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

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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.