聚（乳酸—羟基乙酸）共聚物纳米粒药物载体的制备及性能研究
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摘要
紫杉醇是从太平杉树树皮中提取的抗癌药物,具有高效、低毒、广谱等特性,能够治疗卵巢癌、乳腺癌、肺癌、食管癌、子宫内膜癌、膀胱癌等。由于其在水中以及许多药用溶剂中溶解度差,临床使用时需在紫杉醇注射液中加入聚氧乙烯蓖麻油,该溶剂副作用较大,常引起严重的过敏反应。因此,为了解决上述问题,研究者将紫杉醇制备成脂质体、微球和纳米粒等药物缓释剂型。
本文选用生物相容性好、可生物降解的高分子材料——聚(乳酸-羟基乙酸)共聚物(PLGA)为载体材料,紫杉醇为模型药物,制备载紫杉醇PLGA纳米粒,研究内容主要包括:(1)采用改良的乳化溶剂挥发法制备空白PLGA纳米粒,以纳米粒粒径作为评价指标,考察乳化剂浓度、有机溶剂种类、有机溶剂挥发时间、超声乳化时间、水油相体积比、聚合物浓度、搅拌速度和温度等工艺因素对纳米粒制备的影响。(2)建立高效液相色谱法测定紫杉醇含量,绘制紫杉醇的标准曲线,验证其精密度和回收率。(3)采用改良的乳化溶剂挥发法制备载紫杉醇PLGA纳米粒,对其进行正交设计优化及表征,并研究纳米粒的表面形貌、表面电位、热稳定性、缓释性能,探讨药物释放规律和载药模式。(4)考察乳化剂浓度、搅拌速度、水油相体积比、聚合物浓度、材料性质和药物浓度对纳米粒包封率和载药量的影响,乳化剂浓度对纳米粒表面电位的影响,以及纳米粒载药量与缓释性能的相互关系。
结果表明:综合单因素实验和正交实验的结果,确定最优制备工艺条件,可获得较理想的载药纳米粒,在扫描电镜下观察纳米粒呈规整球形,表面较光滑,分散性良好,载紫杉醇PLGA纳米粒平均粒径为210.1nm,有较窄的粒径分布,药物包封率为85.84%,载药量为6.31%,表面电位为-28.0mv,紫杉醇以分子无定形状态分散在纳米粒中;采用动态透析法研究紫杉醇PLGA纳米粒缓释性能,结果显示载药纳米粒有良好的缓释性能,体外释药曲线拟合证明药物缓释规律符合Weibull方程。
Paclitaxel, isolated from Pacific Ocean Yew Bark, is an efficient, low toxicity, broad-spectrum, anti-tumor drug. It can treat ovarian cancer, breast cancer, lung cancer, esophageal cancer, reproductive tissue tumors, endometrial cancer, leaching Pakistan tumors, bladder cancer. Paclitaxel has poor solubility in water and other commonly used drug solvents, so the Cremorphor EL was used as the solvents of Paclitaxel in clinical, although the solvent has many side effects, such as causing severe allergic reactions and so on. In order to solve these problems, the researchers have manipulated drug into different drug delivery systems, such as liposomes, microspheres and nanoparticles.
This paper planed to prepare paclitaxel-loaded PLGA nanoparticles with biocompatible and biodegradable polymer——poly (lactic acid-glycolic acid) (PLGA) as the carrier material, and the anti-cancer drug paclitaxel as the model drug, the experimental works were carried out as followed. First, PLGA nanoparticles were prepared by modified emulsion solvent evaporation method with nanoparticle size as the evaluation. The experimental prescriptions and preparation were optimized based on single factor such as emulsifier concentration, organic solvent type, the timing of volatile organic solvents, ultrasonic time, aqueous to organic phase, polymer concentration, stirring speed and temperature. Second, we determine the drug contration by high performance liquid chromatography (HPLC), draw paclitaxel standard curve, verify precision and recovery. Third, paclitaxel-loaded PLGA nanoparticles were prepared by modified emulsion solvent evaporation method and optimized by orthogonal experimental method. The nanoparticles were determinated on zeta potential, surface morphology, thermal performance and release properties, while studying influencing factors on drug release properties. Last, we investigated the emulsifier concentration, stirring speed, aqueous to organic phase, polymer concentration, material properties and drug concentration on the encapsulation efficiency and drug loading. We also investigated the emulsifier concentration on zeta potential. Scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were used to characterize the nanoparticles for surface morphology and thermogram property. The high performance liquid chromatography (HPLC) was measured the drug concentration.
The results showed that the shape of nanoparticles were spherical, smooth surface, good dispersion, and the average size of paclitaxel-loaded PLGA nanoparticles was 210.1nm with narrow size distribution, the encapsulation efficiency was 85.84%, the drug loading was 6.31%, and the zeta potential was -28.0mv. The paclitaxel was dispersed in nanoparticles with molecular state. Indicators found that the process parameters, such as emulsifier concentration, stirring speed, aqueous to organic phase, polymer concentration, have greater impact on the encapsulation efficiency and drug loading. Experiment by dialysis method in vitro shows that the paclitaxel-loaded PLGA nanoparticles have good release properties. The in vitro release behavior of the paclitaxel- loading PLGA nanoparticles was fitted to Weibull equation.
