水飞蓟宾、槲皮素固体分散体的热力学性质研究
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摘要
水飞蓟宾、槲皮素均为难溶性药物,溶解度和溶出速度差,提高生物利用度是研究的一个重要方面。将难溶性药物制备成固体分散体是改善其溶出速度有效方法之一。本文分别以水飞蓟宾、槲皮素与不同载体制备成固体分散体,研究其热力学性质和相关光谱性质。研究内容包括:
1.以Poloxamer 188为载体,熔融法制备水飞蓟宾+Poloxamer 188固体分散体,利用差示扫描量热法(DSC)测定固体分散体的DSC曲线,考察相变温度和相变焓随固体分散体组成的变化情况,即T-wt%和ΔfusHw-wt%关系。结合傅立叶红外光谱(IR)和X-射线粉末衍射(XRD)分析水飞蓟宾和Poloxamer 188分子间的相互作用以及样品晶型的变化。并运用Flory-Huggins理论模型对实验结果进行关联。
2.以PEG 6000为载体,熔融法制备槲皮素+PEG 6000固体分散体,利用差示扫描量热法(DSC)测定固体分散体的DSC曲线,考察相变温度和相变焓随分散体组成的变化情况,即T-wt%和ΔfusHw-wt%关系。结合傅立叶红外光谱(IR)和X-射线粉末衍射(XRD)分析槲皮素和PEG 6000分子间的相互作用以及样品晶型的变化。
3.以Poloxamer 188为载体,熔融法制备槲皮素+Poloxamer 188固体分散体,利用差示扫描量热法(DSC)测定固体分散体的DSC曲线,考察相变温度和相变焓随分散体组成的变化情况,即T-wt%和ΔfusHw-wt%关系。结合傅立叶红外光谱(IR)和X-射线粉末衍射(XRD)分析槲皮素和Poloxamer 188分子间的相互作用以及样品晶型的变化。
4.测定胆酸钠+水飞蓟宾混合体系的比热,对比热数据进行分析。
Silybin and Quercetin are mainly hydrophobic organic compounds. Solid dispersion technology can improve the dissolution rate of hydrophobic drugs. Thermodynamic properties of solid dispersions of silybin and quercetin were studied in this work. It included:
1. Solid dispersions of silybin with Poloxamer188 was prepared by fusion-cooling method. In this work, the thermodynamic properties of mixture of silybin + poloxamer 188 were determined. One interest is the study on the possible effect of poloxamer 188 on reducing the melting temperature of silybin + Poloxamer188 solid dispersions. The melting temperature (Tfus) and the enthalpy of fusion,ΔfusH, were measured by differential scanning calorimetry (DSC). The phase diagram and the enthalpy diagram were constructed from experimental data. The data were fitted to the Flory–Huggins model. FT-IR spectroscopy and powder X-ray diffraction were performed to elucidate the structure and possible drug–carrier interactions.
2. Solid dispersion of PEG 6000 with quercetin was prepared by fusion-cooling method. The T-wt% andΔfusHw-wt% diagrams were constructed by DSC method. The melting temperature (Tfus) and the enthalpy of fusion,ΔfusH, were measured by differential scanning calorimetry (DSC). The phase diagram and the enthalpy diagram were constructed from experimental data. FT-IR spectroscopy and powder X-ray diffraction were performed to elucidate the structure and possible drug–carrier interactions.
3. Solid dispersion of quercetin with Poloxamer 188 was prepared by fusion-cooling method. The T-wt% andΔfusHw-wt% diagrams were constructed by DSC method. The melting temperature (Tfus) and the enthalpy of fusion,ΔfusH, were measured by differential scanning calorimetry (DSC). The phase diagram and the enthalpy diagram were constructed from experimental data. FT-IR spectroscopy and powder X-ray diffraction were performed to elucidate the structure and possible drug–carrier interactions.
4.The heat capacity of the system of Sodium cholate + Silybin were determined by DSC.
