TRANSMUCOSAL CONTROLLED SYSTEMIC DELIVERY OF ISOSORBIDE DINITRATE - IN-VIVO IN-VITRO CORRELATION

A bilayer track field-shaped transmucosal therapeutic system (TmTs) ha s been developed for the systemic delivery of therapeutic agents that are subject to an extensive pre-systemic clearance, using isosorbide d initrate (ISDN) as the model drug. The transmucosal systemic delivery of ISDN was investigated by single gingival application of TmTs to bea gle dogs. The cumulative absorption profiles and pharmacokinetic profi les of ISDN were monitored. Both were found to be directly correlated with the release profiles of ISDN determined by in vitro dissolution s tudies. An excellent(1:1) correlation at Level A was achieved when the dissolution test was conducted in a medium of pH 6.8 with the paddle rotating at a rotation speed of 200revs./min. Furthermore, the transmu cosal systemic delivery of ISDN from TmTs was observed to depend on th e release rate of ISDN: as the release rate decreased, the plasma leve l of ISDN was prolonged, but with no reduction in bioavailability. The systemic bioavailability of ISDN following transmucosal delivery thro ugh the oral mucosae can be modulated by controlling the ratio of ISDN loading in the fast- and sustained-release layers (F/S) as well as IS DN content in sustained-release layer. The effect was demonstrated in both in vitro and in vivo studies, which attained an vitro/in vivo cor relation of 1:1. The excellent correlation achieved suggests that the in vivo performance of the TmTs formulation can be accurately predicte d from the in vitro release profiles.