The permeability enhancing mechanism of menthol on skin lipids: a molecular dynamics simulation study

The stratum corneum (SC), the outermost layer of skin, represents the primary barrier to molecules penetrating the skin. Menthol is widely used in clinical medicine as a penetration enhancer due to its high efficiency and relative safety. In this study, molecular dynamics simulations have been performed to investigate the effect of menthol molecules on the structural and permeability of both single component and ternary mixed bilayers. The lipid matrix is modeled as pure ceramide (CER2) or as a 2: 2: 1 mixture of CER2, cholesterol (CHOL), and free fatty acid (FFA). The effect of menthol on the SC bilayer was investigated at various concentrations of menthol. For both models, the area per lipid decreases and the membrane thickness increases with increased menthol concentration, which may be due to the fact that menthol molecules penetrate into the bilayer and aggregate at the bilayer center. As for ternary mixed bilayer at high concentration, the lipids rearranged, and one more layer formed inside the former two leaflets. Our simulation results are consistent with the experimental evidence that high concentrations of menthol fluidize the SC lipids and enhance permeability. The penetration enhancement of menthol may take place through direct interactions with lipids rather than by forming water pores.