Quality by design-based development of thermoresponsive injectable depots for sustained analgesic delivery

The use of thermoresponsive injectable depots that undergo in situ sol-gel transition at physiological temperature represents an attractive strategy for sustained parenteral drug delivery. In the present study, a thermoresponsive injectable depot of nalbuphine hydrochloride, a short-acting opioid analgesic requiring frequent dosing, was developed and optimized via a quality by design (QbD) approach to achieve controlled gelation, injectability, and sustained analgesic release. Poloxamer 407, poloxamer 188, and chitosan were employed as formulation components, and a three-factor, three-level Box-Behnken design (17 runs) was used to optimize their concentrations with respect to gelation temperature, gelation time, and viscosity. The optimized formulation exhibited a sol-gel transition temperature of 35.5 ± 0.5 °C, a gelation time of 97 ± 3 s, and a viscosity of 4200 ± 510 cP at 37 °C, confirming rapid in situ gel formation while maintaining syringeability at room temperature. Injectability evaluation via a universal testing machine demonstrated acceptable extrusion forces through a 21 G needle (maximum force 16.98 ± 0.95 N). In vitro degradation studies revealed progressive enzymatic biodegradation over five days, supporting depot erosion under physiological conditions. Drug release studies revealed a sustained release of approximately 82% over 24 h without an initial burst effect, and kinetic analysis indicated anomalous diffusion-controlled release following the Korsmeyer-Peppas model (R² = 0.9958; n = 0.61). Stability studies conducted for three months under refrigerated and room temperature conditions confirmed the maintenance of critical quality attributes. Overall, the QbD-optimized thermoresponsive injectable depot demonstrates robust physicochemical performance and represents a promising platform for sustained parenteral analgesic delivery, warranting further in vivo validation.