超临界抗溶剂技术在药物微粒化领域的研究进展

总结了超临界抗溶剂技术在微粉化药物和制备缓释药物微球方面的研究现状和发展。在药物微粉化方面,着重介绍了超临界辅助原子化法对水溶性药物的处理,包括该方法的原理、操作方法以及操作参数对产品性能的影响,证明该方法用于改善水溶性药物的微粉化具有良好的效果;在制备药物微球方面,重点介绍了不同操作条件和不同分子质量的载体、不同配比的复合载体对药物微球性能的影响以及表面活性剂在亲脂性及离子型药物微球制备中的应用,指出添加表面活性剂将更有利于得到该类药物的微球。     

Micronization of arbutine using supercritical anti-solvent

Arbutine has been used as skin whitening agent in cosmetics and pharmaceuticals. The objective of this study was to precipitate arbutine micro-particles using a supercritical anti-solvent. Ethanol and supercritical CO₂ were used as solvent and anti-solvent, respectively, under various conditions. The effects of pressure, temperature and solution flow rate on the particles were studied. The particle size and morphology were analyzed by field emission scanning electron microscopy.     

超临界抗溶剂制粒装置的现状及其展望

超临界抗溶剂法是一种新型超细微粒制备技术,现已在许多领域得到广泛应用。本文简要陈述了超临界抗溶剂技术的基本原理、装置组成和操作方式,详细阐述了超临界抗溶剂装置喷嘴部件的演进,从该角度介绍了GAS制粒装置、ASES制粒装置、SEDS制粒装置和SAA制粒装置的发展和优化历程,并对超临界抗溶剂制粒装置的多功能化、喷嘴的进一步优化、结晶釜的可视化等提出展望。     

超临界辅助雾化制备适于气溶胶给药的药物微粒

超临界流体辅助雾化法（SAA）是一种新型的以超临界流体为基础的固体微粒制备工艺,既能用于水溶性,也可用于脂溶性的溶质.该工艺能制备出适用于气溶胶给药要求的微粒,预期可在药物行业内得到应用.综述了SAA过程的形成和特色、工艺流程和操作条件以及相应的造粒结果.评述了6种药物微粒的粒度、粒度分布及其形貌.经SAA加工后的药物质量未见变化,目前该工艺已进入中试阶段,展示出较快的发展速度.比较了SAA和现有的主要以超临界流体为基础的微粒制造工艺.展望了加强应用基础研究的必要性,进一步分析了SAA的机理和过程实质.     

超临界流体抗溶剂技术及微粒成形机理的研究进展

超临界抗溶剂技术是一种新型的超细微粒制备技术,在药物、超导、颜料、炸药和聚合物等领域已有广泛的应用。本文主要介绍了超临界抗溶剂过程和该技术在单组分和多组分无机氧化物纳米粒子制备上的应用,并对超临界抗溶剂微粒成形机理的研究现状和微粒的成形机理进行了简要的概括总结。最后对超临界抗溶剂微粒化技术的发展做了进一步展望。     

水力空化混合强化超临界流体辅助雾化制备罗红霉素超细微粒

分析了超临界流体辅助雾化（SAA）过程,发现饱和器内超临界二氧化碳与溶液的混合是SAA成功的关键因素之一,由此引入了水力空化混合器以强化饱和器内两相间的传质。在自行组建的引入水力空化混合器的超临界流体辅助雾化（SAA-HCM）装置上,以罗红霉素为模型药物,考察了混合器压力、沉淀器温度、溶剂、进料中CO₂与液体溶液流量比（R）和溶液浓度对微粒形态和粒径的影响。结果表明,水力空化混合器能有效地强化两相间的传质,SAA-HCM工艺可制备出罗红霉素超细微粒,大部分微粒形态呈球形,通过改变操作参数可制得粒径在1～3 μm的适于吸入式给药的气溶胶药物微粒和粒径小于1 μm的超细微粒。     

Micronization of taxifolin by supercritical antisolvent process and evaluation of radical scavenging activity

The aim of this study was to prepare micronized taxifolin powder using the supercritical antisolvent precipitation process to improve the dissolution rate of taxifolin. Ethanol was used as solvent and carbon dioxide was used as an antisolvent. The effects of process parameters, such as temperature (35-65 °C), pressure (10-25 MPa), solution flow rate (3-6 mL/min) and concentration of the liquid solution (5-20 mg/mL) on the precipitate crystals were investigated. With a lower temperature, a stronger pressure and a lower concentration of the liquid solution, the size of crystals decreased. The precipitation temperature, pressure and concentration of taxifolin solution had a significant effect. However, the solution flow rate had a negligible effect. It was concluded that the physicochemical properties and dissolution rate of crystalline taxifolin could be improved by physical modification such as particle size reduction using the supercritical antisolvent (SAS) process. Further, the SAS process was a powerful methodology for improving the physicochemical properties and radical scavenging activity of taxifolin.     

