Development of novel percutaneous absorption promoters

考察了薄荷醇乙醚衍生物（MET）对酮洛芬醇凝胶经皮吸收的促进作用。采用膜扩散模型对酮洛芬的经皮渗透进行了分析，并估算了酮洛芬的扩散和分配参数。当MET浓度为0.5%时，扩散系数显著增加，当MET浓度进一步增加（1-3%）时，酮洛芬的经皮渗透略有增加。另一方面，分配参数几乎没有改变，随着MET浓度的增加在水凝胶中。为了评估在体内的经皮吸收酮洛芬从水凝胶含有MET（0-3%），一个药物动力学模型推导出的假设下，一个恒定的渗透率（Rp）。与体外实验获得的结果相似，通过施用含有少量MET（~ 0.5%）的水凝胶，Rp值显著增加。薄荷醇也有这种促进作用，但促进程度不如MET，至少需要2%的薄荷醇才能达到0.5% MET的活性。当在水凝胶中配制少量MET（0.5%）时，观察到对水肿的显著抑制。需要超过2%的薄荷醇，以获得在具有0.5%MET的水凝胶中识别的相等活性，表明酮洛芬吸收的过氧乙酸的药理活性与药代动力学结果良好相关。

The promoting effect of menthol ethylether derivative (MET) on the percutaneous absorption of ketoprofen from alcoholic hydrogels was evaluated in rats. The skin permeation of ketoprofen was analyzed by a membrane diffusion model, and the diffusion and partition parameters of ketoprofen were estimated. The diffusion parameter was remarkably enhanced when the hydrogel containing 0.5% MET was applied, while further increase of MET (1-3%)resulted in a little enhancement of skin permeation of ketoprofen. On the other hand, the partition parameter was hardly changed with an increase of MET concentration in the hydrogels.To evaluate in vivo percutaneous absorption of ketoprofen from hydrogels containing MET (0-3%), a pharmacokinetic model was derived on the assumption of a constant penetration rate (Rp). Similar to the results obtained with the in vitro experiment, Rp values increased significantly by the administration of hydrogels containing a littel amount of MET (-0.5%). Such promoting action was also observed with menthol, however, the degreeof enhancement with menthol was poor, compared with MET.At least 2% of menthol was required so as obtain an equal activity observed with 0.5% MET.The anti-inflammatory action of ketoprofen hydrogels containing MET was investigated with a rat paw edema test. When a little amount of MET (0.5%) was formulated in the hydrogel, a significant inhibition to the edema was observed. More than 2% of menthol was required so as to obtain the equal activity recognized in the hydrogel with 0.5% MET, indicating that the pharmacological activity of ketoprofen absorbed percutaneously correlated well with pharmacokinetic results.