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

• Published in: European journal of pharmaceutics and biopharmaceutics 2008-02, Vol.68 (2), p.352-367
• Main Authors: Hansen, Steffi, Henning, Andreas, Naegel, Arne, Heisig, Michael, Wittum, Gabriel, Neumann, Dirk, Kostka, Karl-Heinz, Zbytovska, Jarmila, Lehr, Claus-Michael, Schaefer, Ulrich F.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Caffeine; Diffusion; Diffusion coefficient; Female; Flufenamic acid; Flufenamic Acid - pharmacokinetics; General pharmacology; Humans; Medical sciences; Modeling skin penetration; Models, Biological; Partition coefficient; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Skin Absorption; Tape-stripping
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2007.05.012

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 / H 2 O 4.8; p K a 3.9) and caffeine ( M W 194.2 g/mol; log K Oct / H 2 O −0.083; p K 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.