Transdermal permeation of novel n-acetyl-glucosamine/NSAIDs mutual prodrugs.
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.
Israel
Bridg'ette
B
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia.
Garner
Solomon T
ST
Thakare
Mohan
M
Elder
Deborah
D
Abney
Trinia
T
Azadi
Parastoo
P
Beach
J Warren
JW
Price
James C
JC
Ahmed
Hisham
H
Capomacchia
Anthony C
AC
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
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