SAS-A技术制备胰岛素微纳米颗粒及其复合微粒
|
摘要
超临界流体(SCF)技术已经在许多领域获得了重要的进展。利用SCF的高膨胀能力、对有机溶剂的萃取能力,SCF技术可应用于对各种物质进行微粒化及其微囊化(或复合微粒化);利用其性质对温度和压力的敏感性,可以调节这些操作条件来控制所得微粒的形貌、粒径大小和分布;另外,SCF技术尤其对热敏感、结构不稳定和具有生物活性的物系的微粒化或微囊化具有明显优势。课题组和国外合作提出了超临界流体抗溶剂-雾化SAS-A(supercritical anti-solvent atomization)技术,该技术以SEDS(solution enhanccd dispersion by supcrcdtical fluids)和PGSS(particle formation fromgas-saturated solution)为基础,能处理含水体系。
首先计算了实验体系所涉及的二元和三元系统高压下液相体积膨胀率。用t-mPR状态方程(EoS)对CO_2+丙酮、CO_2+乙醇二元体系和CO_2+乙醇+水三元体系的高压汽液平衡(VLE)进行计算,并与课题组之前采用PR-EoS得到的结果进行比较。结果表明t-mPR EoS可以对这些体系的VLE取得较好的计算效果。进一步对上述体系的液相体积膨胀率进行预测,t-mPR EoS对二元体系预测结果比PR-EoS的预测结果的精度有所提高,对三元体系的预测表明其在7.8MPa左右能更好地反映实验现象。另外,计算还表明:CO_2+丙酮体系的体积膨胀率要远远大于CO_2+乙醇体系;对CO_2+乙醇+水三元体系的体积膨胀率在7.8MPa左右有一个最大值,提高乙醇在乙醇/水溶液中的摩尔分数,可以提高该溶液的最大体积膨胀率。
以SAS-A技术研究从乙醇、丙酮及乙醇/水中制备聚乙二醇(PEG)微粒。探讨预膨胀压力、溶液浓度和溶液流量等工艺参数对所制备的PEG微粒形态及粒径的影响;重点讨论不同溶剂对颗粒形态和粒径分布的影响。结果表明,制备得到的PEG微粒基本上为球形,利用丙酮和乙醇,粒径分布分别可以控制在1-5μm和2-15μm之间;增大预膨胀压力容易得到分散的球形微粒,并能减小其粒径,粒径分布也随之变窄;对应PEG/丙酮体系,溶液浓度升高,所得到的微粒粒径增大;对应PEG/乙醇体系,溶液浓度对粒径大小影响不大,但溶液浓度增大会使粒径分布变宽;采用乙醇水溶液为溶剂时,初始乙醇浓度越低,移出水的效果越差,易形成结块的不规则微粒。
以SAS-A技术研究从胰岛素/乙醇/水溶液中制备胰岛素微粒。探讨各种操作参数对微粒形态、平均粒径和胰岛素活性的影响。在各种操作条件下制备的胰岛素产品均为球形微粒,粒径分布主要在0.1-1.5μm之间。操作压力在8MPa左右有良好的水移除能力,进一步增大压力会使所得微粒倾向于团聚。通过改变操作条件可以有效地控制微粒的形态和大小:降低溶液流量会使微粒变小,粒径分布变窄,但是流量低于2ml/min时,倾向于生成不规则颗粒;在所选的胰岛素浓度范围内,增大浓度可以使微粒粒径变小,粒径分布也随之变窄;乙醇浓度对微粒形态和大小影响不大,但是对胰岛素活性的起主要影响作用,乙醇浓度越高,胰岛素活性损失越大;其它操作条件的改变对胰岛素活性的影响不明显,活性均保持在90%以上。FTIR与DTA的测试结果表明,胰岛素活性丧失与其二级结构的变化有关,即β-折叠的增强和α螺旋的减小。
以SAS-A技术研究制备PEG/胰岛素复合微粒;改进的SAS-A技术流程研究制备三棕榈酸甘油酯/胰岛素复合微粒。探讨工艺参数和操作条件对微粒形貌、粒径大小、分布的影响。进行复合微粒的胰岛素的溶出(控释)实验,研究复合微粒中蛋白质和载体的结合情况、控释情况。研究表明,不同条件下所得PEG/胰岛素复合微粒为近球形,该复合微粒的控释实验说明其中PEG和胰岛素的结合良好。研究表明,不同温度条件下得到的三棕榈酸甘油酯/胰岛素复合微粒形态不同:45℃时得到块状附着有小球颗粒,50℃时得到较为特殊的菊花状颗粒;该复合微粒的控释实验表明:45℃时得到的复合微粒仍然存在突释,前一分钟的胰岛素释放量达到了36%,50℃时得到的复合微粒有很好的控释效果,完全没有突释现象。
Supercritical fluid(SCF) technology has been widely applied to various areas,and very important progress has been achieved.Among the applications,particle formation or encapsulation with assistance of SCF by using its high solvency power and expansion ability to lots of solvents is a hot research topic in recent decades.It is possible to control the morphology,particle size(PS),and particle size distribution(PSD) for the produced products due to the sensitivity of SCF to the operating temperature and pressure. Furthermore,it is also available for the formulation of those materials such as active substances,thermosensitive substances,which usually cannot be processed by conventional methods.In this thesis,supercritical anti-solvent atomization(SAS-A),which is a combination of SEDS(solution enhanced dispersion by supercritical fluids) and PGSS (particle formation from gas-saturated solution),was employed to study the precipitation of polyethylene glycol 6000(PEG) and insulin microparticles,as well as PEG/insulin and tripalmitin/insulin composite mieroparticles.
Prior to the particle formation study,the volume expansion of the liquid phases for the CO_2/acetone and CO_2/ethanol binary systems and the CO_2/ethanol/water ternary system was investigated using the t-mPR equations of state(t-mPR EoS) and the PR equations of state(PR-EoS).The correlations for the published vapor-liquid equilibrium(VLE) data of the above systems show that both the EoS can provide fairly good VLE calculations for the binary systems,but t-mPR EoS gives slightly better results.The volume expansion prediction for the above systems and the comparison with the published data show that, compared to PR-EoS,t-mPR EoS gives better results for the binary systems but worse results for the ternary system,but provides more reasonable results around 7.8MPa. Moreover,the calculations indicate that the volume expansion of the CO_2/acetone system is always larger than that of the CO_2/ethanol system.The volume expansion of the ternary system shows a maximum point corresponding to about the CO_2/ethanol mixture's critical pressure(about 7.8MPa);increase in the content of ethanol can improve the maximun volume expansion and therefore help to enhance the removal of water.
The SAS-A process was applied to the generation of PEG microparticles from different solvents(acetone,ethanol,and ethanol/water).The effect of the processing conditions,including operating pressure,PEG concentration,and solution flow rate,on the morphology and size of the produced PEG particles was investigated,especially,the influence of using different solvents was evaluated.The PEG particles produced by using acetone and ethanol are generally spherical with sizes of 1-5μm and 2-15μm,respectively. A high pre-expansion pressure can produce spherical and discrete particles with relatively small size and narrow size distribution.Increasing the PEG concentration in acetone can evidently increase the PEG particle sizes and widen the PSD for the PEG/acetone system, while increasing the PEG concentration can slightly widen the PSD,but has little effect on the PEG particle sizes for the PEG/ethanol system in the studied concentration range. Decreasing the content of ethanol in the ethanol/water solution can generate irregular and agglomerated particles due to the difficulty of water removal.
The SAS-A process was employed to produce insulin particles from its ethanol/water solutions at 45℃.The effect of the operating conditions on the morphology,size and bioactivity of the produced insulin particles was evaluated.The formed primary particles are spherical and discrete with sizes of 0.1-1.5μm.The loss of the activity of the insulin particles depends on the ethanol content in the solution;other operating conditions show little effect on the insulin particles' activity.It is possible to produce insulin microparticles with almost no loss of its bioactivity by the SAS-A process at low ethanol content(less than 40%in mass).The FTIR and DTA analyses compared to that of the unprocessed insulin confirm that the changes in the content ofα-helix andβ-sheet decrease the protein activity.
Finally,the SAS-A process was employed to produce PEG/insulin composite microparticles,and a modified SAS-A process was employed to produce tripalmitin/insulin composite microparticles.The effects of different cartier materials,different ratios of carrier/insulin on the particle morphology and PSD and the insulin release from the produced composites were examined.Good combination of insulin to PEG in spherical composites is indicated on the basis of the insulin release from the PEG/insulin composite. Initial burst completely disappears for the insulin release from the tripalmitin/insulin composite particles(particles like flowers) produced at 50℃by the modified SAS-A process,while the intial burst is still high(36%in 1 min) for the tripalmitin/insulin composite particles(large particles attached with spheres) obtained at 45℃.
首先计算了实验体系所涉及的二元和三元系统高压下液相体积膨胀率。用t-mPR状态方程(EoS)对CO_2+丙酮、CO_2+乙醇二元体系和CO_2+乙醇+水三元体系的高压汽液平衡(VLE)进行计算,并与课题组之前采用PR-EoS得到的结果进行比较。结果表明t-mPR EoS可以对这些体系的VLE取得较好的计算效果。进一步对上述体系的液相体积膨胀率进行预测,t-mPR EoS对二元体系预测结果比PR-EoS的预测结果的精度有所提高,对三元体系的预测表明其在7.8MPa左右能更好地反映实验现象。另外,计算还表明:CO_2+丙酮体系的体积膨胀率要远远大于CO_2+乙醇体系;对CO_2+乙醇+水三元体系的体积膨胀率在7.8MPa左右有一个最大值,提高乙醇在乙醇/水溶液中的摩尔分数,可以提高该溶液的最大体积膨胀率。
以SAS-A技术研究从乙醇、丙酮及乙醇/水中制备聚乙二醇(PEG)微粒。探讨预膨胀压力、溶液浓度和溶液流量等工艺参数对所制备的PEG微粒形态及粒径的影响;重点讨论不同溶剂对颗粒形态和粒径分布的影响。结果表明,制备得到的PEG微粒基本上为球形,利用丙酮和乙醇,粒径分布分别可以控制在1-5μm和2-15μm之间;增大预膨胀压力容易得到分散的球形微粒,并能减小其粒径,粒径分布也随之变窄;对应PEG/丙酮体系,溶液浓度升高,所得到的微粒粒径增大;对应PEG/乙醇体系,溶液浓度对粒径大小影响不大,但溶液浓度增大会使粒径分布变宽;采用乙醇水溶液为溶剂时,初始乙醇浓度越低,移出水的效果越差,易形成结块的不规则微粒。
以SAS-A技术研究从胰岛素/乙醇/水溶液中制备胰岛素微粒。探讨各种操作参数对微粒形态、平均粒径和胰岛素活性的影响。在各种操作条件下制备的胰岛素产品均为球形微粒,粒径分布主要在0.1-1.5μm之间。操作压力在8MPa左右有良好的水移除能力,进一步增大压力会使所得微粒倾向于团聚。通过改变操作条件可以有效地控制微粒的形态和大小:降低溶液流量会使微粒变小,粒径分布变窄,但是流量低于2ml/min时,倾向于生成不规则颗粒;在所选的胰岛素浓度范围内,增大浓度可以使微粒粒径变小,粒径分布也随之变窄;乙醇浓度对微粒形态和大小影响不大,但是对胰岛素活性的起主要影响作用,乙醇浓度越高,胰岛素活性损失越大;其它操作条件的改变对胰岛素活性的影响不明显,活性均保持在90%以上。FTIR与DTA的测试结果表明,胰岛素活性丧失与其二级结构的变化有关,即β-折叠的增强和α螺旋的减小。
以SAS-A技术研究制备PEG/胰岛素复合微粒;改进的SAS-A技术流程研究制备三棕榈酸甘油酯/胰岛素复合微粒。探讨工艺参数和操作条件对微粒形貌、粒径大小、分布的影响。进行复合微粒的胰岛素的溶出(控释)实验,研究复合微粒中蛋白质和载体的结合情况、控释情况。研究表明,不同条件下所得PEG/胰岛素复合微粒为近球形,该复合微粒的控释实验说明其中PEG和胰岛素的结合良好。研究表明,不同温度条件下得到的三棕榈酸甘油酯/胰岛素复合微粒形态不同:45℃时得到块状附着有小球颗粒,50℃时得到较为特殊的菊花状颗粒;该复合微粒的控释实验表明:45℃时得到的复合微粒仍然存在突释,前一分钟的胰岛素释放量达到了36%,50℃时得到的复合微粒有很好的控释效果,完全没有突释现象。
Supercritical fluid(SCF) technology has been widely applied to various areas,and very important progress has been achieved.Among the applications,particle formation or encapsulation with assistance of SCF by using its high solvency power and expansion ability to lots of solvents is a hot research topic in recent decades.It is possible to control the morphology,particle size(PS),and particle size distribution(PSD) for the produced products due to the sensitivity of SCF to the operating temperature and pressure. Furthermore,it is also available for the formulation of those materials such as active substances,thermosensitive substances,which usually cannot be processed by conventional methods.In this thesis,supercritical anti-solvent atomization(SAS-A),which is a combination of SEDS(solution enhanced dispersion by supercritical fluids) and PGSS (particle formation from gas-saturated solution),was employed to study the precipitation of polyethylene glycol 6000(PEG) and insulin microparticles,as well as PEG/insulin and tripalmitin/insulin composite mieroparticles.
