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,增强药物在体肠吸收能力。
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,and the main absorption sites were duodenum and jejunum,and the absorption rate constants and apparent absorption coefficients of Tax-PC/BSA NPs were significantly higher than those of Tax-PC and Tax(P<0.05,0.01).Conclusion The optimized preparation technology of Tax-PC/BSA NPs is stable and feasible;prepared TaxPC/BSA NPs effectively improved the liposolubility and water-solubility of the drug,and enhanced the absorption of the drug in the body intestine.
作者
张佳慧
孙敬蒙
张鑫
张诗雨
张欣
张炜煜
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)
出处
《中草药》
CAS
CSCD
北大核心
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)。
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
taxifolin
phospholipid complex
albumin
nanoparticles
preparation technology
intestinal absorption characteristics
unidirectional intestinal perfusion model