1.以Poloxamer 188为载体,熔融法制备水飞蓟宾+Poloxamer 188固体分散体,利用差示扫描量热法(DSC)测定固体分散体的DSC曲线,考察相变温度和相变焓随固体分散体组成的变化情况,即T-wt%和ΔfusHw-wt%关系。结合傅立叶红外光谱(IR)和X-射线粉末衍射(XRD)分析水飞蓟宾和Poloxamer 188分子间的相互作用以及样品晶型的变化。并运用Flory-Huggins理论模型对实验结果进行关联。
2.以PEG 6000为载体,熔融法制备槲皮素+PEG 6000固体分散体,利用差示扫描量热法(DSC)测定固体分散体的DSC曲线,考察相变温度和相变焓随分散体组成的变化情况,即T-wt%和ΔfusHw-wt%关系。结合傅立叶红外光谱(IR)和X-射线粉末衍射(XRD)分析槲皮素和PEG 6000分子间的相互作用以及样品晶型的变化。
3.以Poloxamer 188为载体,熔融法制备槲皮素+Poloxamer 188固体分散体,利用差示扫描量热法(DSC)测定固体分散体的DSC曲线,考察相变温度和相变焓随分散体组成的变化情况,即T-wt%和ΔfusHw-wt%关系。结合傅立叶红外光谱(IR)和X-射线粉末衍射(XRD)分析槲皮素和Poloxamer 188分子间的相互作用以及样品晶型的变化。
4.测定胆酸钠+水飞蓟宾混合体系的比热,对比热数据进行分析。
Silybin and Quercetin are mainly hydrophobic organic compounds. Solid dispersion technology can improve the dissolution rate of hydrophobic drugs. Thermodynamic properties of solid dispersions of silybin and quercetin were studied in this work. It included:
1. Solid dispersions of silybin with Poloxamer188 was prepared by fusion-cooling method. In this work, the thermodynamic properties of mixture of silybin + poloxamer 188 were determined. One interest is the study on the possible effect of poloxamer 188 on reducing the melting temperature of silybin + Poloxamer188 solid dispersions. The melting temperature (Tfus) and the enthalpy of fusion,ΔfusH, were measured by differential scanning calorimetry (DSC). The phase diagram and the enthalpy diagram were constructed from experimental data. The data were fitted to the Flory–Huggins model. FT-IR spectroscopy and powder X-ray diffraction were performed to elucidate the structure and possible drug–carrier interactions.
2. Solid dispersion of PEG 6000 with quercetin was prepared by fusion-cooling method. The T-wt% andΔfusHw-wt% diagrams were constructed by DSC method. The melting temperature (Tfus) and the enthalpy of fusion,ΔfusH, were measured by differential scanning calorimetry (DSC). The phase diagram and the enthalpy diagram were constructed from experimental data. FT-IR spectroscopy and powder X-ray diffraction were performed to elucidate the structure and possible drug–carrier interactions.
3. Solid dispersion of quercetin with Poloxamer 188 was prepared by fusion-cooling method. The T-wt% andΔfusHw-wt% diagrams were constructed by DSC method. The melting temperature (Tfus) and the enthalpy of fusion,ΔfusH, were measured by differential scanning calorimetry (DSC). The phase diagram and the enthalpy diagram were constructed from experimental data. FT-IR spectroscopy and powder X-ray diffraction were performed to elucidate the structure and possible drug–carrier interactions.
4.The heat capacity of the system of Sodium cholate + Silybin were determined by DSC.
引文
(1)鲍廷铮,王庆伦,廖志辉,槲皮素的研究近况[J].江西中医学院学报,1998,10(2):90～91.
(2) Castrillo J.L,Carrasco L, Action of 3 methylquercetin on pohovirus RNA replication [J].J. Viro,1987,61 (10):3319– 3321.
