包载金丝桃苷的磷脂酰胆碱/壳聚糖自组装纳米粒的制备、表征及其口服药动学研究  

Self-assembled phosphatidylcholine/chitosan nanoparticles loaded with hyperoside:Preparation,characterization and oral pharmacokinetics

作　　者：刘艳菊 武月丹 位小杰 方雨欣 李珏泉 决利利 范明松 LIU Yanju;WU Yuedan;WEI Xiaojie;FANG Yuxin;LI Juequan;JUE Lili;FAN Mingsong(Zhengzhou University of Industrial Technology,Zhengzhou 451100,China;Shanghai Leiyunshang Pharmaceutical Co.,Ltd.,Shanghai 201401,China;Heilongjiang Chun Lok Pharmaceutical Co.,Ltd.,Jixi 158100,China)

机构地区：[1]郑州工业应用技术学院,河南郑州451100 [2]上海雷允上药业有限公司,上海201401 [3]黑龙江全乐制药有限公司,黑龙江鸡西158100

出　　处：《中草药》2025年第3期819-830,共12页Chinese Traditional and Herbal Drugs

基　　金：河南省高等学校重点科研项目计划(23B310010);河南省医学教育研究项目(WJLX2023153);黑龙江省重点研发计划(GA22C004)。

摘　　要：目的制备包载金丝桃苷的磷脂酰胆碱/壳聚糖自组装纳米粒(hyperoside self-assembled phosphatidylcholine chitosan nanoparticles,Hyp-PC/CS-NPs),并考察相对口服吸收生物利用度。方法单因素考察Hyp-PC/CS-NPs制备的主要影响因素,使用Box-Behnken设计-效应面法筛选Hyp-PC/CS-NPs处方。透射电子显微镜(transmission electron microscope,TEM)观察Hyp-PC/CS-NPs形貌;制备Hyp-PC/CS-NPs冻干粉并测定其饱和溶解度;傅里叶变换红外光谱(Fourier transform infrared spectroscopy,FTIR)研究Hyp-PC/CS-NPs冻干粉及各组分的结合机制;X射线粉末衍射法(X-ray powder diffraction,XRPD)分析金丝桃苷晶型;考察Hyp-PC/CS-NPs冻干粉及金丝桃苷原料药的体外释药行为;测定Hyp-PC/CS-NPs冻干粉的沉降率并考察其储存稳定性。SD大鼠分别ig给予金丝桃苷原料药和Hyp-PC/CS-NPs冻干粉,考察其口服药动学行为,并计算HypPC/CS-NPs相对口服生物利用度。结果Hyp-PC/CS-NPs最佳处方:药物质量浓度为0.37mg/m L,磷脂酰胆碱与壳聚糖质量比为16.3∶1,磷脂酰胆碱与金丝桃苷质量比为7.9∶1。Hyp-PC/CS-NPs的包封率、载药量、粒径及ζ电位分别为(84.19±1.23)%、(8.81±0.16)%、(166.18±4.03)nm和(32.39±0.95)m V;Hyp-PC/CS-NPs外貌为类球形,金丝桃苷可能与载体发生了氢键络合作用;金丝桃苷以无定型形态存在于Hyp-PC/CS-NPs冻干粉中;与原料药相比,Hyp-PC/CS-NPs冻干粉中的金丝桃苷在模拟胃液、蒸馏水和模拟肠液中的饱和溶解度分别增加了7.22、4.04、5.10倍。药动学结果显示,与金丝桃苷原料药或物理混合物相比,Hyp-PC/CS-NPs药动学参数均极显著性增加(P<0.01);Hyp-PC/CS-NPs中金丝桃苷相对口服生物利用度增加至其原料药的4.11倍。结论成功制备了Hyp-PC/CS-NPs及其冻干粉,Hyp-PC/CS-NPs明显改变了金丝桃苷的体内药动学行为,显著增加了其口服生物利用度,为其后续药效学评价奠定实验基础。Objective To prepare hyperoside self-assembled phosphatidylcholine chitosan nanoparticles(Hyp-PC/CS-NPs),and relative oral bioavailability were studied.Methods The main influencing factors of Hyp-PC/CS-NPs were investigated by single factor experiments,Box-Behnken design-response surface method was employed to optimize prescriptions of Hyp-PC/CS-NPs.Transmission electron microscope(TEM)was employed to observe microscopic appearance of Hyp-PC/CS-NPs,lyophilized powder of Hyp-PC/CS-NPs was prepared and its saturated solubility was determined,Fourier transform infrared spectroscopy(FTIR)was used to investigate the binding mechanism of Hyp-PC/CS-NPs lyophilized powder and each component,and crystal form of hyperoside was analyzed by X-ray powder diffraction(XRPD).Drug release behavior in vitro of Hyp-PC/CS-NPs lyophilized powder and hyperoside was determined,the sedimentation rate of Hyp-PC/CS-NPs lyophilized powder was determined and its storage stability was also investigated.SD rats were administered intragastrically with hyperoside and Hyp-PC/CS-NPs lyophilized powder,its oral pharmacokinetic behavior was studied,and relative oral bioavailability of Hyp-PC/CS-NPs was calculated.Results Optimal formulations of Hyp-PC/CS-NPs:hyperoside concentration was 0.37 mg/mL,phosphatidylcholine to chitosan ratio was 16.3:1,phosphatidylcholine to hyperoside ratio was 7.9:1.Envelopment efficiency,drug loading,particle size and ζ potential were(84.19±1.23)%,(8.81±0.16)%,(166.18±4.03)nm and(32.39±0.95)mV,respectively.Appearance of Hyp-PC/CS-NPs was spherical,hyperoside may have complexed with the carrier by hydrogen bond.The state of hyperoside changed into an amorphous form in Hyp-PC/CS-NPs freeze-dried powder.Solubility of hyperoside in simulated gastric juice,distilled water and simulated intestinal juice was increased by 7.22,4.04 and 5.10 times,respectively.Pharmacokinetic results showed that the pharmacokinetic parameters of Hyp-PC/CS-NPs were significantly increased compared with hyperoside or physical mixture(P<0.01)

关 键 词：金丝桃苷 自组装纳米粒 磷脂酰胆碱 壳聚糖 生物利用度 药动学 Box-Behnken设计-效应面法 

分 类 号：R283.6[医药卫生—中药学]