The numerical simulation of a new double swirl static mixer for gas reactants mixing

For the nitrogen oxide removal processes, high performance gas mixer is deeply needed for the injection of NH₃ or O₃. In this study, a new type of double swirl static mixer in gas mixing was investigated using computational fluid dynamics (CFD). The results obtained using Particle Image Velocimetry (PIV) correlated well with the results obtained from simulation. The comparisons in pressure loss between the experimental results and the simulation results showed that the model was suitable and accurate for the simulation of the static mixer. Optimal process conditions and design were investigated. When L/D equaled 4, coefficient of variation (COV) was < 5%. The inlet velocity did not affect the distributions of turbulent kinetic energy. In terms of both COV and pressure loss, the inner connector is important in the design of the static mixer. The nozzle length should be set at 4 cm. Taking both COV and pressure loss into consideration, the optimal oblique degree is 45°. The averaged kinetic energy changed according to process conditions and design. The new static mixer resulted in improved mixing performance in a more compact design. The new static mixer is more energy efficient compared with other SV static mixers. Therefore, the double swirl static mixer is promising in gas mixing.     

Dissolution rate enhancement of the anti-inflammatory drug diflunisal by coprecipitation with a biocompatible polymer using carbon dioxide as a supercritical fluid antisolvent

Dissolution rate enhancement of the anti-inflammatory drug diflunisal was achieved using for the first time a supercritical fluid technology. The supercritical fluid antisolvent (SAS) method was applied to precipitate diflunisal alone and to coprecipitate the drug together with the biocompatible polymer polyvinylpyrrolidone (PVP K-30 and K-10). The untreated and SAS processed diflunisal, and the coprecipitates were characterized in terms of size, morphology, crystallinity, compositions, drug-polymer interactions, and drug release. SAS processed diflunisal exhibited a polymorphic form different from that of the untreated drug. Diflunisal crystallinity disappeared in the coprecipitates. Three different drug: polymer mass ratios were studied: 75:25, 50:50, and 25:75. Microparticle size decreased and aggregation disappeared as the relative amount of polymer increased. The 25:75 coprecipitate consisted of loose spherical particles exhibiting mean particle size of 410 nm while the 75:25 coprecipitate consisted of bigger aggregated particles. The SAS method was shown to be a suitable technology to form solid dispersions of a poorly soluble drug.     

超临界溶液浸渍法制备缓释药物

超临界溶液浸渍法(supercritical solution impregnation,SSI)是一种将小分子物质负载到聚合物中的过程技术,主要是利用超临界流体的高扩散系数、低黏度及其对聚合物的溶胀作用,使小分子物质通过分子扩散作用迅速进入溶胀的聚合物并包裹于其中。近年来该技术已用于制备缓释药物/聚合物复合微球、薄膜和纤维等。该法的主要优点在于载体结构灵活,拓展了超临界技术在控释药物制备中的应用。本文主要介绍了SSI法的原理、流程及其在缓释药物制备中的应用,并展望了SSI法的发展趋势。     

表面活性剂辅助抗溶剂法制备缬沙坦超微粉体

采用表面活性剂辅助,抗溶剂沉淀法制备了缬沙坦药物微粉,以丙酮为溶剂,水为抗溶剂,考察了表面活性剂种类、浓度、溶剂-抗溶剂体积比对缬沙坦形貌和大小的影响。分别利用扫描电镜（SEM）、X射线衍射（XRD）、红外光谱（ FT-IR）等分析方法对原料及微粉化的产品进行了表征。     

Preparation of liposomes using the supercritical anti-solvent (SAS) process and comparison with a conventional method

Two methods to produce liposomes encapsulating a fluorescent marker were compared: the supercritical anti-solvent (SAS) method and a conventional one (Bangham). Liposome size and encapsulation efficiency were measured to assess the methods. Micronized lecithin produced by the SAS process was characterized in terms of particle size, morphology and residual solvent content in order to investigate the influence of experimental parameters (pressure, CO₂/solvent molar ratio and solute concentration). It appears that when the lecithin concentration increases from 15 to 25 wt.%, at 9 MPa and 308 K, larger (20-60 μm) and less aggregated lecithin particles are formed. As concerns liposomes formed from SAS processed lecithin, size distribution curves are mainly bimodal, spreading in the range of 0.1-100 μm. Liposome encapsulation efficiencies are including between 10 and 20%. As concerns the Bangham method, more dispersed liposomes were formed; encapsulation efficiencies were about 20%, and problems of reproducibility have been raised.     

