注射用多西他赛自乳化微乳制剂研究
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摘要
多西他赛是一种新型抗肿瘤药物,对卵巢癌、乳腺癌、非小细胞肺癌、食管癌、头颈部癌等肿瘤疾病均有良好疗效。目前,多西他赛上市的注射剂用Tween80增溶、乙醇助溶,将其制成一个注射剂浓缩液和一个溶剂的两瓶装。虽然处方中使用了毒性相对较小的Tween80和乙醇作为溶剂体系,但临床使用时仍存在着操作繁琐,Tween80易引起过敏和溶血作用。为了消除现有多西他赛制剂所产生的一系列问题并解决多西他赛溶解度低的缺点,本课题研制注射用的多西他赛自乳化制剂,以期为多西他赛的新剂型开发提供研究基础。本课题研究的主要内容包括：
一、处方前研究：处方前研究中建立了多西他赛自乳化系统的HPLC含量测定方法,该方法灵敏、精密、便捷、专属性强,适用于自乳化系统中药物含量的测定。测定了多西他赛在不同油相中的溶解度。本文以高效液相色谱法测定DOC含量。药物在水及各辅料中溶解度的测定表明药物在水中不溶,在各种油相,乳化剂及助乳化剂中溶解较多。药物的油水分配系数的测定说明药物的亲脂性较强。
二、多西他赛自乳化系统的制备：在处方前研究的基础上,通过对各种油相和不同乳化剂的配伍变化的观察,选出具有较强乳化能力的乳化剂和对药物有较大溶解度的油相和助乳化剂。根据药物在各注射级辅料中的溶解性、通过绘制空白伪三元相图、进行了自乳化给药系统基本处方的初步筛选。最后通过考察载药量对粒径、制剂稳定性的影响,对注射用DOC自乳化微乳制剂进行了处方优化,确定处方组成为：m(MCT):m(Soultol HS15):m(PEG 400)=3:8:4,其中药物含量的质量分数为2%。
三、多西他赛自乳化系统的理化性质研究及其稳定性：对DOC-SEDDS和其自乳化后乳剂的外观性状进行观察,同时对自乳化时间,自乳化后的粒径进行了测定。考察了不同温度,分散介质,分散方法对系统自乳化效率的影响以及不同的分散介质,稀释倍数对自乳化后乳剂粒径的影响。稳定性试验结果表明DOC-SEDDS初步稳定性良好。
四、注射用的多西他赛自乳化制剂在大鼠体内药物动力学研究：建立了大鼠血浆中多西他赛的高效液相色谱法,考察了尾静脉注射多西他赛普通注射剂和多西他赛自乳化后大鼠体内的药物动力学过程。建立了多西他赛体内药物测定的HPLC法,以甲醇处理血浆样品后进行测定。该法简单、快捷、灵敏度高,适合多西他赛的体内分析研究。结果表明多西他赛自乳化药液和参照制剂大鼠尾静脉注射给药后药动学过程均符合双室模型。
Docetaxel is a novel anticancer drugs. It is effective for ovarian cancer,breast cancer、non-small cell lung cancer、esophageal cancer、head and neck cancer and other tumor diseases.At present, the commercial product of docetaxel still adopted Tween 80 and ethanol as injection solvents, Tween 80 was used as solubilizer and ethanol as auxiliary solvent, which was packed separated as condensed injection solution and solvent in two packages. Although the prescription use a relatively less toxic solubilizer Tween 80 and ethanol as solvents, but still exsit complicated operation in clinical use and Tween 80 is easy cause allergies and hemolytic effects.In order to eliminate the existed a series of problems which docetaxel produced in clinical use and solve the lower solubility of docetaxel, a docetaxel self-microemulsion for intravenous injection was developed in this study, so as to provide fundmental work for new dosage form research of docetaxel. The main contents of the research are follows.