(3) Pietta P , Simonetti P , Gardana C , et al. Relationship between rate and extend of catechinabsorption and plasma antioxidant status [J] .Biochem Mol Biol Int ,1998 ,46 (5) :895
(4)张敏,槲皮素与5 - FU对两种人结肠直肠癌细胞株细胞抑制作用的相互关系[J],新医药一植物药分册,1996,11(3):127
(5)张琼,徐明娟,宋亮年等,槲皮素对人卵巢癌细胞系增殖的影响[J],第二军医大学学报,1999,20(6):380-382
(6)林蓉,刘俊田,李旭等,槲皮素对血管内皮细胞损伤的保护作用[J],中国循环杂志,2000,5(5):304-305
(7)张红雨,黄酮类抗氧化剂结构—活性关系的理论解释[J],中国科学(B辑),1999,29(1),91-96
(8)王丽玲,焦必林,曾凡坤,保健功能因子-生物类黄酮[J],粮食与油脂,2004,9,18-20
(9)唐传核,彭志英,类黄酮的最新研究进展(Ⅰ)—抗氧化研究[J],中国食品添加剂,2001,5,12-17
(10)宋丽,臧志和,廖洪利,谢静,槲皮素三种化学结构修饰方法的研究[J],成都医学院学报,2007,2,611,711
(11) Cassady JM,et al.Natural products as a source of potential cancer chemothera-peutic and chemopreventive agents.J NatProd,1990,53 (1):23-41
(12)张敏,槲皮素与5-FU对两种人结肠直肠癌细胞株细胞抑制作用的相互关系,国外医药,植物药分册,1996,11 (3):127
(13)吴承堂,黎沾良,急性坏死性胰腺炎肠通透性及病理改变实验观察[J],第一军医大学学报,1999,19 (1):28-30
(14)苏俊锋,郭长江,韦京豫等,槲皮素体内外抗氧化作用的比较研究[J],中国应用生理学杂志,2002,18(4):382-386
(15)曾云先,刘尚勤,槲皮素对大鼠降糖作用的观察[J],华夏医学,1999,12 (1):34-35
(16) Scambia Gpanici PB, Raneuetti Fo,et al, Quercetin enhance transforming growth factorβ,secretion by human ovanrian cancercells, Int J Cancer,1994 ,57:211-215
(17) Castrillo JL,Carrasco L, Action of 3-methylquercetin on poliovirus RNA replication, J V i rol,1987,61(10):3319～21
(18) Vrijsen R,Everaert L,Boeye A, Antiviral activity of flavones and potentiation by ascorbate, J Genviral , 1988,69 (p17):1749-51
(19) Kaul TN,Middleton B Jn Ogra PL, Antiviral effect of flavonoids on human virus. J Med Virol,1985,15 (1):71-79
(20) Mucsi L, Combined antiviral effects of flavonoids and 5-ethyl-2'-deoxyuridine on the multiplication of herpsviruses, Acta V i rol,1984,28 (5):395-400
(21) Veckenstedi A, Guttner J, Beladi l, Synergistic action of quercetin and mruine alpha/ beta interferon in the treatment of Mengo virus infection in mice, Antiviral Res,1987,7 (3) :169-178
(22) De Meyer Ni, Haemers A, Mishra-L4'-Hydroxy-3-methoxyflavones with potent anti-picornavirus activity, JMe Chem, 1991,34 (2):736-46
(23) Boers F, Deng BL , Lemiere G, An improved synthesis of the anti-picornavirus flavone 3-O-methylquercetin, Arch Pharm Weinheim,1997,330 (9-10) :313-6
(24)毛晓青,陈钧辉,拓扑异构酶抑制剂—一种新型的抗肿瘤药物,中国生化药物杂志,2000,21(1):46-48
(25) Fesen MR, Kohn KN, Leteurtre F, Pommier Y, Inhibitors of human immuno- deficiency virus integrase, Proc Acad Sci-USA,1993,90(6):2399～404
(26) Bombardelli E , Ghione M. Use of Bilobalide and Derivatives Thereof for Treatingtical Compositions Adapted for Such Use[ P]
(27) Bombardelli,E, Mustich,G.Preparation of Bilobalide Complexes With Phospholipid-srope.
(28) Bombardelli E ,Patri G,Pozzi R. Complexes of Saponins and Their Aglycons metic Compositions Containing Them[P] . US.
