Mechanistic skin penetration model by the COSMOperm method: routes of permeation, vehicle effects and skin variations in the healthy and compromised skin

Abstract A computational skin model has been constructed, representing the composition of a human skin, including short- and long chain ceramides, cholesterol and fatty acids in the stratum corneum, and differentiated model systems in the viable epidermis. The COSMOperm based method uses a set of membrane systems to predict skin permeabilities with an accuracy of rmsd  = 0.72 log k p units for both non-polar and polar substances, including ionic protonation states. The membrane systems can be varied to model different grades of hydration and skin penetration enhancers. In addition, the release of substances from vehicle matrices is taken into account. The COSMOperm method calculates substance-specific free energy and diffusion profiles within a biological barrier of interest from COSMO-RScalculations. They are based on first-principle quantum chemical structures and surface polarities. The skin model was constructed using a new methodology called COSMOplex , originally developed for a self-consistent simulation of inhomogeneous surfactant, micelle and microemulsion systems. The skin penetration results are obtained quickly within minutes, i.e., many orders of magnitude faster than with molecular dynamics simulations. It will be shown that this mechanistic model should be able to cover variations of the skin composition and penetration pathways in the healthy and compromised skin.