超临界辅助雾化技术制备脂质纳米给药系统的研究
|
摘要
固体脂质纳米粒(Solid Lipid Nanoparticles, SLN)是20世纪90年代发展起来的微粒给药系统,超临界流体辅助雾化法(Supercritical assisted atomization, SAA)是最近10年左右兴起的一种超临界微粒制备技术,本文将新兴的超临界辅助雾化技术应用于以脂质材料为载体的载药固体脂质纳米粒的制备,可提高SLN的制备效率、减少有机溶剂的残留,获得载药量高、粒径大小可控的载药SLN,有望成为脂质纳米粒制备工艺研究的新方向。
根据超临界辅助雾化法(SAA)原理,我们设计制备了自制超临界辅助雾化制粒设备,选择乙醇为辅助溶剂,硬脂酸为载体材料,制备固体硬脂酸脂质纳米粒,考察脂质浓度、超临界流体CO2与载体溶液流量比、喷嘴孔径等工艺因素对SLN粒径的影响,筛选合适的处方工艺参数。结果显示,气液混合室中负载的脂质浓度越高,制备所得的粒径越大,当载体浓度在1%w/v以下时所得的粒径小于1μm,载体浓度在0.5%w/v以下时可制备得到500 nm以下的纳米粒。气液混合室中泵入超临界流体CO2的速率较快时(超临界CO2与载体溶液流量比加大),制得SLN的粒径较小；当泵入速率为10 mL/min以上时,制得微粒粒径小于1μm；当泵入速率提高至30 mL/min以上时(超临界CO2与载体溶液流量比为3：1以上),可制得平均粒径500 nm以下的固体脂质纳米粒。雾化膨胀的喷嘴孔径与所得的脂质微粒粒径呈正性相关,即喷嘴孔径越大,所得粒径越大并且大小分布不均一,反之相反；当喷嘴孔径为0.2mm或更小时,制得的纳米粒粒径小于400nm。以单硬脂酸甘油酯替换硬脂酸作为脂质载体材料时,制得SLN的理化性质相近,显示此SAA制粒系统也适用于单苷酯纳米粒的制备。
在前述筛选优化的超临界技术工艺条件(脂质浓度0.5% w/v、CO2泵入速率30 mL/min、喷嘴孔径0.2 mm)的基础上,以大分子亲水药物胰岛素为模型药物,采用自制的超临界流体辅助雾化制粒设备,制备胰岛素脂质纳米粒。试验分别以硬脂酸和单硬脂酸甘油酯为载体材料,辅助以亲水性成分进行修饰,考察不同处方所制的SLN的粒径、电位、包封率、载药率等理化性质,并考察了样品的体外释放行为。结果显示,不同处方胰岛素SLN的平均粒径从180nm～300nm不等,包封率约为65%～80%,载药量约为2.8%～3.8%,经泊洛沙姆或PEG修饰的处方粒径更细小均一但药物包封率相对降低；原子力显微镜照片显示胰岛素SLN表面呈球形,外观较平整。体外释放研究结果表明,硬脂酸或单硬脂酸甘油酯为载体材料的SLN均在体外呈现约12小时缓慢释放药物的特性,同时未经修饰的处方释放较缓慢但容易释药不完全,经亲水性表面活性剂泊洛沙姆修饰后,纳米粒累积释药程度提高但伴随着较高的突释现象；在单硬脂酸甘油酯为载体的处方中以无表面活性的PEG 2000替代泊洛沙姆时,胰岛素SLN在获得较高释药率的同时突释率较低。综合胰岛素SLN的粒径、电位、包封率、载药量、体外释放特性以及预期的体内生理腔道吸收水平,以PEG修饰的单硬脂酸甘油酯为载体材料的胰岛素SLN是优选的处方：
本研究进一步以链脲霉素、四氧嘧啶建立了糖尿病模型大鼠和糖尿病模型犬,考察了以SAA法优选处方制备的胰岛素-SLN的动物体内降血糖药效。实验以不给药为空白对照、皮下注射胰岛素为阳性对照,分别以20 IU/kg、15 IU/kg高低两种剂量口服给予大鼠或犬胰岛素脂质纳米粒,通过葡萄糖酶标试剂盒测定给药后24小时内的体内血糖经时变化情况。结果显示,胰岛素脂质纳米粒经大鼠口服后,在0.5h即可产生降血糖作用,并于8h后达到降血糖作用峰值,最大血糖下降幅度可达80%。根据AAC (0-24h)法计算大鼠不同剂量口服胰岛素脂质纳米粒的相对生物利用度分别为36.4%和33.3%。胰岛素脂质纳米粒给予糖尿病模型犬后同样有显著的降血糖作用,较好的控制了模型动物的血糖水平。按照血糖水平-时间曲线的曲线上面积AAC法评价的两种剂量(9IU、30 IU)的相对生物利用度分别为27.0%和21.9%。受限于吸收速率和程度的影响,口服纳米粒的起效时间和强度均不如注射给药方式,但前者的降血糖持续作用时间较皮下注射持久(前者药效持续达8小时以上),这可以归因于脂质纳米粒在体内缓慢释放胰岛素作用产生的治疗效果,体现预期的口服缓释制剂特征药动学,具备相当的临床开发应用价值。
Solid Lipid Nanoparticles(SLN) is one of micronized drug carriers, which developed since 1990s, and Supercritical assisted atomization(SAA) is a novel supercritical technology for microparticles preparation appeared within recent 10 years. In this study, SAA technology was applied to prepare the SLN encapsulating drug. SAA was found to improve the productivity, reduce solvent residue, and to gain high drug-loading, size-controllable SLN, and seems to be a promising method for lipid nanoparticles preparation.
A novel SAA particle-producing equipment was designed based on SAA principle. Using ethanol as an assisted solvent, stearic acid SLN was prepared by this equipment. The effect of lipid concentration, flow ratio of supercritical CO2 and lipid solution and pore size of nozzle, on the particle size of resulted SLN were investigated to explore the appropriate process conditions. The results showed that SLNs with bigger size were obtained when lipid concentration in saturator was higher. When lipid concentration was 1.0% w/v or lower, particle size was smaller than 1μm. When the lipid concentration was lower than 0.5% w/v, diameter of SLN was below 500 nm. Flow ratio of SCF CO2 to lipid solution was negatively correlated with particle size, SLN with below 1μm size was obtained when the flow ratio was 1:1. SLN with below 500 nm size was obtained when flow ratio was more than 3:1. However the particle size was positively correlated with pore size of nozzle. When nozzle size is 0.2 mm or lower, the size of SLN was lower than 400 nm, the size distribution was narrow. The mnostearin SLN prepared by SAA equipment had similar physio-chemical properties with stearic acid SLN.
