title: Transdermal permeation of novel n-acetyl-glucosamine/NSAIDs mutual prodrugs.
abstract: The current investigation reports skin permeation of three novel mutual prodrugs (MP) which couple n-acetyl-glucosamine with an NSAID, either ketoprofen or ibuprofen. They were evaluated for transdermal permeation using shed snakeskin, and to our knowledge represent the first MPs synthesized for this purpose, although they also could be used for subcutaneous delivery. MPs are defined as two active drug compounds usually connected by an ester linkage. Glucosamine administration has been linked to damaged cartilage repair, and pain relief in joints afflicted with osteoarthritis. NSAIDs are commonly used orally in transdermal creams or gels for joint pain relief. Two novel compounds we report (MP1 and MP2) covalently link ibuprofen and ketoprofen directly to the amide nitrogen of n-acetyl-glucosamine (NAG); the other compound (MP3) covalently links ibuprofen to the amide nitrogen, using a short chain acetyl linker. Permeability studies show that the ketoprofen mutual prodrug (MP2) permeates shed snakeskin more than three times greater than either ibuprofen derivative, while ethanol markedly increases the permeation for all three. The ketoprofen mutual prodrug appears the most likely candidate for transdermal administration; all three mutual prodrugs may be candidates for subcutaneous injection.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia.
authors.forename: Bridg'ette
authors.initials: B
authors.lastname: Israel
authors.forename: Solomon T
authors.initials: ST
authors.lastname: Garner
authors.forename: Mohan
authors.initials: M
authors.lastname: Thakare
authors.forename: Deborah
authors.initials: D
authors.lastname: Elder
authors.forename: Trinia
authors.initials: T
authors.lastname: Abney
authors.forename: Parastoo
authors.initials: P
authors.lastname: Azadi
authors.forename: J Warren
authors.initials: JW
authors.lastname: Beach
authors.forename: James C
authors.initials: JC
authors.lastname: Price
authors.forename: Hisham
authors.initials: H
authors.lastname: Ahmed
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Capomacchia
mesh_terms: D000117:Acetylglucosamine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000279:Administration, Cutaneous; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability; D004338:Drug Combinations; D000431:Ethanol / Q000494:pharmacology; D006868:Hydrolysis; D007052:Ibuprofen / Q000008:administration & dosage / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007660:Ketoprofen / Q000008:administration & dosage / Q000493:pharmacokinetics; D007700:Kinetics; D011355:Prodrugs; D012869:Skin Absorption; D012911:Snakes; D012995:Solubility; D012997:Solvents
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D007202:Indicators and Reagents; D011355:Prodrugs; D012997:Solvents; D000431:Ethanol; D007660:Ketoprofen; D000117:Acetylglucosamine; D007052:Ibuprofen