title: In-silico model of skin penetration based on experimentally determined input parameters. Part I: experimental determination of partition and diffusion coefficients.
abstract: 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) 281.24g/mol; logK(Oct/H2O) 4.8; pK(a) 3.9) and caffeine (M(W) 194.2g/mol; logK(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.
authors.affiliation: Saarland University, Department of Biopharmaceutics and Pharmaceutical Technology, Saarbruecken, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Hansen
authors.forename: Andreas
authors.initials: A
authors.lastname: Henning
authors.forename: Arne
authors.initials: A
authors.lastname: Naegel
authors.forename: Michael
authors.initials: M
authors.lastname: Heisig
authors.forename: Gabriel
authors.initials: G
authors.lastname: Wittum
authors.forename: Dirk
authors.initials: D
authors.lastname: Neumann
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Kostka
authors.forename: Jarmila
authors.initials: J
authors.lastname: Zbytovska
authors.forename: Claus-Michael
authors.initials: CM
authors.lastname: Lehr
authors.forename: Ulrich F
authors.initials: UF
authors.lastname: Schaefer
mesh_terms: D004058:Diffusion; D005260:Female; D005439:Flufenamic Acid / Q000493:pharmacokinetics*; D006801:Humans; D008954:Models, Biological; D012869:Skin Absorption
chemical_list: D005439:Flufenamic Acid