Based above optimal process conditions, insulin, a hydrophilic macromolecule drug, was used as model drug to produce SLN loading insulin (INS-SLN). During SLNs preparation, both stearic acid, monostearin, were choosed as matirx, with or without modified by hydrophilic polymers such as poloxamer and PEG 2000. Physico-chemical properties, such as particle size, zeta-potential, drug entrapment efficiency (EE), loading ratio (DL) and in vitro release profile of SLN were investigated. Mean particle size, EE and DL of INS-SLN was variable from 180 nm to 300 nm, EE from 65% to 80%, and DL 2.8% to 3.8% depending on the fomula, respectively. AFM image showed the INS-SLN was spherical with smooth surface. Unmodified formulation by hydrophilic polymers of SLN was found to be larger size and slower drug releasing profile, and nearly 15% of encapsulated INS couldn't be release within 12 hrs in vitro. Poloxamer used as hydrophilic polymers was introduced to modify the lipid carriers. The modified INS-SLN was smaller (180 nm) and uniform size, but the EE was reduced, and burst release was increased significantly. When poloxamer was replaced by PEG 2000 in monostearin formulation, the particle size and releasing behavior were kept, meanwhile the EE and burst release were improved. Thus the PEG modified formulation was preferred formulation for further in vivo study.
Diabetic rats and dogs were established through administration of streptozocin amd/or alloxan, to evaluate the in vivo efficacy of INS-SLN. S.c. injection of INS solution was used as positive control. After oral administration of INS-SLN for 0.5 hr, the blood glucose of rats was decreased, and the maximum hypoglycemic effect of 80% was reached in 8 hr. Relative bioavailability (F) of oral INS-SLN calculated by AAC(0-24h) were 36.4% and 33.3% for dosage of 15 IU/kg and 20 IU/kg. Similar results were observed in diabetic dogs'model, blood glucose was inhibited since 0.5h after administration and maintained for 8 hr or more. Relative bioavailability (F) based on AAC(0-24h) were 27.0% and 21.9% for dosage of 9 IU and 30 IU. Due to the absorption of SLN, the onset time and strength of oral INS-SLN were inferior to s.c. INS injection. However, INS-SLN showed Longer-time hypoglycemic effect (more than 8 hr), which should attribute to extended INS release of SLN. The results indicated clinical development possibility of INS-SLN.
根据超临界辅助雾化法(SAA)原理,我们设计制备了自制超临界辅助雾化制粒设备,选择乙醇为辅助溶剂,硬脂酸为载体材料,制备固体硬脂酸脂质纳米粒,考察脂质浓度、超临界流体CO2与载体溶液流量比、喷嘴孔径等工艺因素对SLN粒径的影响,筛选合适的处方工艺参数。结果显示,气液混合室中负载的脂质浓度越高,制备所得的粒径越大,当载体浓度在1%w/v以下时所得的粒径小于1μm,载体浓度在0.5%w/v以下时可制备得到500 nm以下的纳米粒。气液混合室中泵入超临界流体CO2的速率较快时(超临界CO2与载体溶液流量比加大),制得SLN的粒径较小；当泵入速率为10 mL/min以上时,制得微粒粒径小于1μm；当泵入速率提高至30 mL/min以上时(超临界CO2与载体溶液流量比为3：1以上),可制得平均粒径500 nm以下的固体脂质纳米粒。雾化膨胀的喷嘴孔径与所得的脂质微粒粒径呈正性相关,即喷嘴孔径越大,所得粒径越大并且大小分布不均一,反之相反；当喷嘴孔径为0.2mm或更小时,制得的纳米粒粒径小于400nm。以单硬脂酸甘油酯替换硬脂酸作为脂质载体材料时,制得SLN的理化性质相近,显示此SAA制粒系统也适用于单苷酯纳米粒的制备。
在前述筛选优化的超临界技术工艺条件(脂质浓度0.5% w/v、CO2泵入速率30 mL/min、喷嘴孔径0.2 mm)的基础上,以大分子亲水药物胰岛素为模型药物,采用自制的超临界流体辅助雾化制粒设备,制备胰岛素脂质纳米粒。试验分别以硬脂酸和单硬脂酸甘油酯为载体材料,辅助以亲水性成分进行修饰,考察不同处方所制的SLN的粒径、电位、包封率、载药率等理化性质,并考察了样品的体外释放行为。结果显示,不同处方胰岛素SLN的平均粒径从180nm～300nm不等,包封率约为65%～80%,载药量约为2.8%～3.8%,经泊洛沙姆或PEG修饰的处方粒径更细小均一但药物包封率相对降低；原子力显微镜照片显示胰岛素SLN表面呈球形,外观较平整。体外释放研究结果表明,硬脂酸或单硬脂酸甘油酯为载体材料的SLN均在体外呈现约12小时缓慢释放药物的特性,同时未经修饰的处方释放较缓慢但容易释药不完全,经亲水性表面活性剂泊洛沙姆修饰后,纳米粒累积释药程度提高但伴随着较高的突释现象；在单硬脂酸甘油酯为载体的处方中以无表面活性的PEG 2000替代泊洛沙姆时,胰岛素SLN在获得较高释药率的同时突释率较低。综合胰岛素SLN的粒径、电位、包封率、载药量、体外释放特性以及预期的体内生理腔道吸收水平,以PEG修饰的单硬脂酸甘油酯为载体材料的胰岛素SLN是优选的处方：
本研究进一步以链脲霉素、四氧嘧啶建立了糖尿病模型大鼠和糖尿病模型犬,考察了以SAA法优选处方制备的胰岛素-SLN的动物体内降血糖药效。实验以不给药为空白对照、皮下注射胰岛素为阳性对照,分别以20 IU/kg、15 IU/kg高低两种剂量口服给予大鼠或犬胰岛素脂质纳米粒,通过葡萄糖酶标试剂盒测定给药后24小时内的体内血糖经时变化情况。结果显示,胰岛素脂质纳米粒经大鼠口服后,在0.5h即可产生降血糖作用,并于8h后达到降血糖作用峰值,最大血糖下降幅度可达80%。根据AAC (0-24h)法计算大鼠不同剂量口服胰岛素脂质纳米粒的相对生物利用度分别为36.4%和33.3%。胰岛素脂质纳米粒给予糖尿病模型犬后同样有显著的降血糖作用,较好的控制了模型动物的血糖水平。按照血糖水平-时间曲线的曲线上面积AAC法评价的两种剂量(9IU、30 IU)的相对生物利用度分别为27.0%和21.9%。受限于吸收速率和程度的影响,口服纳米粒的起效时间和强度均不如注射给药方式,但前者的降血糖持续作用时间较皮下注射持久(前者药效持续达8小时以上),这可以归因于脂质纳米粒在体内缓慢释放胰岛素作用产生的治疗效果,体现预期的口服缓释制剂特征药动学,具备相当的临床开发应用价值。
Solid Lipid Nanoparticles(SLN) is one of micronized drug carriers, which developed since 1990s, and Supercritical assisted atomization(SAA) is a novel supercritical technology for microparticles preparation appeared within recent 10 years. In this study, SAA technology was applied to prepare the SLN encapsulating drug. SAA was found to improve the productivity, reduce solvent residue, and to gain high drug-loading, size-controllable SLN, and seems to be a promising method for lipid nanoparticles preparation.
