过程参数对SAS法制备紫杉醇DDS微粒的影响
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摘要
紫杉醇是临床上最有效的抗癌药物之一,但水溶性极低,且在大多数医用溶媒中不溶解或者溶解度较低,现行制剂以无水乙醇和聚乙烯基蓖麻油(v/v,50/50)混合物为溶剂,具有很大的毒副作用。因此,紫杉醇新剂型的研制成为热点。超临界反溶剂(Supercritical anti-solvent, SAS)法通过预设不同的操作参数,可有效控制药物输送系统(Drug delivery system,DDS)微粒的粒径及其分布,是低溶剂残留的DDS绿色制备新技术。本论文以紫杉醇为模型药物,研究各过程参数对SAS法制备DDS的影响。
本文通过单因素实验,以DCM/无水乙醇(EtOH)、DCM/二甲亚砜(DMSO)混合溶液为溶剂,采用SAS法成功制备出紫杉醇DDS微粒;借助扫描电镜(SEM)、激光粒度仪和高效液相色谱等检测手段对DDS微粒进行表征,考察了混和溶剂体系下,过程参数包括压力、温度、溶剂配比、溶液流速和溶质浓度等对DDS微粒的形貌、粒径和包封率的影响。
结果表明,所得紫杉醇DDS微粒的形貌受溶剂性质影响较大,在DCM中加入EtOH有助于改善DDS微粒的表面光滑程度;而当加入DMSO时DDS微粒出现孔状结构,且分散度较差。在实验范围内,增加压力(80-140bar),所得DDS微粒的粒径和包封率增加;增加温度(30-45℃),所得DDS微粒的粒径呈上升趋势。在DCM/EtOH体系中,DDS微粒包封率随温度升高而增加,而在DCM/DMSO溶剂体系中,包封率随温度升高先增加后降低;当温度高于40℃时,微粒之间聚集,甚至形成膜状物质。样品溶液流速增大DDS微粒的平均粒径随之增大。当载体聚乳酸(PLLA)与PTX浓度之比为5:1时,获得DDS微粒的包封率较高为86.8%。
上述研究工作可为SAS法成功制备DDS微粒提供参考。
Paclitaxel (PTX) is one of the most effective anti-cancer drugs. However, PTX is almost insoluble in water (<0.004mg/ml) and common solvents. The current clinical formulation of PTX contains 1:1 blend of Cremophor EL (polyethoxylated castor oil) and dehydrated ethanol. This formulation leads to low bioavailability, toxicity and hypersensitivity. For reduce side effects and increase therapeutic efficiency, much effort has been devoted to developing a new drug delivery system (DDS) without Cremophor EL for PTX. Supercritical anti-solvent (SAS) is an attractive technique for preparing DDS, which can effectively control the particle size and distribution of DDS by changing operating parameters. Also SAS is low residual solvent and environment friendly technique. In this paper, DDS of PTX were prepared by SAS process, and the effects of SAS process parameters on DDS particles were investigated.
The mixed solvents of Dichloromethane (DCM) /ethanol (EtOH) and DCM/Dimethyl sulfoxide (DMSO) were used to dissolve PTX and PLLA, and PTX loaded PLLA submicro-particles were prepared by SAS process. The effect of process parameters on DDS, including temperature (30-45oC), pressure (80-140bar), polymer concentration (5-12g/L) and solution flow rate (0.2-1.5ml/min), were investigated. SEM, laser particle size analyser and HPLC were employed to investigate the effect of process parameters on particles morphology, size and drug loading efficiency.
The results indicate that the solvents ratios have a great effect on the particles morphologies. Good morphology particles were collected when DCM/EtOH was used. Particles drug loading efficiency is changed according to DMSO volume ratio in DCM. It is further demonstrated that the particles size and drug loading efficiency increase with increased pressure. The average size of particles increase when increase the flow rate of the solution. And particles have drug loading efficiency of 86.8% when the concentration ratio of PLLA/PTX is 5:1.
This work will be useful for preparing DDS particles by SAS process.
本文通过单因素实验,以DCM/无水乙醇(EtOH)、DCM/二甲亚砜(DMSO)混合溶液为溶剂,采用SAS法成功制备出紫杉醇DDS微粒;借助扫描电镜(SEM)、激光粒度仪和高效液相色谱等检测手段对DDS微粒进行表征,考察了混和溶剂体系下,过程参数包括压力、温度、溶剂配比、溶液流速和溶质浓度等对DDS微粒的形貌、粒径和包封率的影响。
结果表明,所得紫杉醇DDS微粒的形貌受溶剂性质影响较大,在DCM中加入EtOH有助于改善DDS微粒的表面光滑程度;而当加入DMSO时DDS微粒出现孔状结构,且分散度较差。在实验范围内,增加压力(80-140bar),所得DDS微粒的粒径和包封率增加;增加温度(30-45℃),所得DDS微粒的粒径呈上升趋势。在DCM/EtOH体系中,DDS微粒包封率随温度升高而增加,而在DCM/DMSO溶剂体系中,包封率随温度升高先增加后降低;当温度高于40℃时,微粒之间聚集,甚至形成膜状物质。样品溶液流速增大DDS微粒的平均粒径随之增大。当载体聚乳酸(PLLA)与PTX浓度之比为5:1时,获得DDS微粒的包封率较高为86.8%。
上述研究工作可为SAS法成功制备DDS微粒提供参考。
Paclitaxel (PTX) is one of the most effective anti-cancer drugs. However, PTX is almost insoluble in water (<0.004mg/ml) and common solvents. The current clinical formulation of PTX contains 1:1 blend of Cremophor EL (polyethoxylated castor oil) and dehydrated ethanol. This formulation leads to low bioavailability, toxicity and hypersensitivity. For reduce side effects and increase therapeutic efficiency, much effort has been devoted to developing a new drug delivery system (DDS) without Cremophor EL for PTX. Supercritical anti-solvent (SAS) is an attractive technique for preparing DDS, which can effectively control the particle size and distribution of DDS by changing operating parameters. Also SAS is low residual solvent and environment friendly technique. In this paper, DDS of PTX were prepared by SAS process, and the effects of SAS process parameters on DDS particles were investigated.
