Co-crystals of highly and poorly soluble local anesthetics bidirectionally regulate their release for long-acting...

Slowing down the release of highly soluble drugs, or boosting the release of poorly soluble drugs, are two critical and challenging issues in designing long-acting formulations. Here we reported a co-crystal strategy for two local anesthetics, i.e., highly soluble QX314-OH and poorly soluble levobupivacaine, based on designer self-assembling peptide nanoparticles. Firstly, peptide nanoparticles adsorbed the two drugs through electrostatic interaction to form nanocomplexes. Then, the nanocomplexes induced co-crystallization of the drugs through π-π stacking and hydrogen bond between them. The co-crystals were further formulated in hyaluronic acid hydrogel, achieving slow release of QX314-OH and accelerated release of levobupivacaine. Furthermore, levobupivacaine could also enhance the efficacy of QX314-OH by facilitating its intracellular accumulation. As a result, the co-crystal formulation exhibited long-acting analgesic effect in multiple animal models with considerable safety. This study provided an effective strategy to bidirectionally regulate the release of drugs with different solubility. It also introduced a promising long-acting anesthetic formulation for pain control in clinical practice.