Design and Development of a pH-Responsive In-situ Gel of Brinzolamide for Ocular Delivery Using Quality by Design (QbD): Formulation Optimization, Characterization, and In-vivo Evaluation for Sustained Glaucoma Management

Abstract

The present investigation aims to develop a Brinzolamide-loaded In-situ gelling ophthalmic system using a Quality by Design (QbD) framework to enhance the therapeutic efficacy in the management of glaucoma. Brinzolamide, a carbonic anhydrase inhibitor, was a preferred drug for lowering intraocular pressure. However, its efficacy through conventional eye drops was compromised due to rapid precorneal elimination and Limited residence time. In-situ gels offer a promising alternative by undergoing a phase transition upon exposure to physiological pH, thereby increasing ocular bioavailability and prolonging drug release. A 3² factorial design was applied to optimize the formulation variables concentrations of Carbopol 934P and HPMC K4M and their impact on viscosity and gelation temperature. The optimized formulation demonstrated favorable physicochemical properties, including pH (6.8 ± 0.1), drug content (97.58 ± 0.5%), viscosity (1125 ± 10 cP), and immediate gelation at ocular pH. In-vitro studies revealed a sustained release profile over 8 h (96.42%) following Korsmeyer–Peppas model. Ocular irritation was evaluated via Draize and HET-CAM tests, confirming the non-irritant nature of the formulation. Accelerated stability studies conducted under ICH Q1A (R2) guidelines demonstrated excellent stability for 30 days. The study confirmed that the developed In-situ gel can significantly improve patient compliance and therapeutic outcomes in glaucoma therapy.

Graphical Abstract