The mixed solvents of Dichloromethane (DCM) /ethanol (EtOH) and DCM/Dimethyl sulfoxide (DMSO) were used to dissolve PTX and PLLA, and PTX loaded PLLA submicro-particles were prepared by SAS process. The effect of process parameters on DDS, including temperature (30-45oC), pressure (80-140bar), polymer concentration (5-12g/L) and solution flow rate (0.2-1.5ml/min), were investigated. SEM, laser particle size analyser and HPLC were employed to investigate the effect of process parameters on particles morphology, size and drug loading efficiency.
The results indicate that the solvents ratios have a great effect on the particles morphologies. Good morphology particles were collected when DCM/EtOH was used. Particles drug loading efficiency is changed according to DMSO volume ratio in DCM. It is further demonstrated that the particles size and drug loading efficiency increase with increased pressure. The average size of particles increase when increase the flow rate of the solution. And particles have drug loading efficiency of 86.8% when the concentration ratio of PLLA/PTX is 5:1.
This work will be useful for preparing DDS particles by SAS process.
引文
[1]元英进.抗癌新药紫杉醇和多烯紫杉醇[M].化学工业出版社,2002:1
[2] Rowinsky E. K., Cazenave L. A., Donehower. Taxol: a novel investigational antimicrotubule agent [J]. Journal of National Cancer Institute, 1990, 82 (15):1247-1259
[3] George A Orr, Pascal Verdier-Pinard, Hayley McDaid, et al. Mechanisms of Taxol resistance related to microtubules [J]. Oncogene, 2003, 22(47):7280–7295
[4] Anil K. Singla, Alka Garg, Deepika Aggarwal. Paclitaxel and its formulations [J]. International Journal of Pharmaceutics, 2002, 235(1-2):179–192
[5] Jaehwi Lee, Sang Cheon Lee. Hydrotropic Solubilization of Paclitaxel: Analysis of Chemical Structures for Hydrotropic Property [J]. Pharmaceutical Research, 2003, 20(7):1022-1030
[6] Kramer, I. Heuser, A.. Paclitaxel pharmaceutical and pharmacological issues [J]. European Journal of Hospital Pharmacy, 1995, 1:37-41
[7] Ramesh Panchagnula. Pharmaceutical aspects of paclitaxel [J]. International Journal of Pharmaceutics, 1998, 172:1–15
[8]陈爱政.超临界流体技术制备聚乳酸基药物载体的研究[D].四川大学, 2007
[9] Allen, Theresa M., Cullis, Pieter R.. Drug Delivery Systems: Entering the Mainstream [J]. Science, 2004, 303, 5665:1818-1822
[10] Kewal K., Jain. Strategies and technologies for drug delivery systems [J]. Meeting Report, 1998, 19:155-157
[11] Bhupinder Singh Sekhon. Supercritical Fluid Technology: An Overview of Pharmaceutical Applications [J]. International Journal of PharmTech Research, 2010, 2(1):810-826
[12] Xu Zhenghong, Gu Wangwen, Huang Jun, et al. In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery [J]. International Journal of Pharmaceutics, 2005, 288:361-368
[13]李凤生.超细粉体技术[M].北京:国防工业出版社, 2000:137
[14]张跃庭,董岸杰,邓联东,等.紫杉醇两亲性共聚物纳米胶束体外释药动力学[J].化工学报, 2004, 55(6):952-957
[15] He Wenzhi, Jiang Zhaohua, Suo Quanling, et al. Mechanism of dispersing an active component into a polymeric carrier by the SEDS-PA process [J]. Journal of Materials Science, 2010, 45: 467–474
[16]卢英妹,江燕斌,李黎仙,等.紫杉醇控缓释新剂型的研究进展[J].中药材,2009, 32(3): 457-461
[17] Ramesh Panchagnula. Pharmaceutical aspects of paclitaxel [J]. International Journal of Pharmaceutics, 1998, 172:1–15
[18] Yin Hong, Yu Shi, Casey, et al. Synthesis and properties of poly(L-lactide) drug carrier with maghemite nanoparticles [J]. Materials Science & Engineering, C: Materials for Biological Applications, 2010, 30(4):618-623
[19] Song Tian-Tian, Yuan Xu-Bo, Sun Ai-Ping, et al. Preparation of injectable paclitaxel sustained release microspheres by spray drying for inhibition of glioma in vitro [J]. Journal of Applied Polymer Science, 2010, 115(3):1534-1539
[20] Liggins R.T., Burt H.M.. Paclitaxel loaded poly( -lactic acid) microspheres: properties of microspheres made with low molecular weight polymers [J]. International Journal of Pharmaceutics, 2001, 222:19–33
[21] Liggins R.T., Burt H.M.. Paclitaxel -loaded poly(L-lactic acid) microspheres 3: blending low and high molecular weight polymers to control morphology and drug release [J]. International Journal of Pharmaceutics, 2004, 282(1-2):61-71
[22] Liggins R.T., Burt H.M.. Paclitaxel loaded poly(L-lactic acid) ( PLLA ) microspheres. II. The effect of processing parameters on microsphere morphology and drug release kinetics [J]. International Journal of pharmaceutics, 2004, 281(1-2):103-6
[23] Kang Yunqing, Wu Jiang, Yin Guangfu, et al. Characterization and biological evaluation of paclitaxel -loaded poly(L-lactic acid) microparticles prepared by supercritical CO2 [J]. Langmuir : the ACS journal of surfaces and colloids, 2008, 24(14):7432-41
