Modeling the effect of experimental variables on the in vitro permeation of six model compounds across porcine skin

Abstract

A majority of quantitative structure-permeability relationships (QSPeRs) predict the permeability coefficient (k(p)) of compounds topically applied as infinite, saturated doses from water vehicles. Alternate delivery vehicles and other experimental variables are rarely incorporated in such models. This research presents the development and statistical validation of QSPeR models that incorporate the effects of penetrant, vehicle, and experimental conditions such as dose volume (finite/infinite), and saturation level (saturated/unsaturated). A composite parameter, a mixture factor (MF), was also included to account for the physicochemical properties of the compound/vehicle mixture components. The resultant models effectively described skin flux and absorption, identifying the summation of hydrogen bond acidity and basicity, excess molar refractivity, dose volume, saturation level, and vehicle as the most prominent factors influencing flux values. The main factors influencing absorption values were the summation of hydrogen bond basicity, dipolarity/polarizability, the McGowan characteristic volume, dose volume, saturation level, and vehicle. The same MF (inverse of the melting point) was considered suitable to describe both flux and absorption. For endpoints involving skin deposition, log propylene glycol solubility was a more suitable MF. Such models show potential for use in drug delivery and toxicology research, specifically in assessing percutaneous absorption data collected under different experimental conditions.