BIODEGRADABLE POLYMERIC PRODRUGS OF NALTREXONE

[摘要] The development of a biodegradable polymeric drug delivery system for the narcotic antagonist naltrexone may improve patient compliance in the treatment of opiate addiction. Random copolymers consisting of the alpha-amino acids N5-(3-hydroxypropyl)-L-glutamine and L-leucine were synthesized with equimolar initial monomer feeds. The molecular weight of this chemical carrier was determined by viscometry and wide-angle light scattering. In order to get selective covalent coupling of drug to polymer the 3-acetate derivative and the 14-acetate derivative of naltrexone were synthesized and characterized by NMR. Hydrolytic conversion of each monoacetate to parent drug was monitored by HPLC and the rate constant was determined. Both derivatives were coupled via hydrolytically labile carbonate linkages to the polymer hydroxyl groups. The drug conjugates were prepared as particles of various size ranges between 20 and 350-mu. In vitro studies in phosphate-buffered saline (pH 7.4) demonstrated a release rate dependence on particle size. Nearly constant plasma levels of naltrexone were obtained for one month after subcutaneous injection in rats.

[发布日期] 1991-06-01

[关键词] BIODEGRADABLE;NALTREXONE;NARCOTIC ANTAGONIST;POLY (ALPHA-AMINO ACIDS)