MECHANISM OF OLEIC ACID-INDUCED SKIN PENETRATION ENHANCEMENT IN-VIVO IN HUMANS

The outermost layer of mammalian skin, the stratum corneum (SC), by vi rtue of its unique architecture, presents a significant barrier to the transdermal delivery of drugs. Penetration enhancers such as oleic ac id (OA), which increase skin permeability, appear to act selectively o n the extracellular lipids representing the principal regulatory chann el for the penetration of small molecules. In vitro studies investigat ing the mode of action of OA, have generated two mechanistic scenarios , which may account for the action of this enhancer; (a) lipid fluidiz ation, and (b) lipid phase separation. In the studies presented here, attenuated total reflectance infrared spectroscopy was used to determi ne the mode of action of OA in vivo, in man. The use of perdeuterated OA ([H-2]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 forear m was treated topically with 1 ml of either (a) a solution of 5% (v/v) [H-2] OA in ethanol, or (b) ethanol alone, for a period of 16 h. Afte r removal of the delivery system, the SC at the application site was p rogressively removed by adhesive tape-stripping, while sequential LR s pectra were obtained at each newly exposed surface. In this way, we we re able to monitor (a) the distribution profile of [H-2]OA across the SC, (b) the conformational order of the SC lipids as a function of dep th, and (c) the phase behaviour of the enhancer in the SC. Our results indicate that [H-2] OA induces lipid disordering only in the superfic ial layers of the SC, albeit of a smaller magnitude than that associat ed with a gel to liquid crystalline conformational change. Additionall y, [H-2] 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 invol ving both SC lipid fluidization and phase separation, with the latter probably predominating.