花旗松素磷脂复合物白蛋白纳米粒的构建及其肠吸收研究  

Construction and intestinal absorption of taxifolin phospholipid complex albumin nanoparticles

作　　者：张佳慧 孙敬蒙 张鑫 张诗雨 张欣 张炜煜[1] ZHANG Jia-hui;SUN Jing-meng;ZHANG Xin;ZHANG Shi-yu;ZHANG Xin;ZHANG Wei-yu(Pharmacy College,Changchun University of Chinese Medicine,Changchun 130117,China;Department of Clinical Pharmacy,the First Hospital of Jilin University,Changchun 130061,China)

机构地区：[1]长春中医药大学药学院,吉林长春130117 [2]吉林大学第一医院临床药学部,吉林长春130061

出　　处：《中草药》2023年第24期8043-8054,共12页Chinese Traditional and Herbal Drugs

基　　金：吉林省科技发展计划项目(YDZJ202201ZYTS628);长春中医药大学研究生精品示范课程建设创新示范项目(2022JP06)。

摘　　要：目的 构建花旗松素磷脂复合物白蛋白纳米粒(taxifolin phospholipid complex albumin nanoparticles,Tax-PC/BSA NPs)并优化其制备工艺,考察其肠吸收特性。方法 采用溶剂挥发法和新型白蛋白纳米粒制备技术(Nab~(TM)技术)制备花旗松素磷脂复合物白蛋白纳米粒。采用Box-Behnken设计-响应面法(Box-Behnken design-response surface method,BBDRSM),优化其制备工艺并验证;以透射电子显微镜(transmission electron microscope,TEM)、粒径、多分散指数(polydispersity index,PDI)、ζ电位、差示扫描量热法(differential scanning calorimetry,DSC)、傅里叶变换红外光谱(Fourier transform infrared spectroscopy,FT-IR)及X射线衍射(X-ray diffraction,XRD)技术对Tax-PC/BSA NPs进行表征,测定理化性质并考察制剂稳定性;体外模拟消化释放,探讨制剂在人体消化环境的释放规律;大鼠在体单向肠灌流模型评价Tax-PC/BSA NPs肠吸收特性。结果 Tax-PC/BSA NPs的最优制备工艺为药脂比1∶3,药/BSA比1∶9.39,油水比1∶11.51,超声时间7.76 min;3次验证实验结果显示,Tax-PC/BSA NPs的包封率为(86.14±0.38)%,载药量为(7.27±0.03)%,渗漏率为(0.87±0.04)%。按优化后工艺所制Tax-PC/BSA NPs在TEM下呈类球状,平均粒径为(184.90±0.98)nm、PDI为0.275±0.010、ζ电位为(-36.6±0.53)m V,DSC、FT-IR、XRD进一步验证了Tax-PC/BSA NPs的形成;Tax-PC/BSA NPs溶解度相较花旗松素提高了38.48倍,lg P值>1,脂溶性明显提高;Tax-PC/BSA NPs冻干粉在4℃下存放3个月稳定性良好;花旗松素、Tax-PC、Tax-PC/BSA NPs累积释放率分别为(48.26±0.71)%、(71.86±1.83)%、(82.73±0.62)%;Tax-PC/BSA NPs、Tax-PC和花旗松素在各肠段均有吸收,主要吸收部位分别为十二指肠和空肠,Tax-PC/BSA NPs的吸收速率常数和表观吸收系数均显著高于Tax-PC和花旗松素(P<0.05、0.01)。结论 优化所得Tax-PC/BSA NPs制备工艺稳定、可行;所制Tax-PC/BSA NPs有效提高药物的脂溶性、水溶性,增强药物在体肠吸�Objective To construct taxifolin phospholipid complex albumin nanoparticles(Tax-PC/BSA NPs)and optimize its preparation technology,and investigate its intestinal absorption characteristics.Methods Tax-PC/BSA NPs were prepared by solvent evaporation method and nanoparticle-albumin bound technology(Nab^(TM)).Box-Behnken design-response surface method(BBD-RSM)was used to optimize the preparation process and verify it.Tax-PC/BSA NPs were characterized by transmission electron microscope(TEM),particle size,polydispersity index(PDI),ζpotential,differential scanning calorimetry(DSC),Fourier transform infrared spectroscopy(FT-IR)and X-ray diffraction(XRD)to determine the physicochemical properties and to investigate the stability of the formulation.The absorption characteristics of Tax-PC/BSA NPs were investigated to investigate the release rule of the preparation in human digestive environment.The intestinal absorption characteristics of Tax-PC/BSA NPs were evaluated in rats with unidirectional intestinal perfusion model in situ.Results The optimal preparation process of Tax-PC/BSA NPs included drug-phosphorus ratio of 1:3,drug/BSA ratio of 1:9.39,oil-water ratio of 1:11.51,and sonication time of 7.76 min.Results of three validation experiments showed that the encapsulation efficiency of Tax-PC/BSA NPs was(86.14±0.38)%,the drug loading was(7.27±0.03)%,and the leakage rate was(0.87±0.04)%.The Tax-PC/BSA NPs prepared by the optimal process were spherical,the average particle size was(184.90±0.98)nm,the PDI was 0.275±0.010,and theζpotential was(−36.60±0.53)mV.The formation of Tax-PC/BSA NPs was further verified by DSC,FT-IR,and XRD.The solubility of Tax-PC/BSA NPs increased 38.48 times compared with Tax,lgP>1,and lipid solubility was significantly improved;Tax-PC/BSA NPs lyophilized powder was stable at 4℃for 3 months.The cumulative release rates of Tax,Tax-PC,and Tax-PC/BSA NPs were(48.26±0.71)%,(71.86±1.83)%,(82.73±0.62)%,respectively.Tax-PC/BSA NPs,Tax-PC and Tax were absorbed in all intestinal segments,a

关 键 词：花旗松素 磷脂复合物 白蛋白 纳米粒 制备工艺 肠吸收特性 单向肠灌流模型 

分 类 号：R283.6[医药卫生—中药学]