Injectable thermoresponsive gels offer sustained dual release of bupivacaine hydrochloride and ketorolac tromethamine for up to two weeks

Abstract

Bupivacaine and ketorolac are commonly used in combination to reduce perioperative pain. This study aimed to develop and characterize an injectable system that offers simultaneous and prolonged release of bupivacaine and ketorolac. Formulations were prepared using poloxamer 407 with increasing concentrations of poloxamer 188 and sodium chloride. Small Angle X-ray Scattering (SAXS) experiments demonstrated that the poloxamers form gels with a cubic lattice arrangement regardless of the matrix composition, whereas the system porosity is driven by poloxamers concentration. Drug loading slightly reduced the intermicellar spacing. Fourier transform infrared spectroscopy and thermal analysis suggested electrostatic interactions between the loaded drugs and poloxamers. Mechanical and rheological studies confirmed the formulations exhibit Newtonian-like flow at room temperature followed by a transition to a viscous gel at body temperature. Importantly, the developed formulations demonstrated steady and sustained release of both bupivacaine and ketorolac over two weeks. Sodium chloride reduced the initial burst release over the first six hours for BH, from 8.6 ± 0.18% to 1.6 ± 0.11%, and KT, from 7.7 ± 0.27% to 1.5 ± 0.10%. Hence, poloxamer-based thermoresponsive gelling systems are promising delivery platforms for the sustained delivery of bupivacaine and ketorolac, with potential clinical benefits for managing perioperative pain.