[24] Kang Yunqing, Yin Guangfu, Ouyang Ping, et al. Preparation of PLLA /PLGA microparticles using solution enhanced dispersion by supercritical fluids (SEDS) [J]. Journal of colloid and interface science, 2008, 322(1):87-94
[25] Zeng Jing, Yang Lixin, Liang Qizhi, et al. Influence of the drug compatibility with polymer solution on the release kinetics of electrospun fiber formulation [J]. Journal of Controlled Release, 2005, 105(1-2):43-51
[26] Lai Yeng Lee, Chi Hwa Wang, Kenneth A. Smith. Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel [J]. Journal of Controlled Release, 2008, 125:96–106
[27]谢明,周梁,高召兵.紫杉醇PLGA微球制备及体外性质评估[J].中国新药杂志,2006, 15 (13):1074-1077
[28] Yuancai Dong, Si-Shen Feng. Poly(d, l-lactide-co-glycolide) (PLGA) nanoparticles prepared by high pressure homogenization for paclitaxel chemotherapy [J]. International Journal of Pharmaceutics, 2007, 342 (1-2):208–214
[29] Liu J., Meisner D., Kwong E., et al. A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA–paclitaxel microspheres [J]. Biomaterials, 2007, 28(21): 3236-3244
[30] Bok Ki Kang, Se Kang Chon. Controlled release of paclitaxel from microemulsion containing PLGA and evaluation of anti-tumor activity in vitro and in vivo [J]. International Journal of Pharmaceutics, 2004, 286 (1-2):147-156
[31] Anshul Gupte, Kadriye Ciftci. Formulation and characterization of Paclitaxel, 5-FU and paclitaxel + 5-FU microspheres [J]. International Journal of Pharmaceutics, 2004, 276 (1-2): 93-106
[32] M Konerack′a, M M′uˇckov′a, V Z′aviˇsov′a, et al. Encapsulation of anticancer drug and magnetic particles in biodegradable polymer nanospheres [J]. Journal of Physics: Condensed Matter, 2008, 20 (204151):1-6
[33] Gang Ruana, Si-Shen Feng. Preparation and characterization of poly(lactic acid)-poly (ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA) microspheres for controlled release of paclitaxel [J]. Biomaterials, 2003, 24 (27):5037-5044
[34] Venkatraman S.S., Jie P., Min F., et al. Micelle-like nanoparticles of PLA–PEG–PLA triblock copolymer as chemotherapeutic carrier [J]. International Journal of Pharmaceutics, 2005, 298 (1):219-232
[35] Yuancai Dong, Si-Shen Feng. Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs [J]. Biomaterials, 2004, 25(14): 2843–2849
[36] Huh K.M., Lee S.C., Cho Y.W., et al. Hydrotropic polymer micelle system for delivery of paclitaxel [J]. Journal of Controlled Release, 2005, 101 (1-3):59-68
[37] Xu Z., Gu W., Huang J., et al. In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery [J]. International Journal of Pharmaceutics, 2005, 288 (2):361-368
[38] Hannay J. B., James Hogarth. On the Solubility of Solids in Gases [J]. Proceedings of the Royal Society of London, 1879, 30:178-188
[39] McHugh M.A., Krukonis V.J.. Supercritical Fluid Extraction: principles and practice [M]. Newton, Butterworth-Heinemann, 1994:27
[40] Kenji Mishima. Biodegradable particle formation for drug and gene delivery using supercritical fluid and dense gas [J]. Advanced Drug Delivery Reviews, 2008, 60:411–432
[41] Alan an-lei Chang. Study of Particle formation using supercritical CO2 as an antisolvent [D]. North Carolina State University, 2006
[42] Hanna M., York P.. Salmeterol xinnafoate with controlled particle size [P]. US: PCT/GB94/0145(WO95/01324), 1995,12
[43] Pratibhash Chattopadhyay, Gupta R. B.. Production of Antibiotic Nanoparticles Using Supercritical CO2 as Antisolvent with Enhanced Mass Transfer [J]. Industrial & Engineering Chemistry Research, 2001, 40:3530-3539
[44] Dixon D.J., Johnston K.P., Bodmeier R.P.. Polymeric materials formed by precipitation with a compressed fluid antisolvent [J]. American Institute of Chemical Engineers, 1993, 39(1):127–139
[45] Randolph T.W., Randolph A.D., Mebes M., et al. Submicrometer-sized biodegradable particles of poly (L-lactic acid) via the gas antisolvent spray precipitation process [J]. Biotechnology Progress, 1993, 9:429–435
[46] Lengsfeld C.S., Delplanque J.P., Barocas V.H., et al. Mechanism governing microparticle morphology during precipitation by a compressed antisolvent: atomization vs. nucleation and growth [J]. Journal of Physical Chemistry B, 2000, 104(12):2725–2735
[47] Lefebvre A. H.. Atomization and Sprays [M]. Hemisphere Publishing Corp, 1989:79-102
[48] Reverchon E., Caputo G., Marco I. De.. Role of phase behavior and atomization in the supecritical antisolvent precipitation [J]. Industrial& Engineering Chemistry Research, 2003, 42:6406-6414
[49] Y. P′erez de Diego, Pellikaan H.C., Wubbolts F.E., et al. Operating regimes and mechanism of particle formation during the precipitation of polymers using the PCA process [J]. Journal of Supercritical Fluids, 2005, 35:147–156
