摘要
目的针对硫酸氢氯吡格雷水溶性差的特点,通过将硫酸氢氯吡格雷制备成脂质体,提供一种可供血管内注射给药的硫酸氢氯吡格雷制剂。方法采用薄膜水化超声法和pH梯度法制备载硫酸氢氯吡格雷脂质体,考察其形态、粒径、包封率、载药量、Zeta电位和体外释药行为。采用微型动脉夹夹闭大鼠双侧肾蒂的方法建立雄性SD大鼠肾缺血再灌注损伤模型,初步考察硫酸氢氯吡格雷脂质体预处理对大鼠肾缺血再灌注损伤的影响。结果硫酸氢氯吡格雷脂质体的最佳处方和工艺为:药脂比为1∶10,磷脂和胆固醇之比为6∶1,十八胺和聚乙二醇400与药物的质量比为1.2∶1和1∶1,孵育时间40 min,孵育温度50℃,超声条件为100 W、间隔5 s工作20次,0.1 mol/L柠檬酸pH3.0缓冲液5 mL,采用薄膜分散法制备脂质体样品,并进行pH梯度主动载药,pH值调至7.5。此条件下制备的脂质体微粒圆整,分散性好,平均粒径为(134.13±2.60)nm,多分散系数(polydispersity index,PDI)为0.25±0.02,Zeta电位为(2.12±0.23)mV,包封率为(98.66±0.14)%,载药量为(7.47±0.01)%。体外释放实验结果显示72 h内硫酸氢氯吡格雷脂质体的累积释放率约66.24%。初步药效实验表明经氯吡格雷脂质体预处理的造模大鼠血清肌酐和尿素氮水平较未经处理的造模大鼠低。结论成功制备了硫酸氢氯吡格雷脂质体,为开发硫酸氢氯吡格雷注射液提供了实验基础。
Objective To prepare encapsulated clopidogrel bisulfate(CLP)liposomes so as to deal with the poor water solubility of CLP,and to provide the experimental basis for the development of CLP formulations for intravascular injection.Methods CLP-loaded liposomes were prepared using thin film hydration/sonication method and pH gradient active drug loading technology.Then,the morphology,particle size,encapsulation efficiency,drug loading capacity,Zeta potentials and in vitro release behavior were characterized.Bilateral renal arteries of Sprague-Dawley(SD)rats were clamped with micro-artery clamps to establish the model of renal ischemia-reperfusion injury(IRI)in male SD rats.The study aimed to preliminarily investigate the therapeutic effect of CLP-loaded liposome pretreatment on renal IRI in rats.Results It was found that the optimal formulation and preparation technology of CLP liposomes were as follows:the CLP-to-phospholipid weight ratio of 1∶10,phospholipid-to-cholesterol ratio of 6∶1,octadecylamine-to-CLP ratio of 1.2∶1,PEG400-to-CLP ratio of 1∶1,and incubation at 50℃for 40 min.Then,following ultrasonication of 100 W efficiency at 5-second intervals for 20 times,CLP loading was conducted using 5 mL of 0.1 mol/L citric acid buffer at pH 3.0.Liposome samples were prepared with the film dispersion method,and the pH value was adjusted to 7.5 through pH gradient active drug loading technology.The CLP-loaded liposomes obtained in this way had a rounded shape,good dispersity,an average particle size of(134.13±2.60)nm,polydispersity index(PDI)of 0.25±0.02,and a Zeta potential of(2.12±0.23)mV.The encapsulation efficiency was found to be(98.66±0.14)%,and the drug loading capacity was(7.47±0.01)%.The in vitro release results showed that 66.24%of CLP was released cumulatively within 72 h.Preliminary efficacy experiments showed that animals pretreated with CLP-loaded liposomes had lower serum levels of blood urea nitrogen and creatinine compared to the levels of IRI model rats without any pretreatment.Conclusion
作者
伍邦青
贺英菊
尹宗宁
张志荣
邓黎
WU Bang-qing;HE Ying-ju;YIN Zong-ning;ZHANG Zhi-rong;DENG Li(Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education,West China School of Pharmacy,Sichuan University,Chengdu 610041,China)
出处
《四川大学学报（医学版）》
CAS
CSCD
北大核心
2021年第4期630-636,共7页
Journal of Sichuan University(Medical Sciences)
基金
国家自然科学基金(No.U20A20411)
四川省科技厅应用基础研究项目(No.2021YJ0224)资助。
关键词
硫酸氢氯吡格雷
脂质体
PH梯度法
体外释放特征
肾缺血再灌注损伤
Clopidogrel bisulfate
Liposome
pH gradient method
In vitro release characteristics
Renal ischemia-reperfusion injury
