The development of sustained action preparations of narcotic antagonists

2015

The use of narcotic antagonists in the treatment of opiate addiction is based on the concept of a pharmaceutical agent capable of blocking the reinforcing properties of a dose of opiate taken during an addicts rehabilitation. The rationale for use is that the antagonist blocks the opiate “high” and makes it pleasureless, thus removing the addict’s incentive for continued use. Earlier successful therapy with cyclazocine and naloxone prompted the full-scale development of new and superior antagonists. Presently naltrexone is the drug under the most intensive clinical evaluation and appears to be a promising antagonist candidate.

It was felt from the outset that a most desirable component of antagonist therapy would be long-acting drug, so that the need for an addict to decide to take his medication would be minimized. Naltrexone in oral doses of 70 mg. will provide adequate blocking protection for at least 48 hours, or perhaps 72 hours in certain individuals. This is not felt to be a long enough interval between dosages to aid the addict in becoming dissociated from his drug-taking behavior.

It was recognized very early that in order to achieve the desired one week, one month or longer duration between dosages, it would be necessary to develop a long-acting drug delivery system or a sustained-release preparation of an acceptable but short-acting antagonist. A “drug-delivery system” is the unwieldy but currently favored expression describing any pharmaceutical preparation capable of providing a sustained or long-acting antagonistic effect. This effect may be achieved mechanically (e.g., by implanted discs with timed release capacity) or chemically (e.g., microcapsules, tubes, solid balls, gelatinous masses injected intramuscularly). Distinct from the problem not considered here, of finding an optimum antagonist, is the problem of inventing suitable carriers for the antagonist, releasing it uniformly bit by bit over a period of time.

Efforts to achieve satisfactory drug delivery systems were launched in the early 1970’s by the City of New York Public Health Department and by the NIMH Division of Narcotic Addiction and Drug Abuse, now the National Institute on Drug Abuse (NIDA).

During this early period, the pioneering efforts of Dr. Seymour Yolles, University of Delaware, demonstrated for the first time that a sustained-release of an antagonist could be obtained from a biodegradable polymer, i.e., polylactic acid. This success generated expanded and intensified efforts, a summary of which is the topic of this article. At the present time, the program supported by NIDA includes six contracts that are concerned with the development of new delivery systems and three contracts that have the responsibility of evaluating them for potential clinical trials. The program is now narrowing down on those candidates that appear to have the best combination of essential properties to assure a successful clinical trial.

System design specifications

There are several properties and features that are important characteristics in the design and development of a clinically acceptable and useful delivery system. Some of these are:

  1. 1. Adequate and smooth drug release rate;
  2. 2. Ease of insertion or injection;
  3. 3. Consideration for the difficulty of removal by the patient versus the desirability of possible removal by the physician;
  4. 4. Biocompatability or lack of adverse tissue reaction or pain upon injection;
  5. 5. Ease and expense of manufacture;
  6. 6. Stability to sterilization;
  7. 7. Stability and storage characteristics;
  8. 8. Patient and physician acceptability.

Each of these considerations has a different relative importance and it is the task of the development team to select the optimal compromise of suitable specifications in order to bring a candidate preparation into clinical trial. It is recognized that the first trial preparation may not be the ideal system and that additional refinement may be necessary before a system could be introduced into wide clinical usage.

Development plan

In the Spring of 1973, a new program for the development of a long-acting narcotic antagonist was initiated. It consisted of two contracts and two grants directed at the design and preparation of candidate delivery systems. Each group was also responsible for carrying out preliminary screening of the systems by in vitro and in vivo tests to select those that had the most promising release properties. This group included work on polylactide microcapsules, polylactide-polyglycolide beads, polyglyceride pellets and an insoluble salt complex, the later three having been originated under the earlier program supported by New York City.

In addition to these projects, three contracts were let to carryout in centrallized facilities the evaluation of all promising candidates emerging from the developers. These consist of a multiple level pharmacological and pharmacokinetic testing schedule as well as a range of toxicological measures. The overall scheme was designed in a pyrimidal fashion with more rigorous criteria required to pass from one level to the next.

At the heart of this plan was the recognition that an advisory group composed of scientists from several relevant areas was essential to assist in monitoring progress and making the difficult decisions about which leads to pursue. Their dedication and loyalty to the program has played a critical role in its success. The group has consisted of for more or less of the length of the program: Drs. Sidney Archer, William L. Dewey, James T. Doluisio. Fred A. Kincl. Fred Leonard. and James L. Olsen. Others, including Drs. Joseph Borzelleca, Douglas R. Flanagan, Stanley Kurtz, Grant Wilkinson and Ann Wolven, have also provided important input. Valuable advice and sharing of information has come from Drs. Gabrial Bialy and Henry Gablenick from the Center of Population Research, NICHHD, where a similar Program for long-acting antifertility agents is being supported.

At the present time the program has narrowed down to concentrate on four systems that have demonstrated the most promise. These will be described next.

Candidate delivery systems

Arthur D. Little, Inc.

In order to minimize the amount of animal testing required to receive FDA approval for an early clinical trial, it was felt desirable to select a system that is capable of being removed at the end of a month, but would eventually be able to be left implanted. A preparation that meets these and the other criteria is a tiny hollow tube of a synthetic polypeptide composed of a 35/65 copolymer of glutamic acid and leucine. Slowly biodegradable, these 2 mm by 10 to 20 mm tubes are filled with a solid core of naltrexone free base, which diffuses out through the tube wall. Rates of release may be adjusted by varying the wall thickness.

