Suboptimal control of
postoperative pain following
knee arthroplasty can slow recovery and reduce patient satisfaction. Intraarticular (IA) administration of
bupivacaine and
ketorolac offers efficient
pain control and minimizes
opioid consumption. However, the clinical benefits of this approach are short lived due to rapid clearance of drugs from the joint cavity. Here, we describe a
poloxamer based thermoresponsive in situ gelling system for the sustained IA delivery of
bupivacaine hydrochloride (BH) and
ketorolac tromethamine (KT) following knee surgery in an ovine model.
Drug loaded formulations were prepared using
poloxamer 407,
poloxamer 188 and
sodium chloride. In vitro characterization was conducted, followed by in vivo evaluation of sustained drug release and safety in an ovine model of knee joint surgery. Rheological studies revealed a Newtonian-like flow of the developed formulation at room temperature, confirming its injectability, followed by a transition to a viscous gel as temperature approached body temperature. The developed formulation successfully sustained the in vivo release of BH for 72 h and KT for 48 h, as determined by circulating
drug levels, compared to 24 and 8 h for marketed
drug solutions. The concentrations of BH and KT in the synovial fluids at 72 h were 11.5 and 1.8 times that of marketed products, suggesting a significant increase in the IA residence time. The developed formulation induced a comparable inflammatory response compared to the marketed
drug solutions, however a significantly higher chondrotoxicity was observed following administration of the gel formulations.
Poloxamers based in situ gelling systems are promising delivery platforms for the sustained and localised IA delivery of BH and KT, with potential clinical benefits in managing the
postoperative pain following
knee arthroplasty.