[50] Reverchon E., Adami R., Caputo G., et al. Spherical microparticles production by supercritical antisolvent precipitation: Interpretation of results [J]. Journal of Supercritical Fluids, 2008, 47 : 70–84
[51] He Wenzhi, Jiang Zhaohua, Suo Quanling, et al. Mechanism of dispersing an active component into a polymeric carrier by the SEDS-PA process [J]. Journal Material Science, 2010, 45:467–474
[52] Bell P.W., Stephens A. P., Roberts C.B., et al. High-resolution imaging of the supercritical antisolvent process [J]. Experiments in fluids, 2005, 38:708-719
[53] Henczka M., Baldyga J., Shekunov B.Y.. Particle formation by turbulent mixing with supercritical antisolvent [J]. Chemical Engineering Science, 2005, 60:2193-2201
[54] Martín A., Cocero M.J.. Numerical modeling of jet hydrodynamics, mass transfer and crystallization kinetics in the supercritical antisolvent (SAS) process [J]. Journal of Supercritical Fluids, 2004, 32:203-219
[55] Constantinos G. K., Chrysoula M. M., Constantinos G. P.. Microencapsulation of Amoxicillin in Poly(L-lactic acid) by Supercritical Antisolvent Precipitation [J]. Industrial& Engineering Chemistry Research, 2006, 45:8738-8743
[56] Mi Yeong Kim, Youn Woo Lee, Hun-Soo Byun, et al. Recrystallization of Poly(L-lactic acid) intoSubmicrometer Particles in Supercritical Carbon Dioxide [J]. Industrial& Engineering Chemistry Research, 2006, 45:3388-3392
[57] Daniel L. Obrzut, Philip W. Bell, Christopher B. Roberts, et al. Effect of process conditions on the spray characteristics of a PLA + methylene chloride solution in the supercritical antisolvent precipitation process [J]. Journal of Supercritical Fluids, 2007, 42:299–309
[58] Nicola Elvassore, Alberto Bertucco. Production of Protein-Loaded Polymeric Microcapsules by Compressed CO2 in a Mixed Solvent [J]. Industrial& Engineering Chemistry Research, 2001, 40: 795-800
[59] Boutin O., Badens E., Carretier E., et al. Co-precipitation of a herbicide and biodegradable materials by the supercritical anti-solvent technique [J]. Journal of Supercritical Fluids, 2004, 31: 89–99
[60] Todd M. Martin, Nagesh Bandi, Ryan Shulz, et al. Preparation of Budesonide and Budesonide-PLA Microparticles Us-ing Supercritical Fluid Precipitation Technology [J]. American Association of Pharmaceutical Scientists PharmSciTech, 2002, 3 (3) article 18 (http://www.aapspharmsci.org)
[61] Lee L.Y., Wang C.H., Smith K.A.. Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel [J]. Journal of Controlled Release, 2007, 125(5):96-106
[62] Wang Yulu, Wang Yiping. The application of a supercritical antisolvent process for sustained drug delivery [J]. Powder Technology, 2006, 164:94-102
[63] Moneghini M., Kikic I.. Processing of carbamazepine–PEG 4000 solid dispersions with supercritical carbon dioxide: preparation, characterization, and in vitro dissolution [J]. International Journal of Pharmaceutics, 2001, 222:129-138
[64] Young T.J., Johnston K.P.. Encapsulation of lysozyme in a biodegradable polymer by precipitation with a vapor over-liquid anti-solvent [J]. Journal of Pharmaceutical Science, 1999, 88:640-650
[65]王鈜艳.超临界抗溶剂(SAS)过程流体力学特性研究[D].天津大学化工学院, 2005
[66] Rantakyla M., Jantti M.. Modeling droplet–gas interaction and particle formation in gas–anti-solvent system[J], in: M. Perrut, P. Subra (Eds.), Proceedings of the 5th Meeting on Supercritical Fluids, 1998, 1:333-342
[67] Kenji Mishima. Biodegradable particle formation for drug and gene delivery using supercritical fluid and dense gas [J]. Advanced Drug Delivery Reviews, 2008, 60:411–432
[68] Davies O. R., Lewis A. L., Whitaker M.J., et al. Applications of supercritical CO2 in the fabrication of polymer systems for drug delivery and tissue engineering [J]. Advanced Drug Delivery Reviews, 2008, 60:373–387
[69] Mohammed J. M., Pankaj Pathak, et al. Nanotechnology in Drug Delivery [M]. Springer New York, 2008:69-104
[70] Bhupinder Singh Sekhon. Supercritical Fluid Technology: An Overview of Pharmaceutical Applications [M]. International Journal of PharmTech Research, 2010, 2(1):810-826
[71] Chong G.H., Yunus R., Abdullah N., et al. Coating and Encapsulation of Nanoparticles using Supercritical Antisolvent [J]. American Journal of Applied Sciences, 2009, 6 (7):1352-1358
[72] Woo, Jong Soo, Kim, et al. Method for the preparation of paclitaxle solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby [P]. WO 2004/043437 A1
[73] A. Mart′?n, F. Mattea, L. Guti′errez, et al. Co-precipitation of carotenoids and bio-polymers with the supercritical anti-solvent process [J]. Journal of Supercritical Fluids, 2007, 41:138–147