A novel SAA particle-producing equipment was designed based on SAA principle. Using ethanol as an assisted solvent, stearic acid SLN was prepared by this equipment. The effect of lipid concentration, flow ratio of supercritical CO2 and lipid solution and pore size of nozzle, on the particle size of resulted SLN were investigated to explore the appropriate process conditions. The results showed that SLNs with bigger size were obtained when lipid concentration in saturator was higher. When lipid concentration was 1.0% w/v or lower, particle size was smaller than 1μm. When the lipid concentration was lower than 0.5% w/v, diameter of SLN was below 500 nm. Flow ratio of SCF CO2 to lipid solution was negatively correlated with particle size, SLN with below 1μm size was obtained when the flow ratio was 1:1. SLN with below 500 nm size was obtained when flow ratio was more than 3:1. However the particle size was positively correlated with pore size of nozzle. When nozzle size is 0.2 mm or lower, the size of SLN was lower than 400 nm, the size distribution was narrow. The mnostearin SLN prepared by SAA equipment had similar physio-chemical properties with stearic acid SLN.
Based above optimal process conditions, insulin, a hydrophilic macromolecule drug, was used as model drug to produce SLN loading insulin (INS-SLN). During SLNs preparation, both stearic acid, monostearin, were choosed as matirx, with or without modified by hydrophilic polymers such as poloxamer and PEG 2000. Physico-chemical properties, such as particle size, zeta-potential, drug entrapment efficiency (EE), loading ratio (DL) and in vitro release profile of SLN were investigated. Mean particle size, EE and DL of INS-SLN was variable from 180 nm to 300 nm, EE from 65% to 80%, and DL 2.8% to 3.8% depending on the fomula, respectively. AFM image showed the INS-SLN was spherical with smooth surface. Unmodified formulation by hydrophilic polymers of SLN was found to be larger size and slower drug releasing profile, and nearly 15% of encapsulated INS couldn't be release within 12 hrs in vitro. Poloxamer used as hydrophilic polymers was introduced to modify the lipid carriers. The modified INS-SLN was smaller (180 nm) and uniform size, but the EE was reduced, and burst release was increased significantly. When poloxamer was replaced by PEG 2000 in monostearin formulation, the particle size and releasing behavior were kept, meanwhile the EE and burst release were improved. Thus the PEG modified formulation was preferred formulation for further in vivo study.
Diabetic rats and dogs were established through administration of streptozocin amd/or alloxan, to evaluate the in vivo efficacy of INS-SLN. S.c. injection of INS solution was used as positive control. After oral administration of INS-SLN for 0.5 hr, the blood glucose of rats was decreased, and the maximum hypoglycemic effect of 80% was reached in 8 hr. Relative bioavailability (F) of oral INS-SLN calculated by AAC(0-24h) were 36.4% and 33.3% for dosage of 15 IU/kg and 20 IU/kg. Similar results were observed in diabetic dogs'model, blood glucose was inhibited since 0.5h after administration and maintained for 8 hr or more. Relative bioavailability (F) based on AAC(0-24h) were 27.0% and 21.9% for dosage of 9 IU and 30 IU. Due to the absorption of SLN, the onset time and strength of oral INS-SLN were inferior to s.c. INS injection. However, INS-SLN showed Longer-time hypoglycemic effect (more than 8 hr), which should attribute to extended INS release of SLN. The results indicated clinical development possibility of INS-SLN.
引文
[1]Puri A, Loomis K, Smith B, et al. Lipid-Based Nanoparticles as Pharmaceutical Drug Carriers:From Concepts to Clinic. Crit Rev Ther Drug Carrier Syst.2009; 26(6):523-580.
[2]Muller R H, Mader K, Gohla S. Solid lipid nanoparticles(SLN) for controlled drug delivery-a review of the state of art[J]. Eur J Pharm Biopharm,2000,50(1): 161-177.
[3]Florence A T, Hillery A M, Hussain N, et al. Nanoparticles as carriers for oral peptide absorption:Studies on particle uptake and fate[J]. Control Rel, 1995,36(1-2):39
[4]Antonio J. Almeida, Eliana Souto. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Advanced Drug Delivery Reviews.2007,59: 478-490
[5]Luo Y F, Chen D W, Ren L X et al. Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability[J]. Control Rel.,2006,114:53-59
[6]Florence A T. Nanoparticle uptake by the oral route:fulfilling is potential?[J]. Drug Discovery Today:Technologies,2005,1(2):75
[7]Garcia-Fuentes M, Prego C, Torres D, et al. A comparative study of the potential of solid triglyceride nanostructures coated with chitosan or poly(ethyleneglycol) as carriers for oral calcitonin delivery, Eur. J. Pharm.Sci.25 (2005) 133-143.
[8]Zhang N, Ping Q., Huang G., et al. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin, Int. J. Pharm.327 (2006) 153-159.
[9]程耀,平其能.超临界流体沉析技术及其在药剂学中的应用[J].药学进展,2004,28(2)：63-67.
[10]张诚贤.徐陆忠,吴素香.超临界流体辅助雾化制备药物微粒的研究进展[J].中国医药工业杂志,2009,40(11)：856-861.
[11]蔡美强,关怡新,姚善泾等.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[J].化工学报,2008,59(2)：293-300.
[12]REVERCHON E, DELL A P G. Micronization of antibiotics by supercritical assisted atomization [J]. J Supercrit Fluid,2003,26(3):243-252.
[13]REVERCHON E, ADAMIA R, CAPUTO G. Supercritical assisted atomization:Performance comparison between laboratory and pilot scale [J]. J Supercrit Fluid,2006,37 (3):298-306
[14]郭红星,陈庆华,陈岚等.超临界流体技术在药学领域制备微粒中的应用[J].中国医药工业杂志,2008,39(2)：136-141
[15]Irene Pasqualia, Ruggero Bettinia, Ferdinando Giordano. Supercritical fluid technologies- An innovative approach for manipulating the solid-state of pharmaceuticals[J]. Advanced Drug Delivery Reviews,2008,60:399-410
[16]Reverchon E, Antonacci A. Polymer microparticles production by supercritical assisted atomization[J], J Supercrit Fluid,2007,39(3):444-452
[17]Rodrigues M A, Li J, Padrela L, Almeida A, et al. Anti-solvent effect in the production of lysozyme nanoparticles by supercritical fluid-assisted atomization processes[J]. J Supercrit Fluid,2009,48(3):253-260.
[18]张继明,胡富强,应晓英等.胰岛素固体脂质纳米粒的制备及其理化性质研究[J].中国药学杂志,2004,39(08)：349-352.
[19]袁弘.固体脂质纳米粒口服药物载体经胃肠道转运的研究[博士学位论文].浙江大学,2008年
[20]刘晟,王维,罗贤明等.药物诱导狗Ⅰ型糖尿病的研究[J].湖南医科大学学报.2000年,25(2)：125-129
[21]周娟,陈滋青,胡军.葡萄糖测定方法的比较研究[J].工业微生物,1999年,29(4)：34-36
[22]朱自强,关怡新,姚善泾.超临界辅助雾化制备适于气溶胶给药的药物微粒[J].化工学报,2005,56(2)：187-196
[1]程耀,平其能.超临界流体沉析技术及其在药剂学中的应用[J].药学进展,2004,28(2)：63-67.
