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) 281.24g/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.
Hansen
Steffi
S
Saarland University, Department of Biopharmaceutics and Pharmaceutical Technology, Saarbruecken, Germany.
Henning
Andreas
A
Naegel
Arne
A
Heisig
Michael
M
Wittum
Gabriel
G
Neumann
Dirk
D
Kostka
Karl-Heinz
KH
Zbytovska
Jarmila
J
Lehr
Claus-Michael
CM
Schaefer
Ulrich F
UF
D004058:Diffusion; D005260:Female; D005439:Flufenamic Acid / Q000493:pharmacokinetics*; D006801:Humans; D008954:Models, Biological; D012869:Skin Absorption
D005439:Flufenamic Acid