Reformulating rofecoxib: targeted nanostructured lipid carrier gel for localized treatment of rheumatoid arthritis

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.

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.

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.

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).

ROX-NLCs gel provides a safe, sustained, and effective topical delivery system for RA therapy, enhancing local efficacy while reducing systemic cardiotoxic risk.