SR Drug Delivery for the Treatment of Drug Abuse

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DESCRIPTION (provided by applicant): The long-term objective of this project is to develop a novel treatment for drug abuse. Buprenorphine is a highly lipophilic partial mu-opiate agonist, which is being tested for opiate maintenance program. In order to provide long-term constant buprenorphine delivery, it is desirable to develop a sustained release formulation, which could be implanted subcutaneously. In order to deliver buprenorphine at a constant rate over a prolonged period, we propose to develop sustained release microcapsules. We hypothesize that subcutaneous administration of buprenorphine microcapsules will deliver long-term therapeutic plasma concentrations of buprenorphine. The specific aims of this proposal are to: (1) develop sustained release microcapsules of buprenorphine, (2) evaluate in vitro drug release characteristics of the microcapsules, (3) evaluate in vivo performance of the microcapsules, and (4) evaluate the long-term stability of the microcapsules. Buprenorphine microcapsules will be prepared using poly(lactide-co-glycolide) by a novel microencapsulation technique. This unique microencapsulation technique has been developed in the PI's laboratory, where the active ingredients are incorporated within a hydrogel followed by microencapsulation within a synthetic biodegradable polymer. Preliminary experiments just completed in our laboratory revealed that the use of a crosslinked hydrogel, before the microencapsulation, could significantly increase the drug loading. It also revealed that the drug was present within the hydrogel in the dissolved state. As a result, incorporation of the hydrogel significantly reduced the burst effect and overall dissoluation of the drug. The buprenorphine microcapsules will be tested in rabbits for in vivo release and biocompatibility. The microcapsules will also be tested in a rat model for agonist effect and heroin dose effect. Following the successful preclinical evaluations in rabbits and rats, this novel delivery system can be used, in the future, for evaluation in monkeys followed by human clinical trials.