Microscopic Models of Drug/Chemical Diffusion Through the Skin Barrier: Effects of Diffusional Anisotropy of the Intercellular Lipid

Abstract

Owing to the systematic alignment and ordering of fatty acid and ceramide chains, lipid layers in biological membranes have strongly anisotropic diffusion properties. The diffusivity D∥lip for solute transport in the direction parallel to the lipid layer is typically 103-105 times the diffusivity D⊥lip for the perpendicular direction. This article explores the consequences of this strong degree of anisotropy on solute diffusion through the stratum corneum (barrier) layer of the skin based on a realistic representation of a unit cell of the microstructure. Complementary numerical methods (smoothed particle hydrodynamics, finite differences) are used to solve the steady-state unit-cell diffusion problem leading to the average (homogenized, coarse-grained) diffusion tensor characterizing the tissue as an effective continuum. A parametric study is presented characterizing solute concentration profiles in detail for testosterone- and caffeine-like permeants, and it is shown that the results cannot be mimicked by calculations based on an isotropic lipid-phase diffusivity. The ratio of lateral to transdermal effective diffusivities calculated by the present model is of the order of 40 and 300 for fully hydrated (in vitro) and partially hydrated (in vivo) states, respectively. These values compare favorably with the results of recent experiments.