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

合成了硫代薄荷醇衍生物，并评价了其对酮洛芬水凝胶透皮吸收的促进作用。根据药物动力学模型推算水凝胶中酮洛芬的表观渗透率(Rp)，该模型假定在滞后时间后皮肤渗透速率恒定。作为硫代薄荷醇衍生物促进活性的指标，定义了增强因子(E_F)，即含有增强剂的Rp值与不含增强剂的对照的Rp值之比。这些衍生物引起的皮肤刺激性是通过使用应用酮洛芬水凝胶的切除皮肤的横截面进行显微镜研究的。总刺激性评分(TIS)由皮肤多个部位的每个刺激性评分的总和来估算。计算了硫代薄荷醇衍生物的分配系数(LogP)和空间能等物理化学参数，并在多元回归分析的基础上研究了这些参数与Ef值和TIS值之间的定量关系。结果表明，对数P与E_f之间存在抛物线关系。用核磁共振波谱测定了硫薄荷醇衍生物的化学位移等结构参数，并研究了这些参数与EF值或TIS值之间的定量关系。结果表明，硫代薄荷醇衍生物C-2和C-6位的化学位移对促进剂的促进活性有负面影响，而C-4和H-1位的化学位移对促进剂的促进活性有正影响。在TIS中也观察到了类似的关系，这一结果对于设计具有较强促进活性的增强剂的化学结构是有效的。

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.