Combined effect of d-limonene and temperature on the skin permeation of ketoprofen

Abstract

The effect of temperature on the enhancement action of d-limonene on percutaneous absorption of ketoprofen (KPF) was investigated in rats in vivo and in vitro. The apparent penetration rate ( R p ) of KPF absorbed from alcoholic hydrogels in rats was estimated based on a pharmacokinetic model, which was derived on the assumption of a constant penetration rate through the skin. The R p value increased sigmoidally with increase in the temperature applied, i.e., the R p value was almost constant at the lower temperatures, however, it increased abruptly at the critical temperature ( T c ) of applied heat. The T c value was significantly lowered by increasing the content of d-limonene in the hydrogel. The steady-state permeability coefficients ( P) of KPF through the skin was determined by employing two-chamber diffusion cells in which the excised rat abdominal skin was mounted. The combined effect of d-limonene and temperature on the P value was also clarified. The Arrhenius plots of P values showed a linear relationship when the skin was pretreated with 30% ethanol without d-limonene. The activation energy of permeation of KPF through the skin was estimated to be 6.49 kJ/mol. When the skin was pretreated with 1.5% d-limonene in 30% ethanol, the Arrhenius plots of P exhibited a convex curvature. Morphological changes of the skin surface were also observed microscopically. The application of heat, along with the synergistic effect of d-limonene, may effectively change the dense barrier structure of the stratum corneum.