(29)雍德卿,席延伟,翟光喜,槲皮素磷脂复合物理化性质的研究,中国生化药物杂志,2005,26(5):582-782
(30)高作宁,彭娟,β-CD对离子型表面活性剂CMC影响的研究,宁夏工程技,2004,3(2):166-169
(31)邵伟,谢清春,王春香等,槲皮素-羟丙基-β-环糊精包合物的研究,中药材,2002,25(2),121-122
(32)李厚丽,翟光喜,马玉坤等,均匀设计优化制备槲皮素固体脂质纳米粒,食品与药品,2007,9(2),1-3
(33)李宝红,张立坚,东野广智等,槲皮素-聚乙二醇固体分散体的研制,华西药学杂志,2004,19(1):35-37
(34)肖衍宇,宋 梅,陈志鹏等,水飞蓟素自微乳的制备,中国医药工业杂志,2005,36(11):678-681
(35)吴欧燕,许雪琴,陈国南,水飞蓟宾的电化学行为研究,福州大学学报(自然科学版),2007,35(2):288-290
(36) Katiyar SK. Treatment of silymarin, a plant flavonoid, prevents ultraviolet light-induced immune suppression and oxidative stress in mouse skin, Int J Oncol, 2002,21:1213-1222
(37) Kang JS, Jcon YJ, Kim HM, et al. Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages, J Pharmacol Exp Ther, 2002,302:138-144
(38)任孟军,左国庆,水飞蓟素抗肿瘤作用的研究进展,国外医学中医中药分册,2005,271:19-22
(39)王会敏,廉红兴,徐纪军等,水飞蓟宾对阿霉素心肌毒性的保护作用,药品不良反应杂志,2003,5:371-374
(40) PelterA, Hansel R. The structure of silibin, chem.Ber, 1975,108(3):790-802
(41) ArnoneA,MerliniL,ZanarottiA,Constituents of Silybummarianum Structure of isosilybin and tereochemistry of silybin [J] J Chem Soc Chem Commun,1979,16:696-697
(42) LotterH, WagnerH, Stereochemistry of silybin [J],Z NaturforschC,1983,38C(5-6):339-341
(43) Susan Budavari , Maryadele J . O’Neil, Senior Associate, Ann Smith ,Pa2tricia E. Heckelman, Joanne F , Kinneary, The Merck Index. Twelfth Edition, Merck Research Laboratories Division of Merck & CO. Inc.Whithouse Station, NJ, 1996, 1464
(44)石磊,邓碧玉,张文琴,水飞蓟素的临床应用,河北医学, 2000, 6(4), 352-353
(45)谢京儿,廖锡麟,烫伤后大鼠肝脏药物代谢酶和脂质过氧化活性的变化以及水飞蓟宾的作用,第二军医大学学报,1989,10(5),413-416
(46)张俊平,胡振杯,冯增辉,水飞蓟宾对小鼠肝脏炎症损伤和肿瘤坏死因子的产生及活性的影响,药学学报,1996,31 (8), 577-580
(47)龙晓英,杨帆,李丽,周杏茔,水飞蓟素自乳化给药系统处方设计及溶出度评价,中国药师,2004,7(7),496-498
(48)陈大为,刘立民,丁五芝等,水飞蓟素(益肝灵)片溶出速率的研究[J],中成药,1993,15(6):2
(49)陈大为,刘立民,丁玉芝,李三鸣,刘茜英,水飞蓟素片剂溶出出速率研究,中成药,1993,15(5),2-4
(50) Daniele Savio , Paola Cristina Harrasser ,Gianluca Basso. Softgel Capsule technology as anenhancer device for the absorption of naturalprinciples in humans. Arzneim. - Forsch. / Drug Res. 1998 ,48(Ⅱ) ,1104-1106
(51)谢京儿,廖锡麟,烫伤后大鼠肝脏药物代谢酶和脂质过氧化活性的变化以及水飞蓟宾的作用,第二军医大学学报,1989,10(5),413-416
(52)张俊平,胡振杯,冯增辉,水飞蓟宾对小鼠肝脏炎症损伤和肿瘤坏死因子的产生及活性的影响,药学学报,1996,31 (8),577-580
(53) Sekiguchi K,Obi N,Studies on absorption of eutectic mixture,I A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man Chem, Pharm, Bull,1961,9(11),866-875
(54)朱盛山,药物新剂型,北京:人民卫生出版社,1993,113-115
(55)孙淑英,黎玉珉,冷晓红,联苯双酯的共沉淀物和固体分散体的制备及对温度的稳定性,沈阳药学院学报,1987,4(2),99-102
(56) Hasegawa A, Nakagawa H, Sugimoto I. Bioavaility and stability of nifedipine enteric coating agent solid dispersion. Chem Pharm Bull,1985,33(1), 388-394
(57) Hiroshi Y, Tetsuya O, Yoshio K, Application of the solid dispersion method to controlled release of medicine. I Controlled release of water soluble medicine by using solid dispersion. Chem. Pharm. Bull, 1991, 39(2), 465-473