1. Preformulation research of docetaxel self-microemulsion.
An HPLC method was developed for the assay determination of docetaxel self-emulsifying system on the preformulation study, this method is sensitive、precise、convenient specific to self-emulsifying system for the determination of the drug.The solubility of docetaxel in various oils phase and surfactant and cosurfactant was measured, also observed the effect through a variety of oil phase and surfactant of the compatibility, choose with strong emulsifier and higher solubility for drug an, as the self-emulsifying drug delivery system of basic prescription screening. Determinnation of drug solubility in water and adjuvants showed DOC was insoluble in water and relatively more soluble in various oil、emulsifier and co-emulsifier.The oil-water participate coefficient showed relatively strong lipophlic property of drug.
2. The preparation of docetaxe self-emulsifying system.
Based on the results of the study before formulation, we search for the optimum formulation for the self-microemulsifying drug delivery system of DOC, the drawing of pseudo-ternary phase diagram of blank self-microemulsifying drug delivery system and analysis partical size. The constitution of optimum formulation is as follows:m(MCT): m(Soultol HS15):m(PEG 400)= 3:8:4, with content 2% of drug.
3. Docetaxel self-emulsifying system and the stability of the physical and chemical properties.
According to the appearance of SEDDS, before and after emulsiyfing, the emulsified time, the droplet size after self-emulsification, content and stability test of DOC, the quality of SEDDS of DOC was evaluated.Meanwhile, we also studied the shifts of the self-emulsifying efficiency by changing temperature, dispersed media and dispersed methods and the effect of the different dispersed mdedium, dilution on the droplet size.
4. The pharmacodynamic study of docetaxel self-microemulsion in rats.
An HPLC method was developed for the determination of docetaxel in mouse plasma. Pharmacokinetics of docetaxel injection and docetaxel self-microemulsion in mouse after iv administration were investigated.The plasma samples were dealt with methanol before determination.The method was simple、quick、sensive and very suitable for the drug determination in vivo. The pharmmacokinetics results of docetaxel self-microemulsions showed that docetaxel injection and docetaxel self-microemulsion was accored with double-room double.
一、处方前研究：处方前研究中建立了多西他赛自乳化系统的HPLC含量测定方法,该方法灵敏、精密、便捷、专属性强,适用于自乳化系统中药物含量的测定。测定了多西他赛在不同油相中的溶解度。本文以高效液相色谱法测定DOC含量。药物在水及各辅料中溶解度的测定表明药物在水中不溶,在各种油相,乳化剂及助乳化剂中溶解较多。药物的油水分配系数的测定说明药物的亲脂性较强。
二、多西他赛自乳化系统的制备：在处方前研究的基础上,通过对各种油相和不同乳化剂的配伍变化的观察,选出具有较强乳化能力的乳化剂和对药物有较大溶解度的油相和助乳化剂。根据药物在各注射级辅料中的溶解性、通过绘制空白伪三元相图、进行了自乳化给药系统基本处方的初步筛选。最后通过考察载药量对粒径、制剂稳定性的影响,对注射用DOC自乳化微乳制剂进行了处方优化,确定处方组成为：m(MCT):m(Soultol HS15):m(PEG 400)=3:8:4,其中药物含量的质量分数为2%。
三、多西他赛自乳化系统的理化性质研究及其稳定性：对DOC-SEDDS和其自乳化后乳剂的外观性状进行观察,同时对自乳化时间,自乳化后的粒径进行了测定。考察了不同温度,分散介质,分散方法对系统自乳化效率的影响以及不同的分散介质,稀释倍数对自乳化后乳剂粒径的影响。稳定性试验结果表明DOC-SEDDS初步稳定性良好。
四、注射用的多西他赛自乳化制剂在大鼠体内药物动力学研究：建立了大鼠血浆中多西他赛的高效液相色谱法,考察了尾静脉注射多西他赛普通注射剂和多西他赛自乳化后大鼠体内的药物动力学过程。建立了多西他赛体内药物测定的HPLC法,以甲醇处理血浆样品后进行测定。该法简单、快捷、灵敏度高,适合多西他赛的体内分析研究。结果表明多西他赛自乳化药液和参照制剂大鼠尾静脉注射给药后药动学过程均符合双室模型。
Docetaxel is a novel anticancer drugs. It is effective for ovarian cancer,breast cancer、non-small cell lung cancer、esophageal cancer、head and neck cancer and other tumor diseases.At present, the commercial product of docetaxel still adopted Tween 80 and ethanol as injection solvents, Tween 80 was used as solubilizer and ethanol as auxiliary solvent, which was packed separated as condensed injection solution and solvent in two packages. Although the prescription use a relatively less toxic solubilizer Tween 80 and ethanol as solvents, but still exsit complicated operation in clinical use and Tween 80 is easy cause allergies and hemolytic effects.In order to eliminate the existed a series of problems which docetaxel produced in clinical use and solve the lower solubility of docetaxel, a docetaxel self-microemulsion for intravenous injection was developed in this study, so as to provide fundmental work for new dosage form research of docetaxel. The main contents of the research are follows.
