吸入用瑞德西韦脂质体的制备及其体外评价
Preparation and in vitro characterization of remdesivir-loaded liposomes for inhalation
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摘要: 制备吸入用瑞德西韦脂质体并对其体外性质进行评价。首先对瑞德西韦脂质体制备方法进行考察，通过单因素实验确定了制剂的处方组成和制备工艺。然后对瑞德西韦脂质体吸入剂的基本性质、体外沉积性质和空气动力学粒径等进行了全面评价。结果显示，以薄膜分散法制备并以pH 6.5磷酸盐缓冲液为水化介质制得的脂质体其粒径较小、包封率高、48 h几乎无沉淀产生。优化后的处方中药物与二棕榈酰磷脂酰胆碱（DPPC）的比例为1∶20，胆固醇占总脂材的10%，并加入20%二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000（DSPE-mPEG 2000）以提高脂质体稳定性。在冷冻干燥过程中加入4%海藻糖作为冻干保护剂，得到的冻干剂具有理想的外观并且复溶前后粒径变化较小、稳定性良好。透射电镜下观察到脂质体的微观形态呈表面光滑的球状结构，且粒径分布均匀。体外释放显示，经雾化器雾化前后脂质体混悬液的释放曲线无明显改变；体外沉积性质考察表明，使用新一代撞击器测得的细颗粒占51.4%，质量中值空气动力学粒径小于5 μm。实验结果表明，吸入用瑞德西韦脂质体具有良好的包封率和稳定性，雾化后的脂质体混悬液粒度分布均匀，能够有效地在肺部沉积，为新型冠状病毒肺炎的治疗提供了新的思路。Abstract: Remdesivir-loaded liposomes for inhalation were prepared and the in vitro properties were evaluated. Firstly, preparation methods of remdesivir-loaded liposomes were screened, and single-factor experiments were conducted to optimize the prescription and preparation process. Then the physical property, deposition ratio and aerodynamic particle size distribution of remdesivir-loaded liposomes suspension for inhalation were comprehensively evaluated. As a result, the optimal liposomes were prepared by the thin-film dispersion method with pH 6.5 phosphate-buffered saline as the hydration medium. In the prescription, the ratio of drug to DPPC was 1∶20; the cholesterol accounted for 10% of total lipids; and 20% DSPE-mPEG 2000 was added as stabilizer.4% trehalose was added as lyoprotectant when lyophilizing to obtain ideal appearance, good stability and a small particle size change after reconstitution. Remdesivir-loaded liposomes were spherical with smooth surface and uniform particle size distribution under transmission electron microscope. In vitro release tests showed no significant change for release curves of remdesivir-loaded liposomes suspension before and after nebulization. Deposition experiments indicated that the fine particles fraction of liposomes was 51.4%, and the mass median aerodynamic diameter was less than 5 μm measured by next generation impactor. To sum up, remdesivir-loaded liposomes for inhalation with high encapsulation efficiency and stability can achieve a suitable particle size distribution to effectively deposit in the lung after nebulization, which provides a new approach for the treatment of COVID-19.
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Keywords:
- remdesivir /
- liposomes /
- inhalation /
- preparation /
- aerodynamics
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