人参皂苷Rg1脂质体制备及其生物物理与大鼠生物利用度评价
|
摘要
本论文主要包括以下几部分：
第一部分文献研究
对脂质体给药系统的研究进展、生物物理技术用于生物膜相态的研究进展、Caco-2细胞系体外模型及其药学应用的研究进展以及人参皂苷Rgl药理作用与药代动力学的研究进展进行了综述。
第二部分实验研究
一、人参皂苷Rgl含量测定方法的建立与理化参数研究
实验选用Agilent eclipse XDB-C18色谱柱(4.6×250mm,5μm)；乙腈-水(20：80)为流动相；流速0.8mL·min-1;检测波长203nm,柱温25℃；进样体积10μL,结果表明,HPLC法测定人参皂苷Rgl脂质体的包封率,辅料对人参皂苷Rgl的检测没有干扰；以峰面积(Y)对进样量(X)做线性回归,得人参皂苷Rgl回归方程为：Y=455220X-4275.7(R=1),结果表明人参皂苷Rgl在7.415ng-2996.172ng范围内的线性关系良好；人参皂苷Rgl日内RSD为0.35%(n=5)；日间RSD为2.99%(n=5),精密度满足要求；人参皂苷Rgl/DPPC/CH脂质体高、中、低浓度的回收率分别为98.74±3.00%、95.72±3.20%和103.78±2.16%,RSD分别为3.04%、3.34%、2.08%(n=3)；人参皂苷Rgl/DPPC/ST脂质体高、中、低浓度的回收率分别为96.19±0.95%、103.79±3.69%和100.74±5.75%,RSD分别为0.99%、3.56%、5.70%(n=3),回收率良好；考察人参皂苷Rgl、人参皂苷Rgl/DPPC/CH月(?)质体以及人参皂苷Rgl/DPPC/ST脂质体低、中、高浓度在细胞裂解液中的稳定性,结果表明人参皂苷Rgl室温放置24h的RSD分别为0.57%、1.22%和0.86%(n=5)；人参皂苷Rgl/DPPC/CH脂质体室温放置24h的RSD分别为3.18%、2.66%和4.25%(n=5)；人参皂苷Rgl/DPPC/ST脂质体室温放置24h的RSD分别为0.65%、3.88%和0.81%,(n=5),稳定性良好；人参皂苷Rgl药物纯度为99.15%,RSD=0.62%(n=3),药物纯度满足实验要求。
通过MarvinSketch 5.9.3软件对人参皂苷Rgl的理化参数进行预测研究,结果经计算得人参皂苷Rgl分子量为800.492207012；人参皂苷Rgl及其电离形式在各pH条件下所占比例结果提示其在体内主要以原型形式存在；logP值为0.68,推测其水溶性稍差；分子中含有约10个H供体与14个H受体,预测人参皂苷Rgl口服吸收较差。
二、人参皂苷Rgl脂质体的制备工艺研究
考察人参皂苷Rg1(Rg1)(?)旨质体的制备工艺,以包封率为指标优化制备工艺。以二棕榈酰磷脂酰胆碱DPPC).胆固醇(CH)、豆固醇(ST)为膜材,采用薄膜分散法制备Rgl/DPPC/CH脂质体和Rgl/DPPC/ST脂质体。首先进行了单因素考察,对磷脂与固醇比例、药物百分含量、水化时间以及水化温度进行研究,然后通过星点设计-效应面法优化处方工艺,HPLC法测定脂质体中Rgl的包封率,并对脂质体的稳定性进行了考察,结果发现Rg1/DPPC/CH脂质体的制备工艺参数为：药物百分含量为7.4-8.1%,水化时间为50.0-85.0min,水化温度为60.0-63.0℃；Rgl/DPPC/ST脂质体的制备工艺参数为：药物百分含量为7.6-8.1%,水化时间为95.0-100.0min,水化温度为40.0-63.0℃。采用星点设计-效应面法优化Rg1脂质体制备工艺,所建立的数学模型预测性良好,Rgl/DPPC/CH脂质体与Rgl/DPPC/ST脂质体包封率相近,初步提示可用豆固醇替代胆固醇作为人参皂苷Rgl脂质体制备的膜材。
三、人参皂苷Rgl及其不同固醇脂质体的分子间相互作用规律研究
研究人参皂苷Rgl脂质体中人参皂苷Rgl、磷脂和胆固醇(或豆固醇)三者分子间作用规律。按计量比称取人参皂苷Rgl.DPPC和固醇(DPPC和固醇的摩尔比为2：1),将DPPC和固醇溶于氯仿中,挥尽氯仿后,加入含人参皂苷Rgl的超过量的缓冲溶液(50 mmol·L-1 Tris-HCl,150 mmol·L-1NaCl, 0.1 mmol·L-1 CaCl2,pH 7.2),使水分子与磷脂分子之比为100：1,12000×g离心10min,室温下超声5min,然后将样品在室温和60℃之间进行加热-降温循环处理,最后置4℃冰箱保存24h,得到人参皂苷Rgl脂质体,采用示差扫描量热(DSC)、同步辐射X光衍射(XRD)和拉曼光谱法(Raman)等3种方法,研究脂质体中人参皂苷Rgl、胆固醇(或豆固醇)和二棕榈酰磷脂酰胆碱(DPPC)三者分子间相互作用规律。DSC测定结果表明,随着人参皂苷Rgl浓度的加大,胆固醇脂质体出现分相现象,豆固醇脂质体相态可能发生变化；XRD结果表明,含药量10%的胆固醇脂质体同样出现两个相变信号,豆固醇脂质体变化不明显；拉曼光谱结果表明,随着人参皂苷Rgl的加入,脂质体膜流动性与脂质侧链排列有序性均发生变化。豆固醇脂质体与胆固醇脂质体的相变规律相近,因而进一步证实可用豆固醇替代胆固醇作为人参皂苷Rgl脂质体的膜材。
四、人参皂苷Rgl及其脂质体在Caco-2细胞转运研究
取冻存的Cago-2细胞,37℃水浴,快速解冻,移至10%FBS的MEM完全培养基,在37℃、相对湿度90%、CO2浓度5%的培养箱内培养,隔日更换培养基,当细胞达到约80%融合时(Caco-2细胞基本铺满瓶壁),用0.25%胰蛋白酶-EDTA消化,按2.0×105/cm2密度将Caco-2细胞接种到12孔Millicell板上。采用跨膜电阻值和Lucifer Yellow CH跨膜转运实验对Caco-2细胞单层模型进行评价；MTT法评价药物对Caco-2细胞的抑制作用,选择溶剂的细胞抑制率<5%,受试物的细胞抑制率<10%,作为合适剂量进行实验；对Caco-2细胞摄取实验的影响因素进行研究,具体包括培养时间对Caco-2摄取的影响、pH对Caco-2摄取药物的影响、温度对Caco-2摄取药物的影响以及药物浓度对Caco-2细胞摄取的影响等,并进行药物跨膜转运实验,结果发现,由于脂质体能够破坏细胞膜中脂质双分子层的有序排列,因而有助于促进药物的吸收,胆固醇脂质体与豆固醇脂质体促进人参皂苷Rgl肠吸收作用相近,该结果再次说明可用豆固醇替代胆固醇作为人参皂苷Rgl脂质体的膜材。
五、人参皂苷Rgl及其脂质体的生物利用度评价
选取SD雄性大鼠,分别灌服人参皂苷Rgl及其DPPC/CH和DPPC/ST脂质体,于给药后10min、25min、40min、75min、120min、180min、240min、360min和600min眼眶取血,HPLC测定血清中药物含量,计算药物在大鼠体内的药代动力学参数,结果发现,人参皂苷Rgl的两种脂质体Tmax均增长,AUC结果显示人参皂苷Rg1/DPPC/ST(?)旨质体可显著提高原药物在大鼠体内的生物利用度,本研究达到预期目的。
The paper includes the following sections:
Part 1 Literature Review
The paper first of all has summarized the research progress of liposome delivery systems, biophysical techniques for the progress of the biological membrane phase state, Caco-2 cell lines in vitro model and its pharmaceutical applications of research progress, as well as the pharmacological effects of ginsenoside Rgl and its pharmacokineticsthe studies were reviewed.
Part 2
1 Establishment of the determination method for ginsenoside Rgl Determined ginsenoside Rgl by HPLC. The linear range of ginsenoside Rgl was 7.415ng-2996.172ng respectively, and the repeatability,the recovery and stability of the methods met the requirements. MarvinSketch software was selected to predict the physicochemical parameters of ginsenoside Rgl.The molecular weight of ginsenoside Rgl was calculated to be 800.492207012, logP value was 0.68,10 H bond donor and 14 H bond acceptor was contained. All these parameters predicted that ginsenoside Rgl had poor oral absorption.
2 Optimization preparation of ginsenoside Rgl liposome by central composite design and response surface method
To study the preparation method of ginsenoside Rgl (Rgl) liposome and to screen the optimal technological conditions by the encapsulation efficiencies for ginsenoside Rgl,liposomes were made of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), cholesterol (CH) or stigmasterol (ST) by film evaporation technique, then response surface methodology was adopted to screen the optimal conditions. The optimal technological conditions of Rgl/DPPC/CH liposome were as follows:the quality percentage content of Rgl was 7.4～8.1%, the hydration time was 50.0～85.0min,the hydration temperature was 60.0～63.0℃.The optimal technological conditions of Rgl/DPPC/ST liposome were as follows:The quality percentage content of Rgl was 7.6～8.1%, the hydration time was 95.0～100.Omin,and the hydration temperature was 40.0～63.0℃. The central composite design and response surface methodology is suitable for optimizing the formulation. Stigmasterol could be used in the formulation of ginsenoside Rgl liposome.
3 Study of interaction between Ginsenoside Rg1 and liposomes employing DSC,XRD and Ramam techniques
To investigate molecular interaction among ginsenoside Rgl, cholesterol/ stigmasterol and phospholipid in ginsenoside Rgl-encapsulated liposomes, liposomes were made of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), cholesterol or stigmasterol,and ginsenoside Rgl,then differential scanning calorimetry (DSC),synchrotron x-ray diffraction (XRD) techniques and raman spectra (Raman) were employed to investigate molecular interaction among ginsenoside Rgl, cholesterol/stigmasterol and DPPC in ginsenoside Rgl-encapsulated liposomes. DSC curve displayed two endothermal peaks and curves of SAXS displayed two signals of phase transition when the concentration of ginsenoside Rgl was increased to 20% in ginsenoside Rgl/cholesterol/DPPC liposomes, but in ginsenoside Rgl/stigmasterol/DPPC liposomes,curves of DSC and SAXS just show one signal, Raman spectroscopy results showed that the liposome membrane fluidity changed with the addition of ginsenoside Rg1.Stigmasterol could be used in the formulation of ginsenoside Rgl liposome.
4 Transport characteristics of ginsenoside Rgl and its liposome in Caco-2 cell monolayers
Taken out the freezing of Caco-2 cells, put them into water(37℃), quickly thawed, then moved to the 10% FBS MEM medium at 37℃,90% of relative humidity and the 5% CO2 concentration. Replaced the medium every other day, when the cells reached approximately 80% confluence (Caco-2 cells basically covered sidewall), digested them with 0.25% trypsin-EDTA.2.0×105/cm2 density of Caco-2 cells were vaccinated to 12-well Millicell board. Transmembrane resistance values and Lucifer Yellow CH transmembrane transport experiments used Caco-2 cell monolayer model to evaluate; MTT method was used to evaluate the drug on the inhibition of Caco-2 cells, selected the solvent inhibition rates<5%, the test substance the inhibition rate of<10%, as the appropriate dose experiments; studied the influencing factors on Caco-2 cell uptake experiments, including the effects of incubation time on uptake in Caco-2 and pH on the intake of drugs in Caco-2, the temperature Caco-2 uptake of drugs and drug concentration on the uptake by Caco-2 cells the impact, and the drug transmembrane transport experiments.The results showed that liposomes can destroy the ordered arrangement of the cell membrane lipid bilayer, thus helping to promote drug absorption, cholesterol liposome and beans steroid liposome for ginsenoside Rgl intestinal absorption was similar.