1. Preformulation research of docetaxel self-microemulsion.
An HPLC method was developed for the assay determination of docetaxel self-emulsifying system on the preformulation study, this method is sensitive、precise、convenient specific to self-emulsifying system for the determination of the drug.The solubility of docetaxel in various oils phase and surfactant and cosurfactant was measured, also observed the effect through a variety of oil phase and surfactant of the compatibility, choose with strong emulsifier and higher solubility for drug an, as the self-emulsifying drug delivery system of basic prescription screening. Determinnation of drug solubility in water and adjuvants showed DOC was insoluble in water and relatively more soluble in various oil、emulsifier and co-emulsifier.The oil-water participate coefficient showed relatively strong lipophlic property of drug.
2. The preparation of docetaxe self-emulsifying system.
Based on the results of the study before formulation, we search for the optimum formulation for the self-microemulsifying drug delivery system of DOC, the drawing of pseudo-ternary phase diagram of blank self-microemulsifying drug delivery system and analysis partical size. The constitution of optimum formulation is as follows:m(MCT): m(Soultol HS15):m(PEG 400)= 3:8:4, with content 2% of drug.
3. Docetaxel self-emulsifying system and the stability of the physical and chemical properties.
According to the appearance of SEDDS, before and after emulsiyfing, the emulsified time, the droplet size after self-emulsification, content and stability test of DOC, the quality of SEDDS of DOC was evaluated.Meanwhile, we also studied the shifts of the self-emulsifying efficiency by changing temperature, dispersed media and dispersed methods and the effect of the different dispersed mdedium, dilution on the droplet size.
4. The pharmacodynamic study of docetaxel self-microemulsion in rats.
An HPLC method was developed for the determination of docetaxel in mouse plasma. Pharmacokinetics of docetaxel injection and docetaxel self-microemulsion in mouse after iv administration were investigated.The plasma samples were dealt with methanol before determination.The method was simple、quick、sensive and very suitable for the drug determination in vivo. The pharmmacokinetics results of docetaxel self-microemulsions showed that docetaxel injection and docetaxel self-microemulsion was accored with double-room double.
引文
[1]Mansukhlal C.W, Harold L.T,Monroe E.W,et al. Plant antitumor agents.VI. Isolation and structure of taxol,a novel antileukemic and antitumor agent from Taxus brevifolia[J].Am.Chem.Soc,1971; 93(9):2325-2327.
[2]Kingston D.G,Molinero A.A,Rimoldi J.M.The taxane diterpenoids.In Herz
[3]W.;Kirby G.W.;Moore R.E.;et.al.eds.Progress in the Chemistry of Organic Natural Products.New York:Springer-Verlag.1993,61(1):31-60.(b)Schif,P.B.; Fant,J.; Horwitz,S.B.Promotion of microtubule assembly in vitm by taxo1. Nature.1979; 277(5698):665-667.(c)Manfredi,J.J.; Horwitz,S.B.Taxan antimitotic agent with a new mechanism of action.Pharmacol.Ther.1984; 25(2):83-125.
[4]Nicolaou,K.C,Dai W.M,Guy R.K.Chemistry and biology of taxol[J]. Angewandte Chemie International Edition in English,1994; 33(1):15-44.
[5]叶敏,朱珠,沈铿,等.紫杉醇药代动力学研究进展[J].中国新药杂志,1999；8(5)：302-306.
[6]边原.多西他赛含量测定与药代动力学研究进展[J].中国药业,2009；18(3)：59-60.
