Surfactants and Polymers in Drug Delivery Martin Malmsten Institute for Surface Chemistry and Royal Institute of Technology Stockholm, Sweden

Marcel Dekker, Inc.

New York • Basel

TM

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ISBN: 0-8247-0804-0 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:/ /www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright  2002 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

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Preface

Surfactant and polymer systems play an important role in modern drug delivery, where they may allow control of the drug release rate, enhance effective drug solubility, minimize drug degradation, contribute to reduced drug toxicity, and facilitate control of drug uptake. In all, they contribute significantly to therapeutic efficiency. However, although understanding of the physicochemical properties and behavior of surfactants and polymers in solution and at interfaces has undergone dramatic development in the past couple of decades, the new findings have generally not been fully implemented in drug delivery, most likely as a result of lack of interdisciplinary communication. Things are gradually changing, however, and scientists and engineers in both academia and industry are paying increasing attention to physicochemical aspects of surfactant and polymer systems and recognizing their importance for the design and controlled use of advanced drug delivery formulations. This is fueled by the development of new biopharmaceuticals in the wake of recent advances in genomics and proteomics. In parallel, a push for advanced drug delivery formulations based on surfactants and polymers has originated from the development of many new synthetic drugs that are sparingly soluble and noncrystallizing compounds, which often are difficult to formulate by traditional means. Here, surfactant and polymer systems of various types offer real potential. The present book represents an attempt to discuss the basics of surfactant

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and polymer surface activity and self-assembly, the various types of structures formed by such compounds, and how they may be used in drug delivery. For this purpose, individual chapters are devoted to micelles, liquid crystalline phases, liposomes, microemulsions, emulsions, gels, and solid particles. Because biodegradation of surfactant and polymer systems has a particularly important effect on their use in drug delivery, a separate chapter is devoted to this topic. Finally, further processing of such formulations, for example, through spray-drying and freeze-drying, is discussed. I would like to thank Professors Bjo¨rn Lindman, Thomas Arnebrant, and Per Claesson for fruitful discussions on these topics and for helpful comments on the manuscript. I also express my gratitude to Maud Norberg for her skillful help with the figures and Britt Nystro¨m for help with literature issues.

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.

Martin Malmsten

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Contents

Preface 1.

Introduction 1.1 Introduction to Surfactants 1.2 Introduction to Polymers 1.3 Surface Activity of Drugs 1.4 Introduction to Drug Delivery Bibliography

2.

Micelles 2.1 Structure and Dynamics of Micellar Systems 2.2 Block Copolymer Micelles 2.3 Characterization of Micellar Systems 2.4 Micellar Systems in Drug Delivery Bibliography

3.

Liquid Crystalline Phases 3.1 Association Structures and Packing 3.2 Phase Diagrams 3.3 Association in Nonionic Surfactant Systems 3.4 Association in Ionic Surfactant Systems 3.5 Cubic Phases

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3.6 Liquid Crystalline Phases Formed by PEO-PPO-PEO Block Copolymers 3.7 Characterization of Liquid Crystalline Phases 3.8 Liquid Crystalline Phases as Drug Delivery Systems 3.9 Liquid Crystalline Phases in Drug Delivery Applications Bibliography 4.

Liposomes 4.1 Preparation and Properties of Liposome Systems 4.2 Solubilization and Release from Liposomes 4.3 Methods for Investigating Liposome Systems 4.4 Liposomes in Drug Delivery 4.5 Other Types of Dispersed Liquid Crystalline Phases Bibliography

5.

Microemulsions 5.1 Basics of Microemulsions 5.2 Characterization of Microemulsions 5.3 Drug Release from Microemulsions 5.4 Microemulsions in Drug Delivery Bibliography

6.

Emulsions 6.1 Formation of Emulsions 6.2 Structure of Emulsions 6.3 Phase Inversion of Emulsions 6.4 Rheology of Emulsions 6.5 Destabilization of Emulsions 6.6 Multiple Emulsions 6.7 Emulsions in Drug Delivery 6.8 Emulsions as Precursors for SLN Bibliography

7.

Aerosols, Bubbles, and Foams 7.1 Aerosols 7.2 Bubbles and Foams 7.3 Pharmaceutical Applications of Aerosols 7.4 Pharmaceutical Applications of Bubbles and Foams Bibliography

8.

Polymer Solutions and Gels 8.1 Polymer Solutions 8.2 Polymer-Surfactant Interactions 8.3 Polymer Gels 8.4 Characterization of Polymer Solutions and Gels

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8.5 Responsive Polymer Systems 8.6 Polymer Solutions and Gels in Drug Delivery Bibliography

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9.

Polymer Particles 9.1 Interaction Between Particles 9.2 Interaction Between Particles and Surfaces 9.3 Methods for Studying Polymer Particle Systems 9.4 Polymer Particles in Drug Delivery 9.5 Bioadhesion 9.6 Oral Vaccines Bibliography

10.

Degradation of Surfactants and Polymers in Drug Delivery 10.1 Biodegradation of Polymers 10.2 Biodegradation of Phospholipids Bibliography

11.

Drying of Formulations Containing Surfactants and Polymers 11.1 Spray-Drying 11.2 Freeze-Drying 11.3 Drying of Self-Assembled Structures Bibliography

Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.