聚乙二醇修饰高良姜素纳米结构脂质载体处方优化及口服药动学评价  

Formulation optimization of pegylated galangin nanostructured lipid carriers and oral pharmacokinetics evaluation

作　　者：周敬 郑宝玉 李阳杰 张国民 ZHOU Jing;ZHENG Bao-yu;LI Yang-jie;ZHANG Guo-min(Pharmacy and Chemical Engineering College,Zhengzhou University of Industrial Technology,Zhengzhou 451150,China;Department of Pharmacy,Shanghai Institute of Traditional Chinese Medicine,Shanghai 201401,China)

机构地区：[1]郑州工业应用技术学院药学与化学工程学院,河南郑州451150 [2]上海市中药研究所药学部,上海201401

出　　处：《中草药》2023年第14期4455-4466,共12页Chinese Traditional and Herbal Drugs

基　　金：国家“重大新药创制”(2018ZX09201009-002-09);教育部产学合作协同育人项目(202102028026);教育部产学合作协同育人项目(202101021046)。

摘　　要：目的 优化聚乙二醇修饰高良姜素纳米结构脂质载体(pegylated gallerythrine nanostructured lipid carriers,PEG-GalNLCs)处方,并进行体外释药行为和体内药动学评价。方法 采用乳化法制备PEG-Gal-NLCs。Box-Behnken设计-效应面法(Box Behnken design-response surface methodology,BBD-RSM)筛选PEG-Gal-NLCs最优处方,测定包封率、载药量、粒径及ζ电位。将PEG-Gal-NLCs混悬液制备成冻干粉,X射线粉末衍射(X-ray powder diffraction,XRPD)法分析高良姜素在PEG-Gal-NLCs冻干粉中的存在形式。考察PEG-Gal-NLCs冻干粉在模拟胃肠液中的释药行为,并对释药模型进行拟合。SD大鼠按50 mg/kg剂量ig后采血,HPLC法测定血药浓度,计算主要药动学参数及相对生物利用度。结果 PEG-Gal-NLCs最佳处方为聚乙二醇-单硬脂酸酯(PEG_(2000)-SA)占载体的质量分数为16%、载体与药物比例为13.5∶1、固-液脂质比例为3.6∶1。PEG-Gal-NLCs的包封率为(92.75±1.38)%,载药量为(6.44±0.23)%,平均粒径为(181.05±8.62)nm,ζ电位为(-30.71±1.56)mV。XRPD分析结果表明,高良姜素在PEG-Gal-NLCs冻干粉中以无定形状态存在。PEG-Gal-NLCs冻干粉在模拟胃肠液中体外释药具有缓释特征,释药过程均符合Weibull模型。PEG-Gal-NLCs的半衰期(t1/2)增加至(4.82±0.93)h,血药浓度(C_(max))增加至(1.43±0.42)μg/mL,口服相对生物利用度提高至4.28倍。结论 PEG-Gal-NLCs显著增加了高良姜素口服吸收。Objective To optimize prescriptions of pegylated gallerythrine nanostructured lipid carriers(PEG-Gal-NLCs),and carry out drug release behavior in vitro and oral pharmacokinetics in vivo evaluation.Methods Emulsification method was employed to prepare PEG-Gal-NLCs.Box-Behnken design-response surface methodology(BBD-RSM) was used to investigate the optimal prescriptions of PEG-Gal-NLCs.Entrapment efficiency,drug loading,particle size and ζ potential of PEG-Gal-NLCs were determined.Lyophilized powder of PEG-Gal-NLCs was prepared.The existence of Gal in PEG-Gal-NLCs lyophilized powder was analyzed by Xray powder diffraction(XRPD).In vitro release behavior of PEG-Gal-NLCs lyophilized powder in simulate gastrointestinal fluid was investigated,and the release model was fitted.SD rats were administered intragastrically at a dose of 50 mg/kg and blood samples were collected.Plasma concentrations were determined by HPLC,and main pharmacokinetic parameters and relative bioavailability were calculated.Results Optimal formulation of PEG-Gal-NLCs:content of PEG_(2000)-SA in carriers was 16%,ratio of carriers to drug was 13.5:1,and solid to liquid lipid ratio was 3.6:1.Envelopment efficiency,drug loading,particle size and ζ potential were(92.75 ±1.38)%,(6.44 ± 0.23)%,(181.05 ± 8.62) nm and(-30.71 ± 1.56) mV,respectively.Gal existed as an amorphous state in PEG-GalNLCs lyophilized powder.The drug release in vitro has obvious sustained-release characteristics in simulate gastrointestinal fluid,and the release process conformed to the Weibull model.The t1/2 of PEG-Gal-NLCs was increased to(4.82 ± 0.93) h,C_(max) was enhanced to(1.43 ± 0.42) μg/mL and oral relative bioavailability was increased to 4.28-fold.Conclusion PEG-Gal-NLCs can promote oral absorption of Gal effectively.

关 键 词：高良姜素 纳米结构脂质载体 Box-Behnken设计-效应面法 冻干粉 Weibull模型 药动学 生物利用度 

分 类 号：R283.6[医药卫生—中药学]