Prior to the particle formation study,the volume expansion of the liquid phases for the CO_2/acetone and CO_2/ethanol binary systems and the CO_2/ethanol/water ternary system was investigated using the t-mPR equations of state(t-mPR EoS) and the PR equations of state(PR-EoS).The correlations for the published vapor-liquid equilibrium(VLE) data of the above systems show that both the EoS can provide fairly good VLE calculations for the binary systems,but t-mPR EoS gives slightly better results.The volume expansion prediction for the above systems and the comparison with the published data show that, compared to PR-EoS,t-mPR EoS gives better results for the binary systems but worse results for the ternary system,but provides more reasonable results around 7.8MPa. Moreover,the calculations indicate that the volume expansion of the CO_2/acetone system is always larger than that of the CO_2/ethanol system.The volume expansion of the ternary system shows a maximum point corresponding to about the CO_2/ethanol mixture's critical pressure(about 7.8MPa);increase in the content of ethanol can improve the maximun volume expansion and therefore help to enhance the removal of water.
The SAS-A process was applied to the generation of PEG microparticles from different solvents(acetone,ethanol,and ethanol/water).The effect of the processing conditions,including operating pressure,PEG concentration,and solution flow rate,on the morphology and size of the produced PEG particles was investigated,especially,the influence of using different solvents was evaluated.The PEG particles produced by using acetone and ethanol are generally spherical with sizes of 1-5μm and 2-15μm,respectively. A high pre-expansion pressure can produce spherical and discrete particles with relatively small size and narrow size distribution.Increasing the PEG concentration in acetone can evidently increase the PEG particle sizes and widen the PSD for the PEG/acetone system, while increasing the PEG concentration can slightly widen the PSD,but has little effect on the PEG particle sizes for the PEG/ethanol system in the studied concentration range. Decreasing the content of ethanol in the ethanol/water solution can generate irregular and agglomerated particles due to the difficulty of water removal.
The SAS-A process was employed to produce insulin particles from its ethanol/water solutions at 45℃.The effect of the operating conditions on the morphology,size and bioactivity of the produced insulin particles was evaluated.The formed primary particles are spherical and discrete with sizes of 0.1-1.5μm.The loss of the activity of the insulin particles depends on the ethanol content in the solution;other operating conditions show little effect on the insulin particles' activity.It is possible to produce insulin microparticles with almost no loss of its bioactivity by the SAS-A process at low ethanol content(less than 40%in mass).The FTIR and DTA analyses compared to that of the unprocessed insulin confirm that the changes in the content ofα-helix andβ-sheet decrease the protein activity.
Finally,the SAS-A process was employed to produce PEG/insulin composite microparticles,and a modified SAS-A process was employed to produce tripalmitin/insulin composite microparticles.The effects of different cartier materials,different ratios of carrier/insulin on the particle morphology and PSD and the insulin release from the produced composites were examined.Good combination of insulin to PEG in spherical composites is indicated on the basis of the insulin release from the PEG/insulin composite. Initial burst completely disappears for the insulin release from the tripalmitin/insulin composite particles(particles like flowers) produced at 50℃by the modified SAS-A process,while the intial burst is still high(36%in 1 min) for the tripalmitin/insulin composite particles(large particles attached with spheres) obtained at 45℃.
引文
[1]韩布兴.超临界流体科学与技术[M],北京:中国石化出版社,2005,1:1-14.
[2]谢鸿森.地球深部物质科学导论[M],北京:科学出版社,1997,1:215-220.
[3]DeSimone JM,Tumas W.Green Chemistry Using Liquid and Supercritical Carbon Dioxide[M].New York Oxford University Press(US),2003.
[4]朱自强.超临界流体技术-原理和应用[M],北京:化学工业出版社.2000.
[5]Yasuhiko A,Takeshi F.Characteristics of supercritical fluids[J].The review of high pressure science and technology.The Japan society of high pressure and technology,1993,4:262-264.
[6]Weidner E,Petermann M,Knez Z.Multifunctional composites by high-pressure spray processes[J].Current Opinion in Solid State and Materials Science,2003,7:385-390.
[7]Mandel F S,Wang J D.Manufacturing of specialty materials in supercritical fluid carbon dioxide[J].Inorganica Chimica Acta,1999,294:214-22.
[8]丁廷桢.大学化学教程 原理·应用·前沿[M],北京:高等教育出版社,2003,1:215-220.
[9]祁鲁梁.工业用水节水与水处理技术术语大全[M],北京:中国水利水电出版社,2003,1:519-522.
[10]漆新华,庄源益.超临界流体技术在环境科学中的应用[M],北京:科学出版社,2005.
[11]Jovanovic N,Bouchard A,Hofland GW,Witkamp G,Crommelin D J,Jiskoot W.Stabilization of proteins in dry powder formulations using supercritical fluid technology[J].Pharmaceutical Research,2004,21(11):1955-1979.
[12]Tom JW,Debenedetti PG.Nucleation of biocompatible polymers[A].Proceedings of the 2nd International Symposium on Supercritical Fluids[C].Boston,1991.229-232.
[13]Jennifer J,Michel P.Particle design using supercritical fluids:Literature and patent survey[J],Journal of Supercritical Fluids,2001,20:179-219.
[14]Domingo C,Berends E,Rosmalen G M.Precipitation of ultrafine organic crystals from the rapid expansion of supercritical solutions over a capillary and a flit nozzle[J].Journal of Supercritical Fluids,1997,10(1):39-55.
[15]Reverchon E,Denis G.Salicylic acid solubilization in supercritical CO_2 and its micronization by RESS[J].Journal of Supercritical Fluids,1993,6:241-248.
[16]Mohamed RS,Debenadetti PG,Prud homme RK.Effects of Process Conditions on Crystals Obtained from Supercritical Mixtures[J].AIChE J,1989,35(2):325-328.
[17]刘燕,王威强,李爱菊.超临界流体技术制备超微材料应用[J].化学工程.2004,32:47-51.
[18]赵亚冬.二氧化碳和氮气辅助微粒形成技术[D].厦门大学,2006.
[19]Weidner E,Steiner R,Knez Z,Novak Z.Powder generation form polyethyleneglycols with compressible fluids[J].High Pressure Chemical Engineering,1996,223-228.
[20]Kappler P,Leiner W,Petermann M,Weidner E.Size and morphology of particles generated by spraying polymer-melts with carbon dioxide[A].Proceedings of the Sixth International Symposium on Supercritical Fluids,Versailles(France),2003.
[21]Knez Z.High pressure micronisation of polymers[A].Proceedings of the Sixth International Symposium on Supercritical Fluids,Versailles(France),2003.
[22]Sencar-Bozic P,Srcic S,Kenz Z,Kerc J.Improvement of nfifedipine dissolution characteristics using supercritical CO_2[J].International of Journal of Pharmaceutics,1997,148(2):123-130.
[23]Rodrigues M,Pcirico N,Matos H,de Azevedo EG,Lobato M R,Almeida A J.Microcomposites theophylline/hydrogenatcd palm oil from a PGSS process for controlled drug delivery systems[J].Journal of Supercritical Fluids,2004,29:175-184.
[24]Li J,Rodrigues M,Paiva A,Matos H,de Azevedo EG.Modeling of the PGSS process by Crystallization and Atomization[J].AIChE J,2005,51:2343-2350.
[25]Gallagher P M,Coffey M P,Krukonis V J,Klasutis N.Gas antisolvent recrystallization:New process to recrystallize compounds insoluble in superoritical fluids[A].Supercritical Fluid Science and Technology,American Chemical Society,Washington D.C.,1989,406:334-354.
[26]Bleich J,Muller BW,Wabmus W.Aerosol solventextraction system:a new microparticle production technique[J].International Journal of Pharmaceutics,1993(97):111- 117.
[27]Bodmeier R,Wang H,Dixon DJ,Mawson S,Johnston KP.Polymeric microspheres prepared by spraying into compressed carbon dioxide[J].Pharmaceutical Research,1995,12:1211-1217.
[28]Hanna M,York P.Method and apparatus for the formation of particles[P],WO95/01221,1994.
[29]Vemavarapu C,Mollan MJ,Lodaya M,Needham TE.Design and process aspects of laboratory scale SCF particle formation systems[J].International Journal of Pharrnaccutics 2005,292:1-16.
[30]Krukonis VJ.Supercritical fluid nucleation of difficult-to-comminute solids[A].AIChE Annual Meeting[C].San Francisco,CA.1984,11:140-149.
[31]Krukonis VJ,Gallagher PM,Coffey MP,Gas anti-solvent recrystalization process[P],Patent US,5 360 478,1991.
[32]Berends EM,Bruinsma OSL,Graauw J,van Rosmalen GM.Crystallisation of phcnanthrene from toluene with carbon dioxide as the anti-solvent by the gas-process[A],Proceedings of the 3rd International Symposium on Supercritical Fluids,Tome 3,Brunner G,Perrut M.(Eds.),Strasbourg,1994:223-228.
[33]Kitamura M,Yamamoto M,Yoshinaga Y.Crystal Size Control of Sulfathiazole Using High Pressure Carbon Dioxide[J].Chemistry Engineering Symposium Series.1995,4:200-205.
[34]Dillow AK,Dehghani F,Foster NR.Production of polymeric support materials using a supercritical fluid anti-solvent process[A],The 4th International Symposium on Supercritical Fluids,Sendai,Japan,1997:247-250.
[35]Rcverchon E,De Marco I,Della Porta G.Rifampicin microparticles production by supercritical antisolvent precipitation[J],International Journal of Pharmaceutics,2002,243:83-91.
[36]Reverchon E,De Marco I,Della Porta G.Tailoring nano- and micro-particles of some superconductor precursors by supercritical antisolvent precipitation[J],Journal of Supercritical Fluids,2002,23:81-87.
[37]Chattopadhyay P,Gupta RB.Production of antibiotic nanoparticles using supercritical CO_2 as antisolvent with enhanced mass transfer[J],Industrial and Engineering Chemistry Research,2001,40:3530-3539.