[7]Luca G,Christine M,Antonio G,et al. Nonlinear pharmacokinetics and meta-bolism of paclitaxel and its pharmacokinetic pharmacodynamic relationships in human[J]. Clin Oncol,1995; 13(1):180.
[8]Ghersi D,Wilcken N,Simers R.J.A systematic review of taxane-containing reg-imens for metatic breast cancer[J].Br J Cancer,2005; 93(3):293-301.
[9]姚和际.多西紫杉醇研究进展及市场分析[J].中国制药信息,2001；17(5)：29-30.
[10]童晓华多西他赛医院用药研究报,Http:www.511511.com.
[11]冯刚,张湘如.紫杉类药物治疗卵巢癌[J].中国新药杂志,1998；7(3)：165-167.
[12]孙燕,李雏廉,管忠震.泰索帝治疗晚期乳腺癌和肺癌[J].中国新药杂志,1998；7(3)：165-167.
[13]Szebeni J,Alvzing C.R,Szvzy S,et al. Formation of complement-activating particles in aqueous solutions of Taxol:possible role in hypersensitivity reactions [J].International Immunopharmacol,2001,1(4):721.
[14]冯立艳,王成,胡明继.静脉滴注紫杉醇出现过敏性休克1例[J].中国新药与临床杂志,1999；18(5)：309.
[15]H.A Bardelineijer,M.Ouwehan,T.Buckie,et al.Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir[J].Caneer Research,2002; 62:6158-6164.
[16]宋沁馨,于立洁.多西他赛的临床应用进展[J].中国新药杂志,2001；10(12)：900-903.
[17]伍彬,杨宗发.紫杉类药物药理及临床研究进展[J].中国药业,2001；3(6)：77-78.
[18]李定纲.新一代紫杉类抗癌药物一泰帝素(多西紫杉醇Docetaxel) [J].世界药品信息,2002；3(3)：12-13.
[19]Immordino M.L,Brusa P,Arpicco S,et al.Preparation characterization cytotoxicity and P-harmacokinetics of liposomes containing docetaxel [J]. J Control Release,2003; 91(3):417-429.
[20]张翠霞,王东凯,张文涛,等.多西紫杉醇脂质体的制备及其性质考察[J].中国新药杂志,2007；16(10)：780-783.
[21]刘韬,黄红兵,林子超,等.多西紫杉醇脂质体的制备及稳定性考察[J].中国药房,2007；18(25)：1958-1960.
[22]Le Garrec D,Gori S,Luo, et al. Poly(N-vinylpyrroli-done)-block-poly (D,L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs:in vitro and in vivo evalu-ation[J].Controlled Release,2004; 99(1):83-101.
[23]杜振新,卢秀莲,李大涛,等.一种含有多西他赛的脂肪乳剂及其制备方法:中国,200510084055.6[P].2005-12-21.
[24]徐玉清,文雪梅.多西他赛磁微球的制备[J].哈尔滨医科大学学报,2005；39(6)：537-539.
[25]徐玉清,文雪梅.多西紫杉醇磁微球：中华人民共和国,200410044113.8[P].2005-08-10.
[26]赵秀峰,吴洪林,任岩海.多西他赛微乳制剂的研究[J].医学综述,2009；15(16)：2515-2518.
[27]郑俊民.经皮给药新剂型[M].北京：人民卫生出版社,1997：241-245.
[28]陈洁,李博,吴定伟,等.多西他赛纳米乳的研制和质量评价[J].中国药学杂志,2010；45(7)：534-538.
[29]黄成安.多西他塞与中药挥发油复合静脉注射乳剂及其制备方法：中华人民共和国,CN 1931158A[P].2007-03-21.
[30]郑少辉,王明新.多西紫杉醇静脉注射亚微乳及其制备方法：中华人民共和国,CN 1857222A[P].2006-11-08.
[31]张晓燕,平其能.多西紫杉醇白蛋白纳米粒的制备及体外评价[J].药学进展,2008；(5)：223-228.
[32]Esteva F.J,Valero V,Pusztai L, et al. Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond [J].The Oncologist,2001; 6(2):133-146.
[33]Michaud L.B,Valero V,Hortobagyi G. Risks and benefits of taxanes in breast and ovarian cancer [J].Drug Safety,2000; 23(5):401-428.