(58)余自成,固体分散体技术在缓释制剂中的应用,中国药学杂志,1994,29(6),326-328
(59)吴春,车春波,李俊生等,槲皮素-聚乙二醇固体分散体对亚硝化反应的抑制作用,食品科学,2008,29(3),53-55
(60)王婴,罗虹嘉,王欢,固体分散体在缓释制剂中的应用,中国药业,2002,11(11),72-73
(61)刘善奎,钟延强,孙其荣,盐酸尼卡地平缓释固体分散体的研究,中国医药工业杂志,2000,31(3),107-110
(62)肖玉秀,耿灏,张凯,阿司匹林固体分散物的研究,中国现代应用药学杂志,1999,16(5),20-22
(63)李国栋,周全,赵长文,青蒿素固体分散物的制备及体外溶出研究,中国药学杂志,1999,34(1),26-28
(64)王展,韩立炜,任天池,葛根素-聚乙二醇6000固体分散体的制备及其溶解性能的研究,北京中医药大学学报,2007,30(5),346-349
(65)王烈群,王宏宇,萘普生-聚乙烯吡咯烷酮固体分散体的制备及溶出速率测定,内蒙古医学院学报,1998,20(1),27-31
(66)赵红,环孢素固体分散物一些物性的研究,药学学报,1997 ,32(10),777-781
(67) H?rter,D.; Dressman,J.B. Influence of Physicochemical Properties on Dissolution of Drugs in the Gastrointestinal Tract. Adv. Drug Deliv. Rev. 2001, 46, 75–87.
(68) Bai,T.C.; Yan,G.B.; Hu,J.; Zhang,H.L.; Huang,C.G.. Solubility of silybin in aqueous poly(ethylene glycol) solution. Int. J. Pharm. 2006, 308, 100–106.
(69) Vasconcelos,T; Sarmento,B;Costa, P. Solid Dispersions as Strategy to Improve Oral Bioavailability of Poor Water Soluble Drugs. Drug Discovery Today 2007, 12, 1068-1075.
(70) Yao,W.W.; Bai,T.C.; Sun, J. P.; Zhu,C.W.;Hu,J.; Zhang, H. Li. Thermodynamic Properties for the System of Silybin and Poly(ethylene glycol) 6000. Thermochim. Acta 2005, 437, 17–20.
(71) Naima, Z.; Siro, T.; Juan-Manuel, G. D.; Chantal, C.; René, C.; Jerome, D. Interactions Between Carbamazepine and Polyethylene Glycol (PEG) 6000: Characterisations of the Physical, Solid Dispersed and Eutectic Mixtures. Eur. J. Pharm. Sci. 2001, 12, 395–404.
(72) Damian, F.; Blaton, N.; Naesens, L.; Balzarini, J.; Kinget, R.; Augustijns, P.; Van den Mooter, G.Physicochemical Characterization of Solid Dispersions of the Antiviral Agent UC-781 with Polyethylene Glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000, 10, 311–322.
(73) Verheyen, S.; Augustijins, P.; Kinget, R.; Van den Mooter, G. Melting Behavior of Pure Polyethylene Glycol 6000 and Polyethylene Glycol 6000 in Solid Dispersions Containing Diazepam or Temazepam: a DSC Study, Thermochim. Acta, 2001, 380, 153-164.
(74) Vanden Mooter, G., Augustijins. P., Blaton, N., Kinget, R., Physicochemical Chara-cterization of Solid Dispersions of Temazepam with Polyethylene Glycol 6000 and PVP K30. Int. J. Pharm. 1998, 164, 67-80.
(75) Wagner, H.; Selingman, O.; Lotter, H. Flavonoids and Bioflavonoids; Elsevier: Amsterdam, 1986.
(76) Lee,D.Y.-W.; Liu,Y. Molecular Structure and Stereochemistry of Silybin A, Silybin B, Isosilybin A, and Isosilybin B, Isolated from Silybum marianum (Milk Thistle) J. Nat. Prod 2003, 66, 1171-1174.
(77) Lee,J.I.; Narayan,M.; Barrett,J.S. Analysis and Comparison of Active Constituents in Commercial Standardized Silymarin Extracts by Liquid Chromatography– Electrospray Ionization Mass Spectrometry. J. Chromatogr. B 2007, 845, 95–103.