[38]Yeo SD,Lim GB,Debenedetti PG.Formation of Microparticulate Protein Powers Using a Supercritical Fluid Antisolvent[J].Biotechnology and Bioengineering,1993,41(3):341-346.
[39]Winters MA,Knutson BL,Debenedetti PG.Precipitation of proteins in supercritical carbon dioxide[J].Journal of Pharmaceutical Sciences,1996,85:586-594.
[40]Thiering R,Dehghani F,Dillow A,Foster NR.The influence of operating conditions on the dense gas precipitation of model proteins[J].Journal of Chemical Technology and Biotechnology,2000,75:29-41.
[41]Thiering R,Dehghani F,Dillow A,Foster NR.Solvent effects on the controlled dense gas precipitation of model proteins[J].Journal of Chemical Technology and Biotechnology,2000,75:42- 53.
[42]Muller BW,Fischer W.Method and apparatus for the manufacture of a product having a substance embedded In a carrier[P].US:5043280,1991.
[43]Elvassore N,Bertucco A,Caliceti P.Production of Insulin-Loaded Poly(Ethylene Glycol)/Poly(L-Lactide)(PEG/PLA) Nanoparticles by Gas Antisolvent Techniques[J].Journal of Pharmaceutical Sciences,2001,90,10:1628-1636.
[44]Calicetia P,Salmaso S,Elvassore N,Bertucco A.Effective protein release from PEG/PLA nano-particles produced by compressed gas anti-solvent precipitation techniques[J].Journal of Controlled Release,2004,94:195-205.
[45]Yeo SD,Kiran E.Formation of polymer particles with supercritical fluids:A review[J].Journal of Supercritical Fluids,2005,34:287-308.
[46]Byrappa K,Ohara S,Adschiri T.Nanoparticles synthesis using supercritical fluid technologytowards biomedical applications[J].Advanced Drug Delivery Reviews,2008,60:299-327.
[47]Schmitt WJ.Finely Derided solid crystaline powders via preciptation into anti-solvent[P],US Patent 5707634,1998.
[48]Dixon DJ,Luna-Barcenas G,Johnston KP.Microcellular microspheres and microballoons by precipitation with a vapour-liquid compressed fluid antisolvent[J].Polymer,1994,35:3998-4005.
[49]Debenedetti PG,Lira GB,Prud'Homme RK.Formation of protein microparticles by anti-solvent precipitation[P],European Patent,EP 0542314,1992.
[50]Sze TL,Dehghani F,Foster NR.Micronization and microencapsulation of pharmaceuticals using a carbon dioxide antisolvent[J],Powder Technology,2002,126(2):134-149.
[51]Bustami RT,Hak-Kim C,Dehghani F,Foster NR.Generation of Micro-Particles of Proteins for Aerosol Delivery Using High Pressure Modified Carbon Dioxide[J].Pharmaceutical Research,2000,17(11):1360-1366.
[52]Elvassore N,Bertucco A,Caliceti P.Production of protein loaded polymeric microcapsules by compressed CO_2 in mixed solvent[J],Industrial and Engineering Chemistry Research,2001,40(3):795-800.
[53]Shekunov BY,Baldyga J,York P.Particle formation by mixing with supercritical antisolvent at high Reynolds numbers[J].Chemical Engineering Science,2001,56:2421-2433.
[54]Juppo A M,Boissier C,Khoo C.Evaluation of solid dispersion particles prepared with SEDS[J].International Journal of Pharmaceutics,2003,250:385-401.
[55]Hanna M,York P.Method and apparatus for the formation of particles[P],Patent WO 9600610,1995.
[56]Hanna M,York P.Methods and apparatus for particle formation[P],European Patent WO 9959710,1999.
[57]Ghaderi R,Artursson P,Carlfors J.A new method for preparing biodegradable microparticles and entrapment of hydrocortisone in DL-PLG microparticles using supercritical fluids[J].European Journal of Pharmaceutical Sciences,2000,10:1-9.
[58]Sloan R,Hollowood ME,Humpreys GO.Supercritical fluid processing:preparation of stable protein particles[A],Proceedings of the 5th Meeting on Supercritical Fluids,Tome 1;Perrut M.,Subra P.(Eds.),Nice,1998,301-306.
[59]Sloan R,Tservistas M,Hollowood ME.Controlled particle formation of biological material using supercritical fluids[A],Proceedings of the 6th Meeting on Supercritical Fluids,Chemistry and Materials,Poliakoff M,George MW,.Howdle SM(Eds.),Nottingham,1999,169-174.
[60]Sarup L,Servistas MT,Sloan R,Hoare M,Humphreys GO.Investigation of supercritical fluid technology to produce dry particulate formulations of antibody fragments[J].Institution of Chemical Engineers,Trans IChemE,2000,78:101-104.
[61]York P,Hanna M.Salmeterol Xinafoate with controlled particle size[P].International Patent Publication WO 95/01324,1995.
[62]Sze TL,Dehghani F,Dillow A K,Foster NR.Applications of Dense Gases in Pharmaceutical Processing[A].Proceedings of the 5th Meeting on Supercritical Fluids,Tome 1;M.Perrut,P.Subra (Eds.),ISBN 2-905-267-28-3,23-25 March,Nice,1998,263-269.
[63]Li J,Rodrigues M,Paiva A,Matos H,de Azevedo EG.Vapor-liquid equilibrium and volume expansion of the tetrahydrogenfuran/CO_2 system:applications to a SAS-atomization process[J],Journal of Supercritical Fluids,2007,41:343-351.
[64]Rodrigues M,Li J,Matos H,Almeida A,de Azevedo EG.Control of the morphology of microparticles produced by supercritical CO_2 from water/ethanol solutions[J],2007,in preparation.
[65]Zhao L,Li J,Rodrigues M,Matos H,de Azevedo EG,Using N_2- or CO_2-assisited atomization process to produce polyethylene glycol microparticles[J],Chemical Engineering Research and Design,2007,85(7):987-995.
[66]Li J,Rodrigues M,Mates H,de Azevedo EG.VLE of Carbon dioxide/ethanol/water:application for evaluation the system volume expansion and water removal efficiency[J],Industrial and Engineering Chemistry Research,2005,44(17):6751-6759.
[67]赵磊.超临界流体抗溶剂-雾化技术制备PEG和BSA颗粒[D],厦门大学,2007.
[68]Chang CJ,Chin KL,Day CY.A new apparatus for the determination of P-x-y diagrams and Henry's constants in high pressure alcohols with critical carbon dioxide[J],Journal of Supercritical Fluids,1998,12:223-237.
[69]Bamberger A,Maurera G.High-pressure(vapour + liquid) equilibria in(carbon dioxide +acetone or 2-propanol) at temperatures from 293 K to 333 K[J],The Journal of Chemical Thermodynamics,2000,32:685-700.
[70]Chen JW,Wu WZ,Han BX,Gao L,Mu TC,Liu ZM,Jiang T,Du JM.Phase behavior,densities,and isothermal compressibility of CO2 +pentane and CO2 + acetone systems in various phase regions[J],Journal of Chemical and Engineering Data,2003,48:1544-1548.
[71]Wu JL,Pan QM,and Rempel GL.Pressure-density-temperature behavior of CO_2/acetone,CO_2/toluene,and CO_2/monochlorobenzene mixtures in the near-critical region[J],Journal of Chemical and Engineering Data,2004,49:976-979.
[72]Lazzaroni MJ,Bush D,Brown JS,Eckert CA.High-pressure vapor-liquid equilbria of some carbon dioxide + organic binary systems[J],Journal of Chemical and Engineering Data,2005,50:60-65.
[73]Stievano M,Elvassore N.High-pressure density and vapor-liquid equilibrium for the binary systems carbon dioxide-ethanol,carbon dioxide-acetone and carbon dioxide-dichloromethane[J],Journal of Supercritical Fluids,2005,33:7-14.
[74]Han F,Xue Y,Tian YL,Zhao XF,Chen L.Vapor-liquid equilibria of the carbon dioxide +acetone system at pressures from(2.36 to 11.77) MPa and temperatures from(333.15 to 393.15)K[J],Journal of Chemical and Engineering Data,2005,50:36-39.
[75]Nishiumi H,Fujita M,Agou K.Diffusion of acetone in supercritical carbon dioxide[J],Fluid Phase Equilibria,1996,117:356-363.
[76]Yoon JH,Lee HS,Lee H.High-pressure Vapor-Liquid Equilibria for Carbon Dioxide +Methanol,Carbon Dioxide + Ethanol,and Carbon Dioxide + Methanol + Ethanol[J].Journal of Chemical and Engineering Data,1993,38:53-55.
[77]田宜灵,韩铭,陈丽,冯季军,秦颖.高压下CO_2-乙醇二元系统的汽液平衡[J].物理化学学报.2001,17(2):155-160.
[78]Seung NJ,Chang WY,Hun YS.Measurements and correlation of high-pressure VLE of binary CO2-alcohol systems(methanol,ethanol,2-methoxyethanol and 2-ethoxyethanol)[J],Fluid Phase Equilibria,2001,185:219-230.
[79]Suzuki K,Sue H.Isothermal Vapor-Liquid Equilibrium Data for Binary Systems at High Pressures:Carbon Dioxide-Methanol,Carbon Dioxide-Ethanol,Carbon Dioxide-I-Propanol, Methane-Ethanol,Methane-I-Propanol,Ethane-Ethanol,and Ethane-I-Propanol Systems[J].Journal of Chemical and Engineering Data,1990,35:63-66
[80]Jennlngs DW,Lee R,Teja AS.Vapor-Liquid Equilibria in the Carbon Dioxide + Ethanol and Carbon Dioxide + 1-Butanol Systems[J].Journal of Chemical and Engineering Data,1991,36:303- 307.
[81]Elbaccouch MM,Raymond MB,Elliott JR.High-Pressure Vapor-Liquid Equilibrium for R-22 + Ethanol and R-22 + Ethanol + Water[J].Journal of Chemical and Engineering Data,2000,45:280- 287.
[82]Gilbert ML,Paulaltls ME.Gas-liquid equilibrium for ethanol-water-carbon dioxide mixtures at elevated pressures[J],Journal of Chemical and Engineering Data,1986,31:296-298.
[83]Budich M,Brunner G Supercritical fluid extraction of ethanol from aqueous solutions[J],Journal of Supercritical Fluids,2003,25:45-55.
[84]Durling NE,Catchpole OJ,Tallon SJ,Grey JB.Measurement and modeling of the ternary phase equilibria for high pressure carbon dioxide-ethanol-water mixtures[J],Fluid Phase Equilibria,2007,252:103-113.
[85]Takishima S,Saiki K,Arai K,Saito S.Phase equilibria for the CO_2-C_2H_5OH-H_2O system[J],Journal of Chemical Engineering of Japan,1986,19:48-56.
[86]Inomata H,Arai K,Saito S,Ohba S,Takeuchi K.Measurement and prediction of phase equilibria for the CO_2-ethanol-water system[J],Fluid Phase Equilibria,1989,53:23-30.
[87]Lim JS,Lee YY,Chun HS.Phase equilibria for carbon dioxide-ethanol-water system at Elevated Pressures[J],Journal of Supercritical Fluids,1994,7:219-230.
[88]Feng YS,Du XY,Li CF,Hou YJ.An apparatus for determining high-pressure fluid phase equilibria and its applications to supercritical carbon dioxide mixtures[A],International Symposium on Supercritical Fluids,Perrut M.Ed.,Nice,France,1988,1:75-84.
[89]Dahl S,Dunalewicz A,Fredenslund A,Rasmussen P.The MHV2 model:prediction of phase equilibria at sub- and supercritical conditions[J],Journal of Supercritical Fluids,1992,5:42-47.