[34]刘洁凡,曾谦,蒋亦燕等.单药多西紫杉醇治疗非小细胞肺癌剂量强度与疗效和毒性的关系[J].现代中西医结合杂志,2006,15(8)：1031-1032.
[35]元英进.抗癌药紫杉醇和多西紫杉醇[M].北京：化学工业出版社,2002；163.
[36]梁晓丽,夏路风,刘凤琴,等.多西紫杉醇的药理与临床应用[J].首都医药,1999,6(5)：28-29.
[37]吴海鹰,孙.燕.李管等.泰索帝治疗晚期乳腺癌和肺癌[J].中国新药杂志,1998,7(3)：165.
[38]冯刚,张湘茹.紫杉类药物治疗卵巢癌[J].中国新药杂志,1998,7(4)：273-276
[39]陈为.抗癌药Docetaxel[J].国外医药(合成药,生化药,制剂分册),1997；18(4)：237-238.
[40]汤志强.抗肿瘤药-多西他赛[J].中国药学杂志,1999；34(2)：134.
[41]解红武.多西他赛的合成及临床应用进展[J].天津药学,2008；20(6)：68-71.
[42]巫云立,胡夕春.泰索帝的临床应用进展[J].世界临床药物,2003；24(6)：347-350.
[43]鲁莹,刘英,蒋雪涛.新型药物载体微乳[J].国外医药(合成药,生化药,制剂分册),1999；20(4)：253-260.
[44]崔正刚,殷福珊.微乳化技术及应用[M].北京：中国轻工业出版社,1999；75-79.
[45]刘杰,刘少杰,吕峰等.微乳液体系作为药物载体的研究进展[J].日用化学,2002；32(3)：75-77.
[46]陆彬主编：药物制剂与新技术[M].北京：人民卫生出版社,2002；40-60.
[47]周庆辉,平其能.自乳化药物传递系统的应用与前景[J].药学进展,2001；25(3)：134-138.
[48]陈宗淇,戴闽光.胶体化学[M].北京：高等教育出版社,1985；342-345.
[49]Schechter R.S. Microemulsions and Related Systems [M].New York Marcel Dekker,1998; 1-200.
[50]Craig DQM,Barker SA,Banning D,et al.An investigation into mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy [J]. Int J pharm,1995; 114 (1):103-113.
[51]Pouron C.W. Formulation of self-emulsifying drug deliver system[J].Advan-ced drug delivery reviews,1997; 25(1):47-58.
[52]Melik D.H,Fogler H.S.The turbidimertic determination of particle size disrtibution of colloidal system[J]. Colloid Interface Sci,1983; 92(1):161-180.
[53]全东琴,徐贵霞.全反式维甲酸自乳化给药系统的体内外评价[J].药学学报,2005；40(1)：76-79.
[54]张正权,陆彬.微乳给药系统研究概况[J].中国医药工业杂志,2001；31(3)：139.
[55]于力,张钧寿,周建平.纳米乳的研究及其在制剂学领域的应用[J].药学进展,2006；30(11)：491-496
[56]涂秋榕,陈洁,朱家壁.自乳化药物传递系统[J].国外医药(合成药,生化药,制剂分册),2002；23(3)：170-173.
[57]Holmberg I,Aksnes L,Berlin T. et al. Biopharm Drug Disposition.1990; 11:15.
[58]鲁莹,刘英,蒋雪涛.新型药物载体：微乳.国外医药合成药生化药制剂分册,1999；20(4)：253-250.
[59]Lee MJ, Lee MH, Shim CK.Inverse targeting of drugs to reticuloendothelial system rich organs by lipid microemulsion emulsified with poloxamer 388[J].Int J Pharm,1995; 113(2):175-187.
[60]Lundberg BB,Mortimer BC,Redgrave TG.Submicron lipide mulsion contaming amphipathic polyethylene glycol for use as drugcarries with prolonged circulation time [J].Int J,Pharm,1996; 134(1/2):119-127.
[61]苏德森,王思玲.物理药剂学[M].北京：化学工业出版社,2004；338-361.
