Development of a bupivacaine-loaded in situ gel based on lyotropic liquid crystals for prolonged postoperative analgesia.

Prolonged control of acute postoperative pain remains clinically challenging, particularly during the first 72 h after surgery. In this study, an injectable in situ gel based on lyotropic liquid crystals (LLCs) was developed for sustained delivery of bupivacaine base (BUP). A low-viscosity LLC precursor was formulated using glyceryl monooleate and phospholipids with anhydrous ethanol as a solvent, enabling rapid gelation induced by solvent exchange upon contact with aqueous media. After hydration, the formulation spontaneously transformed into a highly viscous, strongly adhesive bicontinuous cubic phase (Pn3m), as confirmed by polarized light microscopy (PLM) and small-angle X-ray scattering (SAXS). The optimized BUP-loaded LLC (BUP-LLC) system exhibited sustained drug release over 72 h without a significant initial burst, achieving a cumulative release of approximately 84%. Release kinetics were well described by the Ritger-Peppas model, indicating a transition from release controlled by diffusion and swelling at early stages to Fickian diffusion-dominated behavior after structural stabilization. In vivo evaluation in Sprague-Dawley rats demonstrated that a single subcutaneous injection of the BUP-LLC gel provides effective local analgesia for over 96 h, which was fourfold longer than commercial BUP-HCl injection. The gel depot was completely biodegraded within 7 days without systemic toxicity or hepatorenal impairment. This LLC-based in situ gel represents a promising non-opioid platform for prolonged postoperative analgesia.