[90]Inomata H,Arai K,Saito S,Ohbas S,Takeuchi K.Measurement and prediction of phase equilibria for the CO_2- ethanol-water system[J],Fluid Phase Equilibria,1989,53:23-30.
[91]Yao S,Guan Y,Zhu Z.Investigation of phase equilibrium for ternary systems containing ethanol,water and carbon dioxide at elevated pressures[J],Fluid Phase Equilibria,1994,99:249-259.
[92]Kordikowsk A,Schenk AP,Van Nielen RM,Peters CJ.Volume Expansions and Vapor-Liquid Equilibria of Binary Mixtures of a Variety of Polar Solvents and Certain Near-Critical Solvents[J].Journal of Supercrtical Fluids,1995,8:205-216
[93]Peneloux A,Ranzy EA.A consistent correction for Redlich-Kwong-Soave volumes.Fluid Phase Equilibria,1982,8:7-23.
[94]Magoulas K,Tassios D.Thermophysical Properties of n-alkanes from C1 to C20 and their Prediction for Higher Ones.Fluid Phase Equilibria,1990,56:119-140.
[95]林鸿,段远源.卤代烃的Peng-Robinson状态方程的密度修正.工程热物理学报.2006,27:13-16.
[96]Panagiotopoulos AZ,Reid RC.High-pressure phase equilibria in ternary fluid mixtures with a supercritical component[A],In Supercritical Fluids Chemical and Engineering Principles and Applications,Squires TG,Paulaitis ME,Eds.,ACS Symposium Series 329,Washington,DC,1985:115-129.
[97]陈新志,蔡振云,胡望明.化工热力学[M],北京:化学工业出版社,2001,1:88-89,128-146.
[98]Stryjek R,Vera JH.PRSV:An improved peng-robinson equation of state for pure compounds and mixtures[J],The Canadian Journal of Chemical Engineering,1986,64:323-333.
[99]Henczka M,Baldyga J,Shekunov BY.Particle formation by turbulent mixing with supercritical antisolvent[J],Chemical Engineering Science,2005,60:2193-2201.
[100]Li ZY,Xia YJ,Liu XW,Deng XL,Hu DP.Study of the Liquid Phase Volume Expansion for CO2/Organic Solvent Systems.Chinese Journal of Chemical Engineering,2005,13(4):504-509.
[101]严瑞瑄.水溶性高分子[M],北京:化学工业出版社,1998:223-243.
[102]中国药典2005年版.二部[M],北京:化学工业出版社,2005.
[103]Betageri GV,Makarla KR.Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques[J],International Journal of Pharmaceutics,1995,126:155-160.
[104]Nalawade SP,Picchioni F,Janssen LPBM.Batch production of micron size particles from poly(ethylene glycol) using supercritical CO_2 as a processing solvent[J],Chemical Engineering Science,2007,62:1712-1720.
[105]姚悦.高粘度流体气力雾化机理及试验研究[D].浙江大学.2006.
[106]Rantakyla M,Jantti M,Aaltonen O,Hurme M.The effect of initial drop size on particle size in the supercritical antisolvent precipitation(SAS) technique[J],Journal of Supercritical Fluids.2002,24:251-263.
[107]Matsuyama K,Mishima K.Phase behavior of CO_2 + polyethylene glycol + ethanol at pressures up to 20MPa[J].Fluid Phase Equilibria,2006,249:173-178.
[108]Shekunov BY.Production of powders for respiratory drug delivery[A],In Supercritical Fluid Technology for Drug Product Development,Edited by York P,Kompella UB,Shekunov BY,Marcel Dekker INC.Basel,New York,2004,10:247-282.
[109]Patton JS,Bukar J,Nagarajan S.Inhaled insulin[J].Advanced drug delivery reviews,1999,35(223):235-238.
[110]Shoyele SA,Cawthorne S.Particle engineering techniques for inhaled biopharmaceuticals[J],Advanced Drug Delivery Reviews,2006,58(9):1009-1029.
[111]Hakuta Y,Hayashi H,Arai K.Fine particle formation using supercritical fluids[J].Current Opinion in Solid State and Materials Science,2003,7:341-351.
[112]gyle AF,Sanger F,Smith F,Kitai K.The disulphide bonds of insulin[J].Biochemical Journal,1955,60(4):541-556.
[113]黄涛.化学修饰胰岛素的制备、表征和生物活性[D].华中科技大学,2004.
[114]Kaarsholm NC,Ko HC,Dunn MF.Comparison of solution structural flexibility and zinc binding domains for insulin,proinsulin,and mini-proinsulin[J].Biochemistry,1989,28:4427-4435.
[115]Conlon JM.Evolution of the insulin molecule:insights into structure-activity and phylogenetic relationships[J].Peptides,2001,22:1183-1193.
[116]Reverchon E.Supercritical antisolvent precipitation of micro-and nano-particles[J].Journal of Supercritical Fluids,1999,15:1-21.
[117]Gammeltoft S.Insulin receptor binding kinetics and structure-function relationship of insulin[J].Physiological Reviews,1984,64:1321-1378.
[118]刘新奇.单体人胰岛素突变体的晶体学研究[M].北京:中科院生物物理研究所,1999.
[119]Cobb HM,Rose MO.The insulin receptor and tyrosine protein kinase activity[J].Biochimica et Biophysica Acta,1984,738(1-2):1-8.
[120]Pullen RA,Lindsay DG,Wood SP,Tickle IJ,Blundell TL,Wollmer A,Krail G,Brandenburg D,Zahn H,Gliemann J,Gammeltoft S.Receptor-binding region of insulin[J].Nature,1976,259:369-73.
[121]Sven F,Lars H.Pharmaceutical Formulation Development of Peptides and Proteins[M].London:Philadelphia,PA Routledge,2000.
[122]Brange J,Langkjaer L.Chemical stability of insulin.3.Influence of excipients,formulation,and pH[J].Acta Pharmaceutica Nordica.1992,4(3):149-58.
[123]Chance RE.Amino acid sequences of proinsulins and intermediates[J].Diabetes.1972,21(2Suppl):461-467.
[124]安富荣,苏德森,刘刚,何仲贵,唐星.HPLC法研究胰岛素溶液的化学稳定性.中国生化药物杂志,1992,62(4):19-22.
[125]Fisher BV,Porter PB.Stability of bovine insulin[J].Journal of Pharmacy and Pharmacology.1981,33(4):203-206.
[126]Grudzielanek S,Jansen R,Winter R.Solvational Tuning of the Unfolding,Aggregation and Amyloidogenesis of Insulin[J].Journal of Molecular Biology,2005,351:879-894.
[127]Manning MC,Randolph TW,Shefter E,Falk RF.Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same[P].US:5770559,1999
[128]朱月.胰岛素的生理生化作用[J].赤峰学院学报(自然科学版),2007,23(1):52-53.
[129]朱本章,马卫国,南佳彦.胰岛素抗炎作用的研究及应用进展[J].中国实用内科杂志,2006,26(17):1309-1311
[130]Yeo SD,Lim G,Debenedetti PG,Bernestein H.Formulation of microparticulate protein powders using a supercritical fluid antisolvent[J].Biotechnology and Bioengineering,1993,41:341-346.
[131]Yeo SD,Debenedetti PG,Patro SY.Secondary structure characterization of microparticulate insulin powders[J].Journal of Pharmaceutical Sciences,1994,83(5):1651-1656.
[132]Winters MA,Debenedetti PG,Carey J,Sparks H G,Sane S U,Praybycien T M.Long-Term and High-Temperature storage of supercritically-processed microparticulate protein powders[J].Pharmaceutical Research.1997,14(10):1370-1378.
[133]Snavely WK,Subramaniam B,Rajewski RA,Defelippis MR.Micronization of Insulin from Halogenated Alcohol Solution Using Supercritical Carbon Dioxide as an Antisolvent[J].Journal of pharmaceutical sciences,2002,91(9):2026-2039.
[134]Foster NR,Regtop H L,Dehgni F,Bustami RT,Chan HK.Synthesis of small particles[P].WO:45690 A1,2002.
[135]杰弗里·佐贝.生物化学(上册)[M],上海:复旦大学出版社,1989:44-45.
[136]陈钧辉,陶力,李俊,朱婉华,袁玉荪.生物化学实验[M],北京:科学出版社,2003.
[137]Takenaga M,Yamaguchi Y,Kitagawa A,Ogawa Y,Mizushima Y,Igarashi R.A novel sustained-release formulation of insulin with dramatic reduction in initial rapid release[J].Journal of Controlled Release,2002,79:81-91.
[138]Yamaguchi Y,Takenaga M,Kitagawa A,Ogawa Y,Mizushima Y,Igarashi R.Insulin-loaded biodegradable PLGA microcapsules:initial burst release controlled by hydrophilic additives[J].Journal of Controlled Release,2002,81:235-249.
[139]Wang LY,Gub YH,Zhoua QZ,Maa GH,Wan YH,Sua ZG.Preparation and characterization of uniform-sized chitosan microspheres containing insulin by membrane emulsification and a two-step solidification process[J].Colloids and Surfaces B:Biointerfaces,2006,50:126-135.
[140]汪穗福.药品生物检定技术[M].北京:中国医药科技出版社,1999.
[141]李湛君,杨昭鹏,徐康森.重组人胰岛素效价测定中生物测定与理化测定的相关性验证[J],药物分析杂志,1998,18:241-243.
[142]陈西敬,朱家壁,王广基,路丽芳,徐越宁,周明霞,雷芬.HPLC法和生物检定法对胰岛素吸入粉雾访剂含量测定的比较[J],中国药科大学学报,2001,32(4):313-314.
[143]王建华,卫亚丽,文宗河,何建川.蛋白质结构的FT-IR研究进展[J].化学通报,2004,7:482-486.
[144]Jorgeuseu L,Vermehren C,Bjerregaard S,Froekjaer S.Secondary structure alterations in insulin and growth hormone water-in-oil emulsions[J].International Journal of Pharmaceutics,2003,254:7-10.
[145]Sajeesh S,Sharma CP.Cyclodextrin-insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery[J].International Journal of Pharmaceutics,2006,325:147-154.
[146]Rosa G,Larobina D,Immacolata La Rotonda M,Mustoc P,Quaglia F,Ungaro F.How cyclodextrin incorporation affects the properties of protein-loaded PLGA-based microspheres:the case of insulin/hydroxypropyl-h-cyclodextrin system[J].Journal of Controlled Release,2005,102: 71-83.
[147]Sarmento B,Ferreira DC,Jorgensen L,van de Weert M.Probing insulin' s secondary structure after entrapment into alginate/chitosan nanoparticles[J].European Journal of Pharmaceutics and Biopharmaceutics,2007,65:10-17.
[148]Jime'nez JL,Nettleton EJ,Bouchard M,Robinson CV,Dobson CM,Saibil HR.The protofilament structure of insulin amyloid fibrils[J].Proceedings of the National Academy of Sciences of the United States of America,USA,2002,99:9196-9201.
[149]Dzwolak W,Grudzielanek S,Smirnovas V,Ravindra R,Nicolini C,Jansen R,Loksztejn A,Porowski S,Winter R.Ethanol-Perturbed Amyloidogenic Self-Assembly of Insulin:Looking for Origins of Amyloid Strains[J].Biochemistry,2005,44:8948-8958.
[150]Pikal MJ,Rigsbee DR.The stability of insulin in crystalline and amorphous solids:observation of greater stability for the amorphous form[J].Pharmaceutical Research,1997,14,(10):1379-1387.
[151]古练权.生物化学[M].北京:高等教育出版社,2000.
[152]Reithmeier H,Herrmann J,Go"pfericha A.Lipid microparticles as a parenteral controlled release device for peptides[J].Journal of Controlled Release,2001,73:339-350.
