Ll. Christrup et al., IMPROVEMENT OF BUCCAL DELIVERY OF MORPHINE USING THE PRODRUG APPROACH, International journal of pharmaceutics, 154(2), 1997, pp. 157-165
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.