title: Enhancement of transdermal delivery of 6-beta-naltrexol via a codrug linked to hydroxybupropion.
abstract: 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-beta-naltrexol. The purpose of this study was to increase the delivery of 6-beta-naltrexol across human skin in vitro via a novel codrug. A carbonate codrug of 6-beta-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-beta-naltrexol and hydroxybupropion, in the receiver solution. The codrug provided a significantly (p<0.05) higher 6-beta-naltrexol flux across human skin than 6-beta-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-beta-naltrexol delivery rates.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Kiptoo
authors.forename: Mohamed O
authors.initials: MO
authors.lastname: Hamad
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Audra L
authors.initials: AL
authors.lastname: Stinchcomb
mesh_terms: D000279:Administration, Cutaneous; D016642:Bupropion / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D012869:Skin Absorption / Q000187:drug effects* / Q000502:physiology
chemical_list: D004337:Drug Carriers; D016642:Bupropion; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; C496215:radafaxine