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Narcotic Antagonists: NALTREXONE PHARMACOCHEMISTRY and SUSTAINED-RELEASE PREPARATIONS

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Narcotic Antagonists: NALTREXONE PHARMACOCHEMISTRY AND SUSTAINED-RELEASE PREPARATIONS U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service • Alcohol. Drug Abuse • and Mental Health Administration Narcotic Antagonists: Naltrexone Pharmacochemistry and Sustained-Release Preparations Editors: Robert E. Willette, Ph. D. Gene Barnett, Ph. D. NIDA Research Monograph 28 1981 DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse Division of Research 5600 Fishers Lane Rockville, Maryland 20657 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 The NIDA Research Monograph series is prepared by the Division of Research of the National Institute on Drug Abuse. Its primary objective is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, integrative research reviews and significant original research. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community Editorial Advisory Board Avram Goldstein, M.D. Addiction Research Foundation Palo Alto, California Jerome Jaffe, M,D. College of Physicians ond Surgeons Columbia University, New York Reese T. Jones, M.D. Langley Porter Neuropsychiatric Institute University of California Scn Fransico, California William McGlothlin, Ph.D. Department of Psychology, UCLA Los Angeles, California Jack Mendelson, M.D. Alcohol and Drug Abuse Research Center Harvard MedicaI School McLean Hospital Belmont, Massachusetts Helen Nowlis, Ph.D. Office of Drug Education DHHS Washington, D.C. Lee Robins, Ph.D. Washington University School of Medicine St. Louis, Missouri NIDA Research Monograph series William Pollin, M.D. DIRECTOR, NIDA Marvin Snyder, Ph.D. DIRECTOR, DIVISION OF RESEARCH, NIDA Robert C. Petersen, Ph.D. EDITOR-IN-CHIEF Eleanor W. Waldrop MANAGING EDITOR Parklawn Building 5600 Fishers Lane, RockviIle, Maryland 20857 Narcotic Antagonists: Naltrexone Pharmacochemistry and Sustained-Release Preparations ACKNOWLEDGMENTS This monograph is based on papers presented at a technical review on the clinical pharmacochemistry of naltrexone, held at Parklawn Building, Rockville, Maryland, on May 30 and 31, 1919. The National Institute on Drug Abuse has obtained permission from the Pharmaceutical Society of Great Britain to reprint a portion of the data in An Improved Long-Acting Delivery System for Narcotic Antagonists, by Anand L. Misra and Ronald B. Pontani, as noted in the text. Further reproduction of this material without specific permission of the copyright holder is prohibited. All other material, except short quoted passages from copyrighted sources, is in the public domain and may be used and reproduced without permission. Citation as to source is appreciated. The United States Government does not endorse or favor any specific commercial product or commodity. Trade names or sup pliers’ names appearing in this publication are used only be cause they are considered essential in the context of the studies reported herein. Library of Congress catalog card number 81-600021 DHHS publication number (ADM)81-902 Printed 1981 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of BioSciences In- formation Service, Chemical Abstracts, Current Contents, Psy- chological Abstracts, and Psychopharmacology Abstracts. iv FOREWORD With increasing frequency, Federal agencies are being called upon to evaluate and develop new drugs and treatments for a wide variety of diseases and related conditions. The so-called “orphan” drugs, or drugs of little or limited commercial value, are being shunned by the pharmaceutical industry, due primarily to the ever-increasing developmental costs and risks associated with new drugs. Thus, within the Public Health Service, a drug development effort has emerged to fill this void. The United States Congress has charged the National Institute on Drug Abuse with the responsibility to develop and provide drug- dependent people with adequate and, if necessary, new treatment methods. Amongst the many approaches undertaken have been ef- forts to develop drug therapies to serve as adjuncts to psychologic and sociologic efforts. The two principal initiatives have focused on the maintenance drug, levo-alpha-acetylmethadol (LAAM), and the narcotic antagonist, naltrexone. The continuing accounts of mile- stones in their development have been presented in numerous scien- tific and medical articles and summarized in several volumes of this Research Monograph series. We consider this volume to repre- sent volume 5 in our series on Drug Development. The first of this series, Monograph 4, Narcotic Antagonists: The Search for Long-Acting Preparations, represented