Effect of temperature on percutaneous absorption of terodiline, and relationship between penetration and fluidity of the stratum corneum lipids

Abstract

The effect of temperature on the skin permeation of terodiline (TD) hydrochloride and the free base form was examined. The in vitro penetration experiment at 25–50°C was carried out using the full-thickness skin (FS) and the stratum corneum (SC) sheet of Wistar rat. The fluidity of the stratum corneum lipids was measured by ESR. The relationship between the flux and the phase state of the SC lipids was evaluated based on the data obtained. The effect of heating on the in vivo percutaneous absorption was also estimated. Increasing temperatures resulted in increased penetration of both hydrochloride and free base forms. A significant difference in the penetration rates through the FS was not observed between the hydrochloride and free base forms, whereas the fluxes of the free base form through the SC sheet were slightly higher than those of the hydrochloride form at each temperature. The Arrhenius plots of permeability coefficient ( K p) yielded straight lines for both FS and SC sheet. The activation energies (15.5 and 20.0 kJ/mol), calculated from the slope of curves, for the SC sheet were smaller than those (45.7 and 39.3 kJ/mol) for the FS. The spin label mobility of the SC lipids, measured by ESR, was increased with rising temperatures. The plots of apparent rotational correlation time ( τ c) versus temperature represented the temperature dependence, with abrupt breaks at 41.3±0.7°C and 68.1±1.4°C ( n=4), suggesting the phase transition of the lipids. When 1/ τ c was plotted against the K p for the free base form at four temperatures, straight lines were obtained for both skins ( r 2=0.842 and 0.938). This indicates that the penetration of TD free base through the skin was dependent on the temperatures of the SC lipids and the drug penetrated via the lipoidal pathway within the SC. A notable result was not obtained from heating the transdermal system using a heat patch, because of the lesser efficiency of the patch.