DEVELOPMENT AND EVALUATION OF NEPAFENAC OCULAR IN SITU GEL FOR THE TREATMENT OF PAIN AND INFLAMMATION

Abstract

Introduction: Ocular pain and inflammation are common complications associated with postoperative conditions and ocular disorders, requiring effective and sustained drug delivery systems. Conventional eye drops suffer from rapid precorneal elimination, resulting in poor bioavailability and reduced therapeutic efficacy. Nepafenac, a poorly water soluble nonsteroidal anti-inflammatory drug (NSAID), presents additional formulation challenges. In this context, the present study, with potential for patentable innovation, aimed to develop, optimize, and evaluate a pH-triggered ocular In situ gelling system of Nepafenac. The designed formulation seeks to enhance drug solubility, prolong precorneal residence time, and improve overall therapeutic performance. Materials and Methods: Nepafenac was complexed with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) to improve aqueous solubility, and the optimized inclusion complex (1:2 ratio, CD3) was selected based on solubility and drug content. The In situ gel was formulated using Carbopol 940 as a pH-sensitive polymer and HPMC E4M as a viscosity enhancer. The formulation was evaluated for physicochemical properties, including clarity, pH, gelation capacity, and viscosity. Rheological behavior was assessed to determine flow characteristics. In vitro drug release, ex vivo corneal permeation studies, sterility testing, isotonicity, ocular irritation (Draize test), hemocompatibility, and In vivo pharmacokinetic and anti-inflammatory studies in rabbits were conducted. Results: The optimized inclusion complex showed significantly enhanced solubility with high drug content (98.9 ± 0.5%). The developed In situ gel exhibited appropriate clarity, physiological pH, and immediate gelation upon contact with simulated tear fluid. Rheological analysis confirmed pseudoplastic flow behavior with optimal viscosity (420 ± 12 cP), ensuring ease of administration and prolonged retention. In vitro release studies demonstrated sustained drug release (~95.2% over 24 hours), while ex vivo permeation studies revealed enhanced drug permeation (86.9% in 12 hours) with a steady-state flux of approximately 11.2 µg/cm²/h. The formulation was found to be sterile, isotonic, and non-irritant. In vivo studies indicated significantly improved ocular bioavailability and superior anti-inflammatory efficacy compared to conventional formulations. Discussion: The combination of HP-β-CD complexation and pH-sensitive In situ gelling system effectively addressed the limitations of Nepafenac, including poor solubility and rapid ocular clearance. The optimized formulation demonstrated favorable physicochemical and rheological properties, ensuring sustained drug release and enhanced corneal permeation. Improved pharmacokinetic and pharmacodynamic performance confirmed the potential of the system to enhance therapeutic efficacy and patient compliance. Conclusion: The developed pH-triggered ocular In situ gel of Nepafenac represents a safe, stable, and effective drug delivery system for the management of ocular pain and inflammation. This approach significantly improves drug solubility, ocular bioavailability, and therapeutic outcomes, offering a promising alternative to conventional ophthalmic formulations.