注射用白藜芦醇生物可降解缓释微球的研究
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摘要
在缓控释制剂中,高分子材料作为药物的载体具有极其重要的作用。尤其是聚酯类高分子材料聚乳酸羟基乙酸[poly (D,L-lactide-co-glycolide), PLGA],因其具有其他材料无可比拟的优点,如生物可降解性,良好的生物相容性,使用安全以及可通过改变LA和GA单体比例和聚合条件来调节PLGA在体内的降解速度等优点,已成为缓释微球制剂的优良载体材料。
本文以白藜芦醇为模型药物,以PLGA为载体,研究制备了注射用生物可降解缓释微球,并对微球的体内外释药行为进行了较深入地探讨,研究了微球的粒径和PLGA分子量对微球体内外释药行为的影响。
本研究采用高效液相色谱法(HPLC)测定微球中药物含量以及药物从微球中的体内外释放量。采用乳化溶剂挥发法制备了白藜芦醇PLGA缓释微球,以微球的包封率、载药量和突释作为质量评价指标,通过单因素考察试验筛选微球的最优处方和制备工艺。单因素考察结果表明,分散相／连续相体积比、PLGA浓度、理论载药量、搅拌速度、PVA浓度等均是影响微球性质的关键因素。
在微球的体外释药研究中,以0.5%十二烷基硫酸钠(SDS)作为释放介质,采用直接释药法对目标粒径为20μm的微球进行体外释药行为的研究。结果表明PLGA浓度、理论载药量、搅拌速度、PVA浓度是影响微球中药物释放的关键因素,药物从载药微球中的释放主要以Fick扩散机制为主。
采用小鼠皮下注射方式给药后定时测定药物在体内残留量的方法,深入研究了微球粒径和聚合物分子量对白藜芦醇微球体内外释药行为的影响,并进行了体内外相关性(IVIVC)评价。结果显示,粒径为5μm和20μm的低分子量载药微球,当以0.5%的十二烷基硫酸钠水溶液作为释放介质进行体外直接释药时,可以建立良好的体内外相关性(51μm：y=14.519x0·4147,R=0.96；20μm：y=-0.0513x2+8.1116x-212,R=0.97)。固定微球的粒径为20μm,研究了PLGA的分子量对微球体内降解行为的影响,结果表明,由高分子量PLGA制备的微球的体内释放明显快于低分子量的PLGA微球,原因有待于进一步阐明。
Polyester polymers have been widely used as drug carriers. Among them, poly(lactide-co-glycolide)(PLGA) has attracted much attention due to its biodegradability and biocompatibility. In addition, the degradation behavior of PLGA could be controlled by adjusting the ratio of LA and GA. In this paper, using resveratrol as a hydrophobic model drug, PLGA microspheres(MS) were prepared using oil-in-water (o/w) emulsification solvent evaporation method. In vitro drug release behavior and release mechanism from PLGA microspheres prepared under different conditions were studied in detail. Influence of particle size and polymer molecular weight on the in vivo release of resveratrol from the microspheres were investigated in mice and in vitro-in vivo correlation was studied.
High-performance liquid chromatography (HPLC) method was used to measure drug content in resveratrol loaded microspheres and the release of drug from the microspheres. Using entrapment efficiency, drug loading and burst release as the criteria, influence of process parameters on the characteristics of the microspheres were investigated. It was found that the DP/CP ratio, PLGA concentration, theoretical drug loading, PVA concentration and homogenization speed had a significant influence on the properties of resveratrol loaded PLGA microspheres.
In vitro release study was performed in 0.5%SDS aqueous solution and stirred at 30 rpm at 37℃. The results show that PLGA concentration, theoretical drug loading, PVA concentration and homogenization speed had a significant influence on the release of resveratrol from PLGA microspheres. The drug release kinetics from the microspheres can be described with Fick diffusion model.
In vivo release of resveratrol from PLGA microspheres was studied by determining the amount of drug remained in the microspheres at the injection site after subcutaneous injection to five mice. It was demonstrated that in vivo release of resveratrol from PLGA microspheres was influenced by particle size of the microspheres and polymer molecular weight. The correlation between in vitro release and in vivo release was studied. An exponential relationship was established (y=14.519x04147 r=0.96) for 5μm microspheres. In contrast, a polynomial relationship between in vitro and in vivo data was established (y=-0.0513x2+8.1116x-212, r=0.97) for 20μm microspheres. The microspheres prepared with high molecular weight PLGA had a higher in vivo release rate compared to the one with the same particle size but low PLGA molecular weight.
