Transmucosal controlled systemic delivery of isosorbide dinitrate: in vivo/in vitro correlation

Abstract

A bilayer track field-shaped transmucosal therapeutic system (TmTs) has been developed for the systemic delivery of therapeutic agents that are subject to an extensive pre-systemic clearance, using isosorbide dinitrate (ISDN) as the model drug. The transmucosal systemic delivery of ISDN was investigated by single gingival application of TmTs to beagle dogs. The cumulative absorption profiles and pharmacokinetic profiles of ISDN were monitored. Both were found to be directly correlated with the release profiles of ISDN determined by in vitro dissolution studies. 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 transmucosal systemic delivery of ISDN from TmTs was observed to depend on the release rate of ISDN: as the release rate decreased, the plasma level of ISDN was prolonged, but with no reduction in bioavailability. The systemic bioavailability of ISDN following transmucosal delivery through 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 ISDN content in sustained-release layer. The effect was demonstrated in both in vitro and in vivo studies, which attained an vitro/in vivo correlation of 1:1. The excellent correlation achieved suggests that the in vivo performance of the TmTs formulation can be accurately predicted from the in vitro release profiles.