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 commonly involves anti-inflammatory therapies, including intra-articular corticosteroids and oral nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 selective inhibitors like celecoxib (CXB)
Osteoarthritis (OA) is a prevalent chronic joint disease characterized by pain, swelling, and physical disability. Its management commonly involves anti-inflammatory therapies, including intra-articular corticosteroids and oral nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 selective inhibitors like celecoxib (CXB). While intra-articular corticosteroid administration is highly effective, prolonged use may lead to cartilage degradation. Conversely, oral CXB is associated with potential cardiovascular toxicity. Although intra-articular delivery of CXB may reduce systemic exposure, its rapid clearance from the joint limits therapeutic effectiveness.
This study aimed to design, develop, and optimize intra-articular in situ forming implants of CXB (CXB-ISFI) to achieve controlled drug release over 6–8 weeks for the treatment of OA. The formulation was intended to overcome rapid joint elimination and enable sustained local drug exposure.
A Design of Experiments (DoE) approach, based on a two-level factorial design, was employed to optimize the CXB-ISFI formulation. Key variables evaluated included solvent type, polymer type, polymer concentration, and CXB content. The solvent type and polymer concentration significantly influenced the initial drug release phase (%Q2), whereas the polymer type was a critical factor in the late release phase (%Q60). Additionally, all variables significantly affected dissolution efficiency at 60 days (%DE60).
The optimized formulation, consisting of 150 mg of poly(lactic-co-glycolic acid) (PLGA) and dimethyl sulfoxide (DMSO), with a polymer concentration of 50% and a CXB content of 20%, demonstrated controlled drug release over 8 weeks with a minimized burst effect. The formulation also exhibited good injectability through a 21G needle and showed no signs of toxicity in the hen’s egg test–chorioallantoic membrane (HET-CAM) assay.
These findings indicate that the developed CXB-ISFI system is suitable for intra-articular administration and holds significant potential as a safer and effective alternative to intra-articular corticosteroids for the treatment of osteoarthritis.
