Design, development, and optimization of in situ-forming implants for intra-articular delivery of celecoxib in osteoarthritis

Osteoarthritis (OA) is a prevalent chronic joint disease characterized by pain, swelling, and physical disability. Its management includes the use of anti-inflammatory drugs, including intra-articular corticosteroids and oral NSAIDs such as COX-2 selective inhibitors like Celecoxib (CXB). The intra-articular administration of corticosteroids is highly effective. However, long-term corticosteroid use causes cartilage degradation, whereas oral CXB is associated with cardiovascular toxicity. The intra-articular CXB delivery may reduce systemic exposure, yet rapid joint clearance limits its utility. Therefore, this study aimed to design, develop, and optimize intra-articular in situ forming implants of CXB (CXB-ISFI) to provide controlled drug release over 6–8 weeks for the treatment of OA and overcome rapid joint elimination and enable sustained local drug exposure. The DoE approach based on a two-level factorial experimental design was used to optimize a CXB-ISFI formulation with a suitable release profile, evaluating the effect of solvent and polymer type, polymer concentration and CXB content. The type of solvent and the polymer concentration showed a significant influence on CXB release during the initial phase (%Q 2 ). In contrast, the polymer type was a significant factor for the late phase (%Q 60 ). All these factors had a significant impact on dissolution efficiency at 60 days (%DE 60 ). The optimized formulation, prepared with 150 mg of PLGA and DMSO, at a polymer concentration of 50% and a CXB content of 20% showed a controlled drug release over 8 weeks with a minimized burst effect. It exhibited good injectability through a 21G needle and no signs of toxicity in the HET-CAM assay. These findings indicate its suitability for intra-articular administration and its potential use in the treatment of OA as an alternative to intra-articular corticosteroids.