National Institute on Drug Abuse research monograph series最新文献

We evaluated the ability of close to 100 organic acids to form water-soluble salts with methadone, cyclazocine, naloxone, naltrexone and, more recently, diprenorphine. About half the acids yielded insoluble salts. Polybasic acids affording insoluble salts were evaluated for their ability to form drug:acid:metal complexes with the polyvalent metal ions, Zn++, Al+++, Mg++ and Ca++. Optimum conditions for forming complexes have been developed and the consistency of their composition has been established. Salts were analyzed spectrophotometrically for drug content, and complexes were analyzed for drug and metal content. The in vitro degree of dissociation at equilibrium was measured for the preparations suspended in a simulated physiological buffer, pH 7.3. Preparations of the narcotic antagonist drugs showing relatively low degrees of dissociation in vitro, since it early appeared that a high degree of dissociation contraindicated a prolonged duration of pharmacological action, were evaluated in mice after intramuscular administration at several dose levels by the mouse tail-flick test for the potency and duration of their morphine antagonist activity. Our most promising preparations to date, showing the most prolonged durations of action without evidence of gross toxicity, are naltrexone zinc tannate and naltrexone aluminum tannate. These are undergoing detailed evaluation as potential clinical candidates. Thus far, the most useful of several dosage forms studied is s suspension in an aluminum monostearate gel.

Synthetic polypeptides consisting of copolymers of glutamic acid and leucine have been shown to be useful materials for the fabrication of practical, biodegradable delivery vehicles for narcotic antagonists. Model delivery vehicles in film form were prepared from copolymers containing 10 mole percent to 40 mole percent glutamic acid, and loaded with 10% to 40% naltrexone by weight. The naltrexone was found to be released by diffusion, exhibiting diffusion coefficients that varied as a function of the glutamic acid content and the initial naltrexone loading. A wide range in diffusion coefficients were achieved (0.31 x 10(-7) cm2/hr to 120 x 10(-7) cm2/hr), leading to release rates within practical ranges of interest for meeting the program goals. We have demonstrated that the polypeptides can be fabricated into dosage forms that are amenable to administration by trochar. For example, rods 0.4 mm to 0.8 mm in diameter containing as much as 40% naltrexone by weight were extruded using a simple compression mold and die arrangement. An in vitro evaluation of the rods showed that antagonist is released by diffusion at a continuously decreasing rate, a behavior similar to that observed with the film devices that were, nonetheless, capable of blocking an AD80 challenge of morphine sulfate in mice for more than 30 days. One of the most promising delivery vehicles that we have developed to date consists of a polypeptide tube filled with a naltrexone/polypeptide core. Preliminary experiments have shown that these devices may be capable of administering high, constant rates of release for prolonged periods of time. Additional work, however, is required to develop techniques for the preparation of reproducible delivery vehicles.

Solid dispersions of naltrexone in natural glycerides were used to form injectable implants which continously release narcotic antagonists in vivo. The dispersions were formed and tested either as small cylindrical pellets, e.g. 1x3.0 mm in size, or as particles with diameters in size ranges between 125-250 mu, that are suspended in an aqueous methyl cellulose solution. Both types of implants delivered naltrexone to mice at rates that were effective in blocking the antiociceptive action of morphine for at least one month. The rate of naltrexone release was controlled by altering its concentration in the dispersion and by varying the glyceride composition. Degradation and absorption of the implants were found to depend on their composition, dimensions and location in the body. No appreciable tissue incompatibility was seen in mice, rats, rabbits, monkeys and swine, even when long-lasting preparations were removed a year after treatment.