水飞蓟宾脂质体的制备及物理化学性质研究
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摘要
脂质体是由磷脂和胆固醇等物质在水溶液中形成的球状小囊,是一种良好的药物载体,因其具良好的生物相容性和安全性,在药物的输送等方面有其优越性。本文以水飞蓟宾为药物模型,研究其脂质体的制备及物理化学性质,并通过对水飞蓟宾在若干有机溶剂中的溶解度及其关联,为药物的溶解、输运性质提供基础数据和理论参考。研究内容具体包括:
1.采用薄膜超声分散法制备水飞蓟宾脂质体,透析法分离脂质体和药物,用紫外-可见一阶导数分光光度法,测定脂质体中的水飞蓟宾含量,计算包封率。以包封率为衡量指标,选择影响包封率和粒径分布的三个主要因素:磷脂与胆固醇的用量比;水飞蓟宾的用量;水合介质的种类。采用三因素四水平正交实验进行处方优化。确定最优处方为:卵磷脂:胆固醇=100:50,水飞蓟宾10mg,水合介质为0.01M磷酸盐缓冲溶液(pH=6.86),其包封率为86.57%。
2.对水飞蓟宾脂质体物理化学性质:膜材红外光谱、膜材DSC、脂质体TEM、脂质体粒径分布、药物体外释放进行了五个方面研究。结果表明:水飞蓟宾与磷脂只是简单复合,并未发生化学方应;从膜材DSC可看出胆固醇可抑制卵磷脂的相变发生;TEM显示脂质体形态为球状囊泡,粒径大小在64.29-250.00nm之间,平均粒径为123.48nm;分别用零级方程、一级方程、Higuchi方程、Niebergull平方根方程、Hixcon-crowell立方根方程、Weibull方程等释放动力学方程拟合了药物释放数据,释放符合一级动力学方程。
3.采用固液平衡法测定了水飞蓟宾在无水乙醇、丙酮、乙酸乙酯、二甲基甲酰胺等有机溶剂中的溶解度。分别用理想溶液模型、经验模型、Apelblat方程模型和λh方程模型对实验数据进行关联。经验模型和Apelblat方程模型关联的效果较好。
Liposome is a spherical vesicle, which is composed of phospholipid, cholesterol and other substances in water. Liposome is a good drug carrier with good biocompatibility and safety. There are many advantages compared with other drug delivery systems. In this paper, silybin is chosen as a drug model. The technique of the preparation of liposome, the physical -chemistry properties of liposome, and the solubility of silybin in some organic solvents were studied. This study is aimed to provide basic reference data for the preparation and application of silybin liposome. Following cotents are included in this paper.
1. The silybin liposome was prepared by a thin film ultrasonic dispersion method. The liposome and drug was separated by a dialysis method. The solubility of silybin was measured by the UV-visible measurement. The content of silybin in liposome and the entrapment efficiency were determinated from its solubility data. Entrapment efficiency was used to evaluate the efficience of liposome. In experiment, three factors infect the entrapment efficiency and particle size distribution: the ratio of phospholipid to cholesterol, the amount of silybin in liposome, hydration media types. A four-level three - factors orthogonal experiment was designed to optimize the prescription. The optimum prescription is that the ratio of EPC: cholesterol = 100:50, silybin was 10mg, hydration medium was 0.01MPBS (pH = 6.86). The entrapment efficiency of 86.57% is found for the optimum prescription.
2. The physical-chemistry properties of silybin liposome were studied by FT-IR spectroscopy, DSC, TEM and the drug release experiments. The results of FT-IR showed that silybin is simply enclosed in phospholipid liposome. DSC experiment shows that cholesterol could inhibit EPC from phase transition. TEM shows that silybin liposome is a spherical vesicle. The particle size was distributed from 64.29 to 250.00 nm, the average size was 123.48 nm. Drug release experiment was analysed by some kinetic equations. For example the Zero-order equation, the first-order equation, the Higuchi equation, the Niebergull square root equation, the Hixcon-crowell cube root equation and the Weibull equation. The results of data fit indicate that the first-order equation agrees with experimental best.
3. The solubility of silybin in several organic solvents such as ethanol, Acetone, Ethyl Acetate and dimethylformamide was measured by the solid-liquid equilibrium method. Ideal solution model, empirical model, Apelblat model andλh model were used to correlate the experimental data.The empirical model and Apelblat model correlate the solubility data better.
