Synthesis and Enhancing Effect of Transkarbam 12 on the Transdermal Delivery of Theophylline, Clotrimazole, Flobufen, and Griseofulvin
- 227 Downloads
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.
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.
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.
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.
Key Wordsammonium carbamate biodegradability permeation enhancer transdermal drug delivery
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.
- 4.Büyüktimkin, N., Büyüktimkin, S., Rytting, J. H. 1997Chemical means of transdermal drug permeation enhancementGhosh, T. K.Pfister, W. R. eds. Transdermal and Topical Drug Delivery SystemsInterpharm PressBuffalo Grove, IL357476Google Scholar
- 12.A. Hrabálek, P. Doležal, O. Farsa, A. Krebs, A. Kroutil, M. Roman, and Z. Šklubalová. ω-Amino acid derivatives, processes of their preparation and their use. U.S. Pat. 6,187,938 (2001).Google Scholar
- 13.R. Ibuki. Ph.D. Thesis. University of Kansas, Lawrence, 1985.Google Scholar
- 14.Hrabálek, A., Doležal, P., Palát, K. 2000Physico-chemical parameters and skin permeation enhancing effect of ω-amino acid derivativesBrain, K. R.Walters, K. A. eds. Perspectives in Percutaneous Penetration, Vol 7ASTS PublishingCardiff70Google Scholar
- 23.Report No. 031/04/L. Repeated Dose 28-Day Dermal Toxicity Study in Rat with a 14-Day Treatment-Free Period. In accordance with OECD Guidelines for Testing of Chemicals No. 410. Bochemie Ltd., Bohumín, Czech Republic (2005).Google Scholar
- 24.Report No. 017/04/L. Acute Oral Toxicity in Rats, Acute Toxic Class Method. In accordance with OECD Guidelines for Testing of Chemicals No. 423. Bochemie Ltd., Bohumín, Czech Republic (2004).Google Scholar
- 25.Report No. 025/04/L. Acute Dermal Irritation/Corrosion—Rabbit. In accordance with OECD Guidelines for Testing of Chemicals No. 404. Bochemie Ltd., Bohumín, Czech Republic (2004).Google Scholar
- 26.Report No. 024/04/L. Skin Sensitisation in Guinea Pigs. In accordance with OECD Guidelines for Testing of Chemicals No. 406. Bochemie Ltd., Bohumín, Czech Republic (2004).Google Scholar
- 27.Report No. 027/04/L. Bacterial Reverse Mutation Test. In accordance with OECD Guidelines for Testing of Chemicals No. 471. Bochemie Ltd., Bohumín, Czech Republic (2004).Google Scholar
- 28.Report No. 023/04/L. Micronucleus Test in Rats. In accordance with OECD Guidelines for Testing of Chemicals No. 474. Bochemie Ltd., Bohumín, Czech Republic (2004).Google Scholar