[2]郭红星,陈庆华,陈岚等.超临界流体技术在药学领域制备微粒中的应用,中国医药工业杂志,2008,39(2)：136-141
[3]张诚贤,徐陆忠,吴素香.超临界流体辅助雾化制备药物微粒的研究进展Progress on preparation of drug loading microparticles by supercritical assisted atomization [J].中国医药工业杂志,2009,40(11)：856-861.
[4]付强,孙进,何仲贵.超临界流体制备纳米药物的研究进展.沈阳药科大学学报.2010,27(4)：329-334
[5]Rantakyla M. Particle Production by Supercritical Antisolvent Processing Techniques[C]. Helsinki University of Technology. Plant Design Report Series No 76,2004年, ISBN 951-22-7400-0, ISSN 0358-0776
[6]Bala S, Roger A R, Kirk S. Pharmaceutical processing with supercritical carbon dioxide[J]. J Pharm Sci,1997,86 (8):8852889
[7]Michel PERRUT. Pharmaceutical applications of Supercritical Fluids[C].8th Meeting on Supercritical Fluids (Bordeaux-2002)
[8]Irene Pasqualia, Ruggero Bettinia, Ferdinando Giordano. Supercritical fluid technologies- An innovative approach for manipulating the solid-state of pharmaceuticals[J]. Advanced Drug Delivery Reviews 60 (2008) 399-410
[9]Strumendo M, Bertucco A, Elvassore N. Modeling of particle formation processes using gas saturated solution atomization [J]. J Supercrit Fluids,2007, 41(1):115-125.
[10]Li J, Matos HA, Gomes de Azevedo E. Two-phase homogeneous model for particle formation from gassaturated solution processes [J]. J Supercrit Fluids, 32(1-3):275-286.
[11]Reverchon E. Supereritical-assisted atomization to produce micro- and/or nanoparticles of controlled size and distribution [J]. Ind Eng Chem Res,2002, 41(10):2405-2411.
[12]Yeo SD, Kim MS, Lee JC. Recrystallization of sulfathiazole and chlorpropamide using the supercritical fl uid anti solvent process [J]. J Supercrit Fluids,2003,25(2):143-154.
[13]朱自强,关怡新,姚善泾.超临界辅助雾化制备适于气溶胶给药的药物微粒Micronization of drugs suitable for aerosol delivery by supercritical fluid assisted atomization[J]. 化工学报,2005,56(2):187-196.
[14]蔡美强,关怡新,姚善泾,朱自强.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[J].化工学报,2008,59(2)：293-300.
[15]REVERCHON E, DELLA P G. Micronization of antibiotics by supercritical assisted atomization [J]. J Supercrit Fluid,2003,26(3):243-252.
[16]REVERCHON E, AD AMI A R, CAPUTO G. Supercritical assisted atomization:Performance comparison between laboratory and pilot scale[J]. J Supererit Fluid,2006,37 (3):298-306
[17]Della Porta G, De Vittori C, Reverchon E. Supercritical assisted atomization: a novel technology for microparticles preparation of an asthma-controlling drug. AAPS PharmSciTech.2005 Oct 22;6(3):E421-8
[18]Bleich J, Miiller BW, Waβmus W. Aerosol solvent extraction system— a new microparticle production technique[J]. Int J Pharm,1993,97(1-3):111-117.
[19]Palakodaty S, York P. Phase behavioral effects on particle formation processes using supercritical fluids[J]. Pharm Res,1999,16(7):976-985.
[20]He WZ, Suo QL, Jiang ZH, et al. Precipitation of ephedrine by SEDS process using a specially designed prefilming atomizer[J]. J Supercrit Fluids,2004,31(1): 101-110.
[21]Sievers RE, Milewski PD, Sellers SP, et al. Supercritical and near-critical carbon dioxide assisted low-temperature bubble drying[J]. Ind Eng Chem Res, 2000,39(12):4831-4836.
[22]关怡新,余金鹏,姚善泾等.超临界溶液浸渍法制备缓释药物,化工学报,2010,61(2)：
[23]Chang CJ, Rando lph AD. P recip itat ion of m icro size o rganic part icles from supercrit ical fluid [J]. A IChE J,1989,35:187621882.
[24]Reverchon E, Donsi G, Go rgoglione D. Salicylic Acid Solubilization in Supercritical CO2 and its Micronization by RESS [J]. J Supercrit F luids,1993,6: 241-248.
[25]陈鸿雁,蔡建国等.超临界流体溶液快速膨胀法制备灰黄霉素微细颗粒,化工学报,2001,52(1)：
[26]Reverchon E, Della Porta G. Micronization of antibiotics by supercritical assisted atomization [J]. J Supercrit Fluids,2003,26(3):243-252.
[27]Reverchon E, Spada A. Erythromycin micro-particles produced by supercritical fluid atomization [J]. Powder Technol,2004,141(1-2):100-108.
[28]Steckel H, Pichert L, Muller BW. Influence of process parameters in the ASES process on particle properties of budesonide for pulmonary delivery [J]. Eur J Pharm Biopharm,2004,57(3):507-512.
[29]Tandya A. Micronization of cyclosporine using dense gas techniques. J Supercrit Fluids.2006,37:272-278
[30]李志义,赵顺轩,蒋静智,等.超临界辅助雾化法制备红霉素超细微粒[J].高校化学工程学报,2007,21(1)：43-47.
[31]Reverchon E, Della Porta G. Terbutaline microparticles suitable for aerosol delivery produced by supercritical assisted atomization [J]. Int J Pharm,2003, 258(1-2):1-9.
[32]Reverchon E, Adami R, Caputo G. Production of cromolyn sodium microparticles for aerosol delivery by supercritical assisted atomization [J]. AAPS PharmSciTech,2007,8(4):E114.
[33]Kim YH, Shing KS. Supercritical fluidmicronized ipratropium bromide for pulmonary drug delivery. Powder Technol.2008; 182:25-32.
[34]Chingunpitak J, Puttipipatkhachorn S, Tozuka Y, Moribe K, Yamamoto K. icronization of dihydroartemisinin by rapid expansion of supercritical solutions. Drug Dev Ind Pharm.2008; 34:609-617
[35]Zhiyi L. Preparation of griseofulvin microparticles by supercritical fluid expansion depressurization process. Powder Technol.2008,182:459-465.
[36]Martin A, Scholle K, Mattea F, Meterc D.Cocero MJ. Production of polymorphs of Iiuprofen sodium by supercritical antisolvent (SAS) precipitation. Cryst Growth Des.2009; 9:2504-2511.
[37]Su CS, Tang M, Chen YP. Micronization of nabumetone using the rapid expansion of supercritical solution (RESS) process. J Supercrit Fluids.2009; 50; 69-76.
[38]Liu J, Yin 1, Sun Y. Microparticles of theophylline using supercritical antisolvent precipitation.2009 International Symposium on Crystal Engineering & Drug Delivery Systems. September 5-8, Tianjin, China,2009
[39]Perrut M, Jung J, Leboeuf F. Is it possible to enhance the dissolution rate of poorly-soluble active ingredients by supercritical fluid processes? Proceedings of the 9th Meeting on Supercritical Fluids, Trieste (Italy), Kikic I., Perrut M. edtitors, 2004.
