In Situ Gelling System to Provide Prolonged Postoperative Pain Relief Following Arthroplasty

Abstract

Background: Appropriate control of postoperative pain following knee arthroplasty can speed recovery and improve patient satisfaction. The intraarticular administration of bupivacaine hydrochloride (BH) and ketorolac tromethamine (KT) offers efficient pain control. However, the duration of effect is limited by rapid drug clearance from the joint cavity. Objective: Develop and evaluate an injectable poloxamers-based in situ gelling system for the sustained intraarticular delivery of BH with or without KT. Methods: Poloxamers-based in situ gelling systems were prepared using poloxamer 407 (P407), poloxamer 188 (P188) and sodium chloride (NaCl). Selected formulations were loaded with BH alone or in combination with KT, and thoroughly characterized in vitro. In vivo evaluation of the optimized formulation was performed in a sheep model of arthroplasty against marketed products. Results and discussion: Mechanical and rheological studies revealed a Newtonian-like flow of the developed formulations at room temperature, confirming their injectability, followed by a transition to viscous gels at physiological temperature. The inclusion of NaCl in the formulation significantly enhanced the gel mechanical and rheological properties and resulted in five-fold reduction in the in vitro burst release of both BH and KT over the first six hours. A formulation composed of P407 (25% w/w), P188 (11% w/w) and NaCl (0.4% w/w) loaded with BH (2.5% w/w) alone, or with KT (0.3% w/w), was selected and evaluated in a sheep model of arthroplasty. Circulating blood concentrations of both drugs were well below reported toxicity levels (Cmax was 254 ± 186 ng/mL and 121 ± 86 ng/mL for BH and KT, respectively). The developed formulation successfully sustained the in vivo release of BH and KT for 72 and 48 hours, respectively, compared to 24 and 8 hours for marketed drug solutions. BH and KT synovial concentrations at 72 hours were 11.5 and 1.8 times that of marketed products, suggesting a significant increase in the intraarticular residence time. Histological studies revealed the formulations were compatible with the synovial membrane, yet chondrotoxic. Conclusion: Poloxamers-based in situ gelling systems are promising delivery platforms for the sustained intraarticular delivery of BH and KT, with potential clinical benefits in managing postoperative pain following knee arthroplasty.