本文以白藜芦醇为模型药物,以PLGA为载体,研究制备了注射用生物可降解缓释微球,并对微球的体内外释药行为进行了较深入地探讨,研究了微球的粒径和PLGA分子量对微球体内外释药行为的影响。
本研究采用高效液相色谱法(HPLC)测定微球中药物含量以及药物从微球中的体内外释放量。采用乳化溶剂挥发法制备了白藜芦醇PLGA缓释微球,以微球的包封率、载药量和突释作为质量评价指标,通过单因素考察试验筛选微球的最优处方和制备工艺。单因素考察结果表明,分散相／连续相体积比、PLGA浓度、理论载药量、搅拌速度、PVA浓度等均是影响微球性质的关键因素。
在微球的体外释药研究中,以0.5%十二烷基硫酸钠(SDS)作为释放介质,采用直接释药法对目标粒径为20μm的微球进行体外释药行为的研究。结果表明PLGA浓度、理论载药量、搅拌速度、PVA浓度是影响微球中药物释放的关键因素,药物从载药微球中的释放主要以Fick扩散机制为主。
采用小鼠皮下注射方式给药后定时测定药物在体内残留量的方法,深入研究了微球粒径和聚合物分子量对白藜芦醇微球体内外释药行为的影响,并进行了体内外相关性(IVIVC)评价。结果显示,粒径为5μm和20μm的低分子量载药微球,当以0.5%的十二烷基硫酸钠水溶液作为释放介质进行体外直接释药时,可以建立良好的体内外相关性(51μm：y=14.519x0·4147,R=0.96；20μm：y=-0.0513x2+8.1116x-212,R=0.97)。固定微球的粒径为20μm,研究了PLGA的分子量对微球体内降解行为的影响,结果表明,由高分子量PLGA制备的微球的体内释放明显快于低分子量的PLGA微球,原因有待于进一步阐明。
Polyester polymers have been widely used as drug carriers. Among them, poly(lactide-co-glycolide)(PLGA) has attracted much attention due to its biodegradability and biocompatibility. In addition, the degradation behavior of PLGA could be controlled by adjusting the ratio of LA and GA. In this paper, using resveratrol as a hydrophobic model drug, PLGA microspheres(MS) were prepared using oil-in-water (o/w) emulsification solvent evaporation method. In vitro drug release behavior and release mechanism from PLGA microspheres prepared under different conditions were studied in detail. Influence of particle size and polymer molecular weight on the in vivo release of resveratrol from the microspheres were investigated in mice and in vitro-in vivo correlation was studied.
High-performance liquid chromatography (HPLC) method was used to measure drug content in resveratrol loaded microspheres and the release of drug from the microspheres. Using entrapment efficiency, drug loading and burst release as the criteria, influence of process parameters on the characteristics of the microspheres were investigated. It was found that the DP/CP ratio, PLGA concentration, theoretical drug loading, PVA concentration and homogenization speed had a significant influence on the properties of resveratrol loaded PLGA microspheres.
In vitro release study was performed in 0.5%SDS aqueous solution and stirred at 30 rpm at 37℃. The results show that PLGA concentration, theoretical drug loading, PVA concentration and homogenization speed had a significant influence on the release of resveratrol from PLGA microspheres. The drug release kinetics from the microspheres can be described with Fick diffusion model.
In vivo release of resveratrol from PLGA microspheres was studied by determining the amount of drug remained in the microspheres at the injection site after subcutaneous injection to five mice. It was demonstrated that in vivo release of resveratrol from PLGA microspheres was influenced by particle size of the microspheres and polymer molecular weight. The correlation between in vitro release and in vivo release was studied. An exponential relationship was established (y=14.519x04147 r=0.96) for 5μm microspheres. In contrast, a polynomial relationship between in vitro and in vivo data was established (y=-0.0513x2+8.1116x-212, r=0.97) for 20μm microspheres. The microspheres prepared with high molecular weight PLGA had a higher in vivo release rate compared to the one with the same particle size but low PLGA molecular weight.
引文
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