5 Bioavailability Assessment of ginsenoside Rgl liposomes
To assess the Bioavailability of ginsenoside Rgl liposomes, plasma concentrations were determined by HPLC, Kinetica was used to process main pharmacokinetics parameters. The results showed that two kinds of ginsenoside Rgl liposomes'Tmax increased. The AUC results indicated that the ginsenoside Rgl/DPPC/ST liposomes can significantly improve the bioavailability in rats, preparations of ginsenoside Rgl liposomes meets the desired objectives.
第一部分文献研究
对脂质体给药系统的研究进展、生物物理技术用于生物膜相态的研究进展、Caco-2细胞系体外模型及其药学应用的研究进展以及人参皂苷Rgl药理作用与药代动力学的研究进展进行了综述。
第二部分实验研究
一、人参皂苷Rgl含量测定方法的建立与理化参数研究
实验选用Agilent eclipse XDB-C18色谱柱(4.6×250mm,5μm)；乙腈-水(20：80)为流动相；流速0.8mL·min-1;检测波长203nm,柱温25℃；进样体积10μL,结果表明,HPLC法测定人参皂苷Rgl脂质体的包封率,辅料对人参皂苷Rgl的检测没有干扰；以峰面积(Y)对进样量(X)做线性回归,得人参皂苷Rgl回归方程为：Y=455220X-4275.7(R=1),结果表明人参皂苷Rgl在7.415ng-2996.172ng范围内的线性关系良好；人参皂苷Rgl日内RSD为0.35%(n=5)；日间RSD为2.99%(n=5),精密度满足要求；人参皂苷Rgl/DPPC/CH脂质体高、中、低浓度的回收率分别为98.74±3.00%、95.72±3.20%和103.78±2.16%,RSD分别为3.04%、3.34%、2.08%(n=3)；人参皂苷Rgl/DPPC/ST脂质体高、中、低浓度的回收率分别为96.19±0.95%、103.79±3.69%和100.74±5.75%,RSD分别为0.99%、3.56%、5.70%(n=3),回收率良好；考察人参皂苷Rgl、人参皂苷Rgl/DPPC/CH月(?)质体以及人参皂苷Rgl/DPPC/ST脂质体低、中、高浓度在细胞裂解液中的稳定性,结果表明人参皂苷Rgl室温放置24h的RSD分别为0.57%、1.22%和0.86%(n=5)；人参皂苷Rgl/DPPC/CH脂质体室温放置24h的RSD分别为3.18%、2.66%和4.25%(n=5)；人参皂苷Rgl/DPPC/ST脂质体室温放置24h的RSD分别为0.65%、3.88%和0.81%,(n=5),稳定性良好；人参皂苷Rgl药物纯度为99.15%,RSD=0.62%(n=3),药物纯度满足实验要求。
通过MarvinSketch 5.9.3软件对人参皂苷Rgl的理化参数进行预测研究,结果经计算得人参皂苷Rgl分子量为800.492207012；人参皂苷Rgl及其电离形式在各pH条件下所占比例结果提示其在体内主要以原型形式存在；logP值为0.68,推测其水溶性稍差；分子中含有约10个H供体与14个H受体,预测人参皂苷Rgl口服吸收较差。
二、人参皂苷Rgl脂质体的制备工艺研究
考察人参皂苷Rg1(Rg1)(?)旨质体的制备工艺,以包封率为指标优化制备工艺。以二棕榈酰磷脂酰胆碱DPPC).胆固醇(CH)、豆固醇(ST)为膜材,采用薄膜分散法制备Rgl/DPPC/CH脂质体和Rgl/DPPC/ST脂质体。首先进行了单因素考察,对磷脂与固醇比例、药物百分含量、水化时间以及水化温度进行研究,然后通过星点设计-效应面法优化处方工艺,HPLC法测定脂质体中Rgl的包封率,并对脂质体的稳定性进行了考察,结果发现Rg1/DPPC/CH脂质体的制备工艺参数为：药物百分含量为7.4-8.1%,水化时间为50.0-85.0min,水化温度为60.0-63.0℃；Rgl/DPPC/ST脂质体的制备工艺参数为：药物百分含量为7.6-8.1%,水化时间为95.0-100.0min,水化温度为40.0-63.0℃。采用星点设计-效应面法优化Rg1脂质体制备工艺,所建立的数学模型预测性良好,Rgl/DPPC/CH脂质体与Rgl/DPPC/ST脂质体包封率相近,初步提示可用豆固醇替代胆固醇作为人参皂苷Rgl脂质体制备的膜材。
三、人参皂苷Rgl及其不同固醇脂质体的分子间相互作用规律研究
研究人参皂苷Rgl脂质体中人参皂苷Rgl、磷脂和胆固醇(或豆固醇)三者分子间作用规律。按计量比称取人参皂苷Rgl.DPPC和固醇(DPPC和固醇的摩尔比为2：1),将DPPC和固醇溶于氯仿中,挥尽氯仿后,加入含人参皂苷Rgl的超过量的缓冲溶液(50 mmol·L-1 Tris-HCl,150 mmol·L-1NaCl, 0.1 mmol·L-1 CaCl2,pH 7.2),使水分子与磷脂分子之比为100：1,12000×g离心10min,室温下超声5min,然后将样品在室温和60℃之间进行加热-降温循环处理,最后置4℃冰箱保存24h,得到人参皂苷Rgl脂质体,采用示差扫描量热(DSC)、同步辐射X光衍射(XRD)和拉曼光谱法(Raman)等3种方法,研究脂质体中人参皂苷Rgl、胆固醇(或豆固醇)和二棕榈酰磷脂酰胆碱(DPPC)三者分子间相互作用规律。DSC测定结果表明,随着人参皂苷Rgl浓度的加大,胆固醇脂质体出现分相现象,豆固醇脂质体相态可能发生变化；XRD结果表明,含药量10%的胆固醇脂质体同样出现两个相变信号,豆固醇脂质体变化不明显；拉曼光谱结果表明,随着人参皂苷Rgl的加入,脂质体膜流动性与脂质侧链排列有序性均发生变化。豆固醇脂质体与胆固醇脂质体的相变规律相近,因而进一步证实可用豆固醇替代胆固醇作为人参皂苷Rgl脂质体的膜材。
四、人参皂苷Rgl及其脂质体在Caco-2细胞转运研究
取冻存的Cago-2细胞,37℃水浴,快速解冻,移至10%FBS的MEM完全培养基,在37℃、相对湿度90%、CO2浓度5%的培养箱内培养,隔日更换培养基,当细胞达到约80%融合时(Caco-2细胞基本铺满瓶壁),用0.25%胰蛋白酶-EDTA消化,按2.0×105/cm2密度将Caco-2细胞接种到12孔Millicell板上。采用跨膜电阻值和Lucifer Yellow CH跨膜转运实验对Caco-2细胞单层模型进行评价；MTT法评价药物对Caco-2细胞的抑制作用,选择溶剂的细胞抑制率<5%,受试物的细胞抑制率<10%,作为合适剂量进行实验；对Caco-2细胞摄取实验的影响因素进行研究,具体包括培养时间对Caco-2摄取的影响、pH对Caco-2摄取药物的影响、温度对Caco-2摄取药物的影响以及药物浓度对Caco-2细胞摄取的影响等,并进行药物跨膜转运实验,结果发现,由于脂质体能够破坏细胞膜中脂质双分子层的有序排列,因而有助于促进药物的吸收,胆固醇脂质体与豆固醇脂质体促进人参皂苷Rgl肠吸收作用相近,该结果再次说明可用豆固醇替代胆固醇作为人参皂苷Rgl脂质体的膜材。
五、人参皂苷Rgl及其脂质体的生物利用度评价
选取SD雄性大鼠,分别灌服人参皂苷Rgl及其DPPC/CH和DPPC/ST脂质体,于给药后10min、25min、40min、75min、120min、180min、240min、360min和600min眼眶取血,HPLC测定血清中药物含量,计算药物在大鼠体内的药代动力学参数,结果发现,人参皂苷Rgl的两种脂质体Tmax均增长,AUC结果显示人参皂苷Rg1/DPPC/ST(?)旨质体可显著提高原药物在大鼠体内的生物利用度,本研究达到预期目的。
The paper includes the following sections:
Part 1 Literature Review
The paper first of all has summarized the research progress of liposome delivery systems, biophysical techniques for the progress of the biological membrane phase state, Caco-2 cell lines in vitro model and its pharmaceutical applications of research progress, as well as the pharmacological effects of ginsenoside Rgl and its pharmacokineticsthe studies were reviewed.
Part 2
1 Establishment of the determination method for ginsenoside Rgl Determined ginsenoside Rgl by HPLC. The linear range of ginsenoside Rgl was 7.415ng-2996.172ng respectively, and the repeatability,the recovery and stability of the methods met the requirements. MarvinSketch software was selected to predict the physicochemical parameters of ginsenoside Rgl.The molecular weight of ginsenoside Rgl was calculated to be 800.492207012, logP value was 0.68,10 H bond donor and 14 H bond acceptor was contained. All these parameters predicted that ginsenoside Rgl had poor oral absorption.
2 Optimization preparation of ginsenoside Rgl liposome by central composite design and response surface method
To study the preparation method of ginsenoside Rgl (Rgl) liposome and to screen the optimal technological conditions by the encapsulation efficiencies for ginsenoside Rgl,liposomes were made of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), cholesterol (CH) or stigmasterol (ST) by film evaporation technique, then response surface methodology was adopted to screen the optimal conditions. The optimal technological conditions of Rgl/DPPC/CH liposome were as follows:the quality percentage content of Rgl was 7.4～8.1%, the hydration time was 50.0～85.0min,the hydration temperature was 60.0～63.0℃.The optimal technological conditions of Rgl/DPPC/ST liposome were as follows:The quality percentage content of Rgl was 7.6～8.1%, the hydration time was 95.0～100.Omin,and the hydration temperature was 40.0～63.0℃. The central composite design and response surface methodology is suitable for optimizing the formulation. Stigmasterol could be used in the formulation of ginsenoside Rgl liposome.
3 Study of interaction between Ginsenoside Rg1 and liposomes employing DSC,XRD and Ramam techniques
To investigate molecular interaction among ginsenoside Rgl, cholesterol/ stigmasterol and phospholipid in ginsenoside Rgl-encapsulated liposomes, liposomes were made of dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), cholesterol or stigmasterol,and ginsenoside Rgl,then differential scanning calorimetry (DSC),synchrotron x-ray diffraction (XRD) techniques and raman spectra (Raman) were employed to investigate molecular interaction among ginsenoside Rgl, cholesterol/stigmasterol and DPPC in ginsenoside Rgl-encapsulated liposomes. DSC curve displayed two endothermal peaks and curves of SAXS displayed two signals of phase transition when the concentration of ginsenoside Rgl was increased to 20% in ginsenoside Rgl/cholesterol/DPPC liposomes, but in ginsenoside Rgl/stigmasterol/DPPC liposomes,curves of DSC and SAXS just show one signal, Raman spectroscopy results showed that the liposome membrane fluidity changed with the addition of ginsenoside Rg1.Stigmasterol could be used in the formulation of ginsenoside Rgl liposome.
