Transdermal delivery of levonorgestrel. VIII. Effect of enhancers on rat skin, hairless mouse skin, hairless guinea pig skin, and human skin

Abstract

The penetration enhancing effect of ethyl acetate, with or without ethanol as a cosolvent, was evaluated in vitro on rat skin, hairless mouse skin, hairless guinea pig skin, and human cadaver skin using the contraceptive drug levonorgestrel. Under the influence of the enhancers, the relative skin permeability of levonorgestrel through the four skin types showed a clear trend: hairless mouse skin >hairless guinea pig skin ∼ rat skin > human skin. These results show that rodent skins are poor models for human skin under the conditions used. The steady-state flux of levonorgestrel through human skin was increased about 7-fold 0.03 μg/cm 2 h vs 0.2 μg/cm 2 h when neat ethyl acetate was used in place of ethanol as the donor vehicle. Adding polyethylene glycol 400 (PEG 400; 40% v/v in saline) to the receptor solution increased the steady-state flux of levonorgestrel through human skin only slightly relative to saline as a receptor solution. The lag time of levonorgestrel through human skin was longer relative to that for the rodent skins tested. The flux of ethyl acetate and ethanol through all the skins was also measured. The rodent skins were all much more permeable towards both solvents than was human skin. For each skin type tested, there appeared to be a direct correlation between the cumulative amount of solvent permeating through the skin and the cumulative amount of drug permeating through the skin.