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

Abstract

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 intraarticular 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 (%Q2). In contrast, the polymer type was a significant factor for the late phase (%Q60). All these factors had a significant impact on dissolution efficiency at 60 days (%DE60). 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.