可生物降解载药微球的制备和释药动力学的研究
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摘要
可生物降解型载药微球是近年来缓控释给药系统的研究热点,具有体积小、载体材料多样性和多功能性以及适用于多种给药方式等优点,可以通过对释药速率的控制来显著提高临床用药的安全性和有效性。本文以聚乳酸羟基乙酸-聚乙二醇单甲醚共聚物(PLGA-mPEG)为材料进行载药微球的研制,针对目前载药微球释药机理研究的不足,从微球的微观结构和性能关系出发,分析材料的降解对释药行为的作用机理,用于指导缓控释载药微球的处方设计和应用。
以小分子疏水药物甲氨蝶呤(MTX)为模型药物,考察了乳化溶剂挥发法的工艺参数对载药微球性质的影响及成因。通过正交工艺优化,制备了包封率较高且缓释效果明显的MTX微球。实验表明MTX和材料具有良好的相容性。
在一定的载药量下,MTX微球的释药过程呈现明显的三个阶段,包括起始突释期、时滞期和二次突释期。对微球的降解动力学研究显示,微球在降解过程中发生的物理化学变化和形态变化具有一定的规律性,对于不同的释药阶段,控制微球释药的降解因素也有所区别。亲水性嵌段聚乙二醇单甲醚(mPEG)的存在,加快了材料的降解速度,提高了材料的柔韧性,从而降低了微球受外力破坏和崩解释药的风险,同时也使得释药时滞期大大缩短。
微球的降解受到自身的性质以及释药环境等因素的影响,这些因素通过影响材料的降解对药物释放进行了间接的调控。论文系统研究了材料组成、载药量、粒径以及释放环境等四种因素对MTX微球降解动力学的作用方式,进而分析出每种因素对不同释药阶段的控制规律,从中拓展了调节微球释药速率的途径,对实现微球释药速率可控性的研究具有重要指导意义。
采用传质模型描述药物的扩散和材料的降解对MTX微球释药过程的影响,并对模型的适用性进行了考证。分析了影响材料降解的主要因素与药物扩散系数之间的关系,并对影响趋势作出预测。
利用PLGA-mPEG与亲水性药物的相容性,分别制备了硫酸沙丁胺醇(SBS)微球和溶菌酶(LYS)微球。针对亲水性药物微球存在的包封率低、突释严重、活性大分子后期释药停滞等问题,采用添加附加剂、改进制备工艺等方法对微球的质量进行改善。
In recent years, biodegradable polymeric microparticles have attracted more and more attentions as sustained /controlled drug delivery systems. They have many advantages such as small size, diversity and functionality of materials and multiple dose administration, etc. They will be promising in clinical applications because they can release drugs with a controlled speed and thus greatly improve the effectiveness and safety of drugs. This research aimed to investigate the effect of polymer microstructure on controlled drug delivery from Poly (dl-lactide-co-glycolic acid)-methoxypoly (ethyleneglycol) (PLGA-mPEG) microparticles during polymer degradation process. An experimental and theoretical framework was created for the guidance of microparticle application.
PLGA-mPEG microparticles were prepared by O/W solvent evaporation method. MTX, a small hydrophobic drug, was employed as the model drug. The influences of manufacturing parameters on the properties of microparticles were investigated. O/W solvent evaporation method was further optimized by orthogonal design. Microparticles with high encapsulation efficiency and well sustained drug release were prepared. The analytical results indicated that MTX had high compatibility with PLGA-mPEG.
Under a certain drug loading capacity, the MTX release from PLGA-mPEG microparticles showed a triphasic pattern: an initial burst release, followed by a lag period and a subsequently second burst release. The degradation of microparticles induced both physicochemical and morphological changes, and these changes played important roles on the drug release kinetics. For each drug release phase, the controlling factor which correlated with polymer degradation was different. The incorporation of hydrophilic mPEG chain, acting as a surface modifier of hydrophobic PLGA network, increased the polymer hydrolysis rate as well as drug release rate. mPEG chain also enhanced the mechanical strength of PLGA-mPEG microparticles. It reduced the risk of severe drug burst release caused by particle collapse and shortened the lag period of drug release.
The degradation behavior of microparticles could be affected by many external factors. These factors regulated the drug release indirectly by working on the polymer degradation process. In this study, the effects of four external factors, copolymer composition, drug loading, particle size and incubation medium, on the degradation of PLGA-mPEG microparticles were investigated. For each factor, the mechanism of controlling drug release was analyzed. Expanded means of regulating the drug release from PLGA-mPEG microparticles were then developed to achieve the desired drug release rate.
Mass transfer models considering drug diffusion, hydrolysis of polymer chains and matrix erosion were developed for different drug release phases. A diffusion-degradation-erosion model was proposed and successfully described the whole MTX release from PLGA-mPEG microsparticles. The effects of external factors on drug release kinetics were analyzed and the trends of influences were well predicted according to the model.
