Formulation Development and Optimization of Phase-Transition W/O Microemulsion In Situ Gelling System for Ocular Delivery of Timolol Maleate in the Treatment of Glaucoma

Abstract

The present investigation is aimed to prepare and evaluate the micro emulsion-based phase transition ocular system for delivery of Timolol maleate in the treatment of glaucoma. Timolol maleate is used in the first line of treatment in open-angle glaucoma, belonging to BCS class-I having good solubility and permeability. The rapid precorneal elimination of conventional formulation containing class I drugs exhibits poor therapeutic effect and bioavailability. So, microemulsion (ME) based phase transition systems were formulated and characterized. ME based phase transition system was formulated using Ethyl oleate as oil and CremophorEL as a surfactant, Span 20 as Co-surfactant, and Sorbic acid as a preservative. These systems undergo a phase transition from water-in-oil (w/o) ME to liquid crystalline (LC) state and to coarse emulsion (EM) with a change in viscosity depending on dilution with tear fluid & water content. Prepared microemulsions were characterized for average globule size, zeta potential, pH, conductance, in-vitro gelling capacity. The optimized formulation was selected based on desirable attributes and was further characterized and compared with marketed ophthalmic gel-forming marketed solution of Timolol maleate (TIMOPTIC-XE®). All the results of the characterization were satisfactory. The optimized water-in-oil (w/o) microemulsion showed droplet size 23.47 nm, the zeta potential of 0.253mV, pH of 7.2, the conductance of 0.25mS, and drug content of 99.64%. The phase transition w/o ME provides the fluidity for installation with its viscosity being increased due to phase transition after application increasing ocular retention while retaining the therapeutic efficiency. The in- vitro drug release and IOP reduction with optimized formulation were found comparable and less fluctuating compared to marketed formulation. Optimized formulation was found stable during the accelerated stability study. The developed phase transition w/o ME formulation would be able to offer benefits, such as increased residence time, prolonged drug release, reduction in dosing frequency, and thereby it will improve patient compliance.