Skin penetration enhancement of mefenamic acid by ethanol and 1,8-cineole can be explained by the ‘pull’ effect

The simultaneous skin permeation of drug and penetration enhancer have been studied in vitro. Simple formulations of mefenamic acid in PEG400 incorporating various proportions of ethanol or 1,8-cineole were prepared and applied to porcine ear skin in diffusion cells under infinite conditions. Receptor phases were assayed for mefenamic acid by HPLC and ethanol or 1,8-cineole by GC. Concentration-dependent permeation profiles were obtained for both ethanol or 1,8-cineole, in addition to concentration-dependent enhancement of mefenamic acid. When the steady state flux of mefenamic acid was plotted against ethanol or 1,8-cineole, linear relationships were observed with r2 values of 0.988 and 0.999, respectively. The close connection between rates of excipient and solute permeation is generally referred to as the ‘pull’ (or ‘drag’) effect, where in this case permeation of the enhancer facilitated permeation of the solute. This appears to be sufficient to account for the enhancing activity of ethanol and 1,8-cineole, notwithstanding initial modulations that may occur within the stratum corneum.