A carrier-free long-acting ropivacaine formulation using methylprednisolone sodium succinate as a dual-functional...

Rationale: Slow-releasing formulation of local anesthetics (LAs) has been a promising strategy for pursuing long-acting opioid-free analgesia. Although many formulations based on carrier materials have been successfully developed, challenges still remain in addressing not only the biocompatibility and biodegradability issues of carrier materials, but also potential local inflammation caused by LAs. Methods: In this study, we developed a slow-releasing ropivacaine formulation based on methylprednisolone sodium succinate (MP), a small-molecule drug used in clinic. Firstly, we studied the self-assembling behavior of MP and its interaction with ropivacaine hydrochloride (RH). Then we studied how MP could manipulate the crystallization of RH and how the release profile of obtained ropivacaine crystals could be controlled. Lastly, we investigated the long-acting analgesic effect and safety of different formulations in animal models. Meanwhile we also monitored the anti-inflammatory effect of MP on cell and animal levels. Results: MP could self-assemble into nanoparticles, which could adsorb RH and induce the formation of homogeneous ropivacaine microcrystals. Higher MP ratio in the system led to the formation of smaller ropivacaine microcrystals with a moderate release rate, which generated much longer and reliable analgesic effect in animal models with considerable safety. On the other hand, MP in the formulation showed substantial anti-inflammatory effect, which was also helpful to further relieve pain and alleviate local toxicity. Conclusion: Using MP as a dual-functional adjuvant, long-acting LA formulations with considerable safety could be prepared, providing a facile solution for long-term pain management in clinic.