[153]Carter DC,Ho JX.Structure of serum albumin[J],Advances in Protein Chemistry,1994,45:153-203.
[154]Guse C,Koennings S,Kreye F,Siepmann F,Goepferich A,Siepmann J.Drug release from lipid-based implants:Elucidation of the underlying mass transport mechanisms[J].International Journal of Pharmaceutics,2006,314:137-144.
[155]Appel B,Maschke A,Weiser B,Sarhan H,Englert C,Angele P,Blunk T,Gopferich A.Lipidic implants for controlled release of bioactive insulin:Effects on cartilage engineered in vitro[J].International Journal of Pharmaceutics,2006,314:170-178.
[156]Menei P,Venier M C,Gamelin E,Saint-Andre J P,Hayek G,Jadaud E,Fournier D,Mercier P,Guy G,Benoit JP.Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma:a pilot study[J].Cancer,1999,86:325-330.
[157]Menei P,Jadaud E,Faisant N,Boisdron-Celle M,Michalak S,Fournier D,Delhaye M,Benoit JP.Stereotaxic implantation of 5-fluorouracil-releasing microspheres in malignant glioma[J].Cancer,2004,100:405-410.
[158]Menei P,Capelle L,Guyotat J,Fuentes S,Assaker R.,Bataille B,Francois P,Dorwling-Carter D,Paquis P,Bauchet L,Parker F,Sabatier J,Faisant N,Benoit J P.Local and sustained delivery of 5- fluorouracil from biodegradable microspheres for the radiosensitization of malignant glioma:a randomized phase Ⅱ trial[J].Neurosurgery,2005,56:242-248.
[159]Grizzi I,Garrean H.,Li S,Vert M.Hydrolytic degradation of devices based on poly(dl-lactic acid) size-dependence[J].Biomaterials,1995,16:305-311.
[160]Lu L,Garcia C A,Mikos AG.In vitro degradation of thin poly(dllactic-co-glycolic acid) films[J].Journal of Biomedical Materials Research,1999,46:236-244.
[161]Kang J,Schwendeman S P.Comparison of the effects of Mg(OH)_2 and sucrose on the stability of bovine serum albumin encapsulated in injectable poly(d,l-lactide-co-glycolide)implants[J].Biomaterials,2002,23:239-245.
[162]Lucke A,Fustella E,Tessmar J,Gazzaniga A,Goepferich A.The effect of poly(ethylene glycol)-poly(d,l-lactic acid) diblock copolymers on peptide acylation[J].Journal of Control.Release 2002,80:157-168.
[163]Lucke A,Goepferich A.Acylation of peptides by lactic acid solutions[J].European Journal of Pharmaceutics and Biopharmaceutics,2003,55:27-33.
[164]Thomas TT,Kohane DS,Wang A,Langer R.Microparticulate formulations for the controlled release of interleukin-2[J].Journal of Pharmaceutical Sciences,2004,93:1100-1109.
[165]Dellamary L,Smith D J,Bloom A,Bot S,Guo G R,Deshmuk H,Costello M,Bot A.Rational design of solid aerosols for immunoglobulin delivery by modulation of aerodynamic and release characteristics[J].Journal of Controlled Release,2004,95:489-500.
[166]Prego C,Garcia M,Torres D,Alonso M J.Transmucosal macromolecular drug delivery[J].Journal of Controlled Release,2005,101:151-162.
[167]Bustami RT,Chan HK.Generation of protein microparticles using high pressure modified carbon dioxide[A].Proceedings of the 5th International Symposium on Supercritical Fluids,Atlanta,2000.
[168]Domingo C,Vega A,Fanovich MA,Elvira C,Subra P.Behavior of Poly(methylmethacrylate)-Based Systems in Supercritical CO_2 and CO_2 Plus Cosolvent:Solubility Measurements and Process Assessment[J].Journal of Applied Polymer Science,2003,90:3652-3659.
[169]Yoshida E,Imamura H.Synthesis of poly[2-(perfluorooctyl)ethyl acrylate-co-poly(ethylene glycol) methacrylate]and its control of enzyme activity in supercritical carbon dioxide[J].Colloid and Polymer Science,2007,285(13):1463-1470.
[170]Whitaker MJ,Hao JY,Davies OR,Serhatkulu G,Stolnik-Trenkic S,Howdle SM,Shakesheff KM.The production of protein-loaded microparticles by supercritical fluid enhanced mixing and spraying[J].Journal of Controlled Release,2005,101:85-92.
[171]Rosenkranz K,Kasper MM,Werther J,Brunner G.Encapsulation of irregularly shaped solid forms of proteins in a high-pressure fluidized bed,Journal of Supercritical Fluids,2007.
[172]Jovanovi' N,Bouchard A,Hofland GW,Witkamp GJan,Crommelin DJA,Jiskoot W.Distinct effects of sucrose and trehalose on protein stability during supercritical fluid drying and freeze-drying.European Journal of Pharmaceutical Sciences,2006,2 7:336 - 345.
[173]Amidi M,Pellikaan HC,Boer AH,Crommelin DJ.A,Hennink WE,Jiskoot W.Preparation and physicochemical characterization of supercritically dried insulin-loaded microparticles for pulmonary delivery.European Journal of Pharmaceutics and Biopharmaceutics 2008,68:191-200.
[174]Dos Santos IR,Richard J,Pech B,Thies C,Benoit JP.Microencapsulation of protein particles within lipids using a novel supercritical fluid procoss[J].International Journal of Pharmacognosy,2002,242:69-78.
[175]Dos Santos IR,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].Journal of Microencapsulation,2003,20:110-128.
[176]Meziani MJ,Sun YP.Protein-conjugated nanoparticles from rapid expansion of supercritical fluid solution into aqueous solution[J].Journal of the American Chemical Society,2003,125:8015-8018.
[177]Meziani MJ,Rollins HW,Allard LF,Sun YP.Protein-protected nanoparticles from rapid expansion of supercritical solution into aqueous solution[J].Journal of Physical Chemistry B,2002,106:171-178.
[178]Martin RB,Meziani MJ,Pathak P,Riggs JE,Cook DE,Perera S,Sun YP.Optical limiting of silver-containing nanoparticles[J].Optical Materials,2007,29:788-793.
[179]Zhang JL,Han BX,Chen J,Li ZH,Liu ZM,Wu WZ.Synthesis of Ag/BSA Composite Nanospheres from Water-in-Oil Microemulsion Using Compressed CO2 as Antisolvent[J].Biotechnology and Bioengineering,2005,89(3):274-279.
[180]Pathak P,Meziani MJ,Desai T,Sun YP.Formation and stabilization of ibuprofen nanoparticles in supercritical fluid processing[J].Journal of Supercritical Fluids,2006,37:279-286.
[181]Kim YH,Sioutas C,Fine P,Shing KS.Effect of Albumin on Physical Characteristics of Drug Particles Produced by Supercritical Fluid Technology[J].Powder Technology,2008,182:354-363.
[182]孙宝国.日用化工辞典[M].化学工业出版社,2002.
[183]朱明,胡金莲,王利平.用电子显微镜和差热扫描仪等方法研究乳脂的结构和性质[J].冷饮与速冻食品工业,1996:22-23.
[184]Vogelhuber W,Magni E,Mouro M,Spruβ T,Guse C,Gazzaniga A,Goepferich A.Monolithic triglycerides matrices:a controlled release system for proteins[J].Pharmaceutical Development and Technology,2003,8:71-79.
[185]Pongjanyakul,T,Medlicott NJ,Tucker IG.Melted glyceryl palmitostearate(GPS) pellets for protein delivery[J].International Journal of Pharmaceutics,2004,271:53-62.
[186]陈辉.PGSS技术制备布洛芬和肉豆蔻酸微粒及其微胶囊[D].厦门大学,2007.
[187]Johnson RW,Fritz E.工业脂肪酸及其应用[M].轻工业出版社,1992:13.
[188]陆彬.药物新剂型与新技术[M].人民卫生出版社,2005:7.
[189]宗莉,朱辉,吴德平,朱家壁.PEG6000、聚山梨酯80增加尼群地平溶出度的研究[J].中国药科大学学报,2000,1:21-24.
[190]Soares BMC,Gamarra FMC,Paviani LC,Goncalves LAG,Cabral FA.Solubility of triacylglycerols in supercritical carbon dioxide[J].J.of Supercritical Fluids 2007,43:25-31
[2]谢鸿森.地球深部物质科学导论[M],北京:科学出版社,1997,1:215-220.
[3]DeSimone JM,Tumas W.Green Chemistry Using Liquid and Supercritical Carbon Dioxide[M].New York Oxford University Press(US),2003.
[4]朱自强.超临界流体技术-原理和应用[M],北京:化学工业出版社.2000.
[5]Yasuhiko A,Takeshi F.Characteristics of supercritical fluids[J].The review of high pressure science and technology.The Japan society of high pressure and technology,1993,4:262-264.
[6]Weidner E,Petermann M,Knez Z.Multifunctional composites by high-pressure spray processes[J].Current Opinion in Solid State and Materials Science,2003,7:385-390.
[7]Mandel F S,Wang J D.Manufacturing of specialty materials in supercritical fluid carbon dioxide[J].Inorganica Chimica Acta,1999,294:214-22.
[8]丁廷桢.大学化学教程 原理·应用·前沿[M],北京:高等教育出版社,2003,1:215-220.
[9]祁鲁梁.工业用水节水与水处理技术术语大全[M],北京:中国水利水电出版社,2003,1:519-522.
[10]漆新华,庄源益.超临界流体技术在环境科学中的应用[M],北京:科学出版社,2005.
[11]Jovanovic N,Bouchard A,Hofland GW,Witkamp G,Crommelin D J,Jiskoot W.Stabilization of proteins in dry powder formulations using supercritical fluid technology[J].Pharmaceutical Research,2004,21(11):1955-1979.
[12]Tom JW,Debenedetti PG.Nucleation of biocompatible polymers[A].Proceedings of the 2nd International Symposium on Supercritical Fluids[C].Boston,1991.229-232.
[13]Jennifer J,Michel P.Particle design using supercritical fluids:Literature and patent survey[J],Journal of Supercritical Fluids,2001,20:179-219.
[14]Domingo C,Berends E,Rosmalen G M.Precipitation of ultrafine organic crystals from the rapid expansion of supercritical solutions over a capillary and a flit nozzle[J].Journal of Supercritical Fluids,1997,10(1):39-55.
[15]Reverchon E,Denis G.Salicylic acid solubilization in supercritical CO_2 and its micronization by RESS[J].Journal of Supercritical Fluids,1993,6:241-248.
[16]Mohamed RS,Debenadetti PG,Prud homme RK.Effects of Process Conditions on Crystals Obtained from Supercritical Mixtures[J].AIChE J,1989,35(2):325-328.
[17]刘燕,王威强,李爱菊.超临界流体技术制备超微材料应用[J].化学工程.2004,32:47-51.
[18]赵亚冬.二氧化碳和氮气辅助微粒形成技术[D].厦门大学,2006.
[19]Weidner E,Steiner R,Knez Z,Novak Z.Powder generation form polyethyleneglycols with compressible fluids[J].High Pressure Chemical Engineering,1996,223-228.
[20]Kappler P,Leiner W,Petermann M,Weidner E.Size and morphology of particles generated by spraying polymer-melts with carbon dioxide[A].Proceedings of the Sixth International Symposium on Supercritical Fluids,Versailles(France),2003.
[21]Knez Z.High pressure micronisation of polymers[A].Proceedings of the Sixth International Symposium on Supercritical Fluids,Versailles(France),2003.
[22]Sencar-Bozic P,Srcic S,Kenz Z,Kerc J.Improvement of nfifedipine dissolution characteristics using supercritical CO_2[J].International of Journal of Pharmaceutics,1997,148(2):123-130.
