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

Steffi Hansen, Andreas Henning, Arne Naegel, Michael Heisig, Gabriel Wittum, Dirk Neumann, Karl Heinz Kostka, Jarmila Zbytovska, Claus Michael Lehr, Ulrich F. Schaefer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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 (MW 281.24 g/mol; log KOct / H2 O 4.8; pKa 3.9) and caffeine (MW 194.2 g/mol; log KOct / H2 O -0.083; pKa 1.39) using female abdominal skin. Klip/don (lipid-donor partition coefficient) was determined in equilibration experiments with human SC lipids. Kcor/lip (corneocyte-lipid) and KDSL/lip (DSL-lipid) were derived from easily available experimental data, i.e. KSC/don (SC-donor), Klip/don and KSC/DSL (SC-DSL) considering realistic volume fractions of the lipid and corneocyte phases. Lipid and DSL diffusion coefficients Dlip and DDSL were calculated based on steady state flux. The corneocyte diffusion coefficient Dcor 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.

Original languageEnglish (US)
Pages (from-to)352-367
Number of pages16
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume68
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • Caffeine
  • Diffusion coefficient
  • Flufenamic acid
  • Modeling skin penetration
  • Partition coefficient
  • Tape-stripping

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science

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