4 Transport characteristics of ginsenoside Rgl and its liposome in Caco-2 cell monolayers
Taken out the freezing of Caco-2 cells, put them into water(37℃), quickly thawed, then moved to the 10% FBS MEM medium at 37℃,90% of relative humidity and the 5% CO2 concentration. Replaced the medium every other day, when the cells reached approximately 80% confluence (Caco-2 cells basically covered sidewall), digested them with 0.25% trypsin-EDTA.2.0×105/cm2 density of Caco-2 cells were vaccinated to 12-well Millicell board. Transmembrane resistance values and Lucifer Yellow CH transmembrane transport experiments used Caco-2 cell monolayer model to evaluate; MTT method was used to evaluate the drug on the inhibition of Caco-2 cells, selected the solvent inhibition rates<5%, the test substance the inhibition rate of<10%, as the appropriate dose experiments; studied the influencing factors on Caco-2 cell uptake experiments, including the effects of incubation time on uptake in Caco-2 and pH on the intake of drugs in Caco-2, the temperature Caco-2 uptake of drugs and drug concentration on the uptake by Caco-2 cells the impact, and the drug transmembrane transport experiments.The results showed that liposomes can destroy the ordered arrangement of the cell membrane lipid bilayer, thus helping to promote drug absorption, cholesterol liposome and beans steroid liposome for ginsenoside Rgl intestinal absorption was similar.
5 Bioavailability Assessment of ginsenoside Rgl liposomes
To assess the Bioavailability of ginsenoside Rgl liposomes, plasma concentrations were determined by HPLC, Kinetica was used to process main pharmacokinetics parameters. The results showed that two kinds of ginsenoside Rgl liposomes'Tmax increased. The AUC results indicated that the ginsenoside Rgl/DPPC/ST liposomes can significantly improve the bioavailability in rats, preparations of ginsenoside Rgl liposomes meets the desired objectives.
引文
[1]邬瑞光.豆固醇和磷脂二元相图的构建及液态有序相性质的研究[D].北京：清华大学,2007.
[2]Vist MR,Davis JH. Phase equilibria of cholesterol/dipalmitoylphosphati-dylcholine mixtures:2H nuclear magnetic resonance and differentia scanning calorimetry[J]. Biochemistry,1990,29(2):451-464.
[3]Hsueh Y W, Gilbert K, Trandum C, et al. The effect of ergosterol on dipalmitoylphosphatidylcholine bilayers:a deuterium NMR and calorimetric study[J]. Biophys J,2005,88(3):1799-1808.
[1]张兆旺.中药药剂学[M].北京：中国中医药出版社,2003：499.
[2]Bangham AD, Standish MM, Miller N. Cation permeability of phospholipid model membranes:effect of narcotics[J].Nature.1965, 208(5017):1295-1297.
[3]胡玥,王金萍,李爱国等.洛莫司汀热敏脂质体在动物体内的.药代动力学及组织分布[J].药物分析杂志,2010,30(7)：1237-1241.
[4]赵峰,卿三华,王永华.天然大豆磷脂制备热敏脂质体的方法及质量评价[J].中国天然药物,2005,3(4)：231-234.
[5]武鑫朋,孙李妍,慕宏杰等Box-Behnken效应面法优化牛蒡苷pH敏感脂质体处方[J].齐鲁药事,2011,30(11)：625-628.
[6]王弘,胡良平,陈忠斌等.基因转染的pH敏感脂质体的最优处方和制备工艺的研究[J].中国药学杂志,2002,37(1)：29-32.
[7]温演庆,杨斌,钱志勇.光敏纳米脂质体制备及其特性研究[J].中国医学工程,2008,16(2)：84-85.
[8]孟凡旭,许华平,齐燕飞等.光敏性脂质体的初步研究[J].高等学校化学研究,2012,28(2)：319-322.
[9]文晔,刘宏,汤韧等.两性霉素B磁性脂质体的制备与质量控制[J].中国医院药学杂志,2007,27(10)：1344-1346.
[10]黄波涛,段磊,吴小玲等.5-氟尿嘧啶-Fe/Fe304磁性脂质体的制备及其表征[J].南京医科大学学报(自然科学版),2011,31(7)：951-956.
[11]段降龙,龙延滨,李国威.尿素免疫脂质体的制备及理化性质研究[J].陕西医学杂志,2011,40(6)：653-655.
[12]俞功龙,尹宗宁,张霞.纳豆激酶免疫脂质体及其冻干品的制备及药剂学性质评价[J].中国药房,2009,20(4)：276-278.
[13]张冬青,程怡,白丛林等.苦参素空间稳定脂质体的制备及其药剂学性质考察[J].中药材,2011,34(5)：786-789.
[14]时军,程怡,陈伟鸿等.足叶乙苷长循环脂质体的制备及血浆中稳定性研究[J].广州中医药大学学报,2009,26(3)：270-273.
[15]戈延茹,张晓兰,曹恒杰等.钆喷酸葡胺长循环脂质体的制备及其肿瘤细胞摄取能力研究[J].中国药房,2009,20(34)：2667-2668.
[16]Li J, Chen J, Cai BC, et al. Preparation, characterization and tissue distribution of brucine stealth liposomes with different lipid composition[J].Pharm Dev Technol.2011,1-7.
[17]庄宝雄,陈燕铭,张阳德等.奥沙利铂长循环热敏脂质体的制备与理化性质研究[J].中国现代医学杂志,2011,21(36)：4558-4561.
[18]胡雪,曾照芳,陈里里.DEC-205单抗耦联长循环免疫脂质体的制备及其体外靶向[J].生物技术通报,2008,5：154-158.
[19]胡海洋,陈大为,刘彦仿等.蜂毒多肽空间稳定免疫脂质体的制备及体外对肿瘤细胞的选择性[J].药学学报,2007,42(11)：1201-1205.
[20]帅武平,张幸国,陈金亮等.壳聚糖修饰脂质体的制备和性质研究[J].中国药学杂志,2007,42(15)：1159-1163.
[21]吴正红,平其能,陈燕等.N-三甲基壳聚糖盐酸盐包覆胰岛素脂质体的处方与工艺优化[J].中国药科大学学报,2003,34(4)：322-326.
[22]王海刚,翟光喜,吕青志等.壳聚糖包覆葛根素脂质体的制备及理化性质考察[J].中药材,30(1)：89-92.
[23]张娜,平其能,徐文方.麦胚凝集素修饰的胰岛素脂质体对小鼠口服吸收的促进作用[J].中国药学杂志,2004,39(4)：273-275.
[24]张娜,平其能,徐文方.西红柿凝集素修饰脂质体对小鼠口服吸收胰岛素的促进作用[J].药学学报,2004,39(5)：380-384.
[25]Clark MA, Blair H, Liang L, et al.Brayden D, Hirst BH. Targeting polymerised liposome vaccine carriers to intestinal M cells[J]. Vaccine. 2001,20(1-2):208-217.
[26]Conacher M, Alexander J, Brewer JM. Oral immunisation with peptide and protein antigens by formulation in lipid vesicles incorporating bile salts (bilosomes) [J]. Vaccine.2001,19(20-22):2965-2974.
[27]Li H, Song JH, Park JS, Han K. Polyethylene glycol-coated liposomes for oral delivery of recombinant human epidermal growth factor[J].Int J Pharm. 2003,258(1-2):11-19.
[1]Singer SJ, Nicolson GL.The fluid mosaic model of the structure of cell membranes[J].Science,1972,175(4023):720-731.
[2]Jain MK, White HB 3rd. Long-range order in biomembranes[J].Adv Lipid Res,1977,15:1-60.
[3]Wallach DF, Bieri V, Verma SP, et al.Modes of lipid-protein interactions in biomembranes[J].Ann N Y Acad Sci,1975,264:142-160.
[4]Simons K, Ikonen E.Functional rafts in cell membranes[J].Nature, 1997,387(6633):569-572.
[5]Quantitative analysis of biofilm thickness variability.Murga R, Stewart P S, Daly D.Biotechnol Bioeng.1995 Mar 20;45(6):503-510.
[6]Mongrand S, Morel J, Laroche J, et al.Lipid rafts in higher plant cells: purification and characterization of Triton X-100-insoluble microdomains from tobacco plasma membrane9+.J Biol Chem,2004,279(35):36277-36286.
[7]Epand RF, Ramamoorthy A, Epand RM.Membrane lipid composition and the interaction of pardaxin:the role of cholesterol[J]. Protein Pept Lett,2006,13(1):1-5.
[8]Peskan T, Westermann M, Oelmuller R. Identification of low-density Triton X-100-insoluble plasma membrane microdomains in higher plants[J]. Eur J Biochem,2000,267(24):6989-6995.
[9]Mongrand S, Morel J, Laroche J,et al. Lipid rafts in higher plant cells: purification and characterization of Triton X-100-insoluble microdomains from tobacco plasma membrane[J]. J Biol Chem,2004,279(35):36277-36286.
[10]Borner GH, Sherrier DJ, Weimar T,et al.Analysis of detergent-resistant membranes in Arabidopsis. Evidence for plasma membrane lipid rafts[J]. Plant Physiol,2005,137(1):104-116.
[11]Martin SW, Glover BJ, Davies JM. Lipid microdomains--plant membranes get organized[J]. Trends Plant Sci,2005,10(6):263-265.
[12]Borner GH, Sherrier DJ, Weimar T, et al.Analysis of detergent-resistant membranes in Arabidopsis. Evidence for plasma membrane lipid rafts[J].Plant Physiol,2005,137(1):104-116.
[13]Martin RE, Elliott MH, Brush RS, et al.Detailed characterization of the lipid composition of detergent-resistant membranes from photoreceptor rod outer segment membranes[J],Invest Ophthalmol Vis Sci,2005,46(4): 1147-1154.
[14]Xu X, Bittman R, Duportail G, et al.Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide[J].J Biol Chem,2001,276(36):33540-33546.
[15]Hailing KK, Slotte JP.Membrane properties of plant sterols in phospholipid bilayers as determined by differential scanning calorimetry, resonance energy transfer and detergent-induced solubilization[J].Biochim Biophys Acta.2004 Aug 30; 1664(2):161-171.
[16]Halling KK, Ramstedt B, Nystrom JH, Slotte JP, Nyholm TK.Cholesterol interactions with fluid-phase phospholipids:effect on the lateral organization of the bilayer[J].Biophys J.2008,95(8):3861-3871.
[17]WU RG,CHEN L,YU ZW,et al.Phase diagram of stigmasterol-dipalmitoylphosphatidylcholine mixtures dispered in excess water[J]. Biochim Biophys Acta,2006,1758(6):764-771.
[18]Ipsen JH, Karlstrom G, Mouritsen OG, et al.Phase equilibria in the phosphatidylcholine-cholesterol system[J].Biochim Biophys Acta.,1987, 905(1):162-172.
[19]Silvius JR. Role of cholesterol in lipid raft formation:lessons from lipid model systems[J]. Biochim Biophys Acta,2003,1610(2):174-183.
[20]MEER GV.The different hues of lipid rafts [J].Science,2002,296(5569): 855-857.
[21]Verma SP.HIV:a raft-targeting approach for prevention and therapy using plant-derived compounds[J].Curr Drug Targets,2009,10(1):51-59.
[22]Hawkes DJ,Mak J.Lipid membrane; A novel target for viral and bacterial pathogens[J].Curr Drug Targets,2006,7(12):1615-1621.
[23]Chen J, Cheng D, Li J, et al.Influence of lipid composition on the phase transition temperature of liposomes composed of both DPPC and HSPC[J].Drug Dev Ind Pharm,2012.
[24]Paiva JG, Paradiso P, Serro AP, et al.Interaction of local and general anaesthetics with liposomal membrane models:A QCM-D and DSC study[J].Colloids Surf B Biointerfaces,2012,95:65-74.
[25]Mady MM, Shafaa MW, Abbase ER, et al. Interaction of Doxorubicin and dipalmitoylphosphatidylcholine liposomes[J]. Cell Biochem Biophys,2012, 62(3):481-486.
[26]G Krishnamoorthy. Fluorescence spectroscopy in molecular description of biological process[J]. Indian Journal of Biochemistry & Biophysics,2003, 40,147-159.