(78) Kvasnicka, F.; Bíba, B.; ?ev?ík, R.; Vold?ich, M.; Krátká, J. Analysis of the Active Components of Silymarin, J.Chromatogr. A 2003, 990, 239–245.
(79) Ga?ák, R.; Walterová, D.; K?en, V. Silybin and Silymarins– New and Emerging Applications in Medicine. Curr. Med. Chem. 2007, 14, 315.
(80) Wellington, K.; Jarvis, B. Silymarin: A Review of Its Clinical Properties in the Management of Hepatic Disorders. Biodrugs 2001, 15, 465-489.
(81) Saller, R.; Meier, R.; Brignoli, R. The Use of Silymarin in the Treatment of Liver Diseases. Drugs 2001, 61, 2035-2063.
(82) El-Samaligy, M. S.; Afifi, N. N.; Mahmoud, E. A. Increasing Bioavailability of Silymarin Using A Buccal Liposomal Delivery System: Preparation and Experimental Design Investigation, Int. J. Pharm.2006, 308, 140–148.
(83) Nair, L. M.; Konkel, J.; Thomas, M.; Koberda, M. Comparison of Electrospray Ionization Mass Spectrometry and Evaporative Light Scattering Detections for the Determination of Poloxamer 188 in Itraconazole Injectable Formulation. J. Pharm. Biomed. Anal. 2006, 41, 725–730.
(84) Harting, M. T.; Jimenez, F.; Kozar, R. A.; Moore, F. A.; Mercer, D. W.; Hunter, R. L.; Cox, C. S.; Gonzalez, E. A.; Effects of Poloxamer 188 on Human PMN Cells, Surgery, 2008, 144, 198-203.
(85) Mustafi, D.; Smith, C. M.; Makinen, M. W.; Lee, R. C. Multi-block Poloxamer Surfactants Suppress Aggregation of Denatured Proteins, Biochim. Biophys. Acta, 2008, 1780, 7–15.
(86) Woodle, M. C., Newman, M. S., Martin, F. J., Liposome Leakage and Blood Circulation: Comparison of Adsorbed Block Copolymers with Covalent Attachment of PEG. Int. J. Pharm. 1992, 88, 327–334.
(87) Castile, J. D.; Taylor, K. M. G.; Buckton, G. The Influence of Incubation Temperature and Surfactant Concentration on the Interaction between Dimyristoylphosphatidylcholine Liposomes and Poloxamer Surfactants. Int. J. Pharm. 2001, 221, 197–209.
(88) Jamil, A.; Kousksou, T.; Zeraouli, Y.; Dumas, J.-P. Liquidus Temperatures Determination of the Dispersed Binary System. Thermochim. Acta. 2008, 471, 1–6.
(89) Acree, W. E. Thermodynamic Properties of Nonelectrolyte Solutions; Academic Press Inc.: 1984.
(90) Bondi, A. vander Waals Volumes and Radii. J. Phys. Chem. 1964, 68, 441-451.
(2) Castrillo J.L,Carrasco L, Action of 3 methylquercetin on pohovirus RNA replication [J].J. Viro,1987,61 (10):3319– 3321.
