Effect of synthesized cyclohexanol derivatives using L-menthol as a lead compound on the percutaneous absorption of ketoprofen

L-Menthol was selected us a lead compound to synthesize new candidates for percutaneous absorption enhancers. In a previous study, O-ethylmenthol (MET) was the most effective compound and caused relatively little skin irritation. To develop more effective compounds, mono- or disubstitute groups of cyclohexane with an O-ethyl group were synthesized. Some 35 compounds were synthesized and evaluated for their promoting activity and effect on skin. An in vivo percutaneous absorption study was performed using rats with hydrogel containing ketoprofen and each of the synthesized compounds. The plasma concentration of ketoprofen was determined after the application of hydrogel to the abdominal al en of rats. The apparent penetration rate (R-p) was estimated based on the pharmacokinetic model with a constant rate of penetration through the skin after the lag time. The 2-compartment model was applied to the data obtained from the iv administration. As an index to evaluate the promoting activity of each enhancer, an enhancement factor (E-t) was defined as follows. E-r=R-p (with enhancer)/R-p (without enhancer). Irritation to skin was pathologically evaluated. The treated area of rat abdominal skill was exised after the in vivo experiment using total irritation score (TIS). The compound having a C-3 positioned iso-butyl group on the chemical structure was the most effective and caused relatively little irritation among mono-substituted compounds. In the case of di-substituted compounds, all had the same effect as or a stronger effect than MET. Furthermore, the promoting activity almost corresponded to irritation. To estimate log P, one of the physicochemical properties of molecules. a computer program 'CAChe' was employed. The log P was calculated using the atom typing scheme. Multiple regression analysis revealed that the relations between E-r or TIS and log P were parabolic. It was suggested that the optimum log P value reflects the promoting activity to enhance percutaneous absorption of ketoprofen. (C) 2000 Elsevier Science B.V. All rights reserved.