Transdermal delivery of indomethacin and levonorgestrel using clofibric acid amides as penetration enhancers

The enhancing properties of clofibric acid amides on the transdermal delivery of indomethacin and levonorgestrel were studied in vitro using full-thickness hairless mouse skin. The enhancers possessed alkyl side chains varying from 2 (1) to 16 (7) carbons. Indomethacin was applied in propylene glycol and levonorgestrel in 1-butanol, and all enhancers were applied at 0.4 M in propylene glycol 1 h prior to drug treatment. 1-Butanol was chosen as the vehicle for levonorgestrel since it was found to deliver more drug transdermally than propylene glycol. Since this was a volatile solvent, all experiments with levonorgestrel were performed under occlusion. The greatest increases in permeability coefficients and skin retention of model drugs were observed with compounds 4, 5, and 6. The permeability coefficient enhancement ratio (ER) for indomethacin and 4 was 3.1, for 5 was 10.9, and for 6 was 14.6. Skin content ER values were 4.6, 5.3, and 1.8, respectively. Levonorgestrel permeability coefficient ER values were lower, 1.6 for 4, 2.6 for 5, and 1.9 for 6. Skin content ER values for this model drug were 1.7, 4.3, and 2.3, respectively. Azone, however, was less effective than 5 and 6 for both model drugs with respect to permeability coefficients and 24-h receptor concentrations. For skin contents and indomethacin, 2-7 were more effective than Azone, and for levonorgestrel, 5, 6, and 7. Indomethacin enhancement was dependent on concentration of enhancer 6 (0.1, 0.2, 0.4, 0.6, 0.8 M), the maximum being observed for 0.4, 0.6, and 0.8 M. Permeation enhancement of both drugs was dependent on the length of the alkyl side chain of the enhancer. It is proposed that these compounds may be useful for transdermal drug delivery, although further testing needs to be performed.