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.
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Acknowledgments
We thank Iva Vencovská for the measurement of the IR spectra, John MacLeod from The Research School of Chemistry, Australian National University, Canberra, for measurement of the mass spectra, and Bochemie Ltd., Bohumín, Czech Republic, for providing the toxicity data. This work was supported by the “Centre for New Antivirals and Antineoplastics” (1M6138896301) and the Research Project MSM0021620822 of the Ministry of Education, Youth and Sport of the Czech Republic.
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Hrabálek, A., Doležal, P., Vávrová, K. et al. Synthesis and Enhancing Effect of Transkarbam 12 on the Transdermal Delivery of Theophylline, Clotrimazole, Flobufen, and Griseofulvin. Pharm Res 23, 912–919 (2006). https://doi.org/10.1007/s11095-006-9782-y
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DOI: https://doi.org/10.1007/s11095-006-9782-y