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.

Department of Inorganic and Organic Chemistry Faculty of Pharmacy Charles University Prague Heyrovského 1203 50012 Hradec Králové Czech Republic

See more in PubMed

Curr Med Chem. 2005;12(19):2273-91 PubMed

J Pharm Sci. 1996 Feb;85(2):150-4 PubMed

Arzneimittelforschung. 1997 May;47(5):648-52 PubMed

J Invest Dermatol. 1975 Mar;64(3):190-5 PubMed

Chem Phys Lipids. 2004 Apr;129(1):97-109 PubMed

Arch Dermatol. 1982 Jul;118(7):474-7 PubMed

Chem Rev. 2003 Oct;103(10):3857-98 PubMed

J Biophys Biochem Cytol. 1955 Jan;1(1):13-6 PubMed

J Control Release. 2005 May 5;104(1):41-9 PubMed

Drug Des Deliv. 1990 Jun;6(2):87-100 PubMed

Pharm Res. 1993 Jul;10(7):1015-9 PubMed

Nat Rev Drug Discov. 2004 Feb;3(2):115-24 PubMed

Adv Drug Deliv Rev. 2004 Mar 27;56(5):603-18 PubMed

Proline, hydroxyproline, and pyrrolidone carboxylic acid derivatives as highly efficient but reversible transdermal permeation enhancers

Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug Delivery

Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids

Enhanced topical and transdermal delivery of antineoplastic and antiviral acyclic nucleoside phosphonate cPr-PMEDAP

Dimethylamino acid esters as biodegradable and reversible transdermal permeation enhancers: effects of linking chain length, chirality and polyfluorination