[62]魏莉,王东凯.自乳化释药系统的探讨.黑龙江医药,2004,17(4)：299-301.
[63]王秀敏,邓英杰,赵春杰等.β-榄香烯油水分配系数的测定[J].沈阳药科大学学报,2005,22(4)：289-291.
[64]张婷婷,徐文,胡生亮,等.水飞蓟宾在不同介质中平衡溶解度和表观油水分配系数的测定[J].中国药学杂志,2006,41(20)：1569-1571.
[65]徐燕,仲伟玲,马仕珉,等HPLC法测定多西他赛及注射液的含量[J].淮海工学院商报,2006,15(4)：48-50.
[66]金龙宇,邱利炎,金一,等.注射用多西他赛的HPLC测定[J].中国医药工艺杂志社,2006,37(10)：708-709.
[67]杨清敏,邓树海,唐玮.高效液相色谱色谱法测定多西他赛聚乳酸微球中多西他赛的含量[J].中国医院药学杂志,2004,24(10)：650-651.
[68]杨民,王东凯,关世侠,等.蛋白沉淀-HPLC法测定大鼠血浆中多西他赛的含量[J].沈阳药科大学学报,2009,26(2)：131-133.
[69]张学农,唐丽华,阎雪莹,等.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志,2005,24(4)：294-298.
[70]李娜,孙国平,金涌,等.反向高效液相法测定血浆中多西紫杉醇的含量[J].安徽医科大学学报,2006,41(6)：707-709.
[2]Kingston D.G,Molinero A.A,Rimoldi J.M.The taxane diterpenoids.In Herz
[3]W.;Kirby G.W.;Moore R.E.;et.al.eds.Progress in the Chemistry of Organic Natural Products.New York:Springer-Verlag.1993,61(1):31-60.(b)Schif,P.B.; Fant,J.; Horwitz,S.B.Promotion of microtubule assembly in vitm by taxo1. Nature.1979; 277(5698):665-667.(c)Manfredi,J.J.; Horwitz,S.B.Taxan antimitotic agent with a new mechanism of action.Pharmacol.Ther.1984; 25(2):83-125.
[4]Nicolaou,K.C,Dai W.M,Guy R.K.Chemistry and biology of taxol[J]. Angewandte Chemie International Edition in English,1994; 33(1):15-44.
[5]叶敏,朱珠,沈铿,等.紫杉醇药代动力学研究进展[J].中国新药杂志,1999；8(5)：302-306.
[6]边原.多西他赛含量测定与药代动力学研究进展[J].中国药业,2009；18(3)：59-60.
[7]Luca G,Christine M,Antonio G,et al. Nonlinear pharmacokinetics and meta-bolism of paclitaxel and its pharmacokinetic pharmacodynamic relationships in human[J]. Clin Oncol,1995; 13(1):180.
[8]Ghersi D,Wilcken N,Simers R.J.A systematic review of taxane-containing reg-imens for metatic breast cancer[J].Br J Cancer,2005; 93(3):293-301.
[9]姚和际.多西紫杉醇研究进展及市场分析[J].中国制药信息,2001；17(5)：29-30.
[10]童晓华多西他赛医院用药研究报,Http:www.511511.com.
[11]冯刚,张湘如.紫杉类药物治疗卵巢癌[J].中国新药杂志,1998；7(3)：165-167.
[12]孙燕,李雏廉,管忠震.泰索帝治疗晚期乳腺癌和肺癌[J].中国新药杂志,1998；7(3)：165-167.
[13]Szebeni J,Alvzing C.R,Szvzy S,et al. Formation of complement-activating particles in aqueous solutions of Taxol:possible role in hypersensitivity reactions [J].International Immunopharmacol,2001,1(4):721.
[14]冯立艳,王成,胡明继.静脉滴注紫杉醇出现过敏性休克1例[J].中国新药与临床杂志,1999；18(5)：309.
[15]H.A Bardelineijer,M.Ouwehan,T.Buckie,et al.Low systemic exposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir[J].Caneer Research,2002; 62:6158-6164.
[16]宋沁馨,于立洁.多西他赛的临床应用进展[J].中国新药杂志,2001；10(12)：900-903.
