Reformulating Rofecoxib: Targeted Nanostructured Lipid Carrier Gel for Localized Treatment of Rheumatoid Arthritis

Objective: This study aimed to develop and evaluate nanostructured lipid carrier (NLC) gel loaded with rofecoxib (ROX) for topical treatment of rheumatoid arthritis (RA), minimizing systemic exposure and cardiotoxicity. Significance: Despite its withdrawal due to cardiovascular risk, ROX remains a potent COX-2 inhibitor. Reformulating it into a localized NLC delivery system could enable safe therapeutic application in RA by targeting inflamed joints with minimal systemic effects. Method: A Box–Behnken design optimized lipid content, surfactant concentration, and sonication time to achieve minimal particle size, high entrapment efficiency, and stable zeta potential. The optimized formulation was incorporated into a gel and evaluated for physicomechanical properties, drug release, and in vivo performance in a complete Freund’s adjuvant (CFA)-induced arthritic rat model. Radiographic, histopathological, and biodistribution studies were conducted. Results: Optimized ROX-NLCs exhibited particle size of 225 nm, entrapment efficiency of 90.65%, PDI of 0.265, and zeta potential of −38 mV, with good stability and gel compatibility. In vitro drug release followed Higuchi and Korsmeyer–Peppas kinetics, showing higher cumulative release compared to plain ROX gel and oral ROX. In vivo, ROX-NLC gel significantly reduced paw swelling and arthritis scores, preserved joint architecture, and avoided cardiac alterations observed with oral ROX. Biodistribution confirmed negligible systemic drug levels (below LOD: 0.079 µg/mL). Conclusion: ROX-NLCs gel provides a safe, sustained, and effective topical delivery system for RA therapy, enhancing local efficacy while reducing systemic cardiotoxic risk.