预成膜雾化超临界流体强制分散溶液过程及应用

设计了预成膜二流式喷嘴用于超临界流体强制分散溶液(SEDS)过程以获得良好的雾化与传质效果。采用预成膜雾化的SEDS(SEDS-PA)过程对胡萝卜素、麻黄素及黄芩甙进行了超细和聚合物包覆实验以考察该法制备药物微粒和载药聚合物微粒的有效性。通过SEM及光学显微镜照片分析微粒形态,用分光光度法检测药物在聚合物微粒中的含量。实验表明,通过SEDS-PA过程可成功地对天然药物超细化,并用聚合物对其包覆,从而制备药物微粒及载药聚合物微粒。     

Effect of operating parameters on PVP/tadalafil solid dispersions prepared using supercritical anti-solvent process

Supercritical anti-solvent (SAS) process was employed to produce tadalafil solid dispersion sub-micron particles. Three independent variables for the SAS process (temperature, pressure, and drug concentration) were varied in order to investigate the effects on particle size and morphology of PVP/tadalafil solid dispersion (drug to polymer ratio 1:4). The mean particle size decreased with decreasing temperature (50 → 40 °C) and concentration (15 → 5 mg/mL) and increasing pressure (90 → 150 bar). Depending on the experimental variable, the mean particle size varied from 200 nm to 900 nm, and the dominant experimental variable was determined to be the drug concentration. Moreover, at a concentration of 15 mg/mL with any other process conditions, tadalafil tended to partially aggregate in crystalline form with irregular particle shapes. The results of in vitro dissolution experiments showed good correlation with mean particle size and crystallinity of the SAS-processed particles, in that the highest drug concentration showed the least dissolution rate and vice versa. Therefore, among the three variables studied, the drug concentration is the major factor that produces sub-micron particles in the SAS process.     

Purification of algal anti-tyrosinase zeaxanthin from Nannochloropsis oculata using supercritical anti-solvent precipitation

This work investigated the changes in content of algal zeaxanthin in submicronized precipitates generated from the supercritical anti-solvent (SAS) process of extracting microalgae Nannochloropsis oculata. Following a reverse phase elution chromatography, the particulates were successfully generated from feed solutions containing zeaxanthin that ranged from 0.4 to 0.8 mg/mL by a SAS process. The precipitation condition was set at 323 K and pressures ranged from 10 to 20 MPa. Experimental results of a three-factor center composite response surface method for the SAS process indicated that the size of the precipitates was significantly affected by the flow rate of carbon dioxide. The purity of zeaxanthin increased with increasing solvent flow rate and with reducing solution concentration. The recovery of zeaxanthin and the morphology of the precipitates was also examined. The content of zeaxanthin in submicronsized precipitates increased from 485.9 (48.6%) to 673.7 mg/g (67.4%). This work demonstrates that elution chromatography coupled with a SAS process is an environmentally benign method to recover anti-tyrosinase zeaxanthin from Nannochloropsis oculata as well as to generate submicrosized precipitates of the purest zeaxanthin from algal solutions.     

Encapsulation of propolis flavonoids in a water soluble polymer using pressurized carbon dioxide anti-solvent crystallization

This study investigated the pressurized carbon dioxide anti-solvent co-precipitation process (abbr. PAS) on encapsulation of propolis with water soluble polyethylene glycol (PEG). The extent to which recovery of propolis flavonoids, total yield, amount of propolis (i.e. drug content) affects the precipitation was examined using a two-factor central composite schemed experimental design method. Analysis results indicated that the drug content and total yield of the precipitates are conversely related to each other in the PAS process. Additionally, micro-sized amorphous particulates of propolis encapsulated on the surface of PEG were generated, as evidenced by chromatography and X-ray diffraction analyses. Total yield of the PAS co-precipitation process reached 88%, and recovery of propolis flavonoids achieved 97%. Experimental results also indicated that the concentration ratio of propolis to PEG in the feed more significantly affects the drug content than that of the pressure factor. Moreover, nearly spherical and aggregated micro-sized co-precipitated particulates are more soluble in an aqueous solution than those of ethanol extracts.     