[40]Kerc J, Srcic S, Knez Z, et al. Micronization of drugs using supercritical carbon dioxide. [J]. Int J Pharm,1999,182(1):33-39.
[41]Lee S, Nam K, Kim MS, Jun SW, Park JS, Woo JS, Hwang SJ. Preparation and Characterization of Solid Dispersions of Itraconazole by using Aerosol Solvent Extraction System for Improvement in Drug Solubility and Bioavailability. Arch Pharm Res.2005; 28:866-874.
[42]Woo JS, Kim HJ, Kim YH. Method for the preparatin of paclitaxel solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby. USPTO Application #:20060078619.04/13/2006.
[43]Jun SW, Kim MS, Jo GH, Lee S, Woo JS, Park JS, Hwang SJ. Cefuroxime axetil solid dispersions prepared using solution enhanced dispersion by supercritical fluids. J Pharm Pharmacol..2005; 57:1529-1537.
[44]Michael B, Severine J, Leonardo P, Geraldine P, Brigitte E. The supercritical micronization of solid dispersions by particles from gas saturated solutions using experimental design. J Supercrit Fluids.2009; 51:50-56.
[45]Wu K, Li J, Wang W, Winstead DA. Formation and characterization of solid dispersions of piroxicam and polyvinylpyrrolidone using spray drying and precipitation with compressed antisolvent. J Pharm Sci.2009; 98:2422-2431.
[46]Chang YP, Muoi Tang M, Yan-Ping Chen YP. Micronization of sulfamethoxazole using the supercritical anti-solvent process. J Mater Sci 2008; 43:2328-2335.
[47]Van Nijlen T, Brennan, K., Van den Mooter G, et al. Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions. Int J Pharm.2003; 254:173-181.
[48]Charoenchaitrakool M, Dehghani F, Foster NR. Utilization of supercritical carbon dioxide for complex formation of ibuprofen and methyl-beta-cyclodextrin[J]. Int J Pharm.2002 Jun 4;239(1-2):103-12.
[49]Bandi N, Wei W, Roberts CB, et al. Preparation of budesonide- and indomethacin-hydroxypropyl-beta-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur J Pharm Sci. 2004 Oct;23(2):159-68.
[50]Reverchon E, Antonacci A. Cyclodextrins micrometric powders obtained by supercritical fluid processing [J]. Biotechnol Bioeng,2006,94(4):753-761.
[51]Kang Y, Wu J, Yin G, Huang Z, Yao Y, Liao X, et al. Preparation, characterization and in vitro cytotoxicity of indomethacin-loaded PLLA/PLGA microparticles using supercritical CO2 technique. Eur J Pharm Biopharm.2008; 70:85-97.
[52]Kang Y, Wu J, Yin G, et al. Characterization and biological evaluation of paclitaxel-loaded poly(L-lactic acid) microparticles prepared by supercritical CO2. Langmuir.2008 Jul 15;24(14):7432-41.
[53]Reverchon E, Lamberti G, Antonacci A. Supercritical fluid assisted production of HPMC composite microparticles[J].J Supercrit Fluids,2008,46(2): 185-196.
[54]Reverchon E, Antonacci A. Chitosan microparticles production by supercritical fluid processing [J]. Ind Eng Chem Res,2006,45(16):5722-5728
[55]Reverchon E, Antonacci A. Drug-polymer microparticles produced by supercritical assisted atomization[J]. Biotechnol Bioeng.2007 Aug 15;97(6):1626-37.
[56]蔡美强,水力空化混合器强化超临界流体辅助雾化制备超细微粒的研究,浙江大学博士学位论文,2007
[57]Duarte AR, Costa MS, Simplicio AL, et al. Preparation of controlled release microspheres using supercritical fluid technology for delivery of anti-inflammatory drugs[J]. Int J Pharm.2006,308(1-2):168-74
[58]MEM Braga, MTV Pato, HSR Silva, et al. Supercritical solvent impregnation of ophthalmic drugs on chitosan derivatives[J], J Supercrit Fluids,2008,44(2): 245-257
[59]Gong K, Rehman IU, Darr JA. Characterization and drug release investigation of amorphous drug-hydroxypropyl methylcellulose composites made via supercritical carbon dioxide assisted impregnation[J]. J Pharm Biomed Anal.2008,48(4):1112-1119.
[60]Sproule T L, Alex Lee J, Li H B, et al. Bioactive polymer surfaces via supercritical fluids[J]. J Supercrit Fluids,2004,28(2-3):241-248.
[61]Rodrigues M, Peirico N, Matos H, et al. Microcomposites theophylline/hydrogenated palm oil from a PGSS process for controlled drug delivery systems [J]. J Supercrit Fluids,2004,29(1-2):175-184
[62]Kunastitchai S, Pichert L, Sarisuta N, et al. Application of aerosol solvent extraction system(ASES) process for preparation of liposomes in a dry and reconstitutable form [J]. Int J Pharm,2006,316(1-2):93-101.
[63]Salmaso S, Elvassore N, Bertucco A, Caliceti P. Production of solid lipid submicron particles for protein delivery using a novel supercritical gas-assisted melting atomization process. J Pharm Sci.2009; 98:640-650
[64]Young TJ, Johnson KP, Pace GW, Mishra AK. Phospholipid-stabilized nanoparticles of cyclosporine a by rapid expansion from supercritical to aqueous solution. AAPS PharmSciTech.2004; 5(1):E11
[65]PEPRAH RICHARD.微乳液法和超临界流体法制备辅酶Q10固体纳米脂Solid lipid nanoparticles of coenzyme Q10 byml croemulsionandsupercriticalfluid techniques[硕士论文].厦门大学,2009 年7月
[66]王霞,郭燕妮,陈辉等.超临界流体技术制备布洛芬/脂复合粒[J].现代化工,2007年,27(增2)：398-402
[67]三岛健司,山口昌郎,森安恒夫.高分子微粒子の制造方法：日本,8113652[P].1996-05-07.(CA 1996,125:144117)
[68]Meziani MJ, Rollins HW, Allard LF, et al. Protein-protected nanoparticles from rapid expansion of supercritical solution into aqueous solution[J]. J Phys ChemB,2002,106(43):11178-11182.
[69]Mishima K, Matsuyama K, Tanabe D, et al. Microencapsulation of proteins by rapid expansion of supercritical solution with a nonsolvent[J]. AIChE J,2004, 46(4):857-865.
[70]Thies C, Ribeiro Dos Santos I, Richard J, et al. A supercritical fluid-based coating technology 1:process considerations[J]. J Microencapsul,2003,20(1): 87-96.
[71]Ribeiro Dos Santos I, Thies C, Richard J, et al. A supercritical fluid-based coating technology.2:solubility considerations[J]. J Microencapsul,2003,20(1): 97-109.
[72]Ribeiro Dos Santos I, Richard J, Thies C, Pech B, Benoit JP. A supercritical fluid-based coating technology.3:preparation and characterization of bovine serum albumin particles coated with lipids[J]. J Microencapsul.2003 Jan-Feb;20(1):110-28
[73]陈岚,张岩,李保国,等.超临界流体技术制备阿莫西林缓释微囊的初探[J].中国药学杂志,2004,39(11)：842-844.
