ABSORPTION OF ISOSORBIDE DINITRATE AFTER ADMINISTRATION AS SPRAY, OINTMENT AND MICROEMULSION PATCH - AN IN-VITRO STUDY USING THE ISOLATED-PERFUSED BOVINE UDDER

The isolated perfused bovine udder is an in-vitro model, which maintai ns bovine udder skin with an isolated vasculature in a viable state. U sing this in-vitro model, the percutaneous absorption and metabolism o f isosorbide dinitrate (ISDN) was studied. The organ was perfused with gassed Tyrode solution for up to 6 h. A region of udder skin was trea ted topically with 60 mg ISDN as a spray, 60 mg ISDN as an ointment an d with 120 mg ISDN as a microemulsion patch of 30 cm(2). Spray and oin tment were applied onto a skin region of 400 cm(2). The concentrations of ISDN and its metabolites isosorbide-2-mononitrate and isosorbide-5 -mononitrate were measured in perfusate fractions by capillary column gas-liquid chromatography with electron capture detection. Following t opical administration of the different formulations, ISDN as well as i ts metabolites were detected in the perfusate fractions, thus demonstr ating that ISDN is metabolized by the udder skin invitro. A maximum am ount of ISDN was absorbed after administration as a spray followed by ointment and microemulsion (5, 2.5 and 1.8 mu mol. total organic nitra te, respectively). In contrast, the ISDN flux per cm(2) skin was signi ficantly higher after administration of the microemulsion (64.4 pmol c m(-2) min(-1) for the microemulsion compared with 21.9 and 10.2 pmol c m(-2) min(-1) for spray and ointment).