PLGA-mPEG was also applied for encapsulating salbutamol sulphate (SBS) and lysozyme (LYS), by utilizing the compatibility of PLGA-mPEG with hydrophilic or biomacromolecular drugs. Aiming at solving problems of microparticles encapsulating water soluble drugs, such as low encapsulation efficiency, severe initial burst release, and lag release of active biomolecules at the end of incubation period, etc, additives and manufacturing technique improvements were applied to improve the properties of hydrophilic drug-loaded microparticles.
以小分子疏水药物甲氨蝶呤(MTX)为模型药物,考察了乳化溶剂挥发法的工艺参数对载药微球性质的影响及成因。通过正交工艺优化,制备了包封率较高且缓释效果明显的MTX微球。实验表明MTX和材料具有良好的相容性。
在一定的载药量下,MTX微球的释药过程呈现明显的三个阶段,包括起始突释期、时滞期和二次突释期。对微球的降解动力学研究显示,微球在降解过程中发生的物理化学变化和形态变化具有一定的规律性,对于不同的释药阶段,控制微球释药的降解因素也有所区别。亲水性嵌段聚乙二醇单甲醚(mPEG)的存在,加快了材料的降解速度,提高了材料的柔韧性,从而降低了微球受外力破坏和崩解释药的风险,同时也使得释药时滞期大大缩短。
微球的降解受到自身的性质以及释药环境等因素的影响,这些因素通过影响材料的降解对药物释放进行了间接的调控。论文系统研究了材料组成、载药量、粒径以及释放环境等四种因素对MTX微球降解动力学的作用方式,进而分析出每种因素对不同释药阶段的控制规律,从中拓展了调节微球释药速率的途径,对实现微球释药速率可控性的研究具有重要指导意义。
采用传质模型描述药物的扩散和材料的降解对MTX微球释药过程的影响,并对模型的适用性进行了考证。分析了影响材料降解的主要因素与药物扩散系数之间的关系,并对影响趋势作出预测。
利用PLGA-mPEG与亲水性药物的相容性,分别制备了硫酸沙丁胺醇(SBS)微球和溶菌酶(LYS)微球。针对亲水性药物微球存在的包封率低、突释严重、活性大分子后期释药停滞等问题,采用添加附加剂、改进制备工艺等方法对微球的质量进行改善。
In recent years, biodegradable polymeric microparticles have attracted more and more attentions as sustained /controlled drug delivery systems. They have many advantages such as small size, diversity and functionality of materials and multiple dose administration, etc. They will be promising in clinical applications because they can release drugs with a controlled speed and thus greatly improve the effectiveness and safety of drugs. This research aimed to investigate the effect of polymer microstructure on controlled drug delivery from Poly (dl-lactide-co-glycolic acid)-methoxypoly (ethyleneglycol) (PLGA-mPEG) microparticles during polymer degradation process. An experimental and theoretical framework was created for the guidance of microparticle application.
PLGA-mPEG microparticles were prepared by O/W solvent evaporation method. MTX, a small hydrophobic drug, was employed as the model drug. The influences of manufacturing parameters on the properties of microparticles were investigated. O/W solvent evaporation method was further optimized by orthogonal design. Microparticles with high encapsulation efficiency and well sustained drug release were prepared. The analytical results indicated that MTX had high compatibility with PLGA-mPEG.
Under a certain drug loading capacity, the MTX release from PLGA-mPEG microparticles showed a triphasic pattern: an initial burst release, followed by a lag period and a subsequently second burst release. The degradation of microparticles induced both physicochemical and morphological changes, and these changes played important roles on the drug release kinetics. For each drug release phase, the controlling factor which correlated with polymer degradation was different. The incorporation of hydrophilic mPEG chain, acting as a surface modifier of hydrophobic PLGA network, increased the polymer hydrolysis rate as well as drug release rate. mPEG chain also enhanced the mechanical strength of PLGA-mPEG microparticles. It reduced the risk of severe drug burst release caused by particle collapse and shortened the lag period of drug release.
The degradation behavior of microparticles could be affected by many external factors. These factors regulated the drug release indirectly by working on the polymer degradation process. In this study, the effects of four external factors, copolymer composition, drug loading, particle size and incubation medium, on the degradation of PLGA-mPEG microparticles were investigated. For each factor, the mechanism of controlling drug release was analyzed. Expanded means of regulating the drug release from PLGA-mPEG microparticles were then developed to achieve the desired drug release rate.
Mass transfer models considering drug diffusion, hydrolysis of polymer chains and matrix erosion were developed for different drug release phases. A diffusion-degradation-erosion model was proposed and successfully described the whole MTX release from PLGA-mPEG microsparticles. The effects of external factors on drug release kinetics were analyzed and the trends of influences were well predicted according to the model.
PLGA-mPEG was also applied for encapsulating salbutamol sulphate (SBS) and lysozyme (LYS), by utilizing the compatibility of PLGA-mPEG with hydrophilic or biomacromolecular drugs. Aiming at solving problems of microparticles encapsulating water soluble drugs, such as low encapsulation efficiency, severe initial burst release, and lag release of active biomolecules at the end of incubation period, etc, additives and manufacturing technique improvements were applied to improve the properties of hydrophilic drug-loaded microparticles.
引文
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