鞣花酸纳米结构脂质载体处方优化和口服生物利用度研究  

Formulation optimization of ellagic acid nanostructured lipid carriers and oral bioavailability study

作　　者：王小霞 张智强[2] WANG Xiao-xia;ZHANG Zhi-qiang(The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450000,China;Tianjin Institute of Pharmaceutical Research Pharmaceutical Co.,Ltd.,Tianjin 300301,China)

机构地区：[1]郑州大学第一附属医院,河南郑州450000 [2]天津药物研究院药业有限责任公司,天津300301

出　　处：《中草药》2021年第13期3862-3871,共10页Chinese Traditional and Herbal Drugs

基　　金：国家重大科技专项(2017ZX0911002-001-005);河南省重大科技专项(182102731003)。

摘　　要：目的Box-Behnken设计-效应面法优化鞣花酸(EA)纳米结构脂质载体(EA-NLC)处方,并进行药动学研究。方法采用乳化超声法制备EA-NLC。以包封率、载药量和粒径为考察指标,采用单因素考察和Box-Behnken设计-效应面法优化EA-NLC的处方。对最佳处方进行表征,并比较体内药动学行为。结果最佳处方为脂-药比为13.7∶1、固-液脂质比为4.4∶1、泊洛沙姆188的用量为1.2%。EA-NLC包封率为(85.06±0.48)%,载药量为(5.53±0.15)%,粒径为(166.5±4.6)nm。体外释药具有明显的缓释特征,释药过程符合Weibull模型:lnln[1/(1-Mt/M∞)]=0.6821 lnt-2.0284,r=0.9827。体内药动学结果显示,EA-NLC的达峰时间(tmax)、半衰期(t1/2)、达峰浓度(Cmax)、时间-曲线下面积(AUC0~t和AUC0~∞)等主要参数与原料药相比均有显著性差异(P<0.05、0.01),将鞣花酸口服吸收生物利用度提高至4.67倍。结论Box-Behnken设计-效应面法所建立的模型能较好地用于EA-NLC处方优化,准确度高,预测效果较好,且EA-NLC显著增加了EA口服吸收生物利用度。Objective To optimize the formulation of ellagic acid(EA)nanostructured lipid carriers(EA-NLC)using Box-Behnken design-response surface method,and conduct its pharmacokinetics studies.Methods Emulsion ultrasonic method was used to prepare EA-NLC.Encapsulation rate,drug loading and particle size were taken as evaluation index,univariate investigation and Box-Behnken response surface design method were used to optimize the formulation of EA-NLC.The optimal formulation was characterized and pharmacokinetics behavior in vivo was also compared.Results The optimal formulation:lipid-drug ratio was 13.7∶1,solid-liquid lipid ratio was 4.4∶1 and surfactant concentration was 1.2%.Envelopment efficiency,drug loading and particle size of EA-NLC were(85.06±0.48)%,(5.53±0.15)%,and(166.5±4.6)nm,respectively.The drug release in vitro has obvious sustained-release characteristics,and the release process conformed to the Weibull model:lnln[1/(1-Mt/M∞)]=0.6821 lnt-2.0284,r=0.9827.The main pharmacokinetic parameters such as tmax,t1/2,Cmax,AUC0—t and AUC0—∞of EA-NLC had significant difference compared to ellagic acid(P<0.05,0.01).The oral bioavailability of ellagic acid was enhanced to 4.67 times.Conclusion The model established by the Box-Behnken design-response surface method could be used to optimize the formulation of EA-NLC with high accuracy and good prediction effect.And the oral bioavailability of ellagic acid was increased by EA-NLC effectively.

关 键 词：鞣花酸 纳米结构脂质载体 药动学 Box-Behnken设计-效应面法 缓释特征 口服生物利用度 

分 类 号：R283.6[医药卫生—中药学]