a status report on early efforts to develop such a preparation for naltrexone. Mono- graph 8, Rx:3x/Week LAAM, Alternative to Methadone, and Mono- graph 9, Narcotic Antagonists: Naltrexone Progress Report, de- scribed progress on LAAM and naltrexone, respectively, as the In- stitute’s newly established drug development program was fully un- derway. In a departure from these advanced developmental pro- grams, basic concepts in the design of new agents was the subject of Monograph 22, Quantitative Structure Activity Relationships of Analgesics, Narcotic Antagonists, and Hallucinogens. Previous volumes on naltrexone have detailed the conceptual ap- proach to the use of a narcotic antagonist or agent that blocks the effects of heroin or other opioids. Of the early drugs tested, naltrex- one emerged as the most promising. It is currently under clinical v evaluation, with a strong likelihood of being marketed in oral form within the next year or so. Although this will provide a blocking drug with three-times-a-week dosage, it is felt that a longer-acting drug or dosage form would be more desirable in the treatment of narcotic addiction. It has been nearly five years since we published Monograph 4. At that time we summarized many promising ap- proaches and interesting leads. Some of these encouraged us to feel that at least one of the preparations would be ready for clinical trials within the near future. That day has continued to elude us, but we are now much wiser and more experienced and presently have a preparation in hand that awaits a clinical trial. In this volume, we summarize the most promising of the ap- proaches pursued over the past several years. General overviews of the background for chemical and pharmacological decisions are given. In addition, details of the analytical methods for measuring naltrexone levels, the pharmacokinetics of naltrexone in test ani- mals and man, and the development and manufacture of clinical materials are presented. We expect this volume to help serve as a guide to other efforts in the area of drug development for long- acting drug preparations. The Editors vi CONTENTS Foreword The Editors v PART I INTRODUCTION AND OVERVIEW Historical Perspective on the Chemistry and Development of Naltrexone Sydney Archer 3 Treatment of Heroin-Dependent Persons With Antagonists: Current Status Pierre Renault 11 PART II ANALYTICAL METHODS An Electron-Capture Gas Chromatographic Assay for Naltrexone in Biological Fluids R. H. Reuning, S. B. Ashcraft, and B. E. Morrison 25 Quantitative Determination of Naltrexone, 6 ß-Naltrexol and 2-Hydroxy-3-methoxy-6ß-naltrexol (HMN) in Human Plasma, Red Blood Cells, Saliva and Urine by Gas Liquid Chromatography Karl Verebey 36 Analytical Methods for Quantitative and Qualitative Analysis of Naltrexone and Metabolites in Biological Fluids Monroe E. Wall and Dolores R. Brine 52 PART III PHARMACOLOGY Background on Animal Testing in the Drug Delivery Systems Program William L. Dewey 69 Pharmacological Evaluation of Narcotic Antagonist Delivery Systems in Rhesus Monkeys Stephen E. Harrigan and David A. Dawns 77 vii A Comparative Study of the Oral, Intravenous, and Subcutaneous Administration of 3H Naltrexone to Normal Male Volunteers Mario Perez-Reyes and Monroe E. Wall 93 PART IV METABOLISM The Metabolism of Naltrexone in Man Monroe E. Wall, Dolores R. Brine, and Mario Perez-Reyes 105 Current Status of Preclinical Research on Disposition, Pharmacokinetics, and Metabolism of Naltrexone Anand L. Misra 132 The Clinical Pharmacology of Naltrexone: Pharmacology and Pharmacodynamics Karl Verebey 147 PART V PHARMACOKINETICS Overview of Human Pharmacokinetics of Naltrexone Vojtech Licko 161 Pharmacokinetic Quantitation of Naltrexone Release From Several Sustained-Release Delivery Systems R. H. Reuning, S.H.T. Liao, and A.E. Staubus 172 PART VI SUSTAINED-RELEASE SYSTEMS A Review of Parenteral Sustained-Release Naltrexone Systems James L. Olsen and Fred A. Kincl 187 Development of Drug Delivery Systems for use in Treatment of Narcotic Addiction A. Carl Sharon and Donald L. Wise 194 Use of Synthetic Polypeptides in the Preparation of Biodegradable Delivery Systems for Narcotic Antagonists Kenneth R. Sidman, Arthur D. Schwope, William D. Steber, and Stephen E. Rudolph 214 Biodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Application to Contraceptives and Narcotic Antagonists Colin G. Pitt, Thomas A. Marks, and Anton Schindler 232 An Improved Long-Acting Delivery System for Narcotic Antagonists Anand L. Misra and Ronald B. Pontani 254 viii Solid Solutions as Long-Acting Naltrexone Delivery Systems James L. Olsen 265 Participants in Technical Review 272 List of Monographs 274
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