[74]Jin HY, Xia F, Jiang CL et al. Nanoencapsulation of Lutein with Hydroxypropylmethyl Cellulose Phthalate by Supercritical Antisolvent[J]. Chinese J Chem Eng,2009; 17 (4):672
[75]Yeo SD, Lim GB, Debendetti PG. Formation of microparticulate protein powder using a supercritical fluid antisolvent [J]. Biotech Bioeng,1993,41 (30):341-346
[76]Caliceti P, Brossa A, Salmaso S, et al. Elvassore, A. Bertucco, Preparation of protein loaded solid lipid nano-particles by compressed fluid process, Proc. Intern. Symp. Control. Rel. Bioact. Mater., vol.33,2006, p.383.
[77]Elvassore N, Bertucco A, Caliceti P. Production of insulin-loaded poly(ethylene glycol)/poly(1-lactide) (PEG/PLA) nanoparticles by gas antisolvent techniques[J]. J Pharm Sci.2001 Oct;90(10):1628-36.
[78]Elvassore N., Bertucco A., Caliceti P. Production of protein-loaded polymeric microcapsules by compressed CO2 in a mixed solvent. Ind Eng Chem Res. 2001,40:795-800
[79]Velega SP, Carlfors J. Supercritical fluids processing of recombinant human growth hormone[J]. Drug Dev Ind Pharm,2005,31(2):135-149.
[80]RODRIGUES M A, LI J, PADRELA L, Almeida A, et al. Anti-solvent effect in the production of lysozyme nanoparticles by supercritical fluid-assisted atomization processes[J]. J Supercrit Fluid,2009,48(3):253-260.
[2]Muller R H, Mader K, Gohla S. Solid lipid nanoparticles(SLN) for controlled drug delivery-a review of the state of art[J]. Eur J Pharm Biopharm,2000,50(1): 161-177.
[3]Florence A T, Hillery A M, Hussain N, et al. Nanoparticles as carriers for oral peptide absorption:Studies on particle uptake and fate[J]. Control Rel, 1995,36(1-2):39
[4]Antonio J. Almeida, Eliana Souto. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Advanced Drug Delivery Reviews.2007,59: 478-490
[5]Luo Y F, Chen D W, Ren L X et al. Solid lipid nanoparticles for enhancing vinpocetine's oral bioavailability[J]. Control Rel.,2006,114:53-59
[6]Florence A T. Nanoparticle uptake by the oral route:fulfilling is potential?[J]. Drug Discovery Today:Technologies,2005,1(2):75
[7]Garcia-Fuentes M, Prego C, Torres D, et al. A comparative study of the potential of solid triglyceride nanostructures coated with chitosan or poly(ethyleneglycol) as carriers for oral calcitonin delivery, Eur. J. Pharm.Sci.25 (2005) 133-143.
[8]Zhang N, Ping Q., Huang G., et al. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin, Int. J. Pharm.327 (2006) 153-159.
[9]程耀,平其能.超临界流体沉析技术及其在药剂学中的应用[J].药学进展,2004,28(2)：63-67.
[10]张诚贤.徐陆忠,吴素香.超临界流体辅助雾化制备药物微粒的研究进展[J].中国医药工业杂志,2009,40(11)：856-861.
[11]蔡美强,关怡新,姚善泾等.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[J].化工学报,2008,59(2)：293-300.
[12]REVERCHON E, DELL A P G. Micronization of antibiotics by supercritical assisted atomization [J]. J Supercrit Fluid,2003,26(3):243-252.
[13]REVERCHON E, ADAMIA R, CAPUTO G. Supercritical assisted atomization:Performance comparison between laboratory and pilot scale [J]. J Supercrit Fluid,2006,37 (3):298-306
[14]郭红星,陈庆华,陈岚等.超临界流体技术在药学领域制备微粒中的应用[J].中国医药工业杂志,2008,39(2)：136-141
[15]Irene Pasqualia, Ruggero Bettinia, Ferdinando Giordano. Supercritical fluid technologies- An innovative approach for manipulating the solid-state of pharmaceuticals[J]. Advanced Drug Delivery Reviews,2008,60:399-410
[16]Reverchon E, Antonacci A. Polymer microparticles production by supercritical assisted atomization[J], J Supercrit Fluid,2007,39(3):444-452
[17]Rodrigues M A, Li J, Padrela L, Almeida A, et al. Anti-solvent effect in the production of lysozyme nanoparticles by supercritical fluid-assisted atomization processes[J]. J Supercrit Fluid,2009,48(3):253-260.
[18]张继明,胡富强,应晓英等.胰岛素固体脂质纳米粒的制备及其理化性质研究[J].中国药学杂志,2004,39(08)：349-352.
[19]袁弘.固体脂质纳米粒口服药物载体经胃肠道转运的研究[博士学位论文].浙江大学,2008年
[20]刘晟,王维,罗贤明等.药物诱导狗Ⅰ型糖尿病的研究[J].湖南医科大学学报.2000年,25(2)：125-129
[21]周娟,陈滋青,胡军.葡萄糖测定方法的比较研究[J].工业微生物,1999年,29(4)：34-36
[22]朱自强,关怡新,姚善泾.超临界辅助雾化制备适于气溶胶给药的药物微粒[J].化工学报,2005,56(2)：187-196
[1]程耀,平其能.超临界流体沉析技术及其在药剂学中的应用[J].药学进展,2004,28(2)：63-67.
[2]郭红星,陈庆华,陈岚等.超临界流体技术在药学领域制备微粒中的应用,中国医药工业杂志,2008,39(2)：136-141
[3]张诚贤,徐陆忠,吴素香.超临界流体辅助雾化制备药物微粒的研究进展Progress on preparation of drug loading microparticles by supercritical assisted atomization [J].中国医药工业杂志,2009,40(11)：856-861.
[4]付强,孙进,何仲贵.超临界流体制备纳米药物的研究进展.沈阳药科大学学报.2010,27(4)：329-334
[5]Rantakyla M. Particle Production by Supercritical Antisolvent Processing Techniques[C]. Helsinki University of Technology. Plant Design Report Series No 76,2004年, ISBN 951-22-7400-0, ISSN 0358-0776
[6]Bala S, Roger A R, Kirk S. Pharmaceutical processing with supercritical carbon dioxide[J]. J Pharm Sci,1997,86 (8):8852889
[7]Michel PERRUT. Pharmaceutical applications of Supercritical Fluids[C].8th Meeting on Supercritical Fluids (Bordeaux-2002)
[8]Irene Pasqualia, Ruggero Bettinia, Ferdinando Giordano. Supercritical fluid technologies- An innovative approach for manipulating the solid-state of pharmaceuticals[J]. Advanced Drug Delivery Reviews 60 (2008) 399-410
[9]Strumendo M, Bertucco A, Elvassore N. Modeling of particle formation processes using gas saturated solution atomization [J]. J Supercrit Fluids,2007, 41(1):115-125.
[10]Li J, Matos HA, Gomes de Azevedo E. Two-phase homogeneous model for particle formation from gassaturated solution processes [J]. J Supercrit Fluids, 32(1-3):275-286.
