超临界CO_2抗溶剂法制备负载营养药物的纳米颗粒
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摘要
药物微粒化不仅可以减少药物的用量,还可以提高药物的生物利用度。超临界CO_2抗溶剂技术用于制备药物超细微粒,可避免传统方法存在的有机溶剂残留量大,产品粒径大,易变性等问题。该技术反应条件温和,尤其适用于热敏性、易降解物质的加工。本文以玉米蛋白作为载体材料,白藜芦醇和β-胡萝卜素为模型药物,采用超临界CO2抗溶剂法制备负载营养药物的玉米蛋白纳米颗粒,并研究其释放度和稳定性。本论文包括了以下两部分的工作:
第一部分:负载白藜芦醇的玉米蛋白纳米粒的制备、表征及释放度研究。采用超临界CO2抗溶剂法制备了负载白藜芦醇的玉米蛋白纳米粒,用紫外测试考察了过程参数压力、温度以及芯材比对白藜芦醇在纳米粒中负载量的影响。用扫描电镜、X射线衍射等手段对制备的纳米粒进行表征,并且对释放度也进行了研究。结果表明,随着压力从8MPa升高到16MPa,白藜芦醇的负载量从8.16%减小到5.7%;随着温度从35℃升高到55℃,白藜芦醇的负载量从7.23%增加到8.38%;芯材比由1:30提高到1:2,白藜芦醇的负载量从2.16%升高到17.9%。制备的纳米粒为均匀的球形颗粒,玉米蛋白对白藜芦醇有较好的包合。释放度实验结果表明,纳米粒中白藜芦醇的释放速度比原料的释放速度慢,有缓释作用。第二部分:负载β-胡萝卜素的玉米蛋白纳米粒的制备、表征及抗光解稳定性研究。利用响应面设计对制备工艺进行优化,分别以β-胡萝卜素的负载量和包埋率的最大值为优化指标,系统考察了芯材比、温度、压力等主要因素对玉米蛋白包埋β-胡萝卜素的交互影响。采用扫描电镜,纳米粒度分析和X射线衍射等分析方法,对产品形貌,粒径和结构等进行了表征,并考察了其抗光解稳定性。结果表明:芯材比对载药量和包埋率的影响最显著,其次是压力,最后是温度。当芯材比为1:10,温度55℃,压力8MPa时,β-胡萝卜素的负载量达到最大值8.73%;当芯材比为1:30,温度35℃,压力16MPa时,β-胡萝卜素的包埋率有最高值85.4%。玉米蛋白和β-胡萝卜素形成Matrix结构,颗粒平均粒径100~200nm,粒径分布窄,球形度好。抗光解实验表明位于纳米粒子内部的β-胡萝卜素受到了保护,包埋可以提高其抗光解性。
通过本文的研究,掌握了超临界CO_2抗溶剂法制备负载营养药物的纳米颗粒的规律,过程参数温度、压力、芯材比对药物负载量和包埋率的影响,及药物缓释和抗光解情况,提供了以天然高分子材料为载体制备纳米粒子运载系统的新资料。
Drug micronization ont only reduces the amount of administration, but also improves the bioavailability of actives. Comparing the products that prepared by traditional methods, drug micronized by supercritical CO_2 antisolvent (SAS) has some advantages such as small particle size, homogenous distribution, and low toxic solvent. The technology with wild reaction conditions is conducive to process heat-sensitive materials. In this study, using zein as carrier, resveratrol andβ-carotene as model drug, drug-loaded zein nanoparticles are prepared by SAS.
The first part is the study of resvertrol-loaded zein nanoparticles. SAS was tested to prepare zein nanoparticles loaded with resveratrol. The effects of different operating parameters, such as pressure, temperature, and ratio on the loading weight of resveratrol were investigated. SEM and XRD were used to characterize the product, furthermore, in vitro drug release studies were also carried out. Results show that the yield of resveratrol decreases from 8.16% to 5.7% with the pressure from 8MPa up to 16MPa. When temperature rise from 35℃up to 55℃, the amount of drug loaded in zein nanoparticles increases from 7.23% to 8.38%. We also conclude that the yield of resveratrol increases from 2.16% to 17.9% at ratio from 1:30 up to 1:2. The nanoparticles with good sphericity and narrow size distribution can be prepared. The result of in vitro drug release studies proves that products exhibit a slower release than the single resveratrol.
The second part is the study ofβ-carotene-loaded zein nanoparticles. Response surface methodology was used to optimize the preparation ofβ-carotene-loaded zein nanospheres with SAS. The mutual effect of the ratio betweenβ-carotene and zein, temperature, pressure was investigated. The morphology and size of particles were characterized. The stability ofβ-carotene loaded in nanoparticles was studied as well. Results show that the ratio has the most significant influence on the loading and encapsulation efficiency, followed by pressure and, finally, the temperature. Theβ-carotene loading reaches the maximum of 8.73%, when the ratio is 1:10, the temperature is 55℃,the pressure is 8MPa.Theβ-carotene loading achieves the maximum of 85. 4% , when the ratio is 1:30, temperature is 35℃,pressure is 16MPa. The structure ofβ-carotene-loaded zein particles is a Matrix with the sphere shape. The products have narrow size distribution from 100nm to 200nm. Anti-photolysis experiment shows that theβ-carotene encapsulated in nanoparticles is protected so that the stability is increased under exposuring to ultraviolet light.
