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

作　　者：赵笛 李菁菁 张凯 秦超 杨磊 尹莉芳 ZHAO Di;LI Jingjing;ZHANG Kai;QIN Chao;YANG Lei;YIN Lifang(Department of Pharmaceutics,School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]中国药科大学药学院药剂系,南京210009

出　　处：《中国药科大学学报》2021年第5期547-554,共8页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.81871477,No.81673377);重大新药创制国家科技重大专项资助项目(No.2017ZX09101001-004);中国药科大学新型冠状病毒肺炎应急科研专项资助项目(No.2632020ZX007)。

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5μm。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。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 5μm 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.

关 键 词：瑞德西韦 脂质体 吸入制剂 制备 空气动力学 

分 类 号：R944[医药卫生—药剂学]