Multivariate Analytical Approaches to Identify Key Molecular Properties of Vehicles, Permeants and Membranes That Affect Permeation through Membranes

Abstract

There has been considerable recent interest in employing computer models to investigate the relationship between the structure of a molecule and its dermal penetration. Molecular permeation across the epidermis has previously been demonstrated to be determined by a number of physicochemical properties, for example, the lipophilicity, molecular weight and hydrogen bonding ability of the permeant. However little attention has been paid to modeling the combined effects of permeant properties in tandem with the properties of vehicles used to deliver those permeants or to whether data obtained using synthetic membranes can be correlated with those obtained using human epidermis. This work uses Principal Components Analysis (PCA) to demonstrate that, for studies of the diffusion of three model permeants (caffeine, methyl paraben and butyl paraben) through synthetic membranes, it is the properties of the oily vehicle in which they are applied that dominated the rates of permeation and flux. Simple robust and predictive descriptor-based quantitative structure–permeability relationship (QSPR) models have been developed to support these findings by utilizing physicochemical descriptors of the oily vehicles to quantify the differences in flux and permeation of the model compounds. Interestingly, PCA showed that, for the flux of co-applied model permeants through human epidermis, the permeation of the model permeants was better described by a balance between the physicochemical properties of the vehicle and the permeant rather than being dominated solely by the vehicle properties as in the case of synthetic model membranes. The important influence of permeant solubility in the vehicle along with the solvent uptake on overall permeant diffusion into the membrane was substantiated. These results confirm that care must be taken in interpreting permeation data when synthetic membranes are employed as surrogates for human epidermis; they also demonstrate the importance of considering not only the permeant properties but also those of both vehicle and membrane when arriving at any conclusions relating to permeation data.

The Influence of Oily Vehicle Composition and Vehicle-Membrane Interactions on the Diffusion of Model Permeants across Barrier Membranes

“…The sources of materials employed in this study have been given previously [ 11 , 15 ]. All of the materials employed were obtained from commercial suppliers, and used as received.…”

“…The assay used to analyze the permeants has been described previously [ 11 , 15 ]. A Symmetry 5 µm BDS (C18), 150 X 4.6 mm (5 µm) (Waters, Milford, MA, USA) was used for all three permeants.…”

“…Solubility studies were conducted in accordance with previously published methodology [ 11 , 15 ]. In brief, an excess amount of MP, BP or CF was shaken in the medium of interest for 48 h at a temperature of 32 °C.…”

“…Solubility studies were conducted in accordance with previously published methodology [11,15]. In brief, an excess amount of MP, BP or CF was shaken in the medium of interest for 48 h at a temperature of 32 • C. After filtration to remove undissolved material and appropriate dilution, the filtrate was assayed for permeant, using the appropriate assay.…”