摘要：

Purpose This study investigates the effects of heat annealing, drug, and lipid composition on the physical stability of solid lipid microparticles entrapped in hyaluronic acid. Methods Tristearin or glyceryl behenate lipid microparticles were loaded with bupivacaine or ropivacaine using high-shear homogenization at an elevated temperature. Half of each formulation underwent heat annealing at 60 °C for 24 h. Drug entrapment efficiency, in vitro drug release, differential scanning calorimetry, x-ray diffraction, and light microscopy were serially performed to characterize the stability of formulations over time. Results Heat annealed microparticles exhibited higher drug loss than non-annealed microparticles on Day 1 (e.g. 16.29%±0.83 vs. 1.14%±0.08 for tristearin-ropivacaine microparticles). After 6 months at room temperature, non-annealed ropivacaine microparticles exhibited lower drug loss than non-annealed bupivacaine microparticles (tristearin: 2.28%±0.69 vs. 10.06%±1.45; glyceryl behenate: 3.10%±0.10 vs. 20.24%±2.46). Non-annealed ropivacaine microparticles exhibited the longest drug release with 64.49%±5.44 (tristearin) and 59.23%±0.26 (glyceryl behenate) drug released at 80 h, respectively. Conclusions Non-annealed, ropivacaine-containing formulations had the best shelf-life stability and exhibited the highest entrapment efficiencies after 6 months of storage compared to bupivacaine-containing and heat annealed formulations. Upon fabrication of the lipid microparticles, ropivacaine solidifies into a stable crystalline form. In contrast, bupivacaine initially solidifies into an amorphous form which is thermodynamically unstable and leads to drug leaching from the microparticles during storage. Ropivacaine is therefore a better candidate drug for a lipid microparticle entrapped in hyaluronic acid long-acting local anesthetic product.

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