[27]de Oliveira MC, Rosilio V, Lesieur P, et al.pH-sensitive liposomes as a carrier for oligonucleotides:a physico-chemical study of the interaction between DOPE and a 15-mer oligonucleotide in excess water[J]. Biophys Chem,2000,87(2-3):127-137.
[28]Bonarska-Kujawa D, Pruchnik H, Kleszczy ska H.Interaction of selected anthocyanins with erythrocytes and liposome membranes[J].Cell Mol Biol Lett,2012,17(2):289-308.
[29]Nunes C, Brezesinski G, Lopes D, et al.Lipid-drug interaction:biophysical effects of tolmetin on membrane mimetic systems of different dimensionality[J].J Phys Chem B,2011,115(43):12615-12623.
[30]Turker S, Wassall S, Stillwell W, et al.Convulsant agent pentylenetetrazol does not alter the structural and dynamical properties of dipalmitoylphosphatidylcholine model membranes[J].J Pharm Biomed Anal,2011,54(2):379-386.
[31]Bulkin BJ.Raman spectroscopic study of human erythrocyte membranes[J]. Biochim Biophys Acta.1972 Aug 9;274(2):649-651.
[32]Gaber B P,Peicolas W L.On the quantitative interpretation of biomenbrans structure by raman spectroscopy[J].Biochem Biophys Acta,1997,465: 260-274.
[33]Tu A T.Raman Spectroscopy in Biology:pri ncipl es and applications[M].New York:John Wiley & Sons, Inc.1982,187-233.
[34]Turkyilmaz S, Chen WH, Mitomo H, Regen SL.Loosening and reorganization of fluid phospholipid bilayers by chloroform[J].J Am Chem Soc,2009,131(14):5068-5069.
[35]Meier RJ, Csisz a r A, Klumpp E.Detecting the effect of very low amounts of penetrants in lipid bilayers using Raman spectroscopy[J].J Phys Chem B,2006,110(42):20727-20728.
[36]Mady MM, Fathy MM, Youssef T, et al.Biophysical characterization of gold nanoparticles-loaded liposomes[J].Phys Med,2011.
[37]Ekambaram P, Abdul HS.Formulation and evaluation of solid lipid nanoparticles of ramipril[J].J Young Pharm,2011,3(3):216-220.
[38]Hasanovic A, Hollick C, Fischinger K, et al.Improvement in physicochemical parameters of DPPC liposomes and increase in skin permeation of aciclovir and minoxidil by the addition of cationic polymers[J].Eur J Pharm Biopharm,2010,75(2):148-153.
[39]Redondo-Morata L, Giannotti MI, Sanz F.AFM-Based Force-Clamp Monitors Lipid Bilayer Failure Kinetics[J].Langmuir,2012,28(15): 6403-6410.
[40]Augusty ska D, Jemio□ a-Rzemi ska M, Burda K, et al.Atomic force microscopy studies of the adhesive properties of DPPC vesicles containing β-carotene[J]. Acta Biochim Pol,2012,59(1):125-128.
[41]Sheikh K, Giordani C, McManus JJ, et al.Differing modes of interaction between monomeric A β (1-40) peptides and model lipid membranes:an AFM study[J].Chem Phys Lipids,2012,165(2):142-150.
[42]Reuter M, Schwieger C, Meister A, et al.Poly-1-lysines and poly-1-arginines induce leakage of negatively charged phospholipid vesicles and translocate through the lipid bilayer upon electrostatic binding to the membrane[J].Biophys Chem,2009,144(1-2):27-37.
[43]Ntountaniotis D, Mali G, Grdadolnik SG, et al.Thermal, dynamic and structural properties of drug AT1 antagonist olmesartan in lipid bilayers[J].Biochim Biophys Acta,2011,1808(12):2995-3006.
[44]邬瑞光,周洪伟,张小华,等.DSC和XRD法研究丹皮酚和脂质体的相互作用[J].中医药信息,2011,28(5)：10-13.
[45]Rui-Guang Wu, Yu-Rong Wang, Fu-Gen Wu, et al.A DSC study of paeonol-encapsulated liposomes, comparison the effect of cholesterol and stigmasterol on the thermotropic phase behavior of liposomes[J].Journal of Thermal Analysis and Calorimetry,2012.
[1]Hilgers AR, Conradi RA, Burton PS. Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa[J]. Pharmaceutical Research,1990,7 (9):902-910.
[2]刘莱,王东凯,高斐Caco-2细胞模型在药物开发中的应用[J].西北药学杂志,2004,19(2)：88-90.
[3]胡晓渝,姚彤伟,曾苏Caco-2细胞系及其在药物吸收代谢中的应用[J].中国现代应用药学杂志,2002,19(4)：55-90.
[4]Gan L L,Dhiren R T. Applications of the Caco-2 model in the design and development of orally active drugs:elucidation of biochemical and physical barriers posed by the intestinal epithelium[J]. Advanced Drug Delivery Reviews,1997,23(1):77-98(22).
[5]Yee S.In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man--fact or myth[J]. Pharm Res,1997, 14(6):763-766.
[6]Hilgers AR, Conradi RA, Burton PS.Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa[J]. Pharm Res,1990,7(9): 902-910.
[7]Hidalgo IJ, Raub TJ, Borchardt RT.Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability[J]. Gastroenterology.,1989,96(3):736-749.
[8]孟胜男,王欣,张愁播等.5-氟尿嘧啶与卡莫氟的理化特性对其渗透性的影响[J].中国现代应用药学杂志,2009,26(12)：1007-1010.
[9]匡惠芬,涂昌兵,杨星昊等.布洛芬,羟丙基-β-环糊精体系的Caco-2(?)田胞 转运研究[J].中国新药杂志,2008,17(12)：1037-1041.
[10]辛华雯,Matthias Schwab,Ulrich Klotz.5-氨基水杨酸在Caco-2、L-MDR1和MRP2细胞中的转运研究[J].中国临床药理学与治疗学,2006,11(11)：1265-1269.
[11]李苏宁,杨秀伟.6个线型呋喃香豆素类化合物在人源肠Caco-2细胞模型的吸收转运研究[J].中草药,2011,42(1)：96-102.
[12]王元佩,张桂春,孙丽娟等Caco-2细胞中二甲双胍的摄取和转运特征[J].中国药理学通报,2008,24(12)：1565-1569.
[13]王琰,李正荣,潘飞燕等.纳米脂质体包裹胰岛素经Caco-2细胞转运的研究[J].中国药理学通报,2005,21(1)：78-81.
[14]赵荣生,严宝霞.空间稳定脂质体与药物的靶向释放[J].中国药学杂志,1998,33(8)：452-455.
[15]吴正红,平其能,赖家明.小鼠口服多糖包覆胰岛素脂质体的降血糖作用[J].药学学报,2003,38(2)：138-142.
[16]翟光喜,邹立家,张天民等.低分子肝素脂质体喷胶透皮吸收机理的研究[J].山东医科大学学报,1997,35(2)：170-172.
[17]曹健,陆锦芳,壳聚糖在生物大分子药物给药中的应用[J].中国医药杂志,2002,33(7)：353-357.
[18]Sambury Y,Ferruzza S,Ranaldi G,et al.Intestinal cell culture models: applications in toxicology and pharmacology[J].Cell Biol Toxicol, 2001,17(4-5):301-317.
[19]Rossi A,Poverini R, Lullo GD, et al. Heavy metal toxicity following pical and basolateral exposure in the human intestinal cell line Caco-2.Toxicol in Vitro[J].1996,10(1):27-36.
[20]Duizer E,Wulp CVD,Versantvoort CHM,et al.Absorption enhancement, structural changes in tight junctions and cytotoxicity caused by palmitoyl carnitine in Caco-2 and IEC-18 cells[J]. J Pharmacol Exp Ther,1998,287(1):395-402.
[21]Tran CD,Timmins P,Ronway BR,et al.Investigation of the coordinated functional activities of cytochrome 450 3A4 and P-glycoprotein in limiting the absorption of xenobiotics in Caco-2 cell[J]. J Pharm Sci,2002 91(1):117-128.
[22]Meaney CM,O'Driscoll CM.A comparison of the permeation enhancement potential of simple bile salt and mixed bile salt:fatty acid micellar systems using the Caco-2 cell culture model[J].Int J Pharm,2000,207 (1-2):21-30.
[23]程晓华,熊玉卿Caco-2细胞单层模型中熊果酸摄取转运机制的研究[J].中草药,2009,40(12)：1935-1939.
[24]陈彦,贾晓斌,胡明等.淫羊藿苷在Caco-2细胞单层模型中的吸收机制[J].中国中药杂志,2008,33(10)：1164-1167.
[25]谢海棠,王广基,赵小辰等Caco-2细胞对人参皂苷Rg3的摄取及代谢研究[J].中国临床药理学与治疗学,2004,9(3)：257-260.
[26]章新晶,熊淑华,邹霞Caco-2细胞对酸枣仁皂苷A的跨膜转运[J].江西医药,2011,46(1)：8-10.
[27]王玉秀,贾金萍,王玉璧等Caco-2细胞模型比较黄芩苷和黄芩苷滴丸在小肠的吸收[J].中国药物应用与监测,2010,7(6)：344-346.
[28]王来友,关溯,黄民等.补骨脂素在Caco-2细胞模型中的吸收特性研究[J].中国药学杂志,2005,40(24)：1868-1870.
[29]宋娟,唐靖,何娟等.川芎嗪对Caco-2细胞p-糖蛋白功能和表达的影响 [J].中南药学,2007,5(5)：440-443.
[30]朱狄峰,赵筱萍,程翼宇.丹参素在CacO-2细胞单层模型中的跨膜转运研究[J].中国中药杂志,2006,31(18)：1517-1521.
[31]冷薇,郑颖,李绍平等.莪术油在CacO-2细胞模型中的吸收机制研究[J].中国药学杂志,2007,42(16)：1228-1232.
[32]廖音,杨秀伟.麻黄生物碱在人源肠CacO-2细胞单层模型的吸收转运研究[J].中国中药杂志,2010,35(22)：3010-3015.
[33]宋丽,张宁,徐德生.芍药苷在Caco-2细胞模型中吸收机制的研究[J].中草药,2008,39(1)：41-44.
[34]鄢良春,刘青春,赵军宁等.小柴胡汤在Caco-2细胞模型的吸收特性和转运机制研究[J].中国中药杂志,2011,36(8)：1087-1090.
[35]平其能.中药成分的胃肠转运与剂型设计[M].北京：化学工业出版社,2010-231-232.
[1]李玺,刘颖,张欣等.人参皂苷Rgl对大鼠脑片AD模型磷酸化Tau蛋白及NMDA受体亚单位NR1,NR2B表达的影响[J].中国中药杂志2010,35(24)：3339-3343.
[2]郑友生,廖联明,江敏等.人参皂苷Rgl促进神经干细胞增殖的实验研究[J].世界中西医结合杂志,2011,6(12)：1021-1024.
[3]陈云波,张大鹏,冯梅等.人参皂苷Rg1对A β-(25-35)诱导的神经细胞核因子-κB活化的影响[J].中国药理学通报,2007,23(5)：612-617.
[4]叶晓莉,李晓峰.人参皂苷Rgl对1-甲基-4-苯基吡啶离子诱导的PC12细胞凋亡的保护作用[J].第二军医大学学报,2011,32(9)：965-968.
[5]赵保胜,刘洋,徐暾海.人参皂苷Rgl对人胃癌BGC-823的抑制作用研究[J].中国临床药理学与治疗学,2011,16(4)：361-365.
[6]赵保胜,桂海水,徐暾海.人参皂苷Rgl抗炎作用实验研究[J].人参研究,2010,(4)：2-4.
[7]Du J, Cheng B, Zhu X, Ling C. Ginsenoside Rgl, a novel glucocorticoid receptor agonist of plant origin, maintains glucocorticoid efficacy with reduced side effects[J].J Immunol,2011,187(2):942-950.
