Interaction of menthol with mixed-lipid bilayer of stratum corneum: A coarse-grained simulation study

Menthol is a widely used penetration enhancer in clinical medicine due to its high efficiency and relative safety. Although there are many studies focused on the penetration-enhancing activity of menthol, the details of molecular mechanism are rarely involved in the discussion. In this study, we present a series of coarse-grained molecular dynamics simulations to investigate the interaction of menthol with a mixed-lipid bilayer model consisting of ceramides, cholesterol and free fatty acids in a 2:2:1 molar ratio. Taking both the concentration of menthol and temperature into consideration, it was found that a rise in temperature and concentration within a specific range (1-20%) could improve the penetration-enhancing property of menthol and the floppiness of the bilayer. However, at high concentrations (30% and more), menthol completely mixed with the lipids and the membrane can no longer maintain a bilayer structure. Our results elucidates some of the molecular basis for menthol's penetration enhancing effects and may provide some assistance for the development and applications of menthol as a penetration enhancer. Furthermore, we establish a method to investigate the penetration enhancement mechanism of traditional Chinese medicine using the mixed-lipid bilayer model of stratum corneum by molecular dynamics simulations. (C) 2015 Elsevier Inc. All rights reserved.