Formulation, Optimization and Evaluation of a pH-Sensitive Mucoadhesive Hydrogel for Ocular Delivery of Nepafenac

Abstract

Background: Conventional Nepafenac ophthalmic suspensions are limited by rapid tear turnover, blinking and nasolacrimal drainage, which shorten precorneal residence time and reduce ocular bioavailability. Objective: The present study aimed to formulate and evaluate a pH-sensitive mucoadhesive hydrogel of Nepafenac for prolonged ocular retention and sustained anti-inflammatory delivery. Methods: Nepafenac hydrogels were prepared using Carbopol 934P as a pH-responsive gelling polymer and HPMC K15M as a viscosity-enhancing mucoadhesive polymer. A two-factor, three-level experimental design was applied with Carbopol 934P and HPMC K15M as independent variables, and sol and gel viscosity as dependent responses. Formulations were evaluated for preformulation characteristics, UV analytical suitability, FTIR, DSC, pH, gelation time, viscosity, mucoadhesive strength, drug content, in vitro drug release, HET-CAM ocular irritation and short-term stability. Results: Nepafenac was a white, odorless, slightly bitter crystalline powder with a melting range of 178-182°C and UV absorption maximum at 238 nm. The calibration curve was linear over 2-10 µg/mL with a calculated equation of y = 0.04935x - 0.01390 (R² = 0.9833). FTIR peaks of the drug were retained in the mixture and the DSC endothermic peak shifted only slightly, supporting drug-excipient compatibility. The optimized batch F9 contained 100 mg Nepafenac, 350 mg Carbopol 934P and 500 mg HPMC K15M per 100 mL and showed pH 7.3, gelation time 30 s, sol viscosity 503 cps, gel viscosity 706 cps, mucoadhesive strength 615, drug content 97.3% and 98% cumulative drug release at 8 h. The formulation remained stable for 3 months and was non-irritant in the HET-CAM test. Conclusion: The optimized pH-sensitive Nepafenac hydrogel exhibited suitable physicochemical properties, sustained release, stability and ocular tolerability, suggesting its potential as an improved ophthalmic delivery system.

Introduction

Ocular drug delivery is an important approach for treating local eye disorders such as postoperative inflammation, pain, allergic conditions, and infections. Conventional ophthalmic formulations, including eye drops and suspensions, often show poor therapeutic effectiveness because of rapid tear turnover, blinking, nasolacrimal drainage, and limited corneal permeability. These factors result in low ocular bioavailability and frequent dosing requirements, which may reduce patient compliance and increase the risk of irritation and systemic exposure. To overcome these limitations, polymer-based in situ ocular hydrogels have been developed, which are administered as liquids and transform into gels after contact with ocular fluids, providing prolonged residence time and controlled drug release.

The present study focused on the formulation, optimization, and evaluation of a pH-sensitive mucoadhesive hydrogel of Nepafenac using Carbopol 934P as a pH-responsive gelling polymer and HPMC K15M as a viscosity-enhancing and mucoadhesive polymer. Nepafenac is an ophthalmic NSAID prodrug that is converted into the active metabolite amfenac, which inhibits prostaglandin synthesis and is widely used for managing ocular inflammation and pain, particularly after cataract surgery. However, conventional topical formulations provide limited ocular residence time, necessitating improved delivery approaches.

Preformulation studies showed that Nepafenac was a white, odorless, slightly bitter crystalline powder with a melting point of 178–182°C. The drug was practically insoluble in water but soluble in methanol, supporting the need for a specialized polymeric delivery system. UV spectrophotometric analysis established a maximum absorption wavelength of 238 nm, and the calibration curve showed acceptable linearity over the concentration range of 2–10 µg/mL. FTIR and DSC compatibility studies confirmed that Nepafenac was compatible with Carbopol 934P, HPMC K15M, and other formulation excipients, with no significant chemical interactions observed.

A two-factor, three-level experimental design was applied to evaluate the effect of Carbopol 934P and HPMC K15M concentrations on formulation viscosity. Nine hydrogel formulations (F1–F9) were prepared and evaluated for appearance, clarity, pH, viscosity, gelation time, mucoadhesive strength, drug content, in vitro drug release, ocular irritation potential, and stability. The hydrogel preparation involved hydration of polymers, incorporation of Nepafenac, addition of preservatives and tonicity agents, and adjustment of pH to physiological ocular conditions.

The results demonstrated that increasing polymer concentration enhanced both sol and gel viscosity. Design of experiments analysis showed that Carbopol 934P was the major factor influencing viscosity, while HPMC K15M contributed to formulation consistency and mucoadhesion. The optimized hydrogel exhibited suitable physicochemical characteristics, sustained drug release behavior, and compatibility with ocular application requirements. The HET-CAM assay was used to assess ocular irritation potential, and stability studies confirmed maintenance of formulation quality during storage.

Conclusion

A pH-sensitive mucoadhesive hydrogel of Nepafenac was successfully formulated using Carbopol 934P and HPMC K15M. The optimized F9 formulation showed acceptable ocular pH, rapid gelation, suitable sol and gel viscosity, strong mucoadhesion, high drug content and sustained in vitro drug release. FTIR and DSC studies confirmed compatibility between Nepafenac and selected excipients. HET-CAM testing indicated that the optimized formulation was non-irritant, while stability testing showed maintenance of appearance, pH, viscosity, drug content and release performance for 3 months. The developed formulation may serve as a promising ocular delivery platform for prolonged Nepafenac therapy. Further work should include sterility assurance, preservative efficacy testing, ex vivo corneal permeation, in vivo ocular residence studies, pharmacokinetic assessment and clinical evaluation.

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Copyright

Copyright © 2026 Ashwini Kolbhure , Dr. Vaishali Kate. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.