Advances in Delivery Science and Technology Series Editor Michael Rathbone For further volumes: http://www.springer.com/series/8875 wwwwwwwwwwwww Jeremy C. Wright Diane J. Burgess ● Editors Long Acting Injections and Implants Editors Jeremy C. Wright Diane J. Burgess DURECT Corporation Department of Pharmaceutical Sciences Cupertino, CA, USA School of Pharmacy [email protected] University of Connecticut Storrs, CT, USA [email protected] ISSN 2192-6204 ISBN 978-1-4614-0553-5 e-ISBN 978-1-4614-0554-2 DOI 10.1007/978-1-4614-0554-2 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2011937763 © Controlled Release Society, 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identifi ed as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) This book is dedicated to friends and family. Especially both editors dedicate the book to their respective parents (George Gartly Burgess and Violet Isobel Burgess; William C. Wright and Jenny J. Wright). wwwwwwwwwwwww Preface The evolving complexity of human therapeutics requires the development of novel drug delivery systems. This book encapsulates in a single volume the concepts essential for understanding the science and technology associated with the research and development of long acting injections and implants. It provides a comprehen- sive overview of the scientifi c and regulatory challenges associated with these delivery systems. Critical contributions to this area are the array of formulations that make up the spectrum of long acting injections and implant dosage forms. These include micro- spheres, liposomes, in situ forming depots, suspensions, implants, lipophilic solutions, and osmotic implants. Such formulations have the potential to maintain therapeutic drug concentrations for durations from days to months, can be engineered to main- tain characteristics such as zero-order or pulsatile drug release, and, in some cases (e.g., liposomes) can provide targeted drug delivery to the site of action. These attri- butes lead to increased patient compliance and convenience, reduced fl uctuations in plasma profi les, and reduced plasma concentrations making it possible to adminis- ter higher drug concentrations to the site of action while reducing the overall dose. Thus, unwanted side effects can be minimized or reduced. In addition, long acting injections and implants can provide a means for the delivery of drugs that are subject to degradation in the harsh environment of the gastrointestinal tract, that undergo extensive fi rst pass metabolism, or that exhibit poor bioavailability when such molecules are orally administered. Long Acting Injections and Implants begins with chapters that provide basic con- cepts explained in a simple, clear, and concise manner. In subsequent chapters addi- tional material, expansions on the basic scientifi c concepts underpinning research and development of such dosage forms, and examples of technological develop- ments in this area are comprehensively reviewed and discussed. The introductory chapter provides a brief description of the types of systems and major areas of cur- rent application and research. The H istorical Overview chapter provides a chrono- logical overview of the historical developments associated with long acting injections and implants providing suffi cient background to enable the reader to appreciate the historical development of the area and to use that knowledge as a foundation for the vii viii Preface development of the next generation of products. The H ost Response chapter intro- duces the reader to the body’s response to biomaterials/foreign bodies and the infl uence of environmental conditions on the design and development of long acting injections and implants. The A natomy and Physiology chapter describes the biologi- cal features of the site of administration that are relevant to the development of long acting injections and implants. The following two chapters provide comprehensive information on drug candidates, clinical objectives, and disease states. The next series of chapters of the book focus on aspects related to the research and development of specifi c injection and implant dosage form types. In addition to the systems men- tioned above, chapters are also provided on micro- and nanoemulsions, PEGylation of nanocarriers, self-assembling lipid formulations, microfabricated technologies, drug eluting stents, delivery of peptides and proteins, and delivery of vaccines. These overviews are followed by chapters that describe and discuss special consid- erations unique to the injection route including sterilization and in vitro release test- ing (and in vivo/in vitro correlation). In the fi nal chapter of the book, an overview of the regulatory considerations associated with the registration of long acting injec- tions and implants is provided. Long Acting Injections and Implants has been written with the objective of both enlightening someone just starting in the fi eld (e.g., a new scientist or experienced scientist switching fi elds) and while at the same time providing the in-depth know- ledge that is benefi cial for a skilled worker in the fi eld. It is hoped that the reader will fi nd this volume useful and intriguing for both the variety of scientifi c system types that provide long acting therapy and for the wide range of scientifi c and tech- nical topics that are involved in the research, development, and registration of long acting injections and implants that provide state of the art therapy to patients. Cupertino, CA Jeremy C. Wright Storrs, CT Diane J. Burgess Acknowledgments A book with input from groups of contributors requires vision and coordination among a number of people. The editors would especially like to acknowledge the contributions of each team of authors who persevered through changing formats, changing timelines, and numerous e-mails from the editors and the editorial staff. The editorial staff at Springer (Carolyn Honour and Renata Hutter) was extremely cooperative and helpful as the book was compiled and edited. There would not be a book without their work. The editors would also like to acknowledge the vision of Mike Rathbone in championing this book series within the Controlled Release Society. Finally, J.C. Wright would like to acknowledge support from Durect Corporation as this volume was compiled and D.J. Burgess would like to acknow- ledge the support of her past and present graduate students and postdoctoral fellows. ix