In summary, the rule of preparing nutriment-loaded nanoparticles by SAS has been mastered in this study. The effects of different operating parameters, such as pressure, temperature, and ratio on drug loading have been grasped. New information of using natural polymer as carrier to prepare nanoparticle delivery system has been provided.
第一部分:负载白藜芦醇的玉米蛋白纳米粒的制备、表征及释放度研究。采用超临界CO2抗溶剂法制备了负载白藜芦醇的玉米蛋白纳米粒,用紫外测试考察了过程参数压力、温度以及芯材比对白藜芦醇在纳米粒中负载量的影响。用扫描电镜、X射线衍射等手段对制备的纳米粒进行表征,并且对释放度也进行了研究。结果表明,随着压力从8MPa升高到16MPa,白藜芦醇的负载量从8.16%减小到5.7%;随着温度从35℃升高到55℃,白藜芦醇的负载量从7.23%增加到8.38%;芯材比由1:30提高到1:2,白藜芦醇的负载量从2.16%升高到17.9%。制备的纳米粒为均匀的球形颗粒,玉米蛋白对白藜芦醇有较好的包合。释放度实验结果表明,纳米粒中白藜芦醇的释放速度比原料的释放速度慢,有缓释作用。第二部分:负载β-胡萝卜素的玉米蛋白纳米粒的制备、表征及抗光解稳定性研究。利用响应面设计对制备工艺进行优化,分别以β-胡萝卜素的负载量和包埋率的最大值为优化指标,系统考察了芯材比、温度、压力等主要因素对玉米蛋白包埋β-胡萝卜素的交互影响。采用扫描电镜,纳米粒度分析和X射线衍射等分析方法,对产品形貌,粒径和结构等进行了表征,并考察了其抗光解稳定性。结果表明:芯材比对载药量和包埋率的影响最显著,其次是压力,最后是温度。当芯材比为1:10,温度55℃,压力8MPa时,β-胡萝卜素的负载量达到最大值8.73%;当芯材比为1:30,温度35℃,压力16MPa时,β-胡萝卜素的包埋率有最高值85.4%。玉米蛋白和β-胡萝卜素形成Matrix结构,颗粒平均粒径100~200nm,粒径分布窄,球形度好。抗光解实验表明位于纳米粒子内部的β-胡萝卜素受到了保护,包埋可以提高其抗光解性。
通过本文的研究,掌握了超临界CO_2抗溶剂法制备负载营养药物的纳米颗粒的规律,过程参数温度、压力、芯材比对药物负载量和包埋率的影响,及药物缓释和抗光解情况,提供了以天然高分子材料为载体制备纳米粒子运载系统的新资料。
Drug micronization ont only reduces the amount of administration, but also improves the bioavailability of actives. Comparing the products that prepared by traditional methods, drug micronized by supercritical CO_2 antisolvent (SAS) has some advantages such as small particle size, homogenous distribution, and low toxic solvent. The technology with wild reaction conditions is conducive to process heat-sensitive materials. In this study, using zein as carrier, resveratrol andβ-carotene as model drug, drug-loaded zein nanoparticles are prepared by SAS.
The first part is the study of resvertrol-loaded zein nanoparticles. SAS was tested to prepare zein nanoparticles loaded with resveratrol. The effects of different operating parameters, such as pressure, temperature, and ratio on the loading weight of resveratrol were investigated. SEM and XRD were used to characterize the product, furthermore, in vitro drug release studies were also carried out. Results show that the yield of resveratrol decreases from 8.16% to 5.7% with the pressure from 8MPa up to 16MPa. When temperature rise from 35℃up to 55℃, the amount of drug loaded in zein nanoparticles increases from 7.23% to 8.38%. We also conclude that the yield of resveratrol increases from 2.16% to 17.9% at ratio from 1:30 up to 1:2. The nanoparticles with good sphericity and narrow size distribution can be prepared. The result of in vitro drug release studies proves that products exhibit a slower release than the single resveratrol.
The second part is the study ofβ-carotene-loaded zein nanoparticles. Response surface methodology was used to optimize the preparation ofβ-carotene-loaded zein nanospheres with SAS. The mutual effect of the ratio betweenβ-carotene and zein, temperature, pressure was investigated. The morphology and size of particles were characterized. The stability ofβ-carotene loaded in nanoparticles was studied as well. Results show that the ratio has the most significant influence on the loading and encapsulation efficiency, followed by pressure and, finally, the temperature. Theβ-carotene loading reaches the maximum of 8.73%, when the ratio is 1:10, the temperature is 55℃,the pressure is 8MPa.Theβ-carotene loading achieves the maximum of 85. 4% , when the ratio is 1:30, temperature is 35℃,pressure is 16MPa. The structure ofβ-carotene-loaded zein particles is a Matrix with the sphere shape. The products have narrow size distribution from 100nm to 200nm. Anti-photolysis experiment shows that theβ-carotene encapsulated in nanoparticles is protected so that the stability is increased under exposuring to ultraviolet light.
In summary, the rule of preparing nutriment-loaded nanoparticles by SAS has been mastered in this study. The effects of different operating parameters, such as pressure, temperature, and ratio on drug loading have been grasped. New information of using natural polymer as carrier to prepare nanoparticle delivery system has been provided.
引文
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