SUBDERMAL DELIVERY SYSTEMS FOR NARCOTIC ANTAGONISTS

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Controlled drug delivery from synthetic polymers is a sophisticated method of drug administration, with potential application in the study and treatment of drug abuse. To facilitate the ab initio design of delivery systems, we will continue to explore methods of estimating the diffusivity of drugs in polymers. Emphasis will be placed on identifying means by which the permeability and degradability of polymers can be manipulated. To this end, the properties of polymer blends, block copolymers, and conjugate acids and bases will be determined. The diffusion coefficients (D) of a series of peptide derivatives will be measured to establish the dependence of D on the drug MWt for different polymers. The preparation and testing of a one week delivery system for L- methadone will be completed with determination of L-methadone blood levels and evaluation of efficacy in mice. The strategy used to develop this delivery system will be applied to naltrexone: the objective will be zero order delivery of naltrexone, 3 mg/day, for approximately 1 month. Microcapsules will be prepared from epsilon-copolymers and blends of polyesters of L-Tactic acid, glycolic acid and epsilon-caprolactone, the composition being manipulated to optimize the naltrexone delivery rate and the polymer degradation. After in vitro studies, the delivery system will be tested in vivo. Studies of the feasibility of a delivery system for narcotic antagonists that is activated by the appearance of morphine in the circulatory system will be continued. The affinity constant, kinetics, and reversibility of anti-morphine antibody binding to morphine residues at the polymer surface of crosslinked aliphatic polyesters of delta-valerolactone and epsilon-caprolactone will be determined. The effects of changing the spacer arm and the density of morphine residues will be determined. Model studies of the effect of the spacer arm on the accessibility of the hapten will undertaken using a nitroxide spin label. The effect of antibody binding on the enzymatic surface erosion of cross-linked aliphatic polyesters, and the concomitant release of naltrexone, will be measured in rat.