mechanism of percutaneous penetration enhancement: effect of n-alkanols on the permeability barrier of hairless mouse skin

To examine the action of alcohols on skin barrier function, we have: (a) determined, in vitro, how pretreatment of hairless mouse skin with a homologous series of n-alkanols (C₂-C₁₂) enhances the transport of a model penetrant (nicotinamide); (b) measured the skin uptake and permeation of the alkanols themselves during the pretreatment period; and (c) correlated the data from these two sets of experiments with biophysical evaluation of the pretreated murine stratum corneum using Fourier transform infrared spectroscopy (FT-IR). Following 3 or 6 h pretreatment, nicotinamide flux was increasingly enhanced with increasing alkanol carbon number up to C₆. The effect of octanol was similar to that of hexanol, but decanol was less efficacious and dodecanol continued this diminishing trend. While skin uptake of the alkanols increased linearly with increasing lipophilicity (i.e., increasing chain length), the cumulative penetration (in 6 h) of the homologs was a parabolic function of C_n similar to the nicotinamide enhancement profile. FT-IR analysis of ethanol-pretreated hairless mouse skin revealed considerable extraction of stratum corneum intercellular lipids; the appearance of these lipids in the pretreatment liquid could also be measured spectroscopically. The same extraction phenomenon was also apparent when pretreatment was performed with butanol and octanol. For these homologues, removal of stratum corneum lipids was shown unequivocally by FT-IR through the use of perdeuterated alkanols, thereby separating the C-H(D) signals from intercellular lipid and penetration enhancer. Lipid extraction, therefore, is implicated as the mechanism by which alkanols promote transdermal penetration. Because of the efficiency of lipid removal in these experiments, it was not possible to determine if additional, and possibly more subtle, effects (e.g., "fluidization" of stratum corneum lipid domains) are also induced by alkanols.