Modeling the Percutaneous Absorption of Solvent-Deposited Solids Over a Wide Dose Range.

Abstract

The transient absorption of two skin care agents, niacinamide (nicotinamide, NA) and methyl nicotinate (MN), solvent-deposited on ex vivo human skin mounted in Franz diffusion cells has been analyzed according to a new variation on a recently published mechanistic skin permeability model (Yu et al. 2020. J Pharm Sci 110:2149-56). The model follows the absorption and evaporation of two components, solute and solvent, and it includes both a follicular transport component and a dissolution rate limitation for high melting, hydrophilic solids deposited on the skin. Explicit algorithms for improving the simulation of transient diffusion of solvent-deposited solids are introduced. The simulations can account for the ex vivo skin permeation time course of both NA and MN over a dose range exceeding 4.5 orders of magnitude. The model allows one to describe on a mechanistic basis why the percutaneous absorption rate of NA is approximately 60-fold lower than that of its lower melting, more lipophilic analog, MN. It furthermore suggests that MN perturbs stratum corneum barrier lipids and increases their permeability while NA does not, presenting a challenge to molecular modelers engaged in simulating biological lipid barriers.