摘要
目的制备鞣花酸纳米混悬剂(ellagic acid nanosuspensions,EA-NPs),并考察在SD大鼠体内的药动学特征。方法采用高压均质法制备EA-NPs。在单因素实验基础上,以稳定剂与药物用量比例、均质压力、均质次数为主要影响因素,粒径和多分散系数(polydispersity index,PDI)为考察指标,采用Box-Behnken设计-效应面法优化EA-NPs制备工艺。采用透射电子显微镜(TEM)和X射线粉末衍射(XRPD)对EA-NPs进行表征,透析袋法考察体外释药情况。SD大鼠分别ig给予鞣花酸混悬液、物理混合物(比例同EA-NPs)和EA-NPs,HPLC法测定大鼠血浆中的鞣花酸质量浓度,并计算主要药动学参数。结果EA-NPs的最处方工艺:以磷脂-聚乙烯吡咯烷酮(polyvinylpyrrolidone,PVP)K30(2∶3)为稳定剂,稳定剂与药物比例4∶1,制备温度为25℃,均质压力73 MPa,均质次数为11次。EA-NPs呈球形或类球形,粒径为70~400 nm,平均粒径为(148.16±7.61)nm,PDI为0.089±0.014,ζ电位为(-29.64±1.82)m V。鞣花酸在EA-NPs中以无定形状态存在,6 h内药物的累积释放率为96.24%。药动学结果显示,EA-NPs的半衰期(t1/2)延长至(3.17±0.64)h,达峰浓度(Cmax)提高至(1172.04±182.51)ng/mL,相对口服生物利用度提高至5.61倍。结论EA-NPs可促进药物体外溶出,提高鞣花酸在大鼠体内的口服生物利用度。
Objective To prepare ellagic acid nanosuspensions(EA-NPs)and study pharmacokinetics characteristics in SD rats.Methods EA-NPs were prepared by high pressure homogenization method.Based on single factor experiments,ratio of stabilizer to drug,homogenization pressure and homogenization frequency were used as influencing factors,average particles size and polydispersion index(PDI)were employed as evaluation indexes,the formulation of EA-NPs was optimized by Box-Behnken design-response surface method.EA-NPs was characterized by transmission electron microscopy(TEM)and X-ray powder diffraction(XRPD).Dialysis bag method was employed to investigate the drug release in vitro.SD rats in each group were administered intragastrically with ellagic acid suspension,physical mixture(the proportion of excipients were consistent with EA-NPs)and EA-NPs group,respectively.Ellagic acid concentration in plasma was analyzed by HPLC and the main pharmacokinetic parameters were calculated.Results The optimal preparation of EA-NPs:phospholipids-PVP K30(2:3)was employed as stabilizer,the ratio of stabilizer to drug was 4:1,preparation temperature was 25℃,homogenization pressure was 73MPa and homogenization frequencies was 11 times.The shape of EA-NPs was spherical or elliptical.Particle size distributed between 70 nm and 400 nm.Average particle size,PDI andζpotential of EA-NPs were(148.16±7.61)nm,0.089±0.014 and(-29.64±1.82)mV,respectively.Ellagic acid existed in an amorphous state in EA-NPs,and the cumulative dissolution of drug was 96.24%in 6 h.The t1/2 of EA-NPs was prolonged to(3.17±0.64)h,Cmax was increased to(1172.04±182.51)ng/mL and the oral bioavailability was enhanced to 5.61 times.Conclusion EA-NPs could enhance cumulative dissolution of EA in vitro and improve oral bioavailability in vivo.
作者
秦芳芳
彭有梅
苏海波
高守甲
QIN Fang-fang;PENG You-mei;SU Hai-bo;GAO Shou-jia(Zhengzhou Central Hospital Affiliated to Zhengzhou University,Zhengzhou 450007,China;Henan Institute of Medical and Pharmaceutical Sciences,Zhengzhou 450052,China;Technical Center,Shanghai Leiyunshang Pharmaceutical Co.,Ltd.,Shanghai 201401,China)
出处
《中草药》
CAS
CSCD
北大核心
2022年第13期3980-3990,共11页
Chinese Traditional and Herbal Drugs
基金
河南省科技公关项目(202102310159)
上海市科委项目(21S21903400)。
关键词
鞣花酸
纳米混悬剂
Box-Behnken设计-效应面法
表征
溶出
药动学
高压均质法
生物利用度
ellagic acid
nanosuspensions
Box-Behnken design-response surface method
characterization
dissolution
pharmacokinetics
high pressure homogenization method
oral bioavailability
作者简介
秦芳芳(1985—),女,硕士,从事医院药学研究。Tel:(0371)68520039 E-mail:qinfangfang2022@126.com;通信作者:苏海波(1984—),男,硕士,从事药物临床及药理研发工作。Tel:(021)37565578 E-mail:suhb@shlys.com。