[8]Yin H, Liu Z, Li F, et al. Ginsenoside-Rgl enhances angiogenesis and ameliorates ventricular remodeling in a rat model of myocardial infarction[J].J Mol Med (Berl),2011,89(4):363-375.
[9]金岩,刘闺男.急性心肌梗死大鼠梗死区血管内皮生长因子和缺氧诱导因子1 a mRNA表达及人参皂苷Rgl的干预效应[J].中国组织工程研究与临床康复,2007,11(14)：2613-2616.
[10]刘霞,包翠芬,梁佳等.人参皂苷Rgl对脑缺血再灌注大鼠Caspase-3蛋白表达的影响[J].中国组织化学与细胞化学杂志,2010,19(1)：88-92.
[11]马永洁,朱丹,钟芝茵等.人参皂苷Rgl和丹参酮ⅡA配伍对缺氧-复氧损伤心肌细胞的保护作用[J].军事医学科学院院刊,2010,34(3)：243-246.
[12]冯劫.人参皂苷Rg1对四氧嘧啶致小鼠糖尿病降糖作用的研究[J].中华中医药学刊,2010,28(11)：2427-2429.
[13]Lee HM, Lee OH, Kim KJ, et al. Ginsenoside Rgl Promotes Glucose Uptake Through Activated AMPK Pathway in Insulin-resistant Muscle Cells[J]. Phytother Res,2011,26(5).
[14]马岚青,梁兵,柳波等.人参皂苷Rgl抗肝纤维化的实验研究[J].中国中西医结合消化杂志,2007,15(3)：165-168.
[15]董向前,段丽平,梁兵等.人参皂苷Rgl和Rbl抗肝纤维化的体视学研究[J].山东大学学报(医学版),50(1)：85-88.
[16]黄倩,牟正,陈乃宏等.人参皂苷Rgl及其代谢产物Ppt的抗抑郁作用研究[C]中国药理学会补益药药理专业委员会成立大会暨人参及补益药学术研讨会会议论文集,2011.
[17]Jiang B, Xiong Z, Yang J, et al. Antidepressant-like effects of Ginsenoside Rgl produced by activation of BDNF signaling pathway and neurogenesis in the hippocampus[J].Br J Pharmacol,2012,166(2).
[18]Feng L, Wang L, Hu C,et al. Pharmacokinetics, tissue distribution, metabolism, and excretion of ginsenoside Rgl in rats[J], Arch Pharm Res,2010,33(12):1975-1984.
[19]Xu QF, Fang XL. Pharmacokinetics and bioavailability of ginsenosides Rbl and Rgl from Panax notoginseng in rats [J].J Ethnopharmacol,2003, 23:187-192.
[20]Han M, Fang XL. Difference in oral absorption of ginsenoside Rgl between in vitro and in vivo models[J]. Acta Pharmacol Sin.2006 Apr;27(4):499-505.
[21]冯亮,胡昌江,余凌英.人参皂苷Rgl及其代谢产物的药代动力学研究[J].药学学报,2010,45(5)：636-640.
[22]吕天,孙建国,吕华等.人参总皂苷中Rgl的吸收特性研究[J].中国临床药理学与治疗学,2006,11(7)：780-783.
[23]李超英,孙波,陈静芳等.复方血栓通软胶囊药代动力学研究[J].中国中药杂志,2011,36(22)：3194-3197.
[24]萨础拉,吕航,姜艳艳等.三七皂苷在大鼠外翻肠囊中的吸收及与P-糖 蛋白相互作用研究[J].北京中医药大学学报,2011,34(12)：836-842.
[25]冯亮,蒋学华,周静等.三七皂苷R1和人参皂苷Rgl的大鼠在体肠吸收动力学研究[J].中国药学杂志,2006,41(14)：1097-1102.
[26]李文兰,南莉莉,季宇彬等.人参中人参皂苷Rg_1,Rb_1在体肠吸收影响因素的研究[J].中国中药杂志,2009,34(20)：2627-2632.
[27]何百寅,谢友良,刘常青等.三七提取液中三七皂苷R1、人参皂苷Rgl和人参皂苷 Rb1 的透皮规律研究[J].中国实验方剂学杂志,2011,17(21)：130-134.
[28]郭文峰,胡灿,温鹏等.人参皂苷Rgl对Caco-2细胞PepTl转运功能的影响[J].广州中医药大学学报,2011,28(4)：388-392.
[29]韩旻,傅韶,方晓玲.三七皂苷中人参皂苷Rg_1与Rb_1口服吸收及其体内药代动力学的研究和比较[J].药学学报,2007,42(8)：849-853.
[30]韦凤华,宋林,何毅等.人参皂苷Rg_1在大鼠体内的代谢与排泄研究[J].华西药学杂志,2010,25(3)：302-305.
[31]李国信,唐思,夏素霞等.生脉拆方系列注射液中人参皂苷Rg_1和Re药代动力学研究[J].中华中医药学刊,2010,28(11)：2310-2313.
[32]刘奕明,杨柳,曾星等.参麦注射液中人参皂苷Rg_1和Re药代动力学究[J].药学学报,2005,40(4)：365-368.
[33]Hasegawa H, Sung JH, Matsumiya S, et al. Main ginseng saponin metabolites formed by intestinal bacteria[J]. Planta Med.1996 Oct;62(5):453-457.
[34]陈新梅,朱家壁,孙卫东等.用药效学指标筛选人参皂苷Rg1鼻用制剂的促吸收剂[J].中国天然药物,2005,3(6)：361-366.
[35]陈新梅,朱家壁,孙卫东等.冰片对人参皂苷Rgl鼻腔吸收的促进作用及鼻腔纤毛毒性研究[J].中国药学杂志,2006,41(4)：261-264.
[36]缪菊连,黄照昌.羟丙基-β-环糊精对人参皂苷Rgl溶解度的影响[J].中国实验方剂学杂志,2011,17(21)：17-19.
[37]Xiong J, Guo J, Huang L, et al. The use of lipid-based formulations to increase the oral bioavailability of Panax notoginseng sapoinins following a single oral gavage to rats[J].Drug Dev Ind Pharm.2008 Jan;34(1): 65-72.
[1]朱洁,温敏,张洪彬HPLC-ELSD测定三七胶囊中人参皂苷Rgl和Rb1[J].中成药,2004,26(1)：33-35.
[2]刘波,钟关萍,朱兆云等.高效液相色谱法测定伤益凝胶中人参皂苷Rgl的含量[J].云南大学学报(自然科学版),2009,3 1(S1)：310-312.
[3]Lipinski CA, Lombardo F, Dominy BW, et al.Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J]. Adv Drug Deliv Rev,2001, 46(1-3):3-26.
[1]Xu QF,Fang XL,Chen DF. Pharmacokinetics and bioavailability of ginsenoside Rbl and Rgl from Panax notoginseng in rats [J]. Journal of Ethnopharmacology,2003,84(2-3):187-192.
[2]梁平,张旋,吴琳,等.人参皂苷Rgl脂质体的制备及稳定性研究[J].昆明医学院学报2009,30(1)：6-9.
[3]陈新梅,朱家壁.人参皂苷Rg 1的溶解特性与脂质体包封率关系的研究[J].中国药房,2007,18(1)：41-43.
[4]王亮,顾宜,费燕.人参皂苷Rgl脂质体制备工艺的优化[J].中国中药杂志,2006,31(23)：2005-2007.
[5]吴伟,崔光华,陆彬.实验设计中多指标的优化：星点设计和总评“归一值”的应用[J].中国药学杂志,2000,35(8)：530-533.
[6]张囡,康廷国,尹海波.星点设计-响应面法优化穿龙薯蓣多糖提取工艺[J].中药材,2011,34(1)：123-126.
[7]颜军,甘亚,苟小军等.星点设计-效应面法优化槐米中芦丁提取工艺[J].中药材,2011,34(4)：628-631.
[8]杨银花,谢云,吴清等.星点设计优选苦参纤维素酶解提取工艺研究[J].北京中医药大学学报,2011,34(8)：552-557.
[9]Muramatsu K, Maitani Y, Machida Y, et al. Effect of soybean derived steroland its glucoside mixtures on the stability of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylcholine/ cholesterol liposomes [J]. Int. J. Pharm,1994,107(1):1-8.
[10]Muramatsu K, Maitani Y, Nagai T. Dipalmitoylphosphatidylcholine liposomes with soybean derived sterols and cholesterol as a carrier for the oral administration of insulin in rats[J]. Biol. Pharm. Bull,1996,19(8): 1055-1058.
[1]McMullen T P W, McElhaney R. N. New aspects of the interaction of cholesterol with dipalmitoylphosphatidylcholine bilayers as revealed by high-sensitivity differential scanning calorimetry. Biochim Biophys Acta, 1995,1234 (1):90-98.
[2]Zhang Y P, Lewis R N, Hodges R S, et al. Interaction of a peptide model of a hydrophobic transmembrane alpha-helical segment of a membrane protein with phosphatidylethanolamine bilayers:differential scanning calorimetric and Fourier transform infrared spectroscopic studies. Biophys J,1995,68 (3):847-857.
[3]Arouri A, Dathe M, Blume A. Peptide induced demixing in PG/PE lipid mixtures:a mechanism for the specificity of antimicrobial peptides towards bacterial membrane. Biochim Biophys Acta,2009,1788 (3):650-659.
[4]Yu ZW, Quinn PJ. Phase stability of phosphatidylcholine in dimethylsulfoxide solutions. Biophys J,1995,69 (4):1456-1463.
[5]Wu Fugen, JiaQi, Wu Ruiguang,et al. Regional cooperativity in the phase transitions of dipalmitoylphosphatidylcholine bilayers:The lipid tail triggers the isothermal crystallization process. J Phys Chem B,2011, 115(26):8559-8568.
[6]Gao Wenying, Chen Lin, Wu Ruiguang, et al. Phase diagram of androsterol-dipalmitoylphosphatidylcholine mixtures dispersed in excess water. J Phys Chem B,2008,112(28):8375-8382.
[7]赵雨,赵大庆,席时权等.鞘磷脂与胆固醇相互作用的拉曼光谱研究[J].光散射学报,1999,11(2)：165-169.
[8]Muramatsu K,Maitani Y,Machida Y,et al.Effect of soybean derived sterol and its glucoside mixtures on the stability of dipalmitoylphosphatidyl-choline and dipalmitoylphosphatidylcholine/cholesterol liposomes[J].Int Pharm,1994,107(1):1-8.
[9]Muramatsu K,Maitani Y,Nagai T.Dipalmitoylphosphatidylcholine liposomes with soybean derived sterols and cholesterol as a carrier for the oral administration of insulin in rats[J].Biol Pharm Bull,1996,19(8): 1055-1058.
[1]杨贵贞.免疫生物工程纲要与技术[M].长春：吉林科学技术出版社,1991,47-48.
[2]Hilgers AR, Conradi RA, Burton PS. Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa[J]. Pharmaceutical Research,1990,7 (9):902-910.
[3]吴正红,平其能,赖家明.小鼠口服多糖包覆胰岛素脂质体的降血糖作用[J].药学学报,2003,38(2)：138-142.
[4]Santos MR, Rodri guez-Gomez MJ, Justino GC,et al.Influence of the metabolic profile on the in vivo antioxidant activity of quercetin under a low dosage oral regimen in rats[J]. Brit J Pharmacol,2008,153(8): 1750-1761.
[5]Williams RJ, Spencer JP, Rice-Evans C. Flavonoids:antioxidants or signalling molecules? [J]. Free Radic Biol Med,2004,36(7):838-849.
[6]Harborne J.B. The Flavonoids, Advances in Research Since 1986[M]. Chapman & Hall,London,1994,13:378-382.
[7]Kuti JO,Konuru HB.Antioxidant capacity and phenolic content in leaf extracts of tree spinach (Cnidoscolus spp.)[J]. J. Agric. Food Chem,2004, 52(1):117-121.