[23]Rodrigues M,Pcirico N,Matos H,de Azevedo EG,Lobato M R,Almeida A J.Microcomposites theophylline/hydrogenatcd palm oil from a PGSS process for controlled drug delivery systems[J].Journal of Supercritical Fluids,2004,29:175-184.
[24]Li J,Rodrigues M,Paiva A,Matos H,de Azevedo EG.Modeling of the PGSS process by Crystallization and Atomization[J].AIChE J,2005,51:2343-2350.
[25]Gallagher P M,Coffey M P,Krukonis V J,Klasutis N.Gas antisolvent recrystallization:New process to recrystallize compounds insoluble in superoritical fluids[A].Supercritical Fluid Science and Technology,American Chemical Society,Washington D.C.,1989,406:334-354.
[26]Bleich J,Muller BW,Wabmus W.Aerosol solventextraction system:a new microparticle production technique[J].International Journal of Pharmaceutics,1993(97):111- 117.
[27]Bodmeier R,Wang H,Dixon DJ,Mawson S,Johnston KP.Polymeric microspheres prepared by spraying into compressed carbon dioxide[J].Pharmaceutical Research,1995,12:1211-1217.
[28]Hanna M,York P.Method and apparatus for the formation of particles[P],WO95/01221,1994.
[29]Vemavarapu C,Mollan MJ,Lodaya M,Needham TE.Design and process aspects of laboratory scale SCF particle formation systems[J].International Journal of Pharrnaccutics 2005,292:1-16.
[30]Krukonis VJ.Supercritical fluid nucleation of difficult-to-comminute solids[A].AIChE Annual Meeting[C].San Francisco,CA.1984,11:140-149.
[31]Krukonis VJ,Gallagher PM,Coffey MP,Gas anti-solvent recrystalization process[P],Patent US,5 360 478,1991.
[32]Berends EM,Bruinsma OSL,Graauw J,van Rosmalen GM.Crystallisation of phcnanthrene from toluene with carbon dioxide as the anti-solvent by the gas-process[A],Proceedings of the 3rd International Symposium on Supercritical Fluids,Tome 3,Brunner G,Perrut M.(Eds.),Strasbourg,1994:223-228.
[33]Kitamura M,Yamamoto M,Yoshinaga Y.Crystal Size Control of Sulfathiazole Using High Pressure Carbon Dioxide[J].Chemistry Engineering Symposium Series.1995,4:200-205.
[34]Dillow AK,Dehghani F,Foster NR.Production of polymeric support materials using a supercritical fluid anti-solvent process[A],The 4th International Symposium on Supercritical Fluids,Sendai,Japan,1997:247-250.
[35]Rcverchon E,De Marco I,Della Porta G.Rifampicin microparticles production by supercritical antisolvent precipitation[J],International Journal of Pharmaceutics,2002,243:83-91.
[36]Reverchon E,De Marco I,Della Porta G.Tailoring nano- and micro-particles of some superconductor precursors by supercritical antisolvent precipitation[J],Journal of Supercritical Fluids,2002,23:81-87.
[37]Chattopadhyay P,Gupta RB.Production of antibiotic nanoparticles using supercritical CO_2 as antisolvent with enhanced mass transfer[J],Industrial and Engineering Chemistry Research,2001,40:3530-3539.
[38]Yeo SD,Lim GB,Debenedetti PG.Formation of Microparticulate Protein Powers Using a Supercritical Fluid Antisolvent[J].Biotechnology and Bioengineering,1993,41(3):341-346.
[39]Winters MA,Knutson BL,Debenedetti PG.Precipitation of proteins in supercritical carbon dioxide[J].Journal of Pharmaceutical Sciences,1996,85:586-594.
[40]Thiering R,Dehghani F,Dillow A,Foster NR.The influence of operating conditions on the dense gas precipitation of model proteins[J].Journal of Chemical Technology and Biotechnology,2000,75:29-41.
[41]Thiering R,Dehghani F,Dillow A,Foster NR.Solvent effects on the controlled dense gas precipitation of model proteins[J].Journal of Chemical Technology and Biotechnology,2000,75:42- 53.
[42]Muller BW,Fischer W.Method and apparatus for the manufacture of a product having a substance embedded In a carrier[P].US:5043280,1991.
[43]Elvassore N,Bertucco A,Caliceti P.Production of Insulin-Loaded Poly(Ethylene Glycol)/Poly(L-Lactide)(PEG/PLA) Nanoparticles by Gas Antisolvent Techniques[J].Journal of Pharmaceutical Sciences,2001,90,10:1628-1636.
[44]Calicetia P,Salmaso S,Elvassore N,Bertucco A.Effective protein release from PEG/PLA nano-particles produced by compressed gas anti-solvent precipitation techniques[J].Journal of Controlled Release,2004,94:195-205.
[45]Yeo SD,Kiran E.Formation of polymer particles with supercritical fluids:A review[J].Journal of Supercritical Fluids,2005,34:287-308.
[46]Byrappa K,Ohara S,Adschiri T.Nanoparticles synthesis using supercritical fluid technologytowards biomedical applications[J].Advanced Drug Delivery Reviews,2008,60:299-327.
[47]Schmitt WJ.Finely Derided solid crystaline powders via preciptation into anti-solvent[P],US Patent 5707634,1998.
[48]Dixon DJ,Luna-Barcenas G,Johnston KP.Microcellular microspheres and microballoons by precipitation with a vapour-liquid compressed fluid antisolvent[J].Polymer,1994,35:3998-4005.
[49]Debenedetti PG,Lira GB,Prud'Homme RK.Formation of protein microparticles by anti-solvent precipitation[P],European Patent,EP 0542314,1992.
[50]Sze TL,Dehghani F,Foster NR.Micronization and microencapsulation of pharmaceuticals using a carbon dioxide antisolvent[J],Powder Technology,2002,126(2):134-149.
[51]Bustami RT,Hak-Kim C,Dehghani F,Foster NR.Generation of Micro-Particles of Proteins for Aerosol Delivery Using High Pressure Modified Carbon Dioxide[J].Pharmaceutical Research,2000,17(11):1360-1366.
[52]Elvassore N,Bertucco A,Caliceti P.Production of protein loaded polymeric microcapsules by compressed CO_2 in mixed solvent[J],Industrial and Engineering Chemistry Research,2001,40(3):795-800.
[53]Shekunov BY,Baldyga J,York P.Particle formation by mixing with supercritical antisolvent at high Reynolds numbers[J].Chemical Engineering Science,2001,56:2421-2433.
[54]Juppo A M,Boissier C,Khoo C.Evaluation of solid dispersion particles prepared with SEDS[J].International Journal of Pharmaceutics,2003,250:385-401.
[55]Hanna M,York P.Method and apparatus for the formation of particles[P],Patent WO 9600610,1995.
[56]Hanna M,York P.Methods and apparatus for particle formation[P],European Patent WO 9959710,1999.
[57]Ghaderi R,Artursson P,Carlfors J.A new method for preparing biodegradable microparticles and entrapment of hydrocortisone in DL-PLG microparticles using supercritical fluids[J].European Journal of Pharmaceutical Sciences,2000,10:1-9.
[58]Sloan R,Hollowood ME,Humpreys GO.Supercritical fluid processing:preparation of stable protein particles[A],Proceedings of the 5th Meeting on Supercritical Fluids,Tome 1;Perrut M.,Subra P.(Eds.),Nice,1998,301-306.
[59]Sloan R,Tservistas M,Hollowood ME.Controlled particle formation of biological material using supercritical fluids[A],Proceedings of the 6th Meeting on Supercritical Fluids,Chemistry and Materials,Poliakoff M,George MW,.Howdle SM(Eds.),Nottingham,1999,169-174.
[60]Sarup L,Servistas MT,Sloan R,Hoare M,Humphreys GO.Investigation of supercritical fluid technology to produce dry particulate formulations of antibody fragments[J].Institution of Chemical Engineers,Trans IChemE,2000,78:101-104.
[61]York P,Hanna M.Salmeterol Xinafoate with controlled particle size[P].International Patent Publication WO 95/01324,1995.
[62]Sze TL,Dehghani F,Dillow A K,Foster NR.Applications of Dense Gases in Pharmaceutical Processing[A].Proceedings of the 5th Meeting on Supercritical Fluids,Tome 1;M.Perrut,P.Subra (Eds.),ISBN 2-905-267-28-3,23-25 March,Nice,1998,263-269.
[63]Li J,Rodrigues M,Paiva A,Matos H,de Azevedo EG.Vapor-liquid equilibrium and volume expansion of the tetrahydrogenfuran/CO_2 system:applications to a SAS-atomization process[J],Journal of Supercritical Fluids,2007,41:343-351.
[64]Rodrigues M,Li J,Matos H,Almeida A,de Azevedo EG.Control of the morphology of microparticles produced by supercritical CO_2 from water/ethanol solutions[J],2007,in preparation.
[65]Zhao L,Li J,Rodrigues M,Matos H,de Azevedo EG,Using N_2- or CO_2-assisited atomization process to produce polyethylene glycol microparticles[J],Chemical Engineering Research and Design,2007,85(7):987-995.
[66]Li J,Rodrigues M,Mates H,de Azevedo EG.VLE of Carbon dioxide/ethanol/water:application for evaluation the system volume expansion and water removal efficiency[J],Industrial and Engineering Chemistry Research,2005,44(17):6751-6759.
[67]赵磊.超临界流体抗溶剂-雾化技术制备PEG和BSA颗粒[D],厦门大学,2007.
[68]Chang CJ,Chin KL,Day CY.A new apparatus for the determination of P-x-y diagrams and Henry's constants in high pressure alcohols with critical carbon dioxide[J],Journal of Supercritical Fluids,1998,12:223-237.
[69]Bamberger A,Maurera G.High-pressure(vapour + liquid) equilibria in(carbon dioxide +acetone or 2-propanol) at temperatures from 293 K to 333 K[J],The Journal of Chemical Thermodynamics,2000,32:685-700.
[70]Chen JW,Wu WZ,Han BX,Gao L,Mu TC,Liu ZM,Jiang T,Du JM.Phase behavior,densities,and isothermal compressibility of CO2 +pentane and CO2 + acetone systems in various phase regions[J],Journal of Chemical and Engineering Data,2003,48:1544-1548.
[71]Wu JL,Pan QM,and Rempel GL.Pressure-density-temperature behavior of CO_2/acetone,CO_2/toluene,and CO_2/monochlorobenzene mixtures in the near-critical region[J],Journal of Chemical and Engineering Data,2004,49:976-979.
[72]Lazzaroni MJ,Bush D,Brown JS,Eckert CA.High-pressure vapor-liquid equilbria of some carbon dioxide + organic binary systems[J],Journal of Chemical and Engineering Data,2005,50:60-65.
[73]Stievano M,Elvassore N.High-pressure density and vapor-liquid equilibrium for the binary systems carbon dioxide-ethanol,carbon dioxide-acetone and carbon dioxide-dichloromethane[J],Journal of Supercritical Fluids,2005,33:7-14.
[74]Han F,Xue Y,Tian YL,Zhao XF,Chen L.Vapor-liquid equilibria of the carbon dioxide +acetone system at pressures from(2.36 to 11.77) MPa and temperatures from(333.15 to 393.15)K[J],Journal of Chemical and Engineering Data,2005,50:36-39.
[75]Nishiumi H,Fujita M,Agou K.Diffusion of acetone in supercritical carbon dioxide[J],Fluid Phase Equilibria,1996,117:356-363.
