Absorption of indomethacin and its calcium salt through rat skin: Effect of penetration enhancers and relationship between in vivo and in vitro penetration.

Abstract

The in vivo percutaneous absorption and in vitro penetration of indomethacin (IND) and the calcium sale (IND-Ca) in ointments were investigated on rat abdominal skin under occlusions in the presence or absence of penetration enhancers. The absorption of IND-Ca from the gel (Hiviswako) ointment was significantly higher than that from a standard ointment of IND, an approximation of a commercial product. Sorbitan monooleate had no enhancer effect for the IND-Ca gel ointment, while the addition of calcium thioglycolate dramatically decreased the absorption of IND-Ca due to powdering of the ointment. The absorption of drugs was significantly increased by adding Azone in the gel ointment resulting in an approximate 3-fold increase in the parameters, Cmax and AUC. The percutaneous absorption of drugs from white petrolatum base was relatively lower than that from gel ointment. The plasma IND concentrations after a topical application of the gel ointments for 6 h (3.0 cm .times. 3.0 cm area, 1.0 g of 5% IND ointment) were over the therapeutically effective concentrations during 48 h. The bioavailability of IND after application of ointments was 9.1-27.8% for the gel base and 4.5-6.3% for the white petrolatum base. The in vitro penetration behavior of drugs using a Franz diffusion cell resembled the result of the in vivo absorption more closely. The relationship between the in vitro (the permeability coefficient and skin/ointment partition coefficient) and in vivo (Cmax and AUC) penetration parameters was linear and there was a clear correlation between both parameters.