[74] Taki S., Badens E., Charbit G.. Controlled release system formed by supercritical anti-solvent coprecipitation of a herbicide and a biodegradable polymer [J]. Journal of Supercritical Fluids, 2001, 21:61–70
[75] Christelle Roy, Arlette Vega-Gonz′alez, Pascale Subra-Paternault. Theophylline formulation by supercritical antisolvents [J]. International Journal of Pharmaceutics 2007, 343:79–89
[76] Anna Argemí, Arlette Vegaa, Pascale Subra-Paternault, et al. Characterization of azacytidine/poly(l-lactic) acid particles prepared by supercritical antisolvent precipitation [J]. Journal of Pharmaceutical and Biomedical Analysis, 2009, 50:847–852
[77] Yong Ho Kim, Constantinos Sioutas, Katherine S.S.. Influence of Stabilizers on the Physicochemical Characteristics of Inhaled Insulin Powders Produced by Supercritical Antisolvent Process [J]. Pharmaceutical Research, 2009, 26(1):61-71
[78] Elton Franceschia, Alana M. De Cesaroa, Mirian Feitena, et al. Precipitation ofβ-carotene and PHBV and co-precipitation from SEDS technique using supercritical CO2 [J]. Journal of Supercritical Fluids, 2008, 47:259–269
[79] Ai-Zheng Chen, Yi Li, Foo-Tim Chau, et al. Microencapsulation of puerarin nanoparticles by poly(L-lactide) in a supercritical CO2 process [J]. Acta Biomaterialia, 2009, 5:2913–2919
[80] Miguel F., Mart′?n A., Mattea F., et al. Precipitation of lutein and co-precipitation of lutein and poly-lactic acid with the supercritical anti-solvent process [J]. Chemical Engineering and Processing, 2008, 47:1594–1602
[81] Nicola Elvassore, Alberto Bertucco, Paolo Caliceti. 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
[82] Elkharraz K., Faisant N., Guse C., et al. Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: Preparation and physicochemical characterization [J]. International Journal of Pharmaceutics, 2006, 314 (2):127–136
[83] Ya Min Wang, Hitoshi Sato, Isao Adachi, et al. Preparation and characterization of Poly(lactic-co-glycolic acid) Microspheres for Targeted Delivery of a Novel Anticancer Agent,Taxol [J]. Chemical & Pharmaceutical Bulletin, 1996, 44(10):1935-1940
[84] Ernesto Reverchon. Supercritical antisolvent precipitation of micro- and nano-particles [J]. Journal of Supercritical Fluids,1999, 15:1–21
[85] Matteo Stievano, Nicola Elvassore. 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
[86]全大萍,高建文,廖凯荣,等.聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物的降解性能[J].功能高分子学报,2002, 15( 4):391-394
[87]朱自强.超临界流体技术—原理和应用[M].化学工业出版社, 2000: 380
[88] Yulu Wang, Rajesh N. D., Robert Pfeffer. Polymer coating/encapsulation of nanoparticles using a supercritical anti-solvent process [J]. Journal of Supercritical Fluids, 2004, 28:85–99
[89] Kazarian S.G. Polymer processing with supercritical fluids [J]. Polymer Sicence Series C, 2000, 42(1):78-101
[2] Rowinsky E. K., Cazenave L. A., Donehower. Taxol: a novel investigational antimicrotubule agent [J]. Journal of National Cancer Institute, 1990, 82 (15):1247-1259
[3] George A Orr, Pascal Verdier-Pinard, Hayley McDaid, et al. Mechanisms of Taxol resistance related to microtubules [J]. Oncogene, 2003, 22(47):7280–7295
[4] Anil K. Singla, Alka Garg, Deepika Aggarwal. Paclitaxel and its formulations [J]. International Journal of Pharmaceutics, 2002, 235(1-2):179–192
[5] Jaehwi Lee, Sang Cheon Lee. Hydrotropic Solubilization of Paclitaxel: Analysis of Chemical Structures for Hydrotropic Property [J]. Pharmaceutical Research, 2003, 20(7):1022-1030
[6] Kramer, I. Heuser, A.. Paclitaxel pharmaceutical and pharmacological issues [J]. European Journal of Hospital Pharmacy, 1995, 1:37-41
[7] Ramesh Panchagnula. Pharmaceutical aspects of paclitaxel [J]. International Journal of Pharmaceutics, 1998, 172:1–15
[8]陈爱政.超临界流体技术制备聚乳酸基药物载体的研究[D].四川大学, 2007
[9] Allen, Theresa M., Cullis, Pieter R.. Drug Delivery Systems: Entering the Mainstream [J]. Science, 2004, 303, 5665:1818-1822
[10] Kewal K., Jain. Strategies and technologies for drug delivery systems [J]. Meeting Report, 1998, 19:155-157
[11] Bhupinder Singh Sekhon. Supercritical Fluid Technology: An Overview of Pharmaceutical Applications [J]. International Journal of PharmTech Research, 2010, 2(1):810-826
[12] Xu Zhenghong, Gu Wangwen, Huang Jun, et al. In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery [J]. International Journal of Pharmaceutics, 2005, 288:361-368
[13]李凤生.超细粉体技术[M].北京:国防工业出版社, 2000:137
[14]张跃庭,董岸杰,邓联东,等.紫杉醇两亲性共聚物纳米胶束体外释药动力学[J].化工学报, 2004, 55(6):952-957
[15] He Wenzhi, Jiang Zhaohua, Suo Quanling, et al. Mechanism of dispersing an active component into a polymeric carrier by the SEDS-PA process [J]. Journal of Materials Science, 2010, 45: 467–474