[17]伍彬,杨宗发.紫杉类药物药理及临床研究进展[J].中国药业,2001；3(6)：77-78.
[18]李定纲.新一代紫杉类抗癌药物一泰帝素(多西紫杉醇Docetaxel) [J].世界药品信息,2002；3(3)：12-13.
[19]Immordino M.L,Brusa P,Arpicco S,et al.Preparation characterization cytotoxicity and P-harmacokinetics of liposomes containing docetaxel [J]. J Control Release,2003; 91(3):417-429.
[20]张翠霞,王东凯,张文涛,等.多西紫杉醇脂质体的制备及其性质考察[J].中国新药杂志,2007；16(10)：780-783.
[21]刘韬,黄红兵,林子超,等.多西紫杉醇脂质体的制备及稳定性考察[J].中国药房,2007；18(25)：1958-1960.
[22]Le Garrec D,Gori S,Luo, et al. Poly(N-vinylpyrroli-done)-block-poly (D,L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs:in vitro and in vivo evalu-ation[J].Controlled Release,2004; 99(1):83-101.
[23]杜振新,卢秀莲,李大涛,等.一种含有多西他赛的脂肪乳剂及其制备方法:中国,200510084055.6[P].2005-12-21.
[24]徐玉清,文雪梅.多西他赛磁微球的制备[J].哈尔滨医科大学学报,2005；39(6)：537-539.
[25]徐玉清,文雪梅.多西紫杉醇磁微球：中华人民共和国,200410044113.8[P].2005-08-10.
[26]赵秀峰,吴洪林,任岩海.多西他赛微乳制剂的研究[J].医学综述,2009；15(16)：2515-2518.
[27]郑俊民.经皮给药新剂型[M].北京：人民卫生出版社,1997：241-245.
[28]陈洁,李博,吴定伟,等.多西他赛纳米乳的研制和质量评价[J].中国药学杂志,2010；45(7)：534-538.
[29]黄成安.多西他塞与中药挥发油复合静脉注射乳剂及其制备方法：中华人民共和国,CN 1931158A[P].2007-03-21.
[30]郑少辉,王明新.多西紫杉醇静脉注射亚微乳及其制备方法：中华人民共和国,CN 1857222A[P].2006-11-08.
[31]张晓燕,平其能.多西紫杉醇白蛋白纳米粒的制备及体外评价[J].药学进展,2008；(5)：223-228.
[32]Esteva F.J,Valero V,Pusztai L, et al. Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond [J].The Oncologist,2001; 6(2):133-146.
[33]Michaud L.B,Valero V,Hortobagyi G. Risks and benefits of taxanes in breast and ovarian cancer [J].Drug Safety,2000; 23(5):401-428.
[34]刘洁凡,曾谦,蒋亦燕等.单药多西紫杉醇治疗非小细胞肺癌剂量强度与疗效和毒性的关系[J].现代中西医结合杂志,2006,15(8)：1031-1032.
[35]元英进.抗癌药紫杉醇和多西紫杉醇[M].北京：化学工业出版社,2002；163.
[36]梁晓丽,夏路风,刘凤琴,等.多西紫杉醇的药理与临床应用[J].首都医药,1999,6(5)：28-29.
[37]吴海鹰,孙.燕.李管等.泰索帝治疗晚期乳腺癌和肺癌[J].中国新药杂志,1998,7(3)：165.
[38]冯刚,张湘茹.紫杉类药物治疗卵巢癌[J].中国新药杂志,1998,7(4)：273-276
[39]陈为.抗癌药Docetaxel[J].国外医药(合成药,生化药,制剂分册),1997；18(4)：237-238.
[40]汤志强.抗肿瘤药-多西他赛[J].中国药学杂志,1999；34(2)：134.
[41]解红武.多西他赛的合成及临床应用进展[J].天津药学,2008；20(6)：68-71.
[42]巫云立,胡夕春.泰索帝的临床应用进展[J].世界临床药物,2003；24(6)：347-350.
[43]鲁莹,刘英,蒋雪涛.新型药物载体微乳[J].国外医药(合成药,生化药,制剂分册),1999；20(4)：253-260.
