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

[Display omitted] •The penetration enhancing effects and mechanisms of menthol have been clarified on mesoscopic level.•Both concentration of menthol and temperature effect are taken into discussion in this work, which comprehensively provides some assistance for the development and applications of new preparations containing menthol.•The mixed-lipid bilayer model of stratum corneum (SC) consisting CER, CHOL and FFA in a 2:2:1 molar ratio is first adopted in the exploration of penetration enhancement mechanism of traditional Chinese medicine, and we have proved the feasibility of that SC model using in the exploration of this kind of works. 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.