In-Silico Skin Model: A Multiscale Simulation Study of Drug Transport.

Accurate in-silico models are required to predict the release of drug molecules through skin in order to supplement the in-vivo experiments for faster development/testing of drugs. The upper most layer of the skin, stratum corneum (SC), offers the main resistance for permeation of actives. Most of the SC's molecular level models comprise cholesterol and phospholipids only, which is far from reality. In this study we have implemented a multiscale modeling framework to obtain the release profile of three drugs, namely, caffeine, fentanyl, and naphthol, through skin SC. We report for the first time diffusion of drugs through a realistic skin molecular model comprised of ceramides, cholesterol, and free fatty acid. The diffusion coefficients of drugs in the SC lipid matrix were determined from multiple constrained molecular dynamics simulations. The calculated diffusion coefficients were then used in the macroscopic models to predict the release profiles of drugs through the SC. The obtained release profiles were in good agreement with available experimental data. The partition coefficient exhibits a greater effect on the release profiles. The reported multiscale modeling framework would provide insight into the delivery mechanisms of the drugs through the skin and shall act as a guiding tool in performing targeted experiments to come up with a suitable delivery system.