[44]崔正刚,殷福珊.微乳化技术及应用[M].北京：中国轻工业出版社,1999；75-79.
[45]刘杰,刘少杰,吕峰等.微乳液体系作为药物载体的研究进展[J].日用化学,2002；32(3)：75-77.
[46]陆彬主编：药物制剂与新技术[M].北京：人民卫生出版社,2002；40-60.
[47]周庆辉,平其能.自乳化药物传递系统的应用与前景[J].药学进展,2001；25(3)：134-138.
[48]陈宗淇,戴闽光.胶体化学[M].北京：高等教育出版社,1985；342-345.
[49]Schechter R.S. Microemulsions and Related Systems [M].New York Marcel Dekker,1998; 1-200.
[50]Craig DQM,Barker SA,Banning D,et al.An investigation into mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy [J]. Int J pharm,1995; 114 (1):103-113.
[51]Pouron C.W. Formulation of self-emulsifying drug deliver system[J].Advan-ced drug delivery reviews,1997; 25(1):47-58.
[52]Melik D.H,Fogler H.S.The turbidimertic determination of particle size disrtibution of colloidal system[J]. Colloid Interface Sci,1983; 92(1):161-180.
[53]全东琴,徐贵霞.全反式维甲酸自乳化给药系统的体内外评价[J].药学学报,2005；40(1)：76-79.
[54]张正权,陆彬.微乳给药系统研究概况[J].中国医药工业杂志,2001；31(3)：139.
[55]于力,张钧寿,周建平.纳米乳的研究及其在制剂学领域的应用[J].药学进展,2006；30(11)：491-496
[56]涂秋榕,陈洁,朱家壁.自乳化药物传递系统[J].国外医药(合成药,生化药,制剂分册),2002；23(3)：170-173.
[57]Holmberg I,Aksnes L,Berlin T. et al. Biopharm Drug Disposition.1990; 11:15.
[58]鲁莹,刘英,蒋雪涛.新型药物载体：微乳.国外医药合成药生化药制剂分册,1999；20(4)：253-250.
[59]Lee MJ, Lee MH, Shim CK.Inverse targeting of drugs to reticuloendothelial system rich organs by lipid microemulsion emulsified with poloxamer 388[J].Int J Pharm,1995; 113(2):175-187.
[60]Lundberg BB,Mortimer BC,Redgrave TG.Submicron lipide mulsion contaming amphipathic polyethylene glycol for use as drugcarries with prolonged circulation time [J].Int J,Pharm,1996; 134(1/2):119-127.
[61]苏德森,王思玲.物理药剂学[M].北京：化学工业出版社,2004；338-361.
[62]魏莉,王东凯.自乳化释药系统的探讨.黑龙江医药,2004,17(4)：299-301.
[63]王秀敏,邓英杰,赵春杰等.β-榄香烯油水分配系数的测定[J].沈阳药科大学学报,2005,22(4)：289-291.
[64]张婷婷,徐文,胡生亮,等.水飞蓟宾在不同介质中平衡溶解度和表观油水分配系数的测定[J].中国药学杂志,2006,41(20)：1569-1571.
[65]徐燕,仲伟玲,马仕珉,等HPLC法测定多西他赛及注射液的含量[J].淮海工学院商报,2006,15(4)：48-50.
[66]金龙宇,邱利炎,金一,等.注射用多西他赛的HPLC测定[J].中国医药工艺杂志社,2006,37(10)：708-709.
[67]杨清敏,邓树海,唐玮.高效液相色谱色谱法测定多西他赛聚乳酸微球中多西他赛的含量[J].中国医院药学杂志,2004,24(10)：650-651.
[68]杨民,王东凯,关世侠,等.蛋白沉淀-HPLC法测定大鼠血浆中多西他赛的含量[J].沈阳药科大学学报,2009,26(2)：131-133.
[69]张学农,唐丽华,阎雪莹,等.紫杉醇自乳化微乳的制备及其在大鼠体内的药动学[J].中国新药与临床杂志,2005,24(4)：294-298.
[70]李娜,孙国平,金涌,等.反向高效液相法测定血浆中多西紫杉醇的含量[J].安徽医科大学学报,2006,41(6)：707-709.