Distributed diffusion-clearance model for transient drug distribution within the skin

Quantitative predictions of molecular transport rates through the skin are key to the development of topically applied and transdermally delivered drugs, as well as risk assessment associated with dermal exposure. Most research to date has focused on correlations for the permeability of the stratum corneum, and transient diffusion models that oversimplify vascular clearance processes in terms of a perfect-removal boundary condition at an artificially introduced lower boundary. Considerations of the spatially distributed nature and action of blood vessels have usually been limited to the steady-state case. This article describes a more comprehensive transient model of percutaneous absorption formulated in terms of volumetric dispersion and clearance coefficients reflecting the spatial distribution of vascular processes. The model was implemented through an analysis of published experimental results on in vivo permeation of salicylic acid (SA) in de-epidermized rat skin. With regard to the characterization of SA in rat dermis ("de") in vivo, it was found that: (i) SA is likely to have a dermal effective partition coefficient (relative to pH 7.4 aqueous buffer "pH7.4") around unity (K _de/pH7.4 = 0.9 ± 0.3); (ii) vascular processes seem not to increase drug dispersion significantly beyond molecular diffusion [D _de ∼ (D_de)_mol = (8 ± 3) · 10^-7 cm² s^-1]; and (iii) vascular clearance is characterized by a rate coefficient k_de = (7 ± 2) · 10^-4 s^-1. Application of a whole-skin variant of the model (including the stratum corneum and viable epidermis) allowed realistic predictions to be made of transient subsurface concentration levels after application from a finite dose.