Enhancement of transdermal delivery of 6-β-naltrexol via a codrug linked to hydroxybupropion

Naltrexone (NTX) is a potent opioid antagonist used in the treatment of alcohol dependence and heroin abuse. Compared with naloxone, NTX has a longer duration of action largely attributed to its major active metabolite, 6-β-naltrexol. The purpose of this study was to increase the delivery of 6-β-naltrexol across human skin in vitro via a novel codrug. A carbonate codrug of 6-β-naltrexol linked to hydroxybupropion was synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The drug melting points, solubilities, chemical stability, and skin disposition were determined. The carbonate codrug was hydrolyzed on passing through skin and appeared as a combination of intact codrug and parent drugs, 6-β-naltrexol and hydroxybupropion, in the receiver solution. The codrug provided a significantly (p < 0.05) higher 6-β-naltrexol flux across human skin than 6-β-naltrexol base. The extent of parent drug regeneration in the skin ranged from 56 to 86%. A higher stratum corneum partition coefficient and rapid bioconversion of the carbonate codrug in the skin correlated with increased 6-β-naltrexol delivery rates.