Thiomenthol derivatives as novel percutaneous absorption enhancers

Thiomenthol derivatives were synthesized and their promoting activity on th e percutaneous absorption of ketoprofen from hydrogels was evaluated in rat s. The apparent penetration rate (R-p) of ketoprofen absorbed from the hydr ogel was estimated by the pharmacokinetic model derived under the assumptio n of a constant penetration rate through the skin after a lag time. As an i ndex of promoting activity of thiomenthol derivatives, an enhancement facto r (E-f) was defined as the ratio of the R-p value with enhancer to the valu e obtained with the control not containing enhancer. Skin irritancy evoked by these derivatives was investigated microscopically by using a cross-sect ion of the excised skin onto which ketoprofen hydrogel was applied. Total i rritation score (TIS) was estimated by summation of each irritation score i n several parts of the skin. The physicochemical parameters of thiomenthol derivatives such as a partition coefficient (log P) and a steric energy wer e calculated and the quantitative relationships between these parameters an d the E-f values or TIS values were investigated on the basis of multiple r egression 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 .