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 / H2 O} 4.8; pK_a 3.9) and caffeine (M_W 194.2 g/mol; log K_{Oct / H2 O} -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.