In-silico model of skin penetration based on experimentally determined input parameters. Part I: Experimental determination of partition and diffusion coefficients

Mathematical modeling of skin transport is considered a valuable alternative of in-vitro and in-vivo investigations especially considering ethical and economical questions. Mechanistic diffusion models describe skin transport by solving Fick's 2nd law of diffusion in time and space; however models relying entirely on a consistent experimental data set are missing. For a two-dimensional model membrane consisting of a biphasic stratum corneum (SC) and a homogeneous epidermal/dermal compartment (DSL) methods are presented to determine all relevant input parameters. The data were generated for flufenamic acid (M-w 281.24 g/mol; log K-oct/H2O 4.8; pK(a) 3.9) and caffeine (Mw 194.2 g/mol; log K-Oct/H2O -0.083; pK(a) 1.39) using female abdominal skin. K-lip/don. (lipid-donor partition coefficient) was determined in equilibration experiments with human SC lipids. K-cor/lip (corneocyte-lipid) and K-DSL/lip (DSL-lipid) were derived from easily available experimental data, i.e. K-SC/don (SC-donor), K-lip/don, and K-SC/DSL (SC-DSL) considering realistic volume fractions of the lipid and corneocyte phases. Lipid and DSL diffusion coefficients D-lip and D-DSL were calculated based on steady state flux. The corneocyte diffusion coefficient D-cor is not accessible experimentally and needs to be estimated by simulation. Based on these results time-dependent stratum corneum concentration-depth profiles were simulated and compared to experimental profiles in an accompanying study. (c) 2007 Elsevier B.V. All rights reserved.