[76]Yoon JH,Lee HS,Lee H.High-pressure Vapor-Liquid Equilibria for Carbon Dioxide +Methanol,Carbon Dioxide + Ethanol,and Carbon Dioxide + Methanol + Ethanol[J].Journal of Chemical and Engineering Data,1993,38:53-55.
[77]田宜灵,韩铭,陈丽,冯季军,秦颖.高压下CO_2-乙醇二元系统的汽液平衡[J].物理化学学报.2001,17(2):155-160.
[78]Seung NJ,Chang WY,Hun YS.Measurements and correlation of high-pressure VLE of binary CO2-alcohol systems(methanol,ethanol,2-methoxyethanol and 2-ethoxyethanol)[J],Fluid Phase Equilibria,2001,185:219-230.
[79]Suzuki K,Sue H.Isothermal Vapor-Liquid Equilibrium Data for Binary Systems at High Pressures:Carbon Dioxide-Methanol,Carbon Dioxide-Ethanol,Carbon Dioxide-I-Propanol, Methane-Ethanol,Methane-I-Propanol,Ethane-Ethanol,and Ethane-I-Propanol Systems[J].Journal of Chemical and Engineering Data,1990,35:63-66
[80]Jennlngs DW,Lee R,Teja AS.Vapor-Liquid Equilibria in the Carbon Dioxide + Ethanol and Carbon Dioxide + 1-Butanol Systems[J].Journal of Chemical and Engineering Data,1991,36:303- 307.
[81]Elbaccouch MM,Raymond MB,Elliott JR.High-Pressure Vapor-Liquid Equilibrium for R-22 + Ethanol and R-22 + Ethanol + Water[J].Journal of Chemical and Engineering Data,2000,45:280- 287.
[82]Gilbert ML,Paulaltls ME.Gas-liquid equilibrium for ethanol-water-carbon dioxide mixtures at elevated pressures[J],Journal of Chemical and Engineering Data,1986,31:296-298.
[83]Budich M,Brunner G Supercritical fluid extraction of ethanol from aqueous solutions[J],Journal of Supercritical Fluids,2003,25:45-55.
[84]Durling NE,Catchpole OJ,Tallon SJ,Grey JB.Measurement and modeling of the ternary phase equilibria for high pressure carbon dioxide-ethanol-water mixtures[J],Fluid Phase Equilibria,2007,252:103-113.
[85]Takishima S,Saiki K,Arai K,Saito S.Phase equilibria for the CO_2-C_2H_5OH-H_2O system[J],Journal of Chemical Engineering of Japan,1986,19:48-56.
[86]Inomata H,Arai K,Saito S,Ohba S,Takeuchi K.Measurement and prediction of phase equilibria for the CO_2-ethanol-water system[J],Fluid Phase Equilibria,1989,53:23-30.
[87]Lim JS,Lee YY,Chun HS.Phase equilibria for carbon dioxide-ethanol-water system at Elevated Pressures[J],Journal of Supercritical Fluids,1994,7:219-230.
[88]Feng YS,Du XY,Li CF,Hou YJ.An apparatus for determining high-pressure fluid phase equilibria and its applications to supercritical carbon dioxide mixtures[A],International Symposium on Supercritical Fluids,Perrut M.Ed.,Nice,France,1988,1:75-84.
[89]Dahl S,Dunalewicz A,Fredenslund A,Rasmussen P.The MHV2 model:prediction of phase equilibria at sub- and supercritical conditions[J],Journal of Supercritical Fluids,1992,5:42-47.
[90]Inomata H,Arai K,Saito S,Ohbas S,Takeuchi K.Measurement and prediction of phase equilibria for the CO_2- ethanol-water system[J],Fluid Phase Equilibria,1989,53:23-30.
[91]Yao S,Guan Y,Zhu Z.Investigation of phase equilibrium for ternary systems containing ethanol,water and carbon dioxide at elevated pressures[J],Fluid Phase Equilibria,1994,99:249-259.
[92]Kordikowsk A,Schenk AP,Van Nielen RM,Peters CJ.Volume Expansions and Vapor-Liquid Equilibria of Binary Mixtures of a Variety of Polar Solvents and Certain Near-Critical Solvents[J].Journal of Supercrtical Fluids,1995,8:205-216
[93]Peneloux A,Ranzy EA.A consistent correction for Redlich-Kwong-Soave volumes.Fluid Phase Equilibria,1982,8:7-23.
[94]Magoulas K,Tassios D.Thermophysical Properties of n-alkanes from C1 to C20 and their Prediction for Higher Ones.Fluid Phase Equilibria,1990,56:119-140.
[95]林鸿,段远源.卤代烃的Peng-Robinson状态方程的密度修正.工程热物理学报.2006,27:13-16.
[96]Panagiotopoulos AZ,Reid RC.High-pressure phase equilibria in ternary fluid mixtures with a supercritical component[A],In Supercritical Fluids Chemical and Engineering Principles and Applications,Squires TG,Paulaitis ME,Eds.,ACS Symposium Series 329,Washington,DC,1985:115-129.
[97]陈新志,蔡振云,胡望明.化工热力学[M],北京:化学工业出版社,2001,1:88-89,128-146.
[98]Stryjek R,Vera JH.PRSV:An improved peng-robinson equation of state for pure compounds and mixtures[J],The Canadian Journal of Chemical Engineering,1986,64:323-333.
[99]Henczka M,Baldyga J,Shekunov BY.Particle formation by turbulent mixing with supercritical antisolvent[J],Chemical Engineering Science,2005,60:2193-2201.
[100]Li ZY,Xia YJ,Liu XW,Deng XL,Hu DP.Study of the Liquid Phase Volume Expansion for CO2/Organic Solvent Systems.Chinese Journal of Chemical Engineering,2005,13(4):504-509.
[101]严瑞瑄.水溶性高分子[M],北京:化学工业出版社,1998:223-243.
[102]中国药典2005年版.二部[M],北京:化学工业出版社,2005.
[103]Betageri GV,Makarla KR.Enhancement of dissolution of glyburide by solid dispersion and lyophilization techniques[J],International Journal of Pharmaceutics,1995,126:155-160.
[104]Nalawade SP,Picchioni F,Janssen LPBM.Batch production of micron size particles from poly(ethylene glycol) using supercritical CO_2 as a processing solvent[J],Chemical Engineering Science,2007,62:1712-1720.
[105]姚悦.高粘度流体气力雾化机理及试验研究[D].浙江大学.2006.
[106]Rantakyla M,Jantti M,Aaltonen O,Hurme M.The effect of initial drop size on particle size in the supercritical antisolvent precipitation(SAS) technique[J],Journal of Supercritical Fluids.2002,24:251-263.
[107]Matsuyama K,Mishima K.Phase behavior of CO_2 + polyethylene glycol + ethanol at pressures up to 20MPa[J].Fluid Phase Equilibria,2006,249:173-178.
[108]Shekunov BY.Production of powders for respiratory drug delivery[A],In Supercritical Fluid Technology for Drug Product Development,Edited by York P,Kompella UB,Shekunov BY,Marcel Dekker INC.Basel,New York,2004,10:247-282.
[109]Patton JS,Bukar J,Nagarajan S.Inhaled insulin[J].Advanced drug delivery reviews,1999,35(223):235-238.
[110]Shoyele SA,Cawthorne S.Particle engineering techniques for inhaled biopharmaceuticals[J],Advanced Drug Delivery Reviews,2006,58(9):1009-1029.
[111]Hakuta Y,Hayashi H,Arai K.Fine particle formation using supercritical fluids[J].Current Opinion in Solid State and Materials Science,2003,7:341-351.
[112]gyle AF,Sanger F,Smith F,Kitai K.The disulphide bonds of insulin[J].Biochemical Journal,1955,60(4):541-556.
[113]黄涛.化学修饰胰岛素的制备、表征和生物活性[D].华中科技大学,2004.
[114]Kaarsholm NC,Ko HC,Dunn MF.Comparison of solution structural flexibility and zinc binding domains for insulin,proinsulin,and mini-proinsulin[J].Biochemistry,1989,28:4427-4435.
[115]Conlon JM.Evolution of the insulin molecule:insights into structure-activity and phylogenetic relationships[J].Peptides,2001,22:1183-1193.
[116]Reverchon E.Supercritical antisolvent precipitation of micro-and nano-particles[J].Journal of Supercritical Fluids,1999,15:1-21.
[117]Gammeltoft S.Insulin receptor binding kinetics and structure-function relationship of insulin[J].Physiological Reviews,1984,64:1321-1378.
[118]刘新奇.单体人胰岛素突变体的晶体学研究[M].北京:中科院生物物理研究所,1999.
[119]Cobb HM,Rose MO.The insulin receptor and tyrosine protein kinase activity[J].Biochimica et Biophysica Acta,1984,738(1-2):1-8.
[120]Pullen RA,Lindsay DG,Wood SP,Tickle IJ,Blundell TL,Wollmer A,Krail G,Brandenburg D,Zahn H,Gliemann J,Gammeltoft S.Receptor-binding region of insulin[J].Nature,1976,259:369-73.
[121]Sven F,Lars H.Pharmaceutical Formulation Development of Peptides and Proteins[M].London:Philadelphia,PA Routledge,2000.
[122]Brange J,Langkjaer L.Chemical stability of insulin.3.Influence of excipients,formulation,and pH[J].Acta Pharmaceutica Nordica.1992,4(3):149-58.
[123]Chance RE.Amino acid sequences of proinsulins and intermediates[J].Diabetes.1972,21(2Suppl):461-467.
[124]安富荣,苏德森,刘刚,何仲贵,唐星.HPLC法研究胰岛素溶液的化学稳定性.中国生化药物杂志,1992,62(4):19-22.
[125]Fisher BV,Porter PB.Stability of bovine insulin[J].Journal of Pharmacy and Pharmacology.1981,33(4):203-206.
[126]Grudzielanek S,Jansen R,Winter R.Solvational Tuning of the Unfolding,Aggregation and Amyloidogenesis of Insulin[J].Journal of Molecular Biology,2005,351:879-894.
[127]Manning MC,Randolph TW,Shefter E,Falk RF.Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same[P].US:5770559,1999
[128]朱月.胰岛素的生理生化作用[J].赤峰学院学报(自然科学版),2007,23(1):52-53.
[129]朱本章,马卫国,南佳彦.胰岛素抗炎作用的研究及应用进展[J].中国实用内科杂志,2006,26(17):1309-1311
[130]Yeo SD,Lim G,Debenedetti PG,Bernestein H.Formulation of microparticulate protein powders using a supercritical fluid antisolvent[J].Biotechnology and Bioengineering,1993,41:341-346.
[131]Yeo SD,Debenedetti PG,Patro SY.Secondary structure characterization of microparticulate insulin powders[J].Journal of Pharmaceutical Sciences,1994,83(5):1651-1656.
[132]Winters MA,Debenedetti PG,Carey J,Sparks H G,Sane S U,Praybycien T M.Long-Term and High-Temperature storage of supercritically-processed microparticulate protein powders[J].Pharmaceutical Research.1997,14(10):1370-1378.
[133]Snavely WK,Subramaniam B,Rajewski RA,Defelippis MR.Micronization of Insulin from Halogenated Alcohol Solution Using Supercritical Carbon Dioxide as an Antisolvent[J].Journal of pharmaceutical sciences,2002,91(9):2026-2039.
[134]Foster NR,Regtop H L,Dehgni F,Bustami RT,Chan HK.Synthesis of small particles[P].WO:45690 A1,2002.
[135]杰弗里·佐贝.生物化学(上册)[M],上海:复旦大学出版社,1989:44-45.
[136]陈钧辉,陶力,李俊,朱婉华,袁玉荪.生物化学实验[M],北京:科学出版社,2003.
