Straight-chain naltrexone ester prodrugs: diffusion and concurrent esterase biotransformation in human skin.

Naltrexone (NTX) is an opioid antagonist used for treatment of narcotic dependence and alcoholism. Transdermal naltrexone delivery is desirable to help improve patient compliance. The purpose of this study was to increase the delivery rate of NTX across human skin by using lipophilic alkyl ester prodrugs. Straight-chain naltrexone-3-alkyl ester prodrugs of 2-7 carbons in chain length were synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The melting points, solubilities, and skin disposition of the drugs were determined. The prodrugs were almost completely hydrolyzed on passing through the skin and appeared as NTX in the receiver compartment. The mean NTX flux from the prodrug-saturated solutions exceeded the flux of NTX base by approximately 2-7-fold. The amount of drug detected in the skin was significantly greater after treatment with the prodrug solutions compared with treatment with NTX base. The extent of parent drug (NTX) regeneration in the intact skin ranged from 28 to 91%. Higher NTX regeneration percentages in skin appeared to correlate with increased drug delivery rates. Definitively, the highly oil-soluble prodrugs provide a higher NTX flux across human skin in vitro and undergo significant metabolic conversion in the skin. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2571-2578, 2002