Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen

Abstract

The promoting effect of O-ethylmenthol (MET) on the percutaneous absorption of ketoprofen from alcoholic hydrogels was evaluated in rats in vitro and in vivo. Further, the anti-inflammatory action of ketoprofen hydrogels was evaluated with a rat paw edema test. The time course of the cumulative amounts of drug permeated through the rat skin in vitro exhibited a linear relation after an initial time lag. This was analyzed in a membrane diffusion model and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a small quantity of MET (0.5%) was applied. However, at least 2% menthol was required to obtain the same activity as 0.25% MET. A pharmacokinetic model, which was derived on the assumption of a constant penetration rate ( R p) after a lag time, was employed to evaluate in vivo percutaneous absorption of ketoprofen from hydrogels containing MET. Further, the area under the plasma concentration-time curve (AUC 0–8 h) was estimated. Similarly to the results observed in vitro, R p and AUC 0–8 h values were increased significantly by the administration of hydrogels containing a small amount of MET (0.25–0.5%). In order to obtain the significant inhibitory action of ketoprofen on the rat paw edema induced by carrageenan, at least 1% menthol was required in the hydrogel formulation. On the other hand, a small amount of MET (0.25–0.5%) was enough to bring about significant inhibitory action of ketoprofen. Distinguishable changes of the skin surface were microscopically observed with 0.5–2% MET, i.e. the spaces between the stratum corneum cells became extended and the shape of each cell became clear, whereas the morphological changes caused by menthol were relatively weak. Both MET and menthol may change the dense barrier structure of the stratum corneum of skin; however, the efficiency of MET is significantly greater than that of menthol.