本文选用生物相容性好、可生物降解的高分子材料——聚(乳酸-羟基乙酸)共聚物(PLGA)为载体材料,紫杉醇为模型药物,制备载紫杉醇PLGA纳米粒,研究内容主要包括:(1)采用改良的乳化溶剂挥发法制备空白PLGA纳米粒,以纳米粒粒径作为评价指标,考察乳化剂浓度、有机溶剂种类、有机溶剂挥发时间、超声乳化时间、水油相体积比、聚合物浓度、搅拌速度和温度等工艺因素对纳米粒制备的影响。(2)建立高效液相色谱法测定紫杉醇含量,绘制紫杉醇的标准曲线,验证其精密度和回收率。(3)采用改良的乳化溶剂挥发法制备载紫杉醇PLGA纳米粒,对其进行正交设计优化及表征,并研究纳米粒的表面形貌、表面电位、热稳定性、缓释性能,探讨药物释放规律和载药模式。(4)考察乳化剂浓度、搅拌速度、水油相体积比、聚合物浓度、材料性质和药物浓度对纳米粒包封率和载药量的影响,乳化剂浓度对纳米粒表面电位的影响,以及纳米粒载药量与缓释性能的相互关系。
结果表明:综合单因素实验和正交实验的结果,确定最优制备工艺条件,可获得较理想的载药纳米粒,在扫描电镜下观察纳米粒呈规整球形,表面较光滑,分散性良好,载紫杉醇PLGA纳米粒平均粒径为210.1nm,有较窄的粒径分布,药物包封率为85.84%,载药量为6.31%,表面电位为-28.0mv,紫杉醇以分子无定形状态分散在纳米粒中;采用动态透析法研究紫杉醇PLGA纳米粒缓释性能,结果显示载药纳米粒有良好的缓释性能,体外释药曲线拟合证明药物缓释规律符合Weibull方程。
Paclitaxel, isolated from Pacific Ocean Yew Bark, is an efficient, low toxicity, broad-spectrum, anti-tumor drug. It can treat ovarian cancer, breast cancer, lung cancer, esophageal cancer, reproductive tissue tumors, endometrial cancer, leaching Pakistan tumors, bladder cancer. Paclitaxel has poor solubility in water and other commonly used drug solvents, so the Cremorphor EL was used as the solvents of Paclitaxel in clinical, although the solvent has many side effects, such as causing severe allergic reactions and so on. In order to solve these problems, the researchers have manipulated drug into different drug delivery systems, such as liposomes, microspheres and nanoparticles.
This paper planed to prepare paclitaxel-loaded PLGA nanoparticles with biocompatible and biodegradable polymer——poly (lactic acid-glycolic acid) (PLGA) as the carrier material, and the anti-cancer drug paclitaxel as the model drug, the experimental works were carried out as followed. First, PLGA nanoparticles were prepared by modified emulsion solvent evaporation method with nanoparticle size as the evaluation. The experimental prescriptions and preparation were optimized based on single factor such as emulsifier concentration, organic solvent type, the timing of volatile organic solvents, ultrasonic time, aqueous to organic phase, polymer concentration, stirring speed and temperature. Second, we determine the drug contration by high performance liquid chromatography (HPLC), draw paclitaxel standard curve, verify precision and recovery. Third, paclitaxel-loaded PLGA nanoparticles were prepared by modified emulsion solvent evaporation method and optimized by orthogonal experimental method. The nanoparticles were determinated on zeta potential, surface morphology, thermal performance and release properties, while studying influencing factors on drug release properties. Last, we investigated the emulsifier concentration, stirring speed, aqueous to organic phase, polymer concentration, material properties and drug concentration on the encapsulation efficiency and drug loading. We also investigated the emulsifier concentration on zeta potential. Scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were used to characterize the nanoparticles for surface morphology and thermogram property. The high performance liquid chromatography (HPLC) was measured the drug concentration.
The results showed that the shape of nanoparticles were spherical, smooth surface, good dispersion, and the average size of paclitaxel-loaded PLGA nanoparticles was 210.1nm with narrow size distribution, the encapsulation efficiency was 85.84%, the drug loading was 6.31%, and the zeta potential was -28.0mv. The paclitaxel was dispersed in nanoparticles with molecular state. Indicators found that the process parameters, such as emulsifier concentration, stirring speed, aqueous to organic phase, polymer concentration, have greater impact on the encapsulation efficiency and drug loading. Experiment by dialysis method in vitro shows that the paclitaxel-loaded PLGA nanoparticles have good release properties. The in vitro release behavior of the paclitaxel- loading PLGA nanoparticles was fitted to Weibull equation.
引文
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[3]王思玲,苏德森.胶体分散药物制剂[M],北京,人民卫生出版社, 2006: 45-55
[4] Kumari A, Yadav S K, Yadav S C. Biodegradable polymeric nanoparticles based drug delivery systems [J]. Colloids and Surfaces B: Biointerfaces, 2010, 75(1): 1-18
[5] Luan X, Bodmeier R. In situ forming microparticle system for controlled delivery of leuprolide acetate: Influence of the formulation and processing parameters [J]. European Journal of Pharmaceutical Sciences, 2006, 27(2-3): 143-149
[6] Kakizawa Y, Nishio R, Hirano T, et al. Controlled release of protein drugs from newly developed amphiphilic polymer-based microparticles composed of nanoparticles [J]. Journal of Controlled Release, 2009, 10(3): 198-206
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