Fluidity of Stratum Corneum Lipid Lamella and Mechanism of Effect of Penetration Enhancers

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In order to clarify the mechanism of transdermal drug penetration and the mechanism of effect of penetration enhancers, we examined the structure-permeability correlation of benzoic acid derivatives, alkyl parabens and 5-fluorouracil derivatives and the effect of penetration enhancers on the absorption of these drugs and their mechanism. The study on the benzoic acid derivatives in excised quinea pig dorsal skin revealed that permeability of the derivatives was determined by their n-octanol/water partition coefficinent and molecular weight (molecular size). We observed the effects of 15% ethanol, 1% L-menthol in 15% ethanol and N-dodecyl-2-pyrrolidone as penetration enhancers, and found that these enhancers markedly increased the permeability coefficients of hydrophilic durgs and dependency of the permeability coefficients on n-octanol/water partition coefficients significantly decreased. On the other hand, permeability coefficients of relatively hydrophobic drugs rather decreased when ethanol or L-menthol in ethanol was added. Spin label study with stratum corneum lipid liposomes revealed that fluidity of lipid bilayr increased by these penetration enhancers corrsponded with their enhancing effects on skin nenetration of hydrophilic drugs. Electron spin resonance spectra of 5-dyxylstearic acid in excised guinea pig dorsal skin revealed the presence of immobile component and its disappearance in the presence of 1% L-menthol in 15% ethanol. These results suggest that the perturbation of stratum corneum by enhancer system, which is possibly related with its penetration enhancing effect on hydrophilic drugs.