超临界二氧化碳技术制备纳米药物颗粒的研究

发布时间：2019-01-15 07:23

【摘要】：近年来,由于纳米药物可以有效地提高难溶性药物的溶出度以及降低此类药物对胃肠道的刺激性反应,因而纳米药物微粒在药物传递领域的应用越来越广泛,而药物纳米化技术也日渐受到人们的关注和研究。在众多制备纳米药物颗粒的方法中,超临界二氧化碳技术作为一种新型绿色技术被进一步的应用于水难溶性药物纳米颗粒的制备。与其它传统制备技术相比,由超临界二氧化碳技术制备得到的纳米颗粒具有有机溶剂残留少,颗粒粒径小以及形貌可控性高等优点。本文选择非甾体抗炎类药物塞来昔布和酮洛芬以及人参皂苷Rh2为模型药物,考察了超临界二氧化碳技术各因素对纳米药物颗粒制备工艺的影响。首先,本文采用超临界二氧化碳技术中的气溶胶溶剂萃取系统(Aerosol Solvent Extraction System, ASES),以非甾体抗炎类药物塞来昔布和酮洛芬为模型药物,聚合物材料Eudragit S100为载体材料,进行了纳米药物颗粒制备。该过程以颗粒粒径、形貌和载药量为依据,考察了各种因素的影响规律,得到了较优的工艺条件。本文制备出了平均粒径约40 nm的塞来昔布和50 nm的酮洛芬纳米颗粒。实验结果表明,升高体系的温度和压力,降低混合溶液的流速与浓度均有利于得到粒径尺寸较小、分布较窄的纳米药物颗粒。其中,温度对于颗粒载药量的影响因药物种类不同而有着明显的差异。另外,FT-IR和XRD结果显示,ASES过程没有改变两种药物的化学结构,但是却将药物颗粒的晶型由结晶型转变为非结晶型。最后,比较原料药与制备得到的纳米药物在不同pH介质中的溶出度。结果表明,后者溶出度较原料药有大幅度的提高,并呈现出明显的pH相应。随后,本文进一步采用超临界二氧化碳技术中的气体抗溶剂技术(Gas Antisolvent, GAS)对人参皂苷Rh2进行纳米颗粒的制备。结果表明,随着表面活性剂泊洛沙姆188加入量的增大,纳米颗粒粒径尺寸由85～90nm逐渐降低至15～20 nm,并且颗粒粒径分布越来越均匀。FT-IR, XRD和1H NMR结果显示,GAS过程并没有改变药物的化学结构,但是却发生了晶型的转变,即由结晶型转变为非晶型。溶出度结果表明,其溶出速率较原料药提高了4倍。细胞毒性实验结果表明,人参皂苷Rh2纳米颗粒对Hela细胞有明显的抑制作用且有明显的浓度依赖性。
[Abstract]:In recent years, because nanopharmaceuticals can effectively improve the dissolution of insoluble drugs and reduce the irritation of these drugs to the gastrointestinal tract, nanoparticles have become more and more widely used in the field of drug delivery. And the technology of drug nanocrystalline has been paid more and more attention and research day by day. As a new green technology, supercritical carbon dioxide (SCCO _ 2) has been applied to the preparation of water-insoluble drug nanoparticles. Compared with other traditional preparation techniques, the nanoparticles prepared by supercritical carbon dioxide have the advantages of less organic solvent residue, smaller particle size and higher morphology controllability. In this paper, celecoxib and ketoprofen and ginsenoside Rh2 were selected as model drugs to investigate the effects of supercritical carbon dioxide technology on the preparation of nanoparticles. Firstly, the aerosol solvent extraction system (Aerosol Solvent Extraction System, ASES),) in supercritical carbon dioxide (SCC) was used to model the nonsteroidal anti-inflammatory drugs celecoxib and ketoprofen, and the polymer Eudragit S100 was used as the carrier material. Nanoparticles were prepared. On the basis of particle size, morphology and drug loading, the effect of various factors on the process was investigated, and the optimum technological conditions were obtained. Celecoxib and ketoprofen nanoparticles with an average diameter of 40 nm and 50 nm were prepared. The experimental results show that increasing the temperature and pressure of the system and decreasing the flow rate and concentration of the mixed solution can help to obtain the nanoparticles with smaller particle size and narrower distribution. Among them, the effect of temperature on the amount of drug loaded is obviously different with different kinds of drugs. In addition, the results of FT-IR and XRD showed that the chemical structure of the two drugs was not changed by the ASES process, but the crystalline form of the drug particles was changed from crystallized to amorphous. Finally, the dissolution of the raw drug and the prepared nano-drug in different pH media was compared. The results showed that the dissolution rate of the latter was significantly higher than that of the crude drug, and the dissolution rate of the latter was obviously corresponding to that of pH. After that, ginsenoside Rh2 nanoparticles were prepared by gas antisolvent technique (Gas Antisolvent, GAS) in supercritical carbon dioxide (SCCO) technology. The results show that with the increase of the amount of surfactant Poloxamer 188, the particle size decreases from 85~90nm to 1520 nm, and the particle size distribution becomes more and more uniform. The results of FT-IR, XRD and 1H NMR show that the particle size of the nanoparticles increases with the increase of the amount of Poloxamer 188. The GAS process did not change the chemical structure of the drug, but the crystalline form changed from crystallized to amorphous. The dissolution rate was 4 times higher than that of the crude drug. The results of cytotoxicity test showed that ginsenoside Rh2 nanoparticles had obvious inhibitory effect on Hela cells in a dose-dependent manner.
【学位授予单位】：北京化工大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：TQ460.1;TB383.1

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