Effect of Penetration Enhancers on the Permeation of Drugs across a Three-Dimensional Cultured Human Skin Model: Comparison with the Effects Using Excised Hairless Rat Skin
Tetsuya Watanabe1, Tetsuya Hasegawa1, Hidekazu Takahashi2, Takuya Ishibashi2 and Kenji Sugibayashi1
1 Josai University, 2 Toyobo Co., Ltd.
Correspondence: Kenji Sugibayashi, Ph.D.
Faculty of Pharmaceutical Sciences, Josai University
1-1 Keyakidai, Sakado, Saitama 350-0295, Japan.
Tel: 0492-71-7943, Fax: 0492-71-7943, E-mail: sugib@josai.ac.jp

Original paper :AATEX 8(1):15-22
Effect of penetration-enhancers on the skin permeation of drugs was evaluated using a three-dimensional cultured human skin model, Living Skin Equivalent-high (LSE-high), which consists of stratum corneum, viable epidermis and dermis. Seven kinds of potential enhancers (diisopropyl adipiate, isopropyl myristate, lauryl alcohol, d-limomen, l-menthol, N-methyl-2-pyrrolidone and oleic acid) were used, and isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) were selected as a model hydrophilic and a lipophilic drug, respectively. The membrane permeation experiments were carried out using the LSE-high as well as excised hairless rat skin as a control. Every enhancer at a concentration of 3 % showed a penetration-enhancing effect on the drug permeation across the LSE-high as it did across the hairless rat skin. Interestingly, the rank order of the enhancement effect in LSE-high was similar to that in the hairless rat skin, although the effect across the LSE-high was lower than that across the hairless rat skin. In addition, the enhancing effect against the ISMN permeation was more marked than that against the ISDN permeation for both types of skin. Concentration dependence of enhancers for their promoting effect was then evaluated using l-menthol, that showed the highest effect among the enhancer systems used in this study. As results, 3 and 10 % l-menthol exhibited the highest effect on the skin permeation of ISMN and ISDN, respectively, for both skins. These findings suggest that LSE-high may be utilized as an alternative membrane when testing the promoting effect of absorption enhancers on the skin permeation of drugs.
Keywords: three-dimensional cultured human skin model, alternative membrane, penetration enhancer, skin permeation, isosorbide-5-mononitrate, isosorbide dinitrate