超临界抗溶剂法制备微粒的机理研究

超临界抗溶剂法是一种新型环保、具有广阔应用前景的微细颗粒制备技术,在材料科学、食品工业及药物微粒制备方面的应用成为研究的热点。随着实验研究中众多问题的出现,其理论研究越来越被重视,并且取得了一定的进展。着重从体系相平衡及溶液和超临界CO2之间的混合行为等方面,综述了近年来国内外对超临界抗溶剂法制备微细颗粒过程的理论研究进展并分析了部分存在问题。     

超临界快速膨胀法制备植物甾醇超细微粒

通过药物颗粒的微细化,降低其粒度,增大比表面积,进而提高药物颗粒的溶解度,可以有效地改善难溶药物的生物利用度。该文采用超临界流体快速膨胀法(RESS)微细化植物甾醇颗粒。利用SEM分析了沉淀颗粒的形貌及粒径大小。分析了过程参数与所制备颗粒粒度的关系。研究发现,当喷嘴内径Dn从60μm减小到40μm,植物甾醇颗粒粒径由10～20μm减小为5μm;预膨胀压力p0从15MPa增加到25MPa时,颗粒粒径由10～15μm降至5μm;预膨胀温度T0由318K升高到333K时,颗粒粒径由5～10μm减小为1μm,粒径分布也趋于均匀。喷嘴温度Tn对粒径无显著影响。该法制备得到1～20μm无定形植物甾醇微细颗粒,且具有更高的溶解速率,比原料植物甾醇早3h达到饱和溶解度。     

用含夹带剂丙酮的超临界CO2快速膨胀法制备灰黄霉素的微细颗粒

Griseofulvin (GF) is an antifungal drug whose pharmaceutical activity can be improved by reducingparticle size. In this study the rapid expansion of supercritical solution (RESS) was employed to micronize GF.Carbon dioxide with cosolvent acetone was chosen as a supercritical mixed solvent. The solubility of GF in super-critical CO2 with cosolvent acetone was measured using a dynamic apparatus at pressures between 12 and 32 MPa,temperatures at 313, 323 and 333K and cosolvent concentration at 1.5, 3.0, 4.5 and 6.0% (by mole). The effect ofpre-expansion pressure, extraction temperature, spraying distance, nozzle size and concentration of cosolvent on theprecipitated particles was investigated. The results show that the mean particle size of griseofulvin precipitated byRESS was less than 1.2 μm. An increase in pre-expansion pressure, extraction temperature, spraying distance andconcentration of cosolvent resulted in a decrease in particle size under the operating condition studied. With thedecrease of nozzle diameter the particle size reduces. The crystallinity and melting point of the original material andthe processed particle by RESS were tested by X-ray diffraction (XRD) and differential scanning calorimetry (DSC).No evident modification in the crystal habit was found under the experimental conditions tested. The morphologyof particles precipitated was analyzed by scanning electron microscopy (SEM).     

超临界发泡法制备高性能热塑性高分子微/纳孔泡沫材料研究进展

国民经济和高科技领域的飞速发展,对高分子泡沫材料的高强度及耐高低温性能、无毒无烟及本征阻燃、易加工成型等方面的要求进一步提高,通用高分子泡沫材料,如聚乙烯（PE）、聚丙烯（PP）、聚苯乙烯（PS）等难以满足使用要求。因此,聚醚酰亚胺（PEI）、聚酰亚胺（PI）、聚醚砜（PES）、聚芳砜（PPSU）、聚苯硫醚（PPS）、聚醚醚酮（PEEK）等高性能热塑性高分子泡沫材料和制品的研究成为新的热点。本文对超临界流体发泡原理和超临界流体发泡技术进行了系统介绍,重点综述了超临界流体（supercritical fluid）,如scCO₂或scN₂作物理发泡剂,结合各种发泡技术,如釜压发泡、注塑发泡、挤出发泡和珠粒发泡,在高性能热塑性高分子发泡领域中的应用及取得的研究成果,以期为高性能高分子材料的研究及应用提供借鉴。最后,对开发操作简单、所得泡沫制品尺寸精确的发泡技术作了展望。