Formulation, Ex-Vivo and Preclinical In-Vivo Studies of Combined pH and Ion-Sensitive Ocular Sustained In Situ Hydrogel of Timolol Maleate for the Treatment of Glaucoma

Abstract

The aim of the present research work was to develop safe, effective, and stable in situ hydrogel for the ophthalmic drug delivery using the combination of ion-responsive polymer gellan gum and pH-sensitive polymer carbopol 934P to treat glaucoma. Background: Timolol maleate is a BCS class I drug used as the first line of treatment in open-angle glaucoma. The rapid precorneal elimination of conventional formulation containing class I drugs exhibits poor therapeutic effect and bioavailability. So, in situ gelling system was formulated and characterized. Methods: Box-Behnken design was used to statistically optimize the formulation parameters and evaluate the effects of formulation attributes, namely concentration of gellan gum (X1), the concentration of carbopol 934P (X2) and concentration of benzododecenium bromide (X3) on selected critical quality attributes (Y1-Y7). Trial run data were statistically analyzed using the polynomial equation and response surface plots. Optimized formulation was selected based on desirability function, design space, and was further characterized and compared with the marketed formulation. Results: The concentration of both polymers showed a synergistic positive impact on viscosity at the non-physiological and physiological conditions. Trial runs showed controlled drug release with diffusion-controlled mechanism and good mucoadhesive strength due to the presence of Carbopol 934P. The preservative benzododecenium bromide showed the ability to enhance trans-corneal permeation. The optimized formulation has appeared as a clear solution at the non-physiological condition and clear gel at the physiological condition with an acceptable pH range of 5-6. Other quality attributes like rheological properties, gelling capacity, texture analysis, Isotonicity, contact angle, sterility, antimicrobial efficacy, and stability were found in desires values for the ocular application. The safety of in situ gel for human use was confirmed by ocular irritation and histopathology studies in the rabbit eyes. The intraocular pressure (IOP) reduction with optimized formulation was found comparable and less fluctuating compared to ophthalmic gel-forming marketed solution of timolol maleate (TIMOPTIC-XE®). Conclusion: The cross-linking between Carbopol 934P with Gellan gum in the formation showed more viscous gelling at the physiological condition to provide long pre-corneal residence time. The optimized formulation exhibited all the desirable attributes of an ideal ophthalmic in situ gelling formulation, exhibited in-vitro controlled drug release, good gelling capacity, and was found to be stable and non-irritant to the eye.