(3) Pietta P , Simonetti P , Gardana C , et al. Relationship between rate and extend of catechinabsorption and plasma antioxidant status [J] .Biochem Mol Biol Int ,1998 ,46 (5) :895
(4)张敏,槲皮素与5 - FU对两种人结肠直肠癌细胞株细胞抑制作用的相互关系[J],新医药一植物药分册,1996,11(3):127
(5)张琼,徐明娟,宋亮年等,槲皮素对人卵巢癌细胞系增殖的影响[J],第二军医大学学报,1999,20(6):380-382
(6)林蓉,刘俊田,李旭等,槲皮素对血管内皮细胞损伤的保护作用[J],中国循环杂志,2000,5(5):304-305
(7)张红雨,黄酮类抗氧化剂结构—活性关系的理论解释[J],中国科学(B辑),1999,29(1),91-96
(8)王丽玲,焦必林,曾凡坤,保健功能因子-生物类黄酮[J],粮食与油脂,2004,9,18-20
(9)唐传核,彭志英,类黄酮的最新研究进展(Ⅰ)—抗氧化研究[J],中国食品添加剂,2001,5,12-17
(10)宋丽,臧志和,廖洪利,谢静,槲皮素三种化学结构修饰方法的研究[J],成都医学院学报,2007,2,611,711
(11) Cassady JM,et al.Natural products as a source of potential cancer chemothera-peutic and chemopreventive agents.J NatProd,1990,53 (1):23-41
(12)张敏,槲皮素与5-FU对两种人结肠直肠癌细胞株细胞抑制作用的相互关系,国外医药,植物药分册,1996,11 (3):127
(13)吴承堂,黎沾良,急性坏死性胰腺炎肠通透性及病理改变实验观察[J],第一军医大学学报,1999,19 (1):28-30
(14)苏俊锋,郭长江,韦京豫等,槲皮素体内外抗氧化作用的比较研究[J],中国应用生理学杂志,2002,18(4):382-386
(15)曾云先,刘尚勤,槲皮素对大鼠降糖作用的观察[J],华夏医学,1999,12 (1):34-35
(16) Scambia Gpanici PB, Raneuetti Fo,et al, Quercetin enhance transforming growth factorβ,secretion by human ovanrian cancercells, Int J Cancer,1994 ,57:211-215
(17) Castrillo JL,Carrasco L, Action of 3-methylquercetin on poliovirus RNA replication, J V i rol,1987,61(10):3319～21
(18) Vrijsen R,Everaert L,Boeye A, Antiviral activity of flavones and potentiation by ascorbate, J Genviral , 1988,69 (p17):1749-51
(19) Kaul TN,Middleton B Jn Ogra PL, Antiviral effect of flavonoids on human virus. J Med Virol,1985,15 (1):71-79
(20) Mucsi L, Combined antiviral effects of flavonoids and 5-ethyl-2'-deoxyuridine on the multiplication of herpsviruses, Acta V i rol,1984,28 (5):395-400
(21) Veckenstedi A, Guttner J, Beladi l, Synergistic action of quercetin and mruine alpha/ beta interferon in the treatment of Mengo virus infection in mice, Antiviral Res,1987,7 (3) :169-178
(22) De Meyer Ni, Haemers A, Mishra-L4'-Hydroxy-3-methoxyflavones with potent anti-picornavirus activity, JMe Chem, 1991,34 (2):736-46
(23) Boers F, Deng BL , Lemiere G, An improved synthesis of the anti-picornavirus flavone 3-O-methylquercetin, Arch Pharm Weinheim,1997,330 (9-10) :313-6
(24)毛晓青,陈钧辉,拓扑异构酶抑制剂—一种新型的抗肿瘤药物,中国生化药物杂志,2000,21(1):46-48
(25) Fesen MR, Kohn KN, Leteurtre F, Pommier Y, Inhibitors of human immuno- deficiency virus integrase, Proc Acad Sci-USA,1993,90(6):2399～404
(26) Bombardelli E , Ghione M. Use of Bilobalide and Derivatives Thereof for Treatingtical Compositions Adapted for Such Use[ P]
(27) Bombardelli,E, Mustich,G.Preparation of Bilobalide Complexes With Phospholipid-srope.
(28) Bombardelli E ,Patri G,Pozzi R. Complexes of Saponins and Their Aglycons metic Compositions Containing Them[P] . US.
