a viscous solution, release being controlled by diffusion or dilution. 6. Chemical bonding of the active agent to a polymeric backbone and subsequent release by controlled bond cleavage in the target environment. 7. Macromolecular structures of the active agent formed via ionic or covalent linkages with release controlled by hydrolysis, thermodynamic dissociation, or microbial or enzymatic degradation. 8. A capsule of active agent-impermeable polymer membrane, with release occurring 2
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