The tubes are manufactured in a fashion similar to candles, with a fine glass mandrel being dipped at a controlled rate into a heated solution of the polymer. The tubes are removed, filled with a little saline, a solid rod of 90% naltrexone bound in polymer, and sealed with a ca Sterilization is readily achieved with autoclaving.

Samples of these tubes have demonstrated up to 60 day sustained release. Current devices are releasing 10 to 30 micrograms of naltrexone per hour, which may be low for human needs. Devices capable of delivering higher amounts are being tested. Work on variations in polymer structure is being carried out in order to achieve a faster rate of biodegradation.

This work is under the general supervision of Mr. Kenneth Sidman.

Polylactic/glycolic Acid Beads Dynatech Corporation

Potentially removable by a surgeon, these 1/16 inch beads of 90/10 polylactic and glycolic acid copolymer offer flexibility in dose administration. Implantable by means of a trocar, the 70% naltrexone free base loaded beads have shown continuous release for more than a month. Samples of beads have been periodically removed from injection sites and examined for biodegradation. They gradually soften, grow smaller or crumble, and eventually become undetectable.

Problems that remain to be overcome are sterilization, production scale-up and reproducibility of polymer synthesis. The latter still presents some difficulties because of the desire to produce polymers without metal catalysts.

This work has been directed by Dr. Donald Wise.

Polylactic Acid Microcapsules Washington University

Two major advantages of a microcapsule approach to drug delivery is their potential for zero-order release rates and inject-ability. To date microcapsules of less than 180 microns of micronized particles of naltrexone pamoate coated with dl-polylactic acid have shown sustained release for more than forty days. They have been injected to date as a suspension in 2% aluminum monostearate gel in peanut oil. Other vehicles are being tried.

Additional work is still underway on perfecting capsules of naltrexone free base, which is more desirable as higher payloads of drug may be achieved and less toxicology would be required. A suitable sterilization procedure has not been worked out as yet. Several methods are being tested and advanced testing will be initiated as soon as these are ready.

These systems have been developed by Dr. Kurt Thies.

Naltrexone Aluminum Tannate IITRI

Based on older formulation approaches, this insoluble aluminum tannate complex of naltrexone, when injected intramuscularly in a suspension of 2% aluminum monostearate peanut oil gel, gives a sustained release of over thirty days. The complex is readily prepared and easy to sterilize.

In preliminary studies on tissue compatibility, relatively little reaction was seen. It is known, however, that peanut oil suspensions are prone to cause occasional reactions. This preparation would require an extensive amount of toxicological testing in order to undergo human trials.

This preparation was developed by Dr. Allan Gray.

Evaluation procedures

Preliminary Screening

Each developer was responsible for carrying out screening of trial preparations by in vivo and in vitro methods. The test used by all groups was the mouse tail flick method of Dewey and Harris. Animals were injected or implanted with the preparation and at various intervals, different groups were injected with morphine and their analgetic response measured for continued antagonism.

Some variations in in vitro tests were used, with the primary purpose of being to establish a correlation with the animal tests. Eventually, only the in vitro methods became necessary for general screening. As a follow-up to the animal testing, injection sites were examined for gross pathological reactions. Usually if nothing is observed by eye, little is found upon histology.

Advanced Pharmacological Evaluation

At Ohio State University under the direction of Dr. Richard Reuning, all candidate systems selected from preliminary screening were tested in the mouse tail flick test under standard conditions. Those systems showing unusual promise were then tested in rats using radiolabeled drug and the pharmacokinetics of release were studied.

In the course of developing suitable test procedures, considerable work was done on the metabolism and pharmacokinetics of naltrexone. This was essential for the calculation of actual release rates of the systems themselves.

Advanced Toxicological Evaluation

As candidate systems pass on through the pharmacological testing, they were evaluated in parallel at Industrial Bio-Test by Mr. Carmen Mastri. Depending on the dosage form being tested, the systems were implanted or injected into mice, rats and intramuscularly in rabbits. The last is the classical U.S.P. irritation test. When possible suitable positive and negative control materials were run concurrently.

Final Animal Evaluations

The most promising candidates eventually find there way into the most rigorous evaluation. The pharmacological test is carried out in monkeys that are trained to self-administer morphine. Developed at Parke, Davis and Company by Dr. Duncan McCarthy the suppression of morphine administration is an indication of how long the system delivers an effective level of naltrexone. At the same time, samples of plasma are obtained at various intervals and analyzed by the Ohio State group to determine the exact amount of drug released. Correlation of this data with pharmacokinetic measures of naltrexone in the same animals has given a thorough characterization of the candidate systems.

One of these candidates will soon be started in a detailed toxicological evaluation also at Parke-Davis. This will involve three species at three dose levels. Periodic sacrifices will be made to obtain a detailed pathological evaluation. The protocol will be designed so as to assure an early clinical trial based on the idea of removing the test system at the end of one month.

Summary

After several years of tedious and often frustrating efforts, a few promising systems are now near final evaluation with the intention of conducting a human trial in the near future.

 

Selections from the book: “Narcotic Antagonists: Naltrexone”. Editors: Demetrios Julius, M.D., and Pierre Renault, M.D. Progress report of development, pre-clinical and clinical studies of naltrexone, a new drug for treatment of narcotic addiction. National Institute on Drug Abuse Research Monograph 9. September 1976.