Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (Unicamp), Campinas, Brazil.
Faculty of Health Sciences, Federal University of Grande Dourados, Dourados, Brazil.
Int J Pharm. 2021 Sep 5;606:120944. doi: 10.1016/j.ijpharm.2021.120944. Epub 2021 Jul 26.
Bupivacaine is the most employed local anesthetic in surgical procedures, worldwide. Its systemic toxicity has directed the synthesis of the less toxic, S(-) enantiomer. This work describes a formulation of ionic gradient liposomes (IGL) containing BVC, an enantiomeric excess mixture of 75% S(-) and 25% R(+) bupivacaine. IGL prepared with 250 mM (NH)SO in the inner aqueous core of phosphatidylcholine and cholesterol (3:2 mol%) vesicles plus 0.5% BVC showed average sizes of 312.5 ± 4.5 nm, low polydispersity (PDI < 0.18), negative zeta potentials (-14.2 ± 0.2 mV) and were stable for 360 days. The encapsulation efficiency achieved with IGL (%EE = 38.6%) was higher than with IGL prepared with racemic bupivacaine (IGL, %EE = 28.3%). TEM images revealed spherical vesicles and µDSC analysis provided evidence on the interaction of the anesthetic with the lipid bilayer. Then, in vitro - release kinetics and cytotoxicity- and in vivo - toxic effects in Zebrafish and biochemical/histopathological analysis plus analgesia in Wistar rats - tests were performed. IGL exhibited negligible toxicity against Schwann cells and Zebrafish larvae, and it did not affect biochemical markers or the morphology of rat tissues (heart, brain, cerebellum, sciatic nerve). The in vitro release of BVC from IGL was extended from 4 to 24 h, justifying the prolonged anesthetic effect measured in rats (~9 h). The advantages of IGL formulation over IGL and plain bupivacaine formulations (prolonged anesthesia, preferential sensorial blockade, and no toxicity) confirm its potential for clinical use in surgical anesthesia.
布比卡因是全球手术中应用最广泛的局部麻醉剂。其全身毒性促使人们合成毒性较低的 S(-)对映体。本工作描述了一种含有布比卡因的离子梯度脂质体（IGL）的配方，布比卡因是 S(-)对映体过量 75%和 R(+)对映体 25%的混合物。在含有 250 mM（NH）SO 的内水核的磷脂酰胆碱和胆固醇（3:2 mol%）囊泡中制备的 IGL 加上 0.5%的布比卡因，平均粒径为 312.5±4.5nm，低多分散性（PDI<0.18），负的 zeta 电位（-14.2±0.2 mV），并在 360 天内稳定。与用外消旋布比卡因制备的 IGL（IGL，%EE=28.3%）相比，用 IGL 实现的包封效率（%EE=38.6%）更高。TEM 图像显示球形囊泡，µDSC 分析提供了麻醉剂与脂质双层相互作用的证据。然后进行了体外释放动力学、细胞毒性和斑马鱼体内毒性以及生物化学/组织病理学分析加上 Wistar 大鼠的镇痛试验。IGL 对许旺细胞和斑马鱼幼虫的毒性可以忽略不计，也不会影响生化标志物或大鼠组织（心脏、大脑、小脑、坐骨神经）的形态。IGL 中布比卡因的体外释放从 4 小时延长到 24 小时，这解释了在大鼠中测量到的延长的麻醉效果（~9 小时）。与 IGL 和普通布比卡因制剂相比，IGL 制剂的优势（延长的麻醉、感觉阻滞优先和无毒性）证实了其在手术麻醉中的临床应用潜力。
