An improved long-acting delivery system for narcotic antagonists

The feasibility of using cholesterol-glyceryltristearate matrix for prolonged release of naltrexone was evaluated in rats. Implantable cylindrical pellets (cholesterol 105 mg, glyceryl tristearate 15 mg and naltrexone 30 mg), diameter 4.5 mm, length 9 mm, blocked the antinociceptive action (hot plate 55 degrees C) of 10 mg/kg s.c. challenge dose of morphine in rats for 3 months. The release rate of naltrexone from 10 or 50 mg pellets approximated first-order kinetics with t1/2 alpha of 20-26 days and t1/2 beta 40-60 days. The factors affecting the release of drug from the delivery system were the ratio of cholesterol to naltrexone, drug loading level and surface area to unit volume of dosage form. The minimum release rate of naltrexone to block the effect of 10 mg/kg s.c. dose of morphine in rats was about 4 to 5 microgram/kg/hr. The cumulative urinary excretion of radioactivity from 10 mg [3H] naltrexone pellets implanted s.c. in rats after 30, 60, and 90 days was 17.7, 23.7, and 25.7% of dose respectively and the percent dose released from pellets at these times was 55.8, 68.8, and 78.2 respectively. The devices possess the desirable characteristics of simplicity, nontoxicity, nonirritability, ease of sterilization with ethylene oxide, small size for easy insertion and removal, absence of encapsulation by surrounding tissue, and an extended period of drug release unaffected by body metabolism. Neither deterioration of implant nor gross anatomic or histological changes at the site of implant occurred 6 months to 1 year after implantation and aside from some enhanced sexual activity (e.g., spontaneous penile erections) no side effects were observed in rats, which fed well and gained weight during the entire treatment. The concentrations of free morphine in brains of 30 mg naltrexone pellet-implanted rats were significantly lower (24 and 15%) as compared to the placebo controls 0.5 and 1.0 hr after a 10 mg/kg s.c. dose of [6-3H] morphine. We are currently evaluating these long-acting devices for the duration of effective antagonism to morphine in rhesus monkeys.