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<p>Nimodipine (NIMO) is used to treat ischemic nerve injury from subarachnoid hemorrhage (SAH), but its low aqueous solubility limits clinical safety and bioavailability. This study aims to improve NIMO's solubility by preparing inclusion complexes with sulfobutylether-β-cyclodextrin (SBE-β-CD), reducing the limitations of Nimotop<sup>®</sup> injection, including vascular irritation, toxicity, and poor dilution stability. The NIMO-SBE-β-CD inclusion complex (NIMO-CD) was characterized in both liquid and solid states through phase solubility studies and methods including DSC, FT-IR, XRD, and SEM. Dilution stability, hemolysis, vascular irritation, and acute toxicity tests were performed, with pharmacokinetic and pharmacodynamic studies using Nimotop<sup>®</sup> as the control. Physical characterization confirmed the successful formation of the inclusion complex. NIMO’s solubility improved by 1202-fold (from 0.82 to 986.19&#xa0;μg/mL at 25℃). NIMO-CD showed stability for 24&#xa0;h when diluted, exhibited no hemolytic activity, reduced vascular irritation, and its median lethal dose (LD<sub>50</sub>) was 2.49 times higher than that of Nimotop<sup>®</sup>. Both NIMO-CD and Nimotop<sup>®</sup> displayed similar pharmacokinetic profiles. Behavioral assessments (mNSS scoring and CT), along with evaluations of hematoma area and histopathology, demonstrated that NIMO-CD significantly improved outcomes in intracerebral hemorrhage, greatly enhancing neurological recovery, reducing hematoma and edema, and achieving treatment effects comparable to those of Nimotop<sup>®</sup> injection. NIMO-CD significantly improves NIMO's solubility and stability while maintaining bioequivalence with Nimotop<sup>®</sup>. Furthermore, its enhanced safety profile indicates its potential as a superior formulation for treating ischemic nerve injuries.</p> Graphical Abstract <p></p>

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Inclusion Complex of Nimodipine with Sulfobutylether-β-cyclodextrin: Preparation, Characterization, In Vitro and In Vivo Evaluation

  • 期刊论文

  • 发表日期：

    2025年1月8日

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  • Jiahui Liu,
  • Meichai Li,
  • Yongjie Huang,
  • Xinyu Wang,
  • Youfa Xu,
  • Zhiqin Fu,
  • Zhizhe Lin,
  • Jianming Chen,
  • Xin Wu

摘要

Nimodipine (NIMO) is used to treat ischemic nerve injury from subarachnoid hemorrhage (SAH), but its low aqueous solubility limits clinical safety and bioavailability. This study aims to improve NIMO's solubility by preparing inclusion complexes with sulfobutylether-β-cyclodextrin (SBE-β-CD), reducing the limitations of Nimotop® injection, including vascular irritation, toxicity, and poor dilution stability. The NIMO-SBE-β-CD inclusion complex (NIMO-CD) was characterized in both liquid and solid states through phase solubility studies and methods including DSC, FT-IR, XRD, and SEM. Dilution stability, hemolysis, vascular irritation, and acute toxicity tests were performed, with pharmacokinetic and pharmacodynamic studies using Nimotop® as the control. Physical characterization confirmed the successful formation of the inclusion complex. NIMO’s solubility improved by 1202-fold (from 0.82 to 986.19 μg/mL at 25℃). NIMO-CD showed stability for 24 h when diluted, exhibited no hemolytic activity, reduced vascular irritation, and its median lethal dose (LD50) was 2.49 times higher than that of Nimotop®. Both NIMO-CD and Nimotop® displayed similar pharmacokinetic profiles. Behavioral assessments (mNSS scoring and CT), along with evaluations of hematoma area and histopathology, demonstrated that NIMO-CD significantly improved outcomes in intracerebral hemorrhage, greatly enhancing neurological recovery, reducing hematoma and edema, and achieving treatment effects comparable to those of Nimotop® injection. NIMO-CD significantly improves NIMO's solubility and stability while maintaining bioequivalence with Nimotop®. Furthermore, its enhanced safety profile indicates its potential as a superior formulation for treating ischemic nerve injuries.

Graphical Abstract