National Institute on Drug Abuse research monograph series最新文献

The evaluation of the drug release characteristic of four naltrexone delivery systems has been carried out together with the development of analytical techniques and an investigation of the metabolic profile of naltrexone. Pharmacologic evaluation of the four delivery systems in the mouse indicated significant analgesic antagonism for a period of from 16-22 days. Further evaluation of one of these systems by measurement of the rate of excretion of radioactivity after administration of radiolabelled naltrexone in the delivery system confirmed that significant release occurs for a time period of about 15 days. Electron capture gas-liquid chromatographic assays for naltrexone and naloxone in plasma or urine have been developed that yield linear calibration curves and are sensitive to one ng/ml. Studies on naltrexone disposition indicate that (a) binding to plasma proteins in several species varies from 20-26 per cent, (b) distribution of drug from blood is extremely rapid and extensive, (c) beta-naltrexol is a major metabolite of naltrexone in man, monkey and guinea pig among six species studied, whereas alpha-naltrexol is a minor metabolite in the monkey and guinea pig only, and (d) metabolic reduction of naltrexone occurs in the 100,000 x g supernatant of guinea pig liver. Pharmacokinetic studies of naltrexone in the dog and monkey indicate that the drug is rapidly distributed and eliminated, has a very large apparent volume of distribution and a total body clearance greater than the rate of liver blood flow.

Implantable polylactic/glycolic acid matrix systems have successfully provided the sustained release of naltrexone to mice for periods of up to 200 days. In vitro and in vivo release rates have been determined by measuring chemical concentrations in pH 7 buffer solution and urine, respectively, and in vivo efficacy has been measured by direct challenge with morphine (Dewey-Harris mouse tail-flick test). Dosage forms of small inplantable cylinders, 1/16 inch diameter, (25 mg/rod, one rod/mouse) containing 33 per cent by weight naltrexone pamoate in 90 L(+)/10 polylactic/glycolic acid have sustained the delivery of chemical for 200 days. Delivery of chemical from dosage forms of 1/16 inch diameter spherical beads (3 mg/bead, 3 beads/mouse) containing 33 per cent by weight naltrexone base in 90 L(+)/10 polylactic/glycolic acid was sustained for 60 days. Earlier a similar bead type dosage form of 75 L(+)/25 polylactic/glycolic acid containing 50 per cent by weight naltrexone base and coated with the pure polymer provided controlled release for 25 days. Polymerization conditions which incorporate the use of pharmacologically suitable catalysts and yield products reproducibly have beendelineated. Techniques for sterilization of the final implant have been screened.

Injectible microcapsules containing narcotic antagonists have been prepared with dl-poly (lactic acid) as the coating material. The encapsulation technology has been developed to the point that high yields of less than 180 mu capsules can be prepared routinely. Such capsules with an initial payload of 50 wt. per cent naltrexone pamoate provide 60-90 per cent antagonism to the action of morphine 28 days after injection into mice as a peanut oil/aluminum monostearate suspension at a dose level of 40 miligrams naltrexone pamoate/kg. mouse.

The object of this program is to prepare a bioerodable naltrexone delivery system which can be implanted subcataneously in human and which can relieve the narcotic antagonist over 1-6 months at relatively constant and sufficient rates to block the euphoric effect of morphine based drugs. The system is composed of naltrexone uniformly dispersed in a solid hydropholic CHRONOMER matrix which undergoes predictable surface erosion when exposed to an aqueous medium. Kinetic studies in vitro have been carried out during the course of the program to determine the best composition for the system. Toxilogical studies conducted at ALZA during the past 2 years have not revealed limiting adverse effects of either the CHRONOMER materials or their hydrolysis products. The tail-flick test procedure was used to measure the effectiveness of naltrexone to antagonize the analgesis of morphine in rats. Naltrexone infused intravenously at doses of 4 and 16 ug/kg/hr resulted in, after 6 hours, 54 and 89 per cent antagonism, respectively, against a 63.5 per cent effective dose of morphine. Preliminary sterilization studies showed that no adverse effects to CHRONOMER/naltrexone systems occurred after exposure to 2.5 or 5.0 mrads of 60Co irradiation.