超臨界二氧化碳技術(shù)制備納米藥物顆粒的研究
發(fā)布時間：2019-01-15 07:23
【摘要】：近年來,由于納米藥物可以有效地提高難溶性藥物的溶出度以及降低此類藥物對胃腸道的刺激性反應(yīng),因而納米藥物微粒在藥物傳遞領(lǐng)域的應(yīng)用越來越廣泛,而藥物納米化技術(shù)也日漸受到人們的關(guān)注和研究。在眾多制備納米藥物顆粒的方法中,超臨界二氧化碳技術(shù)作為一種新型綠色技術(shù)被進(jìn)一步的應(yīng)用于水難溶性藥物納米顆粒的制備。與其它傳統(tǒng)制備技術(shù)相比,由超臨界二氧化碳技術(shù)制備得到的納米顆粒具有有機(jī)溶劑殘留少,顆粒粒徑小以及形貌可控性高等優(yōu)點(diǎn)。本文選擇非甾體抗炎類藥物塞來昔布和酮洛芬以及人參皂苷Rh2為模型藥物,考察了超臨界二氧化碳技術(shù)各因素對納米藥物顆粒制備工藝的影響。首先,本文采用超臨界二氧化碳技術(shù)中的氣溶膠溶劑萃取系統(tǒng)(Aerosol Solvent Extraction System, ASES),以非甾體抗炎類藥物塞來昔布和酮洛芬為模型藥物,聚合物材料Eudragit S100為載體材料,進(jìn)行了納米藥物顆粒制備。該過程以顆粒粒徑、形貌和載藥量為依據(jù),考察了各種因素的影響規(guī)律,得到了較優(yōu)的工藝條件。本文制備出了平均粒徑約40 nm的塞來昔布和50 nm的酮洛芬納米顆粒。實(shí)驗(yàn)結(jié)果表明,升高體系的溫度和壓力,降低混合溶液的流速與濃度均有利于得到粒徑尺寸較小、分布較窄的納米藥物顆粒。其中,溫度對于顆粒載藥量的影響因藥物種類不同而有著明顯的差異。另外,FT-IR和XRD結(jié)果顯示,ASES過程沒有改變兩種藥物的化學(xué)結(jié)構(gòu),但是卻將藥物顆粒的晶型由結(jié)晶型轉(zhuǎn)變?yōu)榉墙Y(jié)晶型。最后,比較原料藥與制備得到的納米藥物在不同pH介質(zhì)中的溶出度。結(jié)果表明,后者溶出度較原料藥有大幅度的提高,并呈現(xiàn)出明顯的pH相應(yīng)。隨后,本文進(jìn)一步采用超臨界二氧化碳技術(shù)中的氣體抗溶劑技術(shù)(Gas Antisolvent, GAS)對人參皂苷Rh2進(jìn)行納米顆粒的制備。結(jié)果表明,隨著表面活性劑泊洛沙姆188加入量的增大,納米顆粒粒徑尺寸由85～90nm逐漸降低至15～20 nm,并且顆粒粒徑分布越來越均勻。FT-IR, XRD和1H NMR結(jié)果顯示,GAS過程并沒有改變藥物的化學(xué)結(jié)構(gòu),但是卻發(fā)生了晶型的轉(zhuǎn)變,即由結(jié)晶型轉(zhuǎn)變?yōu)榉蔷�。溶出度結(jié)果表明,其溶出速率較原料藥提高了4倍。細(xì)胞毒性實(shí)驗(yàn)結(jié)果表明,人參皂苷Rh2納米顆粒對Hela細(xì)胞有明顯的抑制作用且有明顯的濃度依賴性。
[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.
【學(xué)位授予單位】：北京化工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：TQ460.1;TB383.1
本文編號：2408979
[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.
【學(xué)位授予單位】：北京化工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：TQ460.1;TB383.1
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，本文編號：2408979
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