[16]卢英妹,江燕斌,李黎仙,等.紫杉醇控缓释新剂型的研究进展[J].中药材,2009, 32(3): 457-461
[17] Ramesh Panchagnula. Pharmaceutical aspects of paclitaxel [J]. International Journal of Pharmaceutics, 1998, 172:1–15
[18] Yin Hong, Yu Shi, Casey, et al. Synthesis and properties of poly(L-lactide) drug carrier with maghemite nanoparticles [J]. Materials Science & Engineering, C: Materials for Biological Applications, 2010, 30(4):618-623
[19] Song Tian-Tian, Yuan Xu-Bo, Sun Ai-Ping, et al. Preparation of injectable paclitaxel sustained release microspheres by spray drying for inhibition of glioma in vitro [J]. Journal of Applied Polymer Science, 2010, 115(3):1534-1539
[20] Liggins R.T., Burt H.M.. Paclitaxel loaded poly( -lactic acid) microspheres: properties of microspheres made with low molecular weight polymers [J]. International Journal of Pharmaceutics, 2001, 222:19–33
[21] Liggins R.T., Burt H.M.. Paclitaxel -loaded poly(L-lactic acid) microspheres 3: blending low and high molecular weight polymers to control morphology and drug release [J]. International Journal of Pharmaceutics, 2004, 282(1-2):61-71
[22] Liggins R.T., Burt H.M.. Paclitaxel loaded poly(L-lactic acid) ( PLLA ) microspheres. II. The effect of processing parameters on microsphere morphology and drug release kinetics [J]. International Journal of pharmaceutics, 2004, 281(1-2):103-6
[23] Kang Yunqing, Wu Jiang, Yin Guangfu, et al. Characterization and biological evaluation of paclitaxel -loaded poly(L-lactic acid) microparticles prepared by supercritical CO2 [J]. Langmuir : the ACS journal of surfaces and colloids, 2008, 24(14):7432-41
[24] Kang Yunqing, Yin Guangfu, Ouyang Ping, et al. Preparation of PLLA /PLGA microparticles using solution enhanced dispersion by supercritical fluids (SEDS) [J]. Journal of colloid and interface science, 2008, 322(1):87-94
[25] Zeng Jing, Yang Lixin, Liang Qizhi, et al. Influence of the drug compatibility with polymer solution on the release kinetics of electrospun fiber formulation [J]. Journal of Controlled Release, 2005, 105(1-2):43-51
[26] Lai Yeng Lee, Chi Hwa Wang, Kenneth A. Smith. Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel [J]. Journal of Controlled Release, 2008, 125:96–106
[27]谢明,周梁,高召兵.紫杉醇PLGA微球制备及体外性质评估[J].中国新药杂志,2006, 15 (13):1074-1077
[28] Yuancai Dong, Si-Shen Feng. Poly(d, l-lactide-co-glycolide) (PLGA) nanoparticles prepared by high pressure homogenization for paclitaxel chemotherapy [J]. International Journal of Pharmaceutics, 2007, 342 (1-2):208–214
[29] Liu J., Meisner D., Kwong E., et al. A novel trans-lymphatic drug delivery system: Implantable gelatin sponge impregnated with PLGA–paclitaxel microspheres [J]. Biomaterials, 2007, 28(21): 3236-3244
[30] Bok Ki Kang, Se Kang Chon. Controlled release of paclitaxel from microemulsion containing PLGA and evaluation of anti-tumor activity in vitro and in vivo [J]. International Journal of Pharmaceutics, 2004, 286 (1-2):147-156
[31] Anshul Gupte, Kadriye Ciftci. Formulation and characterization of Paclitaxel, 5-FU and paclitaxel + 5-FU microspheres [J]. International Journal of Pharmaceutics, 2004, 276 (1-2): 93-106
[32] M Konerack′a, M M′uˇckov′a, V Z′aviˇsov′a, et al. Encapsulation of anticancer drug and magnetic particles in biodegradable polymer nanospheres [J]. Journal of Physics: Condensed Matter, 2008, 20 (204151):1-6
[33] Gang Ruana, Si-Shen Feng. Preparation and characterization of poly(lactic acid)-poly (ethylene glycol)–poly(lactic acid) (PLA–PEG–PLA) microspheres for controlled release of paclitaxel [J]. Biomaterials, 2003, 24 (27):5037-5044
[34] Venkatraman S.S., Jie P., Min F., et al. Micelle-like nanoparticles of PLA–PEG–PLA triblock copolymer as chemotherapeutic carrier [J]. International Journal of Pharmaceutics, 2005, 298 (1):219-232
[35] Yuancai Dong, Si-Shen Feng. Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs [J]. Biomaterials, 2004, 25(14): 2843–2849
[36] Huh K.M., Lee S.C., Cho Y.W., et al. Hydrotropic polymer micelle system for delivery of paclitaxel [J]. Journal of Controlled Release, 2005, 101 (1-3):59-68
[37] Xu Z., Gu W., Huang J., et al. In vitro and in vivo evaluation of actively targetable nanoparticles for paclitaxel delivery [J]. International Journal of Pharmaceutics, 2005, 288 (2):361-368
[38] Hannay J. B., James Hogarth. On the Solubility of Solids in Gases [J]. Proceedings of the Royal Society of London, 1879, 30:178-188
[39] McHugh M.A., Krukonis V.J.. Supercritical Fluid Extraction: principles and practice [M]. Newton, Butterworth-Heinemann, 1994:27