[1]周威,石任兵,孙建宁等.不同模型下清脑宣窍方有效组分药代动力学研究[J].北京中医药大学学报,2008,31(4)：265-268.
[2]陈霞,徐济良.血塞通分散片的生物利用度评价[J].时珍国医国药,2007,18(8)：1852-1853.
[3]林力,刘建勋,张颖等LC-MS/MS法测定大鼠口服人参皂苷Rg1,Re,Rb 1和Rd的药动学[J].中国药学杂志,2009,44(5)：373-377.
[4]胡锦芳,温金华,蒋丽华.复方血栓通片中人参皂苷Rb1与Rg1在大鼠体内的药代动力学研究[J].南昌大学学报(医学版),2011,51(11)：6-10.
[2]Vist MR,Davis JH. Phase equilibria of cholesterol/dipalmitoylphosphati-dylcholine mixtures:2H nuclear magnetic resonance and differentia scanning calorimetry[J]. Biochemistry,1990,29(2):451-464.
[3]Hsueh Y W, Gilbert K, Trandum C, et al. The effect of ergosterol on dipalmitoylphosphatidylcholine bilayers:a deuterium NMR and calorimetric study[J]. Biophys J,2005,88(3):1799-1808.
[1]张兆旺.中药药剂学[M].北京：中国中医药出版社,2003：499.
[2]Bangham AD, Standish MM, Miller N. Cation permeability of phospholipid model membranes:effect of narcotics[J].Nature.1965, 208(5017):1295-1297.
[3]胡玥,王金萍,李爱国等.洛莫司汀热敏脂质体在动物体内的.药代动力学及组织分布[J].药物分析杂志,2010,30(7)：1237-1241.
[4]赵峰,卿三华,王永华.天然大豆磷脂制备热敏脂质体的方法及质量评价[J].中国天然药物,2005,3(4)：231-234.
[5]武鑫朋,孙李妍,慕宏杰等Box-Behnken效应面法优化牛蒡苷pH敏感脂质体处方[J].齐鲁药事,2011,30(11)：625-628.
[6]王弘,胡良平,陈忠斌等.基因转染的pH敏感脂质体的最优处方和制备工艺的研究[J].中国药学杂志,2002,37(1)：29-32.
[7]温演庆,杨斌,钱志勇.光敏纳米脂质体制备及其特性研究[J].中国医学工程,2008,16(2)：84-85.
[8]孟凡旭,许华平,齐燕飞等.光敏性脂质体的初步研究[J].高等学校化学研究,2012,28(2)：319-322.
[9]文晔,刘宏,汤韧等.两性霉素B磁性脂质体的制备与质量控制[J].中国医院药学杂志,2007,27(10)：1344-1346.
[10]黄波涛,段磊,吴小玲等.5-氟尿嘧啶-Fe/Fe304磁性脂质体的制备及其表征[J].南京医科大学学报(自然科学版),2011,31(7)：951-956.
[11]段降龙,龙延滨,李国威.尿素免疫脂质体的制备及理化性质研究[J].陕西医学杂志,2011,40(6)：653-655.
[12]俞功龙,尹宗宁,张霞.纳豆激酶免疫脂质体及其冻干品的制备及药剂学性质评价[J].中国药房,2009,20(4)：276-278.
[13]张冬青,程怡,白丛林等.苦参素空间稳定脂质体的制备及其药剂学性质考察[J].中药材,2011,34(5)：786-789.
[14]时军,程怡,陈伟鸿等.足叶乙苷长循环脂质体的制备及血浆中稳定性研究[J].广州中医药大学学报,2009,26(3)：270-273.
[15]戈延茹,张晓兰,曹恒杰等.钆喷酸葡胺长循环脂质体的制备及其肿瘤细胞摄取能力研究[J].中国药房,2009,20(34)：2667-2668.
[16]Li J, Chen J, Cai BC, et al. Preparation, characterization and tissue distribution of brucine stealth liposomes with different lipid composition[J].Pharm Dev Technol.2011,1-7.
[17]庄宝雄,陈燕铭,张阳德等.奥沙利铂长循环热敏脂质体的制备与理化性质研究[J].中国现代医学杂志,2011,21(36)：4558-4561.
[18]胡雪,曾照芳,陈里里.DEC-205单抗耦联长循环免疫脂质体的制备及其体外靶向[J].生物技术通报,2008,5：154-158.
[19]胡海洋,陈大为,刘彦仿等.蜂毒多肽空间稳定免疫脂质体的制备及体外对肿瘤细胞的选择性[J].药学学报,2007,42(11)：1201-1205.
[20]帅武平,张幸国,陈金亮等.壳聚糖修饰脂质体的制备和性质研究[J].中国药学杂志,2007,42(15)：1159-1163.
[21]吴正红,平其能,陈燕等.N-三甲基壳聚糖盐酸盐包覆胰岛素脂质体的处方与工艺优化[J].中国药科大学学报,2003,34(4)：322-326.
[22]王海刚,翟光喜,吕青志等.壳聚糖包覆葛根素脂质体的制备及理化性质考察[J].中药材,30(1)：89-92.
[23]张娜,平其能,徐文方.麦胚凝集素修饰的胰岛素脂质体对小鼠口服吸收的促进作用[J].中国药学杂志,2004,39(4)：273-275.
[24]张娜,平其能,徐文方.西红柿凝集素修饰脂质体对小鼠口服吸收胰岛素的促进作用[J].药学学报,2004,39(5)：380-384.
[25]Clark MA, Blair H, Liang L, et al.Brayden D, Hirst BH. Targeting polymerised liposome vaccine carriers to intestinal M cells[J]. Vaccine. 2001,20(1-2):208-217.
[26]Conacher M, Alexander J, Brewer JM. Oral immunisation with peptide and protein antigens by formulation in lipid vesicles incorporating bile salts (bilosomes) [J]. Vaccine.2001,19(20-22):2965-2974.
[27]Li H, Song JH, Park JS, Han K. Polyethylene glycol-coated liposomes for oral delivery of recombinant human epidermal growth factor[J].Int J Pharm. 2003,258(1-2):11-19.
[1]Singer SJ, Nicolson GL.The fluid mosaic model of the structure of cell membranes[J].Science,1972,175(4023):720-731.
[2]Jain MK, White HB 3rd. Long-range order in biomembranes[J].Adv Lipid Res,1977,15:1-60.
[3]Wallach DF, Bieri V, Verma SP, et al.Modes of lipid-protein interactions in biomembranes[J].Ann N Y Acad Sci,1975,264:142-160.
[4]Simons K, Ikonen E.Functional rafts in cell membranes[J].Nature, 1997,387(6633):569-572.
[5]Quantitative analysis of biofilm thickness variability.Murga R, Stewart P S, Daly D.Biotechnol Bioeng.1995 Mar 20;45(6):503-510.
[6]Mongrand S, Morel J, Laroche J, et al.Lipid rafts in higher plant cells: purification and characterization of Triton X-100-insoluble microdomains from tobacco plasma membrane9+.J Biol Chem,2004,279(35):36277-36286.
[7]Epand RF, Ramamoorthy A, Epand RM.Membrane lipid composition and the interaction of pardaxin:the role of cholesterol[J]. Protein Pept Lett,2006,13(1):1-5.
[8]Peskan T, Westermann M, Oelmuller R. Identification of low-density Triton X-100-insoluble plasma membrane microdomains in higher plants[J]. Eur J Biochem,2000,267(24):6989-6995.
[9]Mongrand S, Morel J, Laroche J,et al. Lipid rafts in higher plant cells: purification and characterization of Triton X-100-insoluble microdomains from tobacco plasma membrane[J]. J Biol Chem,2004,279(35):36277-36286.
[10]Borner GH, Sherrier DJ, Weimar T,et al.Analysis of detergent-resistant membranes in Arabidopsis. Evidence for plasma membrane lipid rafts[J]. Plant Physiol,2005,137(1):104-116.
[11]Martin SW, Glover BJ, Davies JM. Lipid microdomains--plant membranes get organized[J]. Trends Plant Sci,2005,10(6):263-265.
[12]Borner GH, Sherrier DJ, Weimar T, et al.Analysis of detergent-resistant membranes in Arabidopsis. Evidence for plasma membrane lipid rafts[J].Plant Physiol,2005,137(1):104-116.
[13]Martin RE, Elliott MH, Brush RS, et al.Detailed characterization of the lipid composition of detergent-resistant membranes from photoreceptor rod outer segment membranes[J],Invest Ophthalmol Vis Sci,2005,46(4): 1147-1154.
[14]Xu X, Bittman R, Duportail G, et al.Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide[J].J Biol Chem,2001,276(36):33540-33546.
[15]Hailing KK, Slotte JP.Membrane properties of plant sterols in phospholipid bilayers as determined by differential scanning calorimetry, resonance energy transfer and detergent-induced solubilization[J].Biochim Biophys Acta.2004 Aug 30; 1664(2):161-171.
[16]Halling KK, Ramstedt B, Nystrom JH, Slotte JP, Nyholm TK.Cholesterol interactions with fluid-phase phospholipids:effect on the lateral organization of the bilayer[J].Biophys J.2008,95(8):3861-3871.
[17]WU RG,CHEN L,YU ZW,et al.Phase diagram of stigmasterol-dipalmitoylphosphatidylcholine mixtures dispered in excess water[J]. Biochim Biophys Acta,2006,1758(6):764-771.
[18]Ipsen JH, Karlstrom G, Mouritsen OG, et al.Phase equilibria in the phosphatidylcholine-cholesterol system[J].Biochim Biophys Acta.,1987, 905(1):162-172.
[19]Silvius JR. Role of cholesterol in lipid raft formation:lessons from lipid model systems[J]. Biochim Biophys Acta,2003,1610(2):174-183.
[20]MEER GV.The different hues of lipid rafts [J].Science,2002,296(5569): 855-857.
[21]Verma SP.HIV:a raft-targeting approach for prevention and therapy using plant-derived compounds[J].Curr Drug Targets,2009,10(1):51-59.
[22]Hawkes DJ,Mak J.Lipid membrane; A novel target for viral and bacterial pathogens[J].Curr Drug Targets,2006,7(12):1615-1621.
[23]Chen J, Cheng D, Li J, et al.Influence of lipid composition on the phase transition temperature of liposomes composed of both DPPC and HSPC[J].Drug Dev Ind Pharm,2012.
[24]Paiva JG, Paradiso P, Serro AP, et al.Interaction of local and general anaesthetics with liposomal membrane models:A QCM-D and DSC study[J].Colloids Surf B Biointerfaces,2012,95:65-74.
[25]Mady MM, Shafaa MW, Abbase ER, et al. Interaction of Doxorubicin and dipalmitoylphosphatidylcholine liposomes[J]. Cell Biochem Biophys,2012, 62(3):481-486.
[26]G Krishnamoorthy. Fluorescence spectroscopy in molecular description of biological process[J]. Indian Journal of Biochemistry & Biophysics,2003, 40,147-159.
[27]de Oliveira MC, Rosilio V, Lesieur P, et al.pH-sensitive liposomes as a carrier for oligonucleotides:a physico-chemical study of the interaction between DOPE and a 15-mer oligonucleotide in excess water[J]. Biophys Chem,2000,87(2-3):127-137.
[28]Bonarska-Kujawa D, Pruchnik H, Kleszczy ska H.Interaction of selected anthocyanins with erythrocytes and liposome membranes[J].Cell Mol Biol Lett,2012,17(2):289-308.
[29]Nunes C, Brezesinski G, Lopes D, et al.Lipid-drug interaction:biophysical effects of tolmetin on membrane mimetic systems of different dimensionality[J].J Phys Chem B,2011,115(43):12615-12623.
