Relating the concentration-dependent action of Azone and dodecyl-L-pyroglutamate on the structure of excised human stratum corneum to changes in drug diffusivity, partition coefficient and flux

Abstract

The concentration-dependent effects of the two lipophilic permeation enhancers Azone and dodecyl-L-pyroglutamate (dlp) on excised human stratum corneum have been examined. Stratum corneum (SC) memranes were prepared having enhancer loadings within the range 0–30% w/w, and transport and structural experiments conducted with them. The permeation of the model drug diazepam through the enhancer-loaded SC membranes was measured, and drug diffusitives, partition coefficients and fluxes determined. For this calculation, a non-steady state model for permeation through an isotropic membrane valid for non-sink boundary conditions was used. With enhancer loadings up to approx. 12% w/w, the diffusitive increased whilst the partition coefficient remained constant. The diffusivity apparebtly decreased at higher loadings. Careful consideration of the results indicated that the application of the model at high enhancer loadings was questionable. By using differential scanning calorimetry, it was found that the skin lipid ‘melting’ peak progressively disappeared with increasing loading with enhancer. This occurred with approx. 12% Azone; for dlp, more than 25% was required. At high enhancer loadings, crystallized dodecyl-L-pyroglutamate was detected within the stratum corneum preparation. The concentration dependence of these changes in stratum corneum structure and barrier properties could be compared to those found previously with insoluble monolayers of skin lipids.