[11]Reverchon E. Supereritical-assisted atomization to produce micro- and/or nanoparticles of controlled size and distribution [J]. Ind Eng Chem Res,2002, 41(10):2405-2411.
[12]Yeo SD, Kim MS, Lee JC. Recrystallization of sulfathiazole and chlorpropamide using the supercritical fl uid anti solvent process [J]. J Supercrit Fluids,2003,25(2):143-154.
[13]朱自强,关怡新,姚善泾.超临界辅助雾化制备适于气溶胶给药的药物微粒Micronization of drugs suitable for aerosol delivery by supercritical fluid assisted atomization[J]. 化工学报,2005,56(2):187-196.
[14]蔡美强,关怡新,姚善泾,朱自强.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[J].化工学报,2008,59(2)：293-300.
[15]REVERCHON E, DELLA P G. Micronization of antibiotics by supercritical assisted atomization [J]. J Supercrit Fluid,2003,26(3):243-252.
[16]REVERCHON E, AD AMI A R, CAPUTO G. Supercritical assisted atomization:Performance comparison between laboratory and pilot scale[J]. J Supererit Fluid,2006,37 (3):298-306
[17]Della Porta G, De Vittori C, Reverchon E. Supercritical assisted atomization: a novel technology for microparticles preparation of an asthma-controlling drug. AAPS PharmSciTech.2005 Oct 22;6(3):E421-8
[18]Bleich J, Miiller BW, Waβmus W. Aerosol solvent extraction system— a new microparticle production technique[J]. Int J Pharm,1993,97(1-3):111-117.
[19]Palakodaty S, York P. Phase behavioral effects on particle formation processes using supercritical fluids[J]. Pharm Res,1999,16(7):976-985.
[20]He WZ, Suo QL, Jiang ZH, et al. Precipitation of ephedrine by SEDS process using a specially designed prefilming atomizer[J]. J Supercrit Fluids,2004,31(1): 101-110.
[21]Sievers RE, Milewski PD, Sellers SP, et al. Supercritical and near-critical carbon dioxide assisted low-temperature bubble drying[J]. Ind Eng Chem Res, 2000,39(12):4831-4836.
[22]关怡新,余金鹏,姚善泾等.超临界溶液浸渍法制备缓释药物,化工学报,2010,61(2)：
[23]Chang CJ, Rando lph AD. P recip itat ion of m icro size o rganic part icles from supercrit ical fluid [J]. A IChE J,1989,35:187621882.
[24]Reverchon E, Donsi G, Go rgoglione D. Salicylic Acid Solubilization in Supercritical CO2 and its Micronization by RESS [J]. J Supercrit F luids,1993,6: 241-248.
[25]陈鸿雁,蔡建国等.超临界流体溶液快速膨胀法制备灰黄霉素微细颗粒,化工学报,2001,52(1)：
[26]Reverchon E, Della Porta G. Micronization of antibiotics by supercritical assisted atomization [J]. J Supercrit Fluids,2003,26(3):243-252.
[27]Reverchon E, Spada A. Erythromycin micro-particles produced by supercritical fluid atomization [J]. Powder Technol,2004,141(1-2):100-108.
[28]Steckel H, Pichert L, Muller BW. Influence of process parameters in the ASES process on particle properties of budesonide for pulmonary delivery [J]. Eur J Pharm Biopharm,2004,57(3):507-512.
[29]Tandya A. Micronization of cyclosporine using dense gas techniques. J Supercrit Fluids.2006,37:272-278
[30]李志义,赵顺轩,蒋静智,等.超临界辅助雾化法制备红霉素超细微粒[J].高校化学工程学报,2007,21(1)：43-47.
[31]Reverchon E, Della Porta G. Terbutaline microparticles suitable for aerosol delivery produced by supercritical assisted atomization [J]. Int J Pharm,2003, 258(1-2):1-9.
[32]Reverchon E, Adami R, Caputo G. Production of cromolyn sodium microparticles for aerosol delivery by supercritical assisted atomization [J]. AAPS PharmSciTech,2007,8(4):E114.
[33]Kim YH, Shing KS. Supercritical fluidmicronized ipratropium bromide for pulmonary drug delivery. Powder Technol.2008; 182:25-32.
[34]Chingunpitak J, Puttipipatkhachorn S, Tozuka Y, Moribe K, Yamamoto K. icronization of dihydroartemisinin by rapid expansion of supercritical solutions. Drug Dev Ind Pharm.2008; 34:609-617
[35]Zhiyi L. Preparation of griseofulvin microparticles by supercritical fluid expansion depressurization process. Powder Technol.2008,182:459-465.
[36]Martin A, Scholle K, Mattea F, Meterc D.Cocero MJ. Production of polymorphs of Iiuprofen sodium by supercritical antisolvent (SAS) precipitation. Cryst Growth Des.2009; 9:2504-2511.
[37]Su CS, Tang M, Chen YP. Micronization of nabumetone using the rapid expansion of supercritical solution (RESS) process. J Supercrit Fluids.2009; 50; 69-76.
[38]Liu J, Yin 1, Sun Y. Microparticles of theophylline using supercritical antisolvent precipitation.2009 International Symposium on Crystal Engineering & Drug Delivery Systems. September 5-8, Tianjin, China,2009
[39]Perrut M, Jung J, Leboeuf F. Is it possible to enhance the dissolution rate of poorly-soluble active ingredients by supercritical fluid processes? Proceedings of the 9th Meeting on Supercritical Fluids, Trieste (Italy), Kikic I., Perrut M. edtitors, 2004.
[40]Kerc J, Srcic S, Knez Z, et al. Micronization of drugs using supercritical carbon dioxide. [J]. Int J Pharm,1999,182(1):33-39.
[41]Lee S, Nam K, Kim MS, Jun SW, Park JS, Woo JS, Hwang SJ. Preparation and Characterization of Solid Dispersions of Itraconazole by using Aerosol Solvent Extraction System for Improvement in Drug Solubility and Bioavailability. Arch Pharm Res.2005; 28:866-874.
[42]Woo JS, Kim HJ, Kim YH. Method for the preparatin of paclitaxel solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby. USPTO Application #:20060078619.04/13/2006.
[43]Jun SW, Kim MS, Jo GH, Lee S, Woo JS, Park JS, Hwang SJ. Cefuroxime axetil solid dispersions prepared using solution enhanced dispersion by supercritical fluids. J Pharm Pharmacol..2005; 57:1529-1537.
[44]Michael B, Severine J, Leonardo P, Geraldine P, Brigitte E. The supercritical micronization of solid dispersions by particles from gas saturated solutions using experimental design. J Supercrit Fluids.2009; 51:50-56.
[45]Wu K, Li J, Wang W, Winstead DA. Formation and characterization of solid dispersions of piroxicam and polyvinylpyrrolidone using spray drying and precipitation with compressed antisolvent. J Pharm Sci.2009; 98:2422-2431.
[46]Chang YP, Muoi Tang M, Yan-Ping Chen YP. Micronization of sulfamethoxazole using the supercritical anti-solvent process. J Mater Sci 2008; 43:2328-2335.
[47]Van Nijlen T, Brennan, K., Van den Mooter G, et al. Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions. Int J Pharm.2003; 254:173-181.
