基于电喷雾技术的尼达尼布高生物利用度和持续释放纳米递药系统。

BACKGROUND: Nintedanib is a new tyrosine kinase inhibitor and growth factor antagonist. It can be used to treat idiopathic pulmonary fibrosis diseases. Nintedanib has poor solubility in the intestinal tract environment, which leads to low bioavailability of just 4.7%. METHODS: In this study, a nintedanib solid dispersion was prepared by electrospray technology with an optimized formula (nintedanib:PVPK30:Soybean lecithin=1:5:0.25) and electrospray parameters (21 kV voltage, 18 cm receiving distance, 0.3 mL/h solution flow rate, 0.5 mm pinhole inner diameter). RESULTS: The accumulative release rate of the optimized solid dispersion was more than 60% in 30 minutes and 100% in 60 minutes. The size distribution was uniform and the surface observed with scanning electron microscopy (SEM) was smooth. The DSC and X-ray diffraction results showed that nintedanib existed in the solid dispersion through an amorphous form. Nintedanib solid dispersion sustained-release capsules were prepared to prolong drug release, improve patient compliance and reduce side effects. The accumulative release rate from the sustained release capsules was 35.17%, 54.78%, 70.58%, and 93.93% after 2 h, 6 h, 8 h, and 12 h, respectively, having obvious sustained release effects in vitro. The release behavior of solid dispersion sustained-release capsules in vitro was in accordance with the Ritger-Peppas model. The in vivo studies of nintedanib soft capsules, solid dispersion and nintedanib sustained release capsules in SD rats were investigated; the results showed that the T of the soft capsule, solid dispersion and sustained release capsules were 3 h, 2 h, and 6 h, respectively. The C were 2.945 mg/mL, 5.32 mg/mL, and 3.75 mg/mL, respectively, while the AUC0-24 h was 15.124 mg·h/mL, 23.438 mg·h/mL, and 24.584 mg·h/mL, respectively. The relevant bioavailability of the sustained-release capsules was 162.55% compared to the nintedanib soft capsule and 104.89% compared to the nintedanib solid dispersion. CONCLUSION: The results suggested superior bioavailability and a sustained-release effect from nintedanib sustained-release capsules, as compared to the reference (commercial nintedanib soft capsule).

背景：尼达尼布是一种新型的酪氨酸激酶抑制剂和生长因子拮抗剂，可用于治疗特发性肺纤维化疾病。尼达尼布在肠道环境中的溶解度较差，生物利用度仅为 4.7%。

方法：本研究采用电喷雾技术制备尼达尼布固体分散体，优化配方（尼达尼布：PVPK30：大豆卵磷脂=1：5：0.25）和电喷雾参数（21 kV 电压、18 cm 接收距离、0.3 mL/h 溶液流速、0.5 mm 内孔直径）。

结果：优化的固体分散体在 30 分钟内累积释放率超过 60%，60 分钟内达到 100%。粒径分布均匀，扫描电子显微镜（SEM）观察表面光滑。差示扫描量热法（DSC）和 X 射线衍射结果表明，尼达尼布以无定形形式存在于固体分散体中。制备尼达尼布固体分散体缓释胶囊，以延长药物释放时间，提高患者顺应性，降低副作用。缓释胶囊体外 2 h、6 h、8 h、12 h 的累积释放率分别为 35.17%、54.78%、70.58%、93.93%，具有明显的体外缓释效果。固体分散体缓释胶囊的体外释放行为符合 Ritger-Peppas 模型。研究了 SD 大鼠尼达尼布软胶囊、固体分散体和尼达尼布缓释胶囊的体内研究；结果表明，软胶囊、固体分散体和缓释胶囊的 T 分别为 3 h、2 h 和 6 h，C 分别为 2.945 mg/mL、5.32 mg/mL 和 3.75 mg/mL，AUC0-24 h 分别为 15.124 mg·h/mL、23.438 mg·h/mL 和 24.584 mg·h/mL。与尼达尼布软胶囊相比，缓释胶囊的相关生物利用度提高了 162.55%，与尼达尼布固体分散体相比，提高了 104.89%。

结论：与参比制剂（商业尼达尼布软胶囊）相比，尼达尼布缓释胶囊具有更高的生物利用度和缓释效果。