[137]Takenaga M,Yamaguchi Y,Kitagawa A,Ogawa Y,Mizushima Y,Igarashi R.A novel sustained-release formulation of insulin with dramatic reduction in initial rapid release[J].Journal of Controlled Release,2002,79:81-91.
[138]Yamaguchi Y,Takenaga M,Kitagawa A,Ogawa Y,Mizushima Y,Igarashi R.Insulin-loaded biodegradable PLGA microcapsules:initial burst release controlled by hydrophilic additives[J].Journal of Controlled Release,2002,81:235-249.
[139]Wang LY,Gub YH,Zhoua QZ,Maa GH,Wan YH,Sua ZG.Preparation and characterization of uniform-sized chitosan microspheres containing insulin by membrane emulsification and a two-step solidification process[J].Colloids and Surfaces B:Biointerfaces,2006,50:126-135.
[140]汪穗福.药品生物检定技术[M].北京:中国医药科技出版社,1999.
[141]李湛君,杨昭鹏,徐康森.重组人胰岛素效价测定中生物测定与理化测定的相关性验证[J],药物分析杂志,1998,18:241-243.
[142]陈西敬,朱家壁,王广基,路丽芳,徐越宁,周明霞,雷芬.HPLC法和生物检定法对胰岛素吸入粉雾访剂含量测定的比较[J],中国药科大学学报,2001,32(4):313-314.
[143]王建华,卫亚丽,文宗河,何建川.蛋白质结构的FT-IR研究进展[J].化学通报,2004,7:482-486.
[144]Jorgeuseu L,Vermehren C,Bjerregaard S,Froekjaer S.Secondary structure alterations in insulin and growth hormone water-in-oil emulsions[J].International Journal of Pharmaceutics,2003,254:7-10.
[145]Sajeesh S,Sharma CP.Cyclodextrin-insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery[J].International Journal of Pharmaceutics,2006,325:147-154.
[146]Rosa G,Larobina D,Immacolata La Rotonda M,Mustoc P,Quaglia F,Ungaro F.How cyclodextrin incorporation affects the properties of protein-loaded PLGA-based microspheres:the case of insulin/hydroxypropyl-h-cyclodextrin system[J].Journal of Controlled Release,2005,102: 71-83.
[147]Sarmento B,Ferreira DC,Jorgensen L,van de Weert M.Probing insulin' s secondary structure after entrapment into alginate/chitosan nanoparticles[J].European Journal of Pharmaceutics and Biopharmaceutics,2007,65:10-17.
[148]Jime'nez JL,Nettleton EJ,Bouchard M,Robinson CV,Dobson CM,Saibil HR.The protofilament structure of insulin amyloid fibrils[J].Proceedings of the National Academy of Sciences of the United States of America,USA,2002,99:9196-9201.
[149]Dzwolak W,Grudzielanek S,Smirnovas V,Ravindra R,Nicolini C,Jansen R,Loksztejn A,Porowski S,Winter R.Ethanol-Perturbed Amyloidogenic Self-Assembly of Insulin:Looking for Origins of Amyloid Strains[J].Biochemistry,2005,44:8948-8958.
[150]Pikal MJ,Rigsbee DR.The stability of insulin in crystalline and amorphous solids:observation of greater stability for the amorphous form[J].Pharmaceutical Research,1997,14,(10):1379-1387.
[151]古练权.生物化学[M].北京:高等教育出版社,2000.
[152]Reithmeier H,Herrmann J,Go"pfericha A.Lipid microparticles as a parenteral controlled release device for peptides[J].Journal of Controlled Release,2001,73:339-350.
[153]Carter DC,Ho JX.Structure of serum albumin[J],Advances in Protein Chemistry,1994,45:153-203.
[154]Guse C,Koennings S,Kreye F,Siepmann F,Goepferich A,Siepmann J.Drug release from lipid-based implants:Elucidation of the underlying mass transport mechanisms[J].International Journal of Pharmaceutics,2006,314:137-144.
[155]Appel B,Maschke A,Weiser B,Sarhan H,Englert C,Angele P,Blunk T,Gopferich A.Lipidic implants for controlled release of bioactive insulin:Effects on cartilage engineered in vitro[J].International Journal of Pharmaceutics,2006,314:170-178.
[156]Menei P,Venier M C,Gamelin E,Saint-Andre J P,Hayek G,Jadaud E,Fournier D,Mercier P,Guy G,Benoit JP.Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma:a pilot study[J].Cancer,1999,86:325-330.
[157]Menei P,Jadaud E,Faisant N,Boisdron-Celle M,Michalak S,Fournier D,Delhaye M,Benoit JP.Stereotaxic implantation of 5-fluorouracil-releasing microspheres in malignant glioma[J].Cancer,2004,100:405-410.
[158]Menei P,Capelle L,Guyotat J,Fuentes S,Assaker R.,Bataille B,Francois P,Dorwling-Carter D,Paquis P,Bauchet L,Parker F,Sabatier J,Faisant N,Benoit J P.Local and sustained delivery of 5- fluorouracil from biodegradable microspheres for the radiosensitization of malignant glioma:a randomized phase Ⅱ trial[J].Neurosurgery,2005,56:242-248.
[159]Grizzi I,Garrean H.,Li S,Vert M.Hydrolytic degradation of devices based on poly(dl-lactic acid) size-dependence[J].Biomaterials,1995,16:305-311.
[160]Lu L,Garcia C A,Mikos AG.In vitro degradation of thin poly(dllactic-co-glycolic acid) films[J].Journal of Biomedical Materials Research,1999,46:236-244.
[161]Kang J,Schwendeman S P.Comparison of the effects of Mg(OH)_2 and sucrose on the stability of bovine serum albumin encapsulated in injectable poly(d,l-lactide-co-glycolide)implants[J].Biomaterials,2002,23:239-245.
[162]Lucke A,Fustella E,Tessmar J,Gazzaniga A,Goepferich A.The effect of poly(ethylene glycol)-poly(d,l-lactic acid) diblock copolymers on peptide acylation[J].Journal of Control.Release 2002,80:157-168.
[163]Lucke A,Goepferich A.Acylation of peptides by lactic acid solutions[J].European Journal of Pharmaceutics and Biopharmaceutics,2003,55:27-33.
[164]Thomas TT,Kohane DS,Wang A,Langer R.Microparticulate formulations for the controlled release of interleukin-2[J].Journal of Pharmaceutical Sciences,2004,93:1100-1109.
[165]Dellamary L,Smith D J,Bloom A,Bot S,Guo G R,Deshmuk H,Costello M,Bot A.Rational design of solid aerosols for immunoglobulin delivery by modulation of aerodynamic and release characteristics[J].Journal of Controlled Release,2004,95:489-500.
[166]Prego C,Garcia M,Torres D,Alonso M J.Transmucosal macromolecular drug delivery[J].Journal of Controlled Release,2005,101:151-162.
[167]Bustami RT,Chan HK.Generation of protein microparticles using high pressure modified carbon dioxide[A].Proceedings of the 5th International Symposium on Supercritical Fluids,Atlanta,2000.
[168]Domingo C,Vega A,Fanovich MA,Elvira C,Subra P.Behavior of Poly(methylmethacrylate)-Based Systems in Supercritical CO_2 and CO_2 Plus Cosolvent:Solubility Measurements and Process Assessment[J].Journal of Applied Polymer Science,2003,90:3652-3659.
[169]Yoshida E,Imamura H.Synthesis of poly[2-(perfluorooctyl)ethyl acrylate-co-poly(ethylene glycol) methacrylate]and its control of enzyme activity in supercritical carbon dioxide[J].Colloid and Polymer Science,2007,285(13):1463-1470.
[170]Whitaker MJ,Hao JY,Davies OR,Serhatkulu G,Stolnik-Trenkic S,Howdle SM,Shakesheff KM.The production of protein-loaded microparticles by supercritical fluid enhanced mixing and spraying[J].Journal of Controlled Release,2005,101:85-92.
[171]Rosenkranz K,Kasper MM,Werther J,Brunner G.Encapsulation of irregularly shaped solid forms of proteins in a high-pressure fluidized bed,Journal of Supercritical Fluids,2007.
[172]Jovanovi' N,Bouchard A,Hofland GW,Witkamp GJan,Crommelin DJA,Jiskoot W.Distinct effects of sucrose and trehalose on protein stability during supercritical fluid drying and freeze-drying.European Journal of Pharmaceutical Sciences,2006,2 7:336 - 345.
[173]Amidi M,Pellikaan HC,Boer AH,Crommelin DJ.A,Hennink WE,Jiskoot W.Preparation and physicochemical characterization of supercritically dried insulin-loaded microparticles for pulmonary delivery.European Journal of Pharmaceutics and Biopharmaceutics 2008,68:191-200.
[174]Dos Santos IR,Richard J,Pech B,Thies C,Benoit JP.Microencapsulation of protein particles within lipids using a novel supercritical fluid procoss[J].International Journal of Pharmacognosy,2002,242:69-78.
[175]Dos Santos IR,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].Journal of Microencapsulation,2003,20:110-128.
[176]Meziani MJ,Sun YP.Protein-conjugated nanoparticles from rapid expansion of supercritical fluid solution into aqueous solution[J].Journal of the American Chemical Society,2003,125:8015-8018.
[177]Meziani MJ,Rollins HW,Allard LF,Sun YP.Protein-protected nanoparticles from rapid expansion of supercritical solution into aqueous solution[J].Journal of Physical Chemistry B,2002,106:171-178.
[178]Martin RB,Meziani MJ,Pathak P,Riggs JE,Cook DE,Perera S,Sun YP.Optical limiting of silver-containing nanoparticles[J].Optical Materials,2007,29:788-793.
[179]Zhang JL,Han BX,Chen J,Li ZH,Liu ZM,Wu WZ.Synthesis of Ag/BSA Composite Nanospheres from Water-in-Oil Microemulsion Using Compressed CO2 as Antisolvent[J].Biotechnology and Bioengineering,2005,89(3):274-279.
[180]Pathak P,Meziani MJ,Desai T,Sun YP.Formation and stabilization of ibuprofen nanoparticles in supercritical fluid processing[J].Journal of Supercritical Fluids,2006,37:279-286.
[181]Kim YH,Sioutas C,Fine P,Shing KS.Effect of Albumin on Physical Characteristics of Drug Particles Produced by Supercritical Fluid Technology[J].Powder Technology,2008,182:354-363.
[182]孙宝国.日用化工辞典[M].化学工业出版社,2002.
[183]朱明,胡金莲,王利平.用电子显微镜和差热扫描仪等方法研究乳脂的结构和性质[J].冷饮与速冻食品工业,1996:22-23.
[184]Vogelhuber W,Magni E,Mouro M,Spruβ T,Guse C,Gazzaniga A,Goepferich A.Monolithic triglycerides matrices:a controlled release system for proteins[J].Pharmaceutical Development and Technology,2003,8:71-79.
[185]Pongjanyakul,T,Medlicott NJ,Tucker IG.Melted glyceryl palmitostearate(GPS) pellets for protein delivery[J].International Journal of Pharmaceutics,2004,271:53-62.
[186]陈辉.PGSS技术制备布洛芬和肉豆蔻酸微粒及其微胶囊[D].厦门大学,2007.
[187]Johnson RW,Fritz E.工业脂肪酸及其应用[M].轻工业出版社,1992:13.
[188]陆彬.药物新剂型与新技术[M].人民卫生出版社,2005:7.
[189]宗莉,朱辉,吴德平,朱家壁.PEG6000、聚山梨酯80增加尼群地平溶出度的研究[J].中国药科大学学报,2000,1:21-24.
[190]Soares BMC,Gamarra FMC,Paviani LC,Goncalves LAG,Cabral FA.Solubility of triacylglycerols in supercritical carbon dioxide[J].J.of Supercritical Fluids 2007,43:25-31