[30]Turker S, Wassall S, Stillwell W, et al.Convulsant agent pentylenetetrazol does not alter the structural and dynamical properties of dipalmitoylphosphatidylcholine model membranes[J].J Pharm Biomed Anal,2011,54(2):379-386.
[31]Bulkin BJ.Raman spectroscopic study of human erythrocyte membranes[J]. Biochim Biophys Acta.1972 Aug 9;274(2):649-651.
[32]Gaber B P,Peicolas W L.On the quantitative interpretation of biomenbrans structure by raman spectroscopy[J].Biochem Biophys Acta,1997,465: 260-274.
[33]Tu A T.Raman Spectroscopy in Biology:pri ncipl es and applications[M].New York:John Wiley & Sons, Inc.1982,187-233.
[34]Turkyilmaz S, Chen WH, Mitomo H, Regen SL.Loosening and reorganization of fluid phospholipid bilayers by chloroform[J].J Am Chem Soc,2009,131(14):5068-5069.
[35]Meier RJ, Csisz a r A, Klumpp E.Detecting the effect of very low amounts of penetrants in lipid bilayers using Raman spectroscopy[J].J Phys Chem B,2006,110(42):20727-20728.
[36]Mady MM, Fathy MM, Youssef T, et al.Biophysical characterization of gold nanoparticles-loaded liposomes[J].Phys Med,2011.
[37]Ekambaram P, Abdul HS.Formulation and evaluation of solid lipid nanoparticles of ramipril[J].J Young Pharm,2011,3(3):216-220.
[38]Hasanovic A, Hollick C, Fischinger K, et al.Improvement in physicochemical parameters of DPPC liposomes and increase in skin permeation of aciclovir and minoxidil by the addition of cationic polymers[J].Eur J Pharm Biopharm,2010,75(2):148-153.
[39]Redondo-Morata L, Giannotti MI, Sanz F.AFM-Based Force-Clamp Monitors Lipid Bilayer Failure Kinetics[J].Langmuir,2012,28(15): 6403-6410.
[40]Augusty ska D, Jemio□ a-Rzemi ska M, Burda K, et al.Atomic force microscopy studies of the adhesive properties of DPPC vesicles containing β-carotene[J]. Acta Biochim Pol,2012,59(1):125-128.
[41]Sheikh K, Giordani C, McManus JJ, et al.Differing modes of interaction between monomeric A β (1-40) peptides and model lipid membranes:an AFM study[J].Chem Phys Lipids,2012,165(2):142-150.
[42]Reuter M, Schwieger C, Meister A, et al.Poly-1-lysines and poly-1-arginines induce leakage of negatively charged phospholipid vesicles and translocate through the lipid bilayer upon electrostatic binding to the membrane[J].Biophys Chem,2009,144(1-2):27-37.
[43]Ntountaniotis D, Mali G, Grdadolnik SG, et al.Thermal, dynamic and structural properties of drug AT1 antagonist olmesartan in lipid bilayers[J].Biochim Biophys Acta,2011,1808(12):2995-3006.
[44]邬瑞光,周洪伟,张小华,等.DSC和XRD法研究丹皮酚和脂质体的相互作用[J].中医药信息,2011,28(5)：10-13.
[45]Rui-Guang Wu, Yu-Rong Wang, Fu-Gen Wu, et al.A DSC study of paeonol-encapsulated liposomes, comparison the effect of cholesterol and stigmasterol on the thermotropic phase behavior of liposomes[J].Journal of Thermal Analysis and Calorimetry,2012.
[1]Hilgers AR, Conradi RA, Burton PS. Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa[J]. Pharmaceutical Research,1990,7 (9):902-910.
[2]刘莱,王东凯,高斐Caco-2细胞模型在药物开发中的应用[J].西北药学杂志,2004,19(2)：88-90.
[3]胡晓渝,姚彤伟,曾苏Caco-2细胞系及其在药物吸收代谢中的应用[J].中国现代应用药学杂志,2002,19(4)：55-90.
[4]Gan L L,Dhiren R T. Applications of the Caco-2 model in the design and development of orally active drugs:elucidation of biochemical and physical barriers posed by the intestinal epithelium[J]. Advanced Drug Delivery Reviews,1997,23(1):77-98(22).
[5]Yee S.In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man--fact or myth[J]. Pharm Res,1997, 14(6):763-766.
[6]Hilgers AR, Conradi RA, Burton PS.Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa[J]. Pharm Res,1990,7(9): 902-910.
[7]Hidalgo IJ, Raub TJ, Borchardt RT.Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability[J]. Gastroenterology.,1989,96(3):736-749.
[8]孟胜男,王欣,张愁播等.5-氟尿嘧啶与卡莫氟的理化特性对其渗透性的影响[J].中国现代应用药学杂志,2009,26(12)：1007-1010.
[9]匡惠芬,涂昌兵,杨星昊等.布洛芬,羟丙基-β-环糊精体系的Caco-2(?)田胞 转运研究[J].中国新药杂志,2008,17(12)：1037-1041.
[10]辛华雯,Matthias Schwab,Ulrich Klotz.5-氨基水杨酸在Caco-2、L-MDR1和MRP2细胞中的转运研究[J].中国临床药理学与治疗学,2006,11(11)：1265-1269.
[11]李苏宁,杨秀伟.6个线型呋喃香豆素类化合物在人源肠Caco-2细胞模型的吸收转运研究[J].中草药,2011,42(1)：96-102.
[12]王元佩,张桂春,孙丽娟等Caco-2细胞中二甲双胍的摄取和转运特征[J].中国药理学通报,2008,24(12)：1565-1569.
[13]王琰,李正荣,潘飞燕等.纳米脂质体包裹胰岛素经Caco-2细胞转运的研究[J].中国药理学通报,2005,21(1)：78-81.
[14]赵荣生,严宝霞.空间稳定脂质体与药物的靶向释放[J].中国药学杂志,1998,33(8)：452-455.
[15]吴正红,平其能,赖家明.小鼠口服多糖包覆胰岛素脂质体的降血糖作用[J].药学学报,2003,38(2)：138-142.
[16]翟光喜,邹立家,张天民等.低分子肝素脂质体喷胶透皮吸收机理的研究[J].山东医科大学学报,1997,35(2)：170-172.
[17]曹健,陆锦芳,壳聚糖在生物大分子药物给药中的应用[J].中国医药杂志,2002,33(7)：353-357.
[18]Sambury Y,Ferruzza S,Ranaldi G,et al.Intestinal cell culture models: applications in toxicology and pharmacology[J].Cell Biol Toxicol, 2001,17(4-5):301-317.
[19]Rossi A,Poverini R, Lullo GD, et al. Heavy metal toxicity following pical and basolateral exposure in the human intestinal cell line Caco-2.Toxicol in Vitro[J].1996,10(1):27-36.
[20]Duizer E,Wulp CVD,Versantvoort CHM,et al.Absorption enhancement, structural changes in tight junctions and cytotoxicity caused by palmitoyl carnitine in Caco-2 and IEC-18 cells[J]. J Pharmacol Exp Ther,1998,287(1):395-402.
[21]Tran CD,Timmins P,Ronway BR,et al.Investigation of the coordinated functional activities of cytochrome 450 3A4 and P-glycoprotein in limiting the absorption of xenobiotics in Caco-2 cell[J]. J Pharm Sci,2002 91(1):117-128.
[22]Meaney CM,O'Driscoll CM.A comparison of the permeation enhancement potential of simple bile salt and mixed bile salt:fatty acid micellar systems using the Caco-2 cell culture model[J].Int J Pharm,2000,207 (1-2):21-30.
[23]程晓华,熊玉卿Caco-2细胞单层模型中熊果酸摄取转运机制的研究[J].中草药,2009,40(12)：1935-1939.
[24]陈彦,贾晓斌,胡明等.淫羊藿苷在Caco-2细胞单层模型中的吸收机制[J].中国中药杂志,2008,33(10)：1164-1167.
[25]谢海棠,王广基,赵小辰等Caco-2细胞对人参皂苷Rg3的摄取及代谢研究[J].中国临床药理学与治疗学,2004,9(3)：257-260.
[26]章新晶,熊淑华,邹霞Caco-2细胞对酸枣仁皂苷A的跨膜转运[J].江西医药,2011,46(1)：8-10.
[27]王玉秀,贾金萍,王玉璧等Caco-2细胞模型比较黄芩苷和黄芩苷滴丸在小肠的吸收[J].中国药物应用与监测,2010,7(6)：344-346.
[28]王来友,关溯,黄民等.补骨脂素在Caco-2细胞模型中的吸收特性研究[J].中国药学杂志,2005,40(24)：1868-1870.
[29]宋娟,唐靖,何娟等.川芎嗪对Caco-2细胞p-糖蛋白功能和表达的影响 [J].中南药学,2007,5(5)：440-443.
[30]朱狄峰,赵筱萍,程翼宇.丹参素在CacO-2细胞单层模型中的跨膜转运研究[J].中国中药杂志,2006,31(18)：1517-1521.
[31]冷薇,郑颖,李绍平等.莪术油在CacO-2细胞模型中的吸收机制研究[J].中国药学杂志,2007,42(16)：1228-1232.
[32]廖音,杨秀伟.麻黄生物碱在人源肠CacO-2细胞单层模型的吸收转运研究[J].中国中药杂志,2010,35(22)：3010-3015.
[33]宋丽,张宁,徐德生.芍药苷在Caco-2细胞模型中吸收机制的研究[J].中草药,2008,39(1)：41-44.
[34]鄢良春,刘青春,赵军宁等.小柴胡汤在Caco-2细胞模型的吸收特性和转运机制研究[J].中国中药杂志,2011,36(8)：1087-1090.
[35]平其能.中药成分的胃肠转运与剂型设计[M].北京：化学工业出版社,2010-231-232.
[1]李玺,刘颖,张欣等.人参皂苷Rgl对大鼠脑片AD模型磷酸化Tau蛋白及NMDA受体亚单位NR1,NR2B表达的影响[J].中国中药杂志2010,35(24)：3339-3343.
[2]郑友生,廖联明,江敏等.人参皂苷Rgl促进神经干细胞增殖的实验研究[J].世界中西医结合杂志,2011,6(12)：1021-1024.
[3]陈云波,张大鹏,冯梅等.人参皂苷Rg1对A β-(25-35)诱导的神经细胞核因子-κB活化的影响[J].中国药理学通报,2007,23(5)：612-617.
[4]叶晓莉,李晓峰.人参皂苷Rgl对1-甲基-4-苯基吡啶离子诱导的PC12细胞凋亡的保护作用[J].第二军医大学学报,2011,32(9)：965-968.
[5]赵保胜,刘洋,徐暾海.人参皂苷Rgl对人胃癌BGC-823的抑制作用研究[J].中国临床药理学与治疗学,2011,16(4)：361-365.
[6]赵保胜,桂海水,徐暾海.人参皂苷Rgl抗炎作用实验研究[J].人参研究,2010,(4)：2-4.
[7]Du J, Cheng B, Zhu X, Ling C. Ginsenoside Rgl, a novel glucocorticoid receptor agonist of plant origin, maintains glucocorticoid efficacy with reduced side effects[J].J Immunol,2011,187(2):942-950.
[8]Yin H, Liu Z, Li F, et al. Ginsenoside-Rgl enhances angiogenesis and ameliorates ventricular remodeling in a rat model of myocardial infarction[J].J Mol Med (Berl),2011,89(4):363-375.
[9]金岩,刘闺男.急性心肌梗死大鼠梗死区血管内皮生长因子和缺氧诱导因子1 a mRNA表达及人参皂苷Rgl的干预效应[J].中国组织工程研究与临床康复,2007,11(14)：2613-2616.
[10]刘霞,包翠芬,梁佳等.人参皂苷Rgl对脑缺血再灌注大鼠Caspase-3蛋白表达的影响[J].中国组织化学与细胞化学杂志,2010,19(1)：88-92.
