DEVELOPMENT OF LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) DELIVERY SYSTEMS FOR VAGINAL MUCOSAL ROUTE

The objective of this study was to find a rational dosage form for vaginal mucosal delivery of LHRH. Vaginal absorption of LHRH was estimated by measuring its ovulation inducing effect in rat and in vitro vaginal membrane permeation study in rabbit. The effects of different hydrogel bases, such as Polycarbophil and Pemulen compared with solutions on vaginal membrane permeation of LHRH were investigated. Sodium laurate, disodium ethylenediamine tetraacetate (EDTA) and sodium tauro-24,25-dihydrofusidate (STDHF), which are effective peptidase inhibitors were chosen as additives to a LHRH hydrogel delivery system and LHRH solutions. A Polycarbophil hydrogel formulation showed 3.4 times increase in LHRH vaginal membrane permeability compared with a solution formulation. Vaginal membrane permeability from the Polycarbophil was greater than that from Pemulen hydrogels. This may be due to the larger bioadhesive values. LHRH solution with EDTA(2%), STDHF(1%) and sod. laurate(0.5%) showed 4.1 times, 4.8 times and 6.0 times of ovulation inducing activity compared with control. These results suggest that enzyme inhibition effect of EDTA, STDHF and sod. laurate may result in substantial enhancement of vaginal absorption. By administration of Polycarbophil hydrogels containing LHRH the ovulation inducing activity was 3.3 times greater than the solutions. This result indicates the bioadhesive hydrogels as well as peptidase inhibition significantly improved absorption of LHRH. By coadministration with these inhibitors the ovulation inducing activity of Polycarbophil hydrogel containing LHRH was comparable with subcutaneous administration in ovulation inducing activity.