Laboratory of Inflammation and Immunology, Guarulhos University, Guarulhos, São Paulo, Brazil.
Department of Pharmacology, Biological Sciences Sector, Federal University of Parana, Curitiba, Parana, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2022 Nov;395(11):1405-1417. doi: 10.1007/s00210-022-02278-4. Epub 2022 Aug 1.
Bupivacaine hydrochloride (BVC) represents an option to produce long-lasting analgesia, and complexation in cyclodextrins has shown improvements in biopharmaceutical properties. This study aimed to characterize and test the cytotoxicity and antinociceptive effects of BVC complexed in sulfobutylether-β-cyclodextrin (SBEβCD). The kinetics and stoichiometry of complexation and BVC-SBEβCD association constant were evaluated by phase solubility study and Job's plot. Evidence of the BVC-SBEβCD complex formation was obtained from scanning electron microscopy (SEM), infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The cytotoxicity was evaluated in keratinocyte (HaCaT) and neuroblastoma (SH-SY5Y). Antinociceptive effects were registered via orofacial pain models: the formalin test, carrageenan-induced hyperalgesia, and postoperative pain (intraoral incision). The complex formation occurred at a 1:1 BVC-SBEβCD molar ratio, with a low association constant (13.2 M). SEM, DSC, and FTIR results demonstrated the host-guest interaction. The IC values determined in SH-SY5Y were 216 µM and 149 µM for BVC and BVC-SBEβCD, respectively (p < 0.05). There was no difference in HaCaT IC. In orofacial pain model, BVC-SBEβCD significantly prolonged antinociceptive effect, in about 2 h, compared to plain BVC. SBEβCD can be used as a drug delivery system for bupivacaine, whereas the complex showed long-lasting analgesic effects.
盐酸布比卡因（BVC）是一种可产生长效镇痛效果的药物，其与环糊精形成复合物后可改善生物药剂学性质。本研究旨在对盐酸布比卡因与磺丁基醚-β-环糊精（SBEβCD）形成的复合物进行特征描述和细胞毒性及镇痛效果检测。通过相溶解度研究和 Job 作图评估了复合物形成的动力学和化学计量学以及 BVC-SBEβCD 结合常数。通过扫描电子显微镜（SEM）、红外光谱（FTIR）和差示扫描量热法（DSC）获得了 BVC-SBEβCD 复合物形成的证据。在角质细胞（HaCaT）和神经母细胞瘤（SH-SY5Y）中评估了细胞毒性。通过口腔疼痛模型（福尔马林试验、角叉菜胶诱导的痛觉过敏和术后疼痛（口腔内切口））记录了镇痛效果。复合物形成的 BVC-SBEβCD 摩尔比为 1:1，结合常数较低（13.2 M）。SEM、DSC 和 FTIR 结果表明存在主体-客体相互作用。在 SH-SY5Y 中测定的 IC 值分别为 216 µM 和 149 µM（p<0.05）。在 HaCaT 中，BVC 和 BVC-SBEβCD 的 IC 值没有差异。在口腔疼痛模型中，与 BVC 相比，BVC-SBEβCD 可显著延长约 2 小时的镇痛效果。SBEβCD 可用作布比卡因的药物递送系统，而该复合物显示出持久的镇痛效果。
