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.
Highlights
The in vitro and in vivo experimental measurement of skin permeability is a difficult and complex process, due in part to ethical concerns regarding human and animal experimentation
The fluxes and permeability coefficients of model permeants penetrating the skin when the compounds were applied in IHD as a vehicle were found to be significantly higher (p ≤ 0.05) than those which diffused from any other vehicles
Hansen Solubility Parameter (HSP) components to those of the membrane, and this can be evaluated by the HSP distance value being small. These results show that the use of synthetic membranes to determine the flux of permeants from oils across epidermis should be treated with care
Summary
The in vitro and in vivo experimental measurement of skin permeability is a difficult and complex process, due in part to ethical concerns regarding human and animal experimentation. A number of attempts have been made to develop quantitative structure–permeability relationship (QSPR) models of skin permeability by seeking linear correlations between observed experimental values for permeation and the physicochemical properties and/or molecular structure parameters of the chemical compounds being studied (see, e.g., [1,2,3,4,5,6,7,8,9]). Such models have been used by environmental agencies for the safety assessment of dermal exposure to industrial and environmental hazards, and by pharmaceutical companies to screen and select drugs for possible transdermal delivery potential. Different studies have showed that vehicles penetrate into the membranes and skin, affecting it through different mechanisms; these involve disruption of the intercellular lipids of the highly ordered stratum corneum (SC), interaction with intracellular proteins, or improvement of the drug partition into the stratum SC, including lipid fluidization, disruption of lipid structure, lipid extraction and irreversible protein denaturation in SC [12,13]
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