MECHANISM AND ENHANCEMENT OF SOLUTE TRANSPORT ACROSS THE STRATUM-CORNEUM

This paper summarizes recent biophysical investigations of (a) stratum corneum (SC) barrier function, and (b) percutaneous penetration enhancement. Specifically, applications of differential scanning calorimetry (DSC) and infrared spectroscopy (IR) to probe the intercellular lipid domains of the SC are described. In vitro DSC experiments on isolated SC have determined the thermal melting behavior of the membrane and have indicated the presence of lipid phase transitions in the range 65-85-degrees-C. Corresponding IR studies have confirmed this observation and, in conjunction with measurements of tritiated water permeability (K(p)), have shown that solute flux increases with the number of gauche conformers along the lipid acyl hydrocarbon chains. There is an excellent correlation between K(p) and the absorbance shift (to higher wavenumber) of the C-H antisymmetric stretching vibration associated with the SC lipids. Furthermore, it was found that certain putative penetration enhancers (e.g., cis-unsaturated fatty acids, such as oleic and vaccenic acids) induced similar shifts when applied to excised SC at ambient temperature. Concomitantly, the flux of another model solute (salicylic acid) was significantly enhanced by the treatment. The implied mechanism of penetration promotion (i.e., through the overall increased freedom of motion of the lipid acyl chains) was then examined in vivo, in humans, using attenuated total reflectance IR. Again, significant and sustained lipid disordering was induced by (in this case) oleic acid. In addition, through the assignment of unique absorbances, it was possible to obtain semi-quantitative measurements of (1) the enhancer in the upper layers of the SC, (2) the co-applied penetrant (4-cyanophenol, unequivocally identified by the intense C = N absorbance) and (3) the major vehicle component used (namely, propylene glycol, via the C-O stretching vibration). In this way, we have (i) documented the effect of the enhancer on the SC lipids, (ii) assessed the relative amount of the enhancer responsible for this action, and (iii) observed the kinetics of penetrant (solute) and solvent transport (in the presence and absence of enhancer) through the SC, from a single series of spectroscopic experiments in vivo in man. We suggest, therefore, that biophysical measurements of this type have considerable potential, often in clinically relevant situations, to reveal the crucial details of the mechanism and enhancement of solute transport across the SC.