[48]Charoenchaitrakool M, Dehghani F, Foster NR. Utilization of supercritical carbon dioxide for complex formation of ibuprofen and methyl-beta-cyclodextrin[J]. Int J Pharm.2002 Jun 4;239(1-2):103-12.
[49]Bandi N, Wei W, Roberts CB, et al. Preparation of budesonide- and indomethacin-hydroxypropyl-beta-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur J Pharm Sci. 2004 Oct;23(2):159-68.
[50]Reverchon E, Antonacci A. Cyclodextrins micrometric powders obtained by supercritical fluid processing [J]. Biotechnol Bioeng,2006,94(4):753-761.
[51]Kang Y, Wu J, Yin G, Huang Z, Yao Y, Liao X, et al. Preparation, characterization and in vitro cytotoxicity of indomethacin-loaded PLLA/PLGA microparticles using supercritical CO2 technique. Eur J Pharm Biopharm.2008; 70:85-97.
[52]Kang Y, Wu J, Yin G, et al. Characterization and biological evaluation of paclitaxel-loaded poly(L-lactic acid) microparticles prepared by supercritical CO2. Langmuir.2008 Jul 15;24(14):7432-41.
[53]Reverchon E, Lamberti G, Antonacci A. Supercritical fluid assisted production of HPMC composite microparticles[J].J Supercrit Fluids,2008,46(2): 185-196.
[54]Reverchon E, Antonacci A. Chitosan microparticles production by supercritical fluid processing [J]. Ind Eng Chem Res,2006,45(16):5722-5728
[55]Reverchon E, Antonacci A. Drug-polymer microparticles produced by supercritical assisted atomization[J]. Biotechnol Bioeng.2007 Aug 15;97(6):1626-37.
[56]蔡美强,水力空化混合器强化超临界流体辅助雾化制备超细微粒的研究,浙江大学博士学位论文,2007
[57]Duarte AR, Costa MS, Simplicio AL, et al. Preparation of controlled release microspheres using supercritical fluid technology for delivery of anti-inflammatory drugs[J]. Int J Pharm.2006,308(1-2):168-74
[58]MEM Braga, MTV Pato, HSR Silva, et al. Supercritical solvent impregnation of ophthalmic drugs on chitosan derivatives[J], J Supercrit Fluids,2008,44(2): 245-257
[59]Gong K, Rehman IU, Darr JA. Characterization and drug release investigation of amorphous drug-hydroxypropyl methylcellulose composites made via supercritical carbon dioxide assisted impregnation[J]. J Pharm Biomed Anal.2008,48(4):1112-1119.
[60]Sproule T L, Alex Lee J, Li H B, et al. Bioactive polymer surfaces via supercritical fluids[J]. J Supercrit Fluids,2004,28(2-3):241-248.
[61]Rodrigues M, Peirico N, Matos H, et al. Microcomposites theophylline/hydrogenated palm oil from a PGSS process for controlled drug delivery systems [J]. J Supercrit Fluids,2004,29(1-2):175-184
[62]Kunastitchai S, Pichert L, Sarisuta N, et al. Application of aerosol solvent extraction system(ASES) process for preparation of liposomes in a dry and reconstitutable form [J]. Int J Pharm,2006,316(1-2):93-101.
[63]Salmaso S, Elvassore N, Bertucco A, Caliceti P. Production of solid lipid submicron particles for protein delivery using a novel supercritical gas-assisted melting atomization process. J Pharm Sci.2009; 98:640-650
[64]Young TJ, Johnson KP, Pace GW, Mishra AK. Phospholipid-stabilized nanoparticles of cyclosporine a by rapid expansion from supercritical to aqueous solution. AAPS PharmSciTech.2004; 5(1):E11
[65]PEPRAH RICHARD.微乳液法和超临界流体法制备辅酶Q10固体纳米脂Solid lipid nanoparticles of coenzyme Q10 byml croemulsionandsupercriticalfluid techniques[硕士论文].厦门大学,2009 年7月
[66]王霞,郭燕妮,陈辉等.超临界流体技术制备布洛芬/脂复合粒[J].现代化工,2007年,27(增2)：398-402
[67]三岛健司,山口昌郎,森安恒夫.高分子微粒子の制造方法：日本,8113652[P].1996-05-07.(CA 1996,125:144117)
[68]Meziani MJ, Rollins HW, Allard LF, et al. Protein-protected nanoparticles from rapid expansion of supercritical solution into aqueous solution[J]. J Phys ChemB,2002,106(43):11178-11182.
[69]Mishima K, Matsuyama K, Tanabe D, et al. Microencapsulation of proteins by rapid expansion of supercritical solution with a nonsolvent[J]. AIChE J,2004, 46(4):857-865.
[70]Thies C, Ribeiro Dos Santos I, Richard J, et al. A supercritical fluid-based coating technology 1:process considerations[J]. J Microencapsul,2003,20(1): 87-96.
[71]Ribeiro Dos Santos I, Thies C, Richard J, et al. A supercritical fluid-based coating technology.2:solubility considerations[J]. J Microencapsul,2003,20(1): 97-109.
[72]Ribeiro Dos Santos I, Richard J, Thies C, Pech B, Benoit JP. A supercritical fluid-based coating technology.3:preparation and characterization of bovine serum albumin particles coated with lipids[J]. J Microencapsul.2003 Jan-Feb;20(1):110-28
[73]陈岚,张岩,李保国,等.超临界流体技术制备阿莫西林缓释微囊的初探[J].中国药学杂志,2004,39(11)：842-844.
[74]Jin HY, Xia F, Jiang CL et al. Nanoencapsulation of Lutein with Hydroxypropylmethyl Cellulose Phthalate by Supercritical Antisolvent[J]. Chinese J Chem Eng,2009; 17 (4):672
[75]Yeo SD, Lim GB, Debendetti PG. Formation of microparticulate protein powder using a supercritical fluid antisolvent [J]. Biotech Bioeng,1993,41 (30):341-346
[76]Caliceti P, Brossa A, Salmaso S, et al. Elvassore, A. Bertucco, Preparation of protein loaded solid lipid nano-particles by compressed fluid process, Proc. Intern. Symp. Control. Rel. Bioact. Mater., vol.33,2006, p.383.
[77]Elvassore N, Bertucco A, Caliceti P. Production of insulin-loaded poly(ethylene glycol)/poly(1-lactide) (PEG/PLA) nanoparticles by gas antisolvent techniques[J]. J Pharm Sci.2001 Oct;90(10):1628-36.
[78]Elvassore N., Bertucco A., Caliceti P. Production of protein-loaded polymeric microcapsules by compressed CO2 in a mixed solvent. Ind Eng Chem Res. 2001,40:795-800
[79]Velega SP, Carlfors J. Supercritical fluids processing of recombinant human growth hormone[J]. Drug Dev Ind Pharm,2005,31(2):135-149.
[80]RODRIGUES M A, LI J, PADRELA L, Almeida A, et al. Anti-solvent effect in the production of lysozyme nanoparticles by supercritical fluid-assisted atomization processes[J]. J Supercrit Fluid,2009,48(3):253-260.