罗伊婷,邓黎,张志荣,何黎黎
LUO Yiting,DENG Li,ZHANG Zhirong,HE Lili

• 1:西南民族大学药学院
• 2:四川大学华西药学院

摘要(Abstract)：

目的 制备以聚乙二醇-12-羟基硬脂酸酯(Solutol HS 15,HS 15)作为稳定剂，人血清白蛋白(human serum albumin, HSA)修饰的硫酸氢氯吡格雷(clopidogrel bisulfate, CLP)纳米粒(HS 15 and HSA-clopidogrel bisulfate-nanoparticles, HH-CLP-NPs),对处方进行优化，筛选合适的冻干保护剂以提高制剂稳定性。方法 采用反溶剂沉淀法制备硫酸氢氯吡格雷纳米粒，通过单因素试验考察优化处方和工艺。以外观和粒径为指标，筛选冻干保护剂及其含量。采用激光散射粒度仪、透射电子显微镜和扫描电子显微镜对HH-CLP-NPs冻干制剂的粒径、电位、形态、晶体结构进行表征，采用粉末X-射线衍射分析对制剂的晶型进行表征，并考察制剂的稳定性。结果 确定HH-CLP-NPs的最优处方和制备工艺：CLP与稳定剂HS 15、HSA的质量比为1∶1∶1,磁力搅拌速度为1 500 r·min~(-1),搅拌时间为2 h,水浴温度为30℃,蠕动泵速度为100μL·min~(-1)。此条件下制备的HH-CLP-NPs呈类球形，分布均匀，平均粒径为(185.21±3.30)nm,多分散系数(PDI)为0.224±0.020,Zeta电位为(-17.56±1.30)mV,包封率为(99.26±0.28)%,载药量为(26.75±0.45)%。以甘露醇和丙氨酸作为冻干保护剂，冻干制剂的冻干形态良好，外形饱满，无萎缩及爬壁现象。结论 成功制备了HH-CLP-NPs冻干制剂，为开发注射用硫酸氢氯吡格雷纳米粒制剂提供了潜在可行的办法。
Objective To prepare polyethylene glycol-12-hydroxystearate(Solutol HS 15,HS 15)and human serum albumin(HSA)-modified clopidogrel bisulfate(CLP)nanoparticles(HS 15 and HSA-clopidogrel bisulfate-nanoparticles, HH-CLP-NPs),to optimize the formulation and evaluate their physicochemical properties.Cryoprotectants were screened to improve the formulation stability.Methods HH-CLP-NPs were prepared by anti-solvent precipitation method.The formulation and preparation methods were optimized based on the single factor tests.Cryoprotectants and their contents were screened based upon the appearance and mean particle sizes.The size distributions and Zeta potentials of lyophilized HH-CLP-NPs were investigated using dynamic light scattering analysis.The morphology was observed under the transmission electron microscope(TEM),and the morphology of lyophilized HH-CLP-NPs was characterized by scanning electron microscope(SEM).The crystal structure of HH-CLP-NPs was further evaluated by PXRD method.Results The optimal formulation and preparation process were as follows: the mass ratio of CLP to HS 15 was 1∶1∶1.The magnetic stirring speed was 1 500 r·min~(-1),stirring time was 2 h, the temperature of the water bath was maintained at 30 ℃,the pump speed was 100 μL·min~(-1).The obtained HH-CLP-NPs displayed a near spherical shape with an average particle size of(185.21±3.30)nm, polydispersity index(PDI) of 0.224±0.020,and Zeta potential of(-17.56±1.30) mV.The encapsulation efficiency was(99.26±0.28)%,and the drug loading capacity was(26.75±0.45)%.When mannitol and alanine were used as cryoprotectants, the appearance of the freeze-dried formulation was off-white powders without atrophy and wall-climbing phenomenon.Conclusion HH-CLP-NPs have been successfully developed, thus providing the experimental foundation for further development of clopidogrel bisulfate nanoparticles for intravenous administration.

关键词(KeyWords)： 硫酸氢氯吡格雷;静脉注射;纳米粒;冻干保护剂;反溶剂沉淀法
clopidogrel bisulfate;intravenous injection;nanoparticle;cryoprotectant;anti-solvent precipitation

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金资助项目(U20A20411);; 四川省科技厅应用基础研究资助项目(2021YJ0224);四川省科技厅应用基础资助项目(2022NSFSC1437)

作者(Author): 罗伊婷,邓黎,张志荣,何黎黎
LUO Yiting,DENG Li,ZHANG Zhirong,HE Lili

DOI: 10.14066/j.cnki.cn21-1349/r.2022.0682

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