[11]马永洁,朱丹,钟芝茵等.人参皂苷Rgl和丹参酮ⅡA配伍对缺氧-复氧损伤心肌细胞的保护作用[J].军事医学科学院院刊,2010,34(3)：243-246.
[12]冯劫.人参皂苷Rg1对四氧嘧啶致小鼠糖尿病降糖作用的研究[J].中华中医药学刊,2010,28(11)：2427-2429.
[13]Lee HM, Lee OH, Kim KJ, et al. Ginsenoside Rgl Promotes Glucose Uptake Through Activated AMPK Pathway in Insulin-resistant Muscle Cells[J]. Phytother Res,2011,26(5).
[14]马岚青,梁兵,柳波等.人参皂苷Rgl抗肝纤维化的实验研究[J].中国中西医结合消化杂志,2007,15(3)：165-168.
[15]董向前,段丽平,梁兵等.人参皂苷Rgl和Rbl抗肝纤维化的体视学研究[J].山东大学学报(医学版),50(1)：85-88.
[16]黄倩,牟正,陈乃宏等.人参皂苷Rgl及其代谢产物Ppt的抗抑郁作用研究[C]中国药理学会补益药药理专业委员会成立大会暨人参及补益药学术研讨会会议论文集,2011.
[17]Jiang B, Xiong Z, Yang J, et al. Antidepressant-like effects of Ginsenoside Rgl produced by activation of BDNF signaling pathway and neurogenesis in the hippocampus[J].Br J Pharmacol,2012,166(2).
[18]Feng L, Wang L, Hu C,et al. Pharmacokinetics, tissue distribution, metabolism, and excretion of ginsenoside Rgl in rats[J], Arch Pharm Res,2010,33(12):1975-1984.
[19]Xu QF, Fang XL. Pharmacokinetics and bioavailability of ginsenosides Rbl and Rgl from Panax notoginseng in rats [J].J Ethnopharmacol,2003, 23:187-192.
[20]Han M, Fang XL. Difference in oral absorption of ginsenoside Rgl between in vitro and in vivo models[J]. Acta Pharmacol Sin.2006 Apr;27(4):499-505.
[21]冯亮,胡昌江,余凌英.人参皂苷Rgl及其代谢产物的药代动力学研究[J].药学学报,2010,45(5)：636-640.
[22]吕天,孙建国,吕华等.人参总皂苷中Rgl的吸收特性研究[J].中国临床药理学与治疗学,2006,11(7)：780-783.
[23]李超英,孙波,陈静芳等.复方血栓通软胶囊药代动力学研究[J].中国中药杂志,2011,36(22)：3194-3197.
[24]萨础拉,吕航,姜艳艳等.三七皂苷在大鼠外翻肠囊中的吸收及与P-糖 蛋白相互作用研究[J].北京中医药大学学报,2011,34(12)：836-842.
[25]冯亮,蒋学华,周静等.三七皂苷R1和人参皂苷Rgl的大鼠在体肠吸收动力学研究[J].中国药学杂志,2006,41(14)：1097-1102.
[26]李文兰,南莉莉,季宇彬等.人参中人参皂苷Rg_1,Rb_1在体肠吸收影响因素的研究[J].中国中药杂志,2009,34(20)：2627-2632.
[27]何百寅,谢友良,刘常青等.三七提取液中三七皂苷R1、人参皂苷Rgl和人参皂苷 Rb1 的透皮规律研究[J].中国实验方剂学杂志,2011,17(21)：130-134.
[28]郭文峰,胡灿,温鹏等.人参皂苷Rgl对Caco-2细胞PepTl转运功能的影响[J].广州中医药大学学报,2011,28(4)：388-392.
[29]韩旻,傅韶,方晓玲.三七皂苷中人参皂苷Rg_1与Rb_1口服吸收及其体内药代动力学的研究和比较[J].药学学报,2007,42(8)：849-853.
[30]韦凤华,宋林,何毅等.人参皂苷Rg_1在大鼠体内的代谢与排泄研究[J].华西药学杂志,2010,25(3)：302-305.
[31]李国信,唐思,夏素霞等.生脉拆方系列注射液中人参皂苷Rg_1和Re药代动力学研究[J].中华中医药学刊,2010,28(11)：2310-2313.
[32]刘奕明,杨柳,曾星等.参麦注射液中人参皂苷Rg_1和Re药代动力学究[J].药学学报,2005,40(4)：365-368.
[33]Hasegawa H, Sung JH, Matsumiya S, et al. Main ginseng saponin metabolites formed by intestinal bacteria[J]. Planta Med.1996 Oct;62(5):453-457.
[34]陈新梅,朱家壁,孙卫东等.用药效学指标筛选人参皂苷Rg1鼻用制剂的促吸收剂[J].中国天然药物,2005,3(6)：361-366.
[35]陈新梅,朱家壁,孙卫东等.冰片对人参皂苷Rgl鼻腔吸收的促进作用及鼻腔纤毛毒性研究[J].中国药学杂志,2006,41(4)：261-264.
[36]缪菊连,黄照昌.羟丙基-β-环糊精对人参皂苷Rgl溶解度的影响[J].中国实验方剂学杂志,2011,17(21)：17-19.
[37]Xiong J, Guo J, Huang L, et al. The use of lipid-based formulations to increase the oral bioavailability of Panax notoginseng sapoinins following a single oral gavage to rats[J].Drug Dev Ind Pharm.2008 Jan;34(1): 65-72.
[1]朱洁,温敏,张洪彬HPLC-ELSD测定三七胶囊中人参皂苷Rgl和Rb1[J].中成药,2004,26(1)：33-35.
[2]刘波,钟关萍,朱兆云等.高效液相色谱法测定伤益凝胶中人参皂苷Rgl的含量[J].云南大学学报(自然科学版),2009,3 1(S1)：310-312.
[3]Lipinski CA, Lombardo F, Dominy BW, et al.Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings[J]. Adv Drug Deliv Rev,2001, 46(1-3):3-26.
[1]Xu QF,Fang XL,Chen DF. Pharmacokinetics and bioavailability of ginsenoside Rbl and Rgl from Panax notoginseng in rats [J]. Journal of Ethnopharmacology,2003,84(2-3):187-192.
[2]梁平,张旋,吴琳,等.人参皂苷Rgl脂质体的制备及稳定性研究[J].昆明医学院学报2009,30(1)：6-9.
[3]陈新梅,朱家壁.人参皂苷Rg 1的溶解特性与脂质体包封率关系的研究[J].中国药房,2007,18(1)：41-43.
[4]王亮,顾宜,费燕.人参皂苷Rgl脂质体制备工艺的优化[J].中国中药杂志,2006,31(23)：2005-2007.
[5]吴伟,崔光华,陆彬.实验设计中多指标的优化：星点设计和总评“归一值”的应用[J].中国药学杂志,2000,35(8)：530-533.
[6]张囡,康廷国,尹海波.星点设计-响应面法优化穿龙薯蓣多糖提取工艺[J].中药材,2011,34(1)：123-126.
[7]颜军,甘亚,苟小军等.星点设计-效应面法优化槐米中芦丁提取工艺[J].中药材,2011,34(4)：628-631.
[8]杨银花,谢云,吴清等.星点设计优选苦参纤维素酶解提取工艺研究[J].北京中医药大学学报,2011,34(8)：552-557.
[9]Muramatsu K, Maitani Y, Machida Y, et al. Effect of soybean derived steroland its glucoside mixtures on the stability of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylcholine/ cholesterol liposomes [J]. Int. J. Pharm,1994,107(1):1-8.
[10]Muramatsu K, Maitani Y, Nagai T. Dipalmitoylphosphatidylcholine liposomes with soybean derived sterols and cholesterol as a carrier for the oral administration of insulin in rats[J]. Biol. Pharm. Bull,1996,19(8): 1055-1058.
[1]McMullen T P W, McElhaney R. N. New aspects of the interaction of cholesterol with dipalmitoylphosphatidylcholine bilayers as revealed by high-sensitivity differential scanning calorimetry. Biochim Biophys Acta, 1995,1234 (1):90-98.
[2]Zhang Y P, Lewis R N, Hodges R S, et al. Interaction of a peptide model of a hydrophobic transmembrane alpha-helical segment of a membrane protein with phosphatidylethanolamine bilayers:differential scanning calorimetric and Fourier transform infrared spectroscopic studies. Biophys J,1995,68 (3):847-857.
[3]Arouri A, Dathe M, Blume A. Peptide induced demixing in PG/PE lipid mixtures:a mechanism for the specificity of antimicrobial peptides towards bacterial membrane. Biochim Biophys Acta,2009,1788 (3):650-659.
[4]Yu ZW, Quinn PJ. Phase stability of phosphatidylcholine in dimethylsulfoxide solutions. Biophys J,1995,69 (4):1456-1463.
[5]Wu Fugen, JiaQi, Wu Ruiguang,et al. Regional cooperativity in the phase transitions of dipalmitoylphosphatidylcholine bilayers:The lipid tail triggers the isothermal crystallization process. J Phys Chem B,2011, 115(26):8559-8568.
[6]Gao Wenying, Chen Lin, Wu Ruiguang, et al. Phase diagram of androsterol-dipalmitoylphosphatidylcholine mixtures dispersed in excess water. J Phys Chem B,2008,112(28):8375-8382.
[7]赵雨,赵大庆,席时权等.鞘磷脂与胆固醇相互作用的拉曼光谱研究[J].光散射学报,1999,11(2)：165-169.
[8]Muramatsu K,Maitani Y,Machida Y,et al.Effect of soybean derived sterol and its glucoside mixtures on the stability of dipalmitoylphosphatidyl-choline and dipalmitoylphosphatidylcholine/cholesterol liposomes[J].Int Pharm,1994,107(1):1-8.
[9]Muramatsu K,Maitani Y,Nagai T.Dipalmitoylphosphatidylcholine liposomes with soybean derived sterols and cholesterol as a carrier for the oral administration of insulin in rats[J].Biol Pharm Bull,1996,19(8): 1055-1058.
[1]杨贵贞.免疫生物工程纲要与技术[M].长春：吉林科学技术出版社,1991,47-48.
[2]Hilgers AR, Conradi RA, Burton PS. Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa[J]. Pharmaceutical Research,1990,7 (9):902-910.
[3]吴正红,平其能,赖家明.小鼠口服多糖包覆胰岛素脂质体的降血糖作用[J].药学学报,2003,38(2)：138-142.
[4]Santos MR, Rodri guez-Gomez MJ, Justino GC,et al.Influence of the metabolic profile on the in vivo antioxidant activity of quercetin under a low dosage oral regimen in rats[J]. Brit J Pharmacol,2008,153(8): 1750-1761.
[5]Williams RJ, Spencer JP, Rice-Evans C. Flavonoids:antioxidants or signalling molecules? [J]. Free Radic Biol Med,2004,36(7):838-849.
[6]Harborne J.B. The Flavonoids, Advances in Research Since 1986[M]. Chapman & Hall,London,1994,13:378-382.
[7]Kuti JO,Konuru HB.Antioxidant capacity and phenolic content in leaf extracts of tree spinach (Cnidoscolus spp.)[J]. J. Agric. Food Chem,2004, 52(1):117-121.
[1]周威,石任兵,孙建宁等.不同模型下清脑宣窍方有效组分药代动力学研究[J].北京中医药大学学报,2008,31(4)：265-268.
[2]陈霞,徐济良.血塞通分散片的生物利用度评价[J].时珍国医国药,2007,18(8)：1852-1853.
[3]林力,刘建勋,张颖等LC-MS/MS法测定大鼠口服人参皂苷Rg1,Re,Rb 1和Rd的药动学[J].中国药学杂志,2009,44(5)：373-377.
[4]胡锦芳,温金华,蒋丽华.复方血栓通片中人参皂苷Rb1与Rg1在大鼠体内的药代动力学研究[J].南昌大学学报(医学版),2011,51(11)：6-10.