1.采用薄膜超声分散法制备水飞蓟宾脂质体,透析法分离脂质体和药物,用紫外-可见一阶导数分光光度法,测定脂质体中的水飞蓟宾含量,计算包封率。以包封率为衡量指标,选择影响包封率和粒径分布的三个主要因素:磷脂与胆固醇的用量比;水飞蓟宾的用量;水合介质的种类。采用三因素四水平正交实验进行处方优化。确定最优处方为:卵磷脂:胆固醇=100:50,水飞蓟宾10mg,水合介质为0.01M磷酸盐缓冲溶液(pH=6.86),其包封率为86.57%。
2.对水飞蓟宾脂质体物理化学性质:膜材红外光谱、膜材DSC、脂质体TEM、脂质体粒径分布、药物体外释放进行了五个方面研究。结果表明:水飞蓟宾与磷脂只是简单复合,并未发生化学方应;从膜材DSC可看出胆固醇可抑制卵磷脂的相变发生;TEM显示脂质体形态为球状囊泡,粒径大小在64.29-250.00nm之间,平均粒径为123.48nm;分别用零级方程、一级方程、Higuchi方程、Niebergull平方根方程、Hixcon-crowell立方根方程、Weibull方程等释放动力学方程拟合了药物释放数据,释放符合一级动力学方程。
3.采用固液平衡法测定了水飞蓟宾在无水乙醇、丙酮、乙酸乙酯、二甲基甲酰胺等有机溶剂中的溶解度。分别用理想溶液模型、经验模型、Apelblat方程模型和λh方程模型对实验数据进行关联。经验模型和Apelblat方程模型关联的效果较好。
Liposome is a spherical vesicle, which is composed of phospholipid, cholesterol and other substances in water. Liposome is a good drug carrier with good biocompatibility and safety. There are many advantages compared with other drug delivery systems. In this paper, silybin is chosen as a drug model. The technique of the preparation of liposome, the physical -chemistry properties of liposome, and the solubility of silybin in some organic solvents were studied. This study is aimed to provide basic reference data for the preparation and application of silybin liposome. Following cotents are included in this paper.
1. The silybin liposome was prepared by a thin film ultrasonic dispersion method. The liposome and drug was separated by a dialysis method. The solubility of silybin was measured by the UV-visible measurement. The content of silybin in liposome and the entrapment efficiency were determinated from its solubility data. Entrapment efficiency was used to evaluate the efficience of liposome. In experiment, three factors infect the entrapment efficiency and particle size distribution: the ratio of phospholipid to cholesterol, the amount of silybin in liposome, hydration media types. A four-level three - factors orthogonal experiment was designed to optimize the prescription. The optimum prescription is that the ratio of EPC: cholesterol = 100:50, silybin was 10mg, hydration medium was 0.01MPBS (pH = 6.86). The entrapment efficiency of 86.57% is found for the optimum prescription.
2. The physical-chemistry properties of silybin liposome were studied by FT-IR spectroscopy, DSC, TEM and the drug release experiments. The results of FT-IR showed that silybin is simply enclosed in phospholipid liposome. DSC experiment shows that cholesterol could inhibit EPC from phase transition. TEM shows that silybin liposome is a spherical vesicle. The particle size was distributed from 64.29 to 250.00 nm, the average size was 123.48 nm. Drug release experiment was analysed by some kinetic equations. For example the Zero-order equation, the first-order equation, the Higuchi equation, the Niebergull square root equation, the Hixcon-crowell cube root equation and the Weibull equation. The results of data fit indicate that the first-order equation agrees with experimental best.
3. The solubility of silybin in several organic solvents such as ethanol, Acetone, Ethyl Acetate and dimethylformamide was measured by the solid-liquid equilibrium method. Ideal solution model, empirical model, Apelblat model andλh model were used to correlate the experimental data.The empirical model and Apelblat model correlate the solubility data better.
引文
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[14]余江南,徐希明,朱源,等。水飞蓟宾脂质体包封率及其水飞蓟宾含量测定.中国中药杂志.2003,28(11):1027-1030
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[10]Xiao Yanyu, Song Yunmei, Chen Zhipeng.The preparation of silybin–phospholipid complex and the study on its pharmacokinetics in rats. Int.J.Pharm.2006,307,77-82
[11]Gary A. Reineccius.Liposomes for Controlled Release in the Food Industry. 1995,Chapter 11, 113–131
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[1]张光军,许建文,陈正跃.水飞蓟宾-卵磷脂复合物红外光谱和磷核磁共振波谱特征.中国新药杂志,2002,11(6):470-471
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[6]托尔钦林(Torchilin,V.p.),魏西希(Weissig,V.)编,邓意辉,徐晖主译.脂质体(原著第二版),北京,化学工业出版社,2007
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[9]李卫,邵友元,黄光斗.卵磷脂的精制及TG-DTA-DTG热分析.食品工业科技.2001,22(3):9-11
[10]Xiao Yanyu, Song Yunmei, Chen Zhipeng.The preparation of silybin–phospholipid complex and the study on its pharmacokinetics in rats. Int.J.Pharm.2006,307,77-82
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