A multiscale study of the penetration-enhancing mechanism of menthol

Abstract

Abstract Objective Transdermal drug delivery systems represent a critical focus in the pharmaceutics field; however, their use is limited by the fact that many drugs usually pass through the skin with low permeability. Menthol is a common penetration enhancer because of its high penetration-enhancing efficiency and safety. Our research aimed to reveal the penetration-enhancing mechanisms of menthol via a multiscale study. Methods First, the interaction of menthol with the stratum corneum was studied using vertical Franz diffusion cells obtained from the abdominal skin of rats as a model. Then, the skin samples were observed via transmission electron microscopy. Finally, the interaction of different concentrations of menthol with a mixed lipid model of the stratum corneum was investigated via molecular dynamics simulation using the GROMOS 54A7 force field on a microcosmic level. Results At concentrations of 3.5% or lower, menthol changed the original structure of the stratum corneum to varying degrees, which increased its fluidity and facilitated the permeation and storage of menthol. Menthol increased the fluidity of the stratum corneum mainly via two mechanisms. First, menthol had strong hydrogen-bonding capability, and it could compete for the lipid–lipid hydrogen bonding sites, thereby weakening the stability of the hydrogen-bonding network connecting the skin lipids. In addition, menthol had strong affinity for cholesterol, probably due to their similar molecular structures, suggesting that the incorporation of menthol would increase the fluidity of the lipid membrane similarly to cholesterol. Conclusion The penetration-enhancing mechanism of menthol was explained using in vitro and molecular dynamics simulation methods. These findings may advance the basic research of transdermal drug delivery systems and facilitate the discoveries of novel penetration enhancers.