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

为了阐明药物的透皮机制和促渗剂的作用机制，我们研究了苯甲酸衍生物、对羟基苯甲酸烷基酯和5-氟尿嘧啶衍生物的结构-渗透性相关性，以及促渗剂对这些药物的吸收的影响及其作用机制。对苯甲酸衍生物在离体猪背部皮肤中的渗透性研究表明，苯甲酸衍生物的渗透性是由其正辛醇/水分配系数和分子量（分子大小）决定的。观察了15%乙醇、1%薄荷醇的15%乙醇溶液和N-十二烷基-2-吡咯烷酮作为渗透促进剂的作用，发现这些促进剂能显著提高亲水性药物的渗透系数，并显著降低渗透系数对正辛醇/水分配系数的依赖性。另一方面，当加入乙醇或L-薄荷醇乙醇溶液时，相对疏水性药物的渗透系数反而降低。角质层脂质体的自旋标记研究表明，这些透皮促进剂增加脂质双层的流动性与其促进亲水性药物经皮渗透的作用相一致。离体豚鼠背部皮肤中5-dyxylstearic酸的电子自旋共振光谱显示存在不动组分，并且在15%乙醇中的1%L-薄荷醇存在下其消失。结果提示，促渗剂系统对角质层的扰动可能与其对亲水性药物的促渗作用有关。

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.