Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline, clotrimazole, flobufen, and griseofulvin.

Author(s): Hrabalek A, Dolezal P, Vavrova K, Zbytovska J, Holas T, Klimentova J, Novotny J

Affiliation(s): Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, 50012 Hradec Kralove, Czech Republic. Alexandr.Hrabalek@faf.cuni.cz

Publication date & source: 2006-05, Pharm Res., 23(5):912-9. Epub 2006 May 2.

Publication type: Research Support, Non-U.S. Gov't

PURPOSE: Dodecyl-6-aminohexanoate (DDEAC) is a transdermal permeation enhancer with excellent activity, low toxicity, and no dermal irritation. We hypothesized that DDEAC reacts with air CO2 to form a two-chain ammonium carbamate--Transkarbam 12 (T12)--which is responsible for the enhancing effect. METHODS: DDEAC and T12 were synthesized, their structures were confirmed by spectral methods, and their enhancing activity was studied using the Franz diffusion cell and human skin. A high-performance liquid chromatography method was developed for determination of T12, and its biodegradability was evaluated using porcine esterase. RESULTS: Only the carbamate salt T12 was responsible for the high enhancing activity; DDEAC tested under argon to avoid reaction with CO2 was inactive. T12 enhanced transdermal permeation of drugs covering a wide range of physicochemical properties, including theophylline (enhancement ratio up to 55.6), clotrimazole (7.7), flobufen (5.0), and griseofulvin (24). The activity was pH-dependent, further confirming the importance of the carbamate structure. The metabolization of T12 followed a second-order kinetics with t(1/2) = 31 min. CONCLUSION: Our results indicate that T12 is a promising biodegradable permeation enhancer for a wide range of drugs, and the structurally novel group of carbamate enhancers warrants further investigation.