Mechanism of oleic acid-induced skin penetration enhancement in vivo in humans

Abstract The outermost layer of mammalian skin, the stratum corneum (SC), by virtue of its unique architecture, presents a significant barrier to the transdermal delivery of drugs. Penetration enhancers such as oleic acid (OA), which increase skin permeability, appear to act selectively on the extracellular lipids representing the principal regulatory channel for the penetration of small molecules. In vitro studies investigating the mode of action of OA, have generated two mechanistic scenarios, which may account for the action of this enhancer; (a) lipid fluidization, and (b) lipid phase separation. In the studies presented here, attenuated total reflectance infrared spectroscopy was used to determine the mode of action of OA in vivo, in man. The use of perdeuterated OA ( [ 2 H]OA) enabled the behaviour of endogenous lipids to be observed independently to that of the exogenously applied enhancer as a result of their spectrally distinct methylene group vibrations. Human forearm was treated topically with 1 ml of either (a) a solution of 5% (v/v) [ 2 H] OA in ethanol, or (b) ethanol alone, for a period of 16 h. After removal of the delivery system, the SC at the application site was progressively removed by adhesive tape-stripping, while sequential IR spectra were obtained at each newly exposed surface. In this way, we were able to monitor (a) the distribution profile of [ 2 H] OA across the SC, (b) the conformational order of the SC lipids as a function of depth, and (c) the phase behaviour of the enhancer in the SC. Our results indicate that [ 2 H ] OA induces lipid disordering only in the superficial layers of the SC, albeit of a smaller magnitude than that associated with a gel to liquid crystalline conformational change. Additionally, [ 2 H] OA was found to exist in a liquid phase at all levels of the SC spectroscopically examined. These results suggest, therefore, that OA-induced skin penetration enhancement results from a mechanism involving both SC lipid fluidization and phase separation, with the latter probably predominating.