[40] Kenji Mishima. Biodegradable particle formation for drug and gene delivery using supercritical fluid and dense gas [J]. Advanced Drug Delivery Reviews, 2008, 60:411–432
[41] Alan an-lei Chang. Study of Particle formation using supercritical CO2 as an antisolvent [D]. North Carolina State University, 2006
[42] Hanna M., York P.. Salmeterol xinnafoate with controlled particle size [P]. US: PCT/GB94/0145(WO95/01324), 1995,12
[43] Pratibhash Chattopadhyay, Gupta R. B.. Production of Antibiotic Nanoparticles Using Supercritical CO2 as Antisolvent with Enhanced Mass Transfer [J]. Industrial & Engineering Chemistry Research, 2001, 40:3530-3539
[44] Dixon D.J., Johnston K.P., Bodmeier R.P.. Polymeric materials formed by precipitation with a compressed fluid antisolvent [J]. American Institute of Chemical Engineers, 1993, 39(1):127–139
[45] Randolph T.W., Randolph A.D., Mebes M., et al. Submicrometer-sized biodegradable particles of poly (L-lactic acid) via the gas antisolvent spray precipitation process [J]. Biotechnology Progress, 1993, 9:429–435
[46] Lengsfeld C.S., Delplanque J.P., Barocas V.H., et al. Mechanism governing microparticle morphology during precipitation by a compressed antisolvent: atomization vs. nucleation and growth [J]. Journal of Physical Chemistry B, 2000, 104(12):2725–2735
[47] Lefebvre A. H.. Atomization and Sprays [M]. Hemisphere Publishing Corp, 1989:79-102
[48] Reverchon E., Caputo G., Marco I. De.. Role of phase behavior and atomization in the supecritical antisolvent precipitation [J]. Industrial& Engineering Chemistry Research, 2003, 42:6406-6414
[49] Y. P′erez de Diego, Pellikaan H.C., Wubbolts F.E., et al. Operating regimes and mechanism of particle formation during the precipitation of polymers using the PCA process [J]. Journal of Supercritical Fluids, 2005, 35:147–156
[50] Reverchon E., Adami R., Caputo G., et al. Spherical microparticles production by supercritical antisolvent precipitation: Interpretation of results [J]. Journal of Supercritical Fluids, 2008, 47 : 70–84
[51] He Wenzhi, Jiang Zhaohua, Suo Quanling, et al. Mechanism of dispersing an active component into a polymeric carrier by the SEDS-PA process [J]. Journal Material Science, 2010, 45:467–474
[52] Bell P.W., Stephens A. P., Roberts C.B., et al. High-resolution imaging of the supercritical antisolvent process [J]. Experiments in fluids, 2005, 38:708-719
[53] Henczka M., Baldyga J., Shekunov B.Y.. Particle formation by turbulent mixing with supercritical antisolvent [J]. Chemical Engineering Science, 2005, 60:2193-2201
[54] Martín A., Cocero M.J.. Numerical modeling of jet hydrodynamics, mass transfer and crystallization kinetics in the supercritical antisolvent (SAS) process [J]. Journal of Supercritical Fluids, 2004, 32:203-219
[55] Constantinos G. K., Chrysoula M. M., Constantinos G. P.. Microencapsulation of Amoxicillin in Poly(L-lactic acid) by Supercritical Antisolvent Precipitation [J]. Industrial& Engineering Chemistry Research, 2006, 45:8738-8743
[56] Mi Yeong Kim, Youn Woo Lee, Hun-Soo Byun, et al. Recrystallization of Poly(L-lactic acid) intoSubmicrometer Particles in Supercritical Carbon Dioxide [J]. Industrial& Engineering Chemistry Research, 2006, 45:3388-3392
[57] Daniel L. Obrzut, Philip W. Bell, Christopher B. Roberts, et al. Effect of process conditions on the spray characteristics of a PLA + methylene chloride solution in the supercritical antisolvent precipitation process [J]. Journal of Supercritical Fluids, 2007, 42:299–309
[58] Nicola Elvassore, Alberto Bertucco. Production of Protein-Loaded Polymeric Microcapsules by Compressed CO2 in a Mixed Solvent [J]. Industrial& Engineering Chemistry Research, 2001, 40: 795-800
[59] Boutin O., Badens E., Carretier E., et al. Co-precipitation of a herbicide and biodegradable materials by the supercritical anti-solvent technique [J]. Journal of Supercritical Fluids, 2004, 31: 89–99
[60] Todd M. Martin, Nagesh Bandi, Ryan Shulz, et al. Preparation of Budesonide and Budesonide-PLA Microparticles Us-ing Supercritical Fluid Precipitation Technology [J]. American Association of Pharmaceutical Scientists PharmSciTech, 2002, 3 (3) article 18 (http://www.aapspharmsci.org)
[61] Lee L.Y., Wang C.H., Smith K.A.. Supercritical antisolvent production of biodegradable micro- and nanoparticles for controlled delivery of paclitaxel [J]. Journal of Controlled Release, 2007, 125(5):96-106
[62] Wang Yulu, Wang Yiping. The application of a supercritical antisolvent process for sustained drug delivery [J]. Powder Technology, 2006, 164:94-102
[63] Moneghini M., Kikic I.. Processing of carbamazepine–PEG 4000 solid dispersions with supercritical carbon dioxide: preparation, characterization, and in vitro dissolution [J]. International Journal of Pharmaceutics, 2001, 222:129-138
