Menthol is an often used skin penetration enhancer because of its high efficiency and relative safety, but the mechanism how it works has not been fully understood up to date. In this study, quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. The skin is modeled as a ceramide (CER2) bilayer. Potential of mean force (PMF) calculations on quercetin in both CER2 and menthol-involved CER2 bilayers have been performed. The results show that the free energy minimum of quercetin in the presence of menthol molecules shifts toward the headgroup region of the bilayer, and the central energy barrier decreases, facilitating the penetration of quercetin. The presence of menthol molecules enhances the permeability of quercetin. This study may shed light on the mechanism of penetration enhancer, providing useful information in the design of more efficient transdermal drug delivery system. Graphical abstract Quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. Potential of mean force calculations reveal that the central energy barrier of quercetin decreases in the presence of menthol, facilitating the penetration of quercetin. Our results are helpful to understand the mechanism of penetration enhancer, aiding in the design of more efficient transdermal drug delivery system.
Keywords: Ceramide; Menthol; Molecular dynamics; Permeability enhancer; Quercetin.