ABSTRACT
The present investigation is concerned with the development and in vivo evaluation of a longacting ocular vehicle for the α-adrenergic blocking drug dapiprazole (DAP). The approaches tested for prolonging the activity were (a) using the drug base with polygalacturonic acid (PGA) and (b) formulation as a highly viscous hydrogel. The vehicles prepared by applying (singly or in combination) these techniques, and two reference aqueous vehicles containing DAP-HCl, were submitted to a series of biological tests on rabbits (miosis and reversion of mydriasis). When compared with an aqueous solution containing an equivalent amount of DAP-HCl, the polyanionic complex DAP-base-PGA increased significantly some activity parameters (maximal miotic intensity, duration, AUC) of the drug, while the hydrogel vehicle containing DAP-HCl prolonged the apparent absorption and elimination phases of the drug, mainly by virtue of a prolonged ocular retention. The combination of the two approaches, as in the hydrogels containing the DAP-PGA complex, permitted the best control of pharmacological activity parameters, which corresponded to a prolonged-pulse release of the drug. In the miosis test, the AUC values did not show any dose-dependent increase, while this effect was evident in the mydriasis-reversion experiments. The possible mechanism(s), by which the examined techniques may influence the activity parameters and the overall ocular bioavailability of DAP are discussed.
