IMPROVEMENT OF BUCCAL DELIVERY OF MORPHINE USING THE PRODRUG APPROACH

The feasibility of achieving buccal delivery of morphine using the pro drug approach was assessed by studies of bioactivation, in vitro perme ation and in vivo absorption. The bioactivation of various morphine-3- esters was studied in human plasma and saliva. The in vitro permeation of morphine and various morphine-3-esters was studied using porcine b uccal mucosa mounted in Ussing chambers and finally the in vivo absorp tion of the compounds evaluated following administration in rats. Both the results from the in vitro permeation and from the absorption of t he prodrugs studied suggested a parabolic relationship to the lipophil icity of the compounds. In the in vitro studies the optimal permeation was achieved for the prodrug morphine-3-propionate having a log P val ue of approximately 0.7. In contrast to that optimal in vivo absorptio n was obtained for the prodrug morphine-3-acetate having a log P value of 0.2. This discrepancy could however be explained by the enzymatic stability of the two esters in saliva, since it was found that morphin e-3-propionate was more rapidly hydrolysed in saliva than was morphine -3-acetate. The study demonstrates that the buccal delivery of morphin e can be markedly improved by using ester prodrugs with higher lipophi licity than morphine itself. However, the enzymatic stability of the p rodrugs in saliva also play an important role for the overall improvem ent in absorption properties. (C) 1997 Elsevier Science B.V.