[64] Young T.J., Johnston K.P.. Encapsulation of lysozyme in a biodegradable polymer by precipitation with a vapor over-liquid anti-solvent [J]. Journal of Pharmaceutical Science, 1999, 88:640-650
[65]王鈜艳.超临界抗溶剂(SAS)过程流体力学特性研究[D].天津大学化工学院, 2005
[66] Rantakyla M., Jantti M.. Modeling droplet–gas interaction and particle formation in gas–anti-solvent system[J], in: M. Perrut, P. Subra (Eds.), Proceedings of the 5th Meeting on Supercritical Fluids, 1998, 1:333-342
[67] Kenji Mishima. Biodegradable particle formation for drug and gene delivery using supercritical fluid and dense gas [J]. Advanced Drug Delivery Reviews, 2008, 60:411–432
[68] Davies O. R., Lewis A. L., Whitaker M.J., et al. Applications of supercritical CO2 in the fabrication of polymer systems for drug delivery and tissue engineering [J]. Advanced Drug Delivery Reviews, 2008, 60:373–387
[69] Mohammed J. M., Pankaj Pathak, et al. Nanotechnology in Drug Delivery [M]. Springer New York, 2008:69-104
[70] Bhupinder Singh Sekhon. Supercritical Fluid Technology: An Overview of Pharmaceutical Applications [M]. International Journal of PharmTech Research, 2010, 2(1):810-826
[71] Chong G.H., Yunus R., Abdullah N., et al. Coating and Encapsulation of Nanoparticles using Supercritical Antisolvent [J]. American Journal of Applied Sciences, 2009, 6 (7):1352-1358
[72] Woo, Jong Soo, Kim, et al. Method for the preparation of paclitaxle solid dispersion by using the supercritical fluid process and paclitaxel solid dispersion prepared thereby [P]. WO 2004/043437 A1
[73] A. Mart′?n, F. Mattea, L. Guti′errez, et al. Co-precipitation of carotenoids and bio-polymers with the supercritical anti-solvent process [J]. Journal of Supercritical Fluids, 2007, 41:138–147
[74] Taki S., Badens E., Charbit G.. Controlled release system formed by supercritical anti-solvent coprecipitation of a herbicide and a biodegradable polymer [J]. Journal of Supercritical Fluids, 2001, 21:61–70
[75] Christelle Roy, Arlette Vega-Gonz′alez, Pascale Subra-Paternault. Theophylline formulation by supercritical antisolvents [J]. International Journal of Pharmaceutics 2007, 343:79–89
[76] Anna Argemí, Arlette Vegaa, Pascale Subra-Paternault, et al. Characterization of azacytidine/poly(l-lactic) acid particles prepared by supercritical antisolvent precipitation [J]. Journal of Pharmaceutical and Biomedical Analysis, 2009, 50:847–852
[77] Yong Ho Kim, Constantinos Sioutas, Katherine S.S.. Influence of Stabilizers on the Physicochemical Characteristics of Inhaled Insulin Powders Produced by Supercritical Antisolvent Process [J]. Pharmaceutical Research, 2009, 26(1):61-71
[78] Elton Franceschia, Alana M. De Cesaroa, Mirian Feitena, et al. Precipitation ofβ-carotene and PHBV and co-precipitation from SEDS technique using supercritical CO2 [J]. Journal of Supercritical Fluids, 2008, 47:259–269
[79] Ai-Zheng Chen, Yi Li, Foo-Tim Chau, et al. Microencapsulation of puerarin nanoparticles by poly(L-lactide) in a supercritical CO2 process [J]. Acta Biomaterialia, 2009, 5:2913–2919
[80] Miguel F., Mart′?n A., Mattea F., et al. Precipitation of lutein and co-precipitation of lutein and poly-lactic acid with the supercritical anti-solvent process [J]. Chemical Engineering and Processing, 2008, 47:1594–1602
[81] Nicola Elvassore, Alberto Bertucco, Paolo Caliceti. 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
[82] Elkharraz K., Faisant N., Guse C., et al. Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: Preparation and physicochemical characterization [J]. International Journal of Pharmaceutics, 2006, 314 (2):127–136
[83] Ya Min Wang, Hitoshi Sato, Isao Adachi, et al. Preparation and characterization of Poly(lactic-co-glycolic acid) Microspheres for Targeted Delivery of a Novel Anticancer Agent,Taxol [J]. Chemical & Pharmaceutical Bulletin, 1996, 44(10):1935-1940
[84] Ernesto Reverchon. Supercritical antisolvent precipitation of micro- and nano-particles [J]. Journal of Supercritical Fluids,1999, 15:1–21
[85] Matteo Stievano, Nicola Elvassore. 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
[86]全大萍,高建文,廖凯荣,等.聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物的降解性能[J].功能高分子学报,2002, 15( 4):391-394
[87]朱自强.超临界流体技术—原理和应用[M].化学工业出版社, 2000: 380
[88] Yulu Wang, Rajesh N. D., Robert Pfeffer. Polymer coating/encapsulation of nanoparticles using a supercritical anti-solvent process [J]. Journal of Supercritical Fluids, 2004, 28:85–99
[89] Kazarian S.G. Polymer processing with supercritical fluids [J]. Polymer Sicence Series C, 2000, 42(1):78-101