(T1530-09-57) Development of Long-Acting Bupivacaine-Loaded Multivesicular Liposomes Using Prilling Technique

Purpose: This study aimed to develop long-acting injectable multivesicular liposomes (MVL) encapsulating bupivacaine (BPV), a local anesthetic, using a novel prilling technique. MVL systems can extend the drug release duration beyond the intrinsic 8–12 hour efficacy of BPV to provide postoperative analgesia lasting multiple days, thus reducing opioid usage and improving patient outcomes.

Methods: Pre-formulation studies were conducted to evaluate the solubility and stability of BPV freebase and hydrochloride in various organic solvents and lysine buffer systems. MVLs were prepared using either a conventional double emulsion method or the prilling technique employing a vibrating nozzle encapsulator. A D-optimal experimental design was used to optimize three prilling parameters: vibration frequency, core flow rate, and nozzle diameter. Particle morphology, size distribution, encapsulation efficiency (%EE), and yield were characterized. In vitro drug release was assessed using a dialysis method over 144 hours.

Results: Eighteen formulations were prepared via a D-optimal design varying vibration frequency (100–2000 Hz), core flow rate (2.5–7.5 mL/min), and nozzle diameter (80 or 120 μm). Among these, the optimized formulation (100 Hz, 4.08 mL/min, 120 μm) showed the highest encapsulation efficiency (%EE, 80.3%) and yield (41.9%), compared to the conventional double emulsion method (%EE 52.9%, yield 5.4%). Particle size analysis revealed a mean diameter of 25.9 μm and SPAN value of 1.00, indicating uniform size distribution. Morphological examination under optical microscopy confirmed spherical, well-defined MVLs for the prilled formulation, while some aggregation and structural deformity were observed in emulsion-derived MVLs. The in vitro drug release profiles demonstrated sustained release from prilled MVLs: 23.9% at 24 hours, 57.9% at 72 hours, and 97.9% at 144 hours, suggesting a near-complete release over 6 days. In contrast, the double emulsion MVLs reached 50% release by 48 hours and completed release by 120 hours. The BPV HCl solution showed immediate release exceeding 90% within 8 hours. These results validate the prilling process as a promising technique for producing multivesicular liposomes with high reproducibility, scalability, and favorable release kinetics tailored for prolonged local anesthesia.

Conclusion: The prilling technique enabled the successful preparation of BPV-loaded MVLs with superior encapsulation efficiency, yield, and extended release compared to the conventional method. This formulation strategy holds promise as a scalable alternative for the development of long-acting local anesthetic injectables.