Promoting activity of menthol derivatives containing sulfur atom on the percutaneous absorption of drugs

合成硫薄荷酚衍生物，并评价其对大鼠酮洛芬经皮吸收的促进作用。在假定酮洛芬在皮肤中经过一段时间后的透入速率恒定的前提下，建立了酮洛芬在水凝胶中吸收的表观透入速率（R_p）。作为硫薄荷酚衍生物促进活性的指标，将增强因子E_f定义为含有增强剂的R_p值与不含增强剂的对照的R_p值之比。这些衍生物引起的皮肤刺激是用显微镜下研究切除皮肤的横截面上的酮洛芬水凝胶应用。总刺激评分（TIS）是通过皮肤几个部位的每个刺激评分的总和来估计的。计算了硫薄荷酚衍生物的配分系数（log P）和位阻能等理化参数，并通过多元回归分析考察了这些参数与E_f值或TIS值之间的定量关系。结果表明，log P与E_f之间呈抛物线关系。在TIS病例中也观察到类似的关系。采用核磁共振光谱法测定硫薄荷酚衍生物的化学位移等结构参数，并考察其与Ef值或TIS值之间的定量关系。结果表明，硫薄荷酚衍生物的C-2和C-6位置的化学位移对促进剂的促进活性有负向影响，而C-4和H-1位置的化学位移对促进剂的促进活性有正向影响。在TIS病例中也观察到类似的关系。这些结果对设计具有较强促进活性的增强剂的化学结构具有一定的指导意义。

Thiomenthol derivatives were synthesized and their promoting activity on the percutaneous absorption of ketoprofen from hydrogels was evaluated in rats. The apparent penetration rate (R_p) of ketoprofen absorbed from the hydrogel was estimated by the pharmacokinetic model derived under the assumption of a constant penetration rate through the skin after a lag time. As an index of promoting activity of thiomenthol derivatives, an enhancement factor (E_f) was defined as the ratio of the R_p value with enhancer to the value obtained with the control not containing enhancer. Skin irritancy evoked by these derivatives was investigated microscopically by using a cross section of the excised skin on to which ketoprofen hydrogel was applied. Total irritation score (TIS) was estimated by summation of each irritation score in several parts of the skin. The physicochemical parameters of thiomenthol derivatives such as a partition coefficient (log P) and a steric energy were calculated and the quantitative relationships between these parameters and the E_f values or TIS values were investigated on the basis of multiple regression analysis. As a result, a parabolic relationship between log P and E_f was noted. A similar relationship was also observed in the case of TIS.The structure parameters of thiomenthol derivatives such as chemical shifts were measured by NMR spectroscopy, and the quantitative relationships between these parameters and the Ef values or TIS values were investigated. It was concluded that the chemical shift at C-2 and C-6 positions of thiomenthol derivatives negatively affected the promoting activity of enhancers, but those of C-4 and H-1 positions positively affected it. A similar relationship was also observed in the case of TIS.These results is effective in order to design chemical structure of enhancers with strong promoting activity.