title: A duplex "Gemini" prodrug of naltrexone for transdermal delivery.
abstract: Transdermal naltrexone delivery is desirable in the treatment of narcotic dependence and alcoholism. The purpose of this study was to increase the delivery rate of naltrexone (NTX) across human skin by using a novel prodrug. A duplex "gemini" prodrug of naltrexone was synthesized and evaluated. In vitro human skin permeation rates of naltrexone and prodrug were measured using a flow-through diffusion cell system. Drug concentrations in the skin were quantitated at the end of the diffusion experiment. The prodrug was hydrolyzed on passing through the skin and appeared mainly as naltrexone in the receiver compartment. The prodrug provided a significantly higher naltrexone equivalent flux across human skin in vitro than naltrexone base. The naltrexone equivalent solubilities of naltrexone and the prodrug in the donor solution were not significantly different. No significant increase in drug concentration in the skin after prodrug treatment, as compared to naltrexone, was observed. The naltrexone equivalent permeability from the prodrug exceeded the permeability of naltrexone base by two-fold. Due to the design of this prodrug, toxicities associated with this compound should be nonexistent, because only naltrexone and carbon dioxide (carbonic acid) are released when the prodrug is cleaved.
authors.affiliation: Division of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, 900 Rose St., Lexington, KY 40536-0082, USA.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Hammell
authors.forename: Mohamed
authors.initials: M
authors.lastname: Hamad
authors.forename: Haranath K
authors.initials: HK
authors.lastname: Vaddi
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; D002152:Calorimetry, Differential Scanning; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects; D012995:Solubility; D013997:Time Factors
chemical_list: C500352:3,3'-di-(N-cyclopropylmethyl-4,5-epoxy-14-hydroxymorphinan-6-one-3-yl)carbonate; D009292:Narcotic Antagonists; D011355:Prodrugs; D009271:Naltrexone