(29)雍德卿,席延伟,翟光喜,槲皮素磷脂复合物理化性质的研究,中国生化药物杂志,2005,26(5):582-782
(30)高作宁,彭娟,β-CD对离子型表面活性剂CMC影响的研究,宁夏工程技,2004,3(2):166-169
(31)邵伟,谢清春,王春香等,槲皮素-羟丙基-β-环糊精包合物的研究,中药材,2002,25(2),121-122
(32)李厚丽,翟光喜,马玉坤等,均匀设计优化制备槲皮素固体脂质纳米粒,食品与药品,2007,9(2),1-3
(33)李宝红,张立坚,东野广智等,槲皮素-聚乙二醇固体分散体的研制,华西药学杂志,2004,19(1):35-37
(34)肖衍宇,宋 梅,陈志鹏等,水飞蓟素自微乳的制备,中国医药工业杂志,2005,36(11):678-681
(35)吴欧燕,许雪琴,陈国南,水飞蓟宾的电化学行为研究,福州大学学报(自然科学版),2007,35(2):288-290
(36) Katiyar SK. Treatment of silymarin, a plant flavonoid, prevents ultraviolet light-induced immune suppression and oxidative stress in mouse skin, Int J Oncol, 2002,21:1213-1222
(37) Kang JS, Jcon YJ, Kim HM, et al. Inhibition of inducible nitric-oxide synthase expression by silymarin in lipopolysaccharide-stimulated macrophages, J Pharmacol Exp Ther, 2002,302:138-144
(38)任孟军,左国庆,水飞蓟素抗肿瘤作用的研究进展,国外医学中医中药分册,2005,271:19-22
(39)王会敏,廉红兴,徐纪军等,水飞蓟宾对阿霉素心肌毒性的保护作用,药品不良反应杂志,2003,5:371-374
(40) PelterA, Hansel R. The structure of silibin, chem.Ber, 1975,108(3):790-802
(41) ArnoneA,MerliniL,ZanarottiA,Constituents of Silybummarianum Structure of isosilybin and tereochemistry of silybin [J] J Chem Soc Chem Commun,1979,16:696-697
(42) LotterH, WagnerH, Stereochemistry of silybin [J],Z NaturforschC,1983,38C(5-6):339-341
(43) Susan Budavari , Maryadele J . O’Neil, Senior Associate, Ann Smith ,Pa2tricia E. Heckelman, Joanne F , Kinneary, The Merck Index. Twelfth Edition, Merck Research Laboratories Division of Merck & CO. Inc.Whithouse Station, NJ, 1996, 1464
(44)石磊,邓碧玉,张文琴,水飞蓟素的临床应用,河北医学, 2000, 6(4), 352-353
(45)谢京儿,廖锡麟,烫伤后大鼠肝脏药物代谢酶和脂质过氧化活性的变化以及水飞蓟宾的作用,第二军医大学学报,1989,10(5),413-416
(46)张俊平,胡振杯,冯增辉,水飞蓟宾对小鼠肝脏炎症损伤和肿瘤坏死因子的产生及活性的影响,药学学报,1996,31 (8), 577-580
(47)龙晓英,杨帆,李丽,周杏茔,水飞蓟素自乳化给药系统处方设计及溶出度评价,中国药师,2004,7(7),496-498
(48)陈大为,刘立民,丁五芝等,水飞蓟素(益肝灵)片溶出速率的研究[J],中成药,1993,15(6):2
(49)陈大为,刘立民,丁玉芝,李三鸣,刘茜英,水飞蓟素片剂溶出出速率研究,中成药,1993,15(5),2-4
(50) Daniele Savio , Paola Cristina Harrasser ,Gianluca Basso. Softgel Capsule technology as anenhancer device for the absorption of naturalprinciples in humans. Arzneim. - Forsch. / Drug Res. 1998 ,48(Ⅱ) ,1104-1106
(51)谢京儿,廖锡麟,烫伤后大鼠肝脏药物代谢酶和脂质过氧化活性的变化以及水飞蓟宾的作用,第二军医大学学报,1989,10(5),413-416
(52)张俊平,胡振杯,冯增辉,水飞蓟宾对小鼠肝脏炎症损伤和肿瘤坏死因子的产生及活性的影响,药学学报,1996,31 (8),577-580
(53) Sekiguchi K,Obi N,Studies on absorption of eutectic mixture,I A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man Chem, Pharm, Bull,1961,9(11),866-875
(54)朱盛山,药物新剂型,北京:人民卫生出版社,1993,113-115
(55)孙淑英,黎玉珉,冷晓红,联苯双酯的共沉淀物和固体分散体的制备及对温度的稳定性,沈阳药学院学报,1987,4(2),99-102
(56) Hasegawa A, Nakagawa H, Sugimoto I. Bioavaility and stability of nifedipine enteric coating agent solid dispersion. Chem Pharm Bull,1985,33(1), 388-394
(57) Hiroshi Y, Tetsuya O, Yoshio K, Application of the solid dispersion method to controlled release of medicine. I Controlled release of water soluble medicine by using solid dispersion. Chem. Pharm. Bull, 1991, 39(2), 465-473
(58)余自成,固体分散体技术在缓释制剂中的应用,中国药学杂志,1994,29(6),326-328
(59)吴春,车春波,李俊生等,槲皮素-聚乙二醇固体分散体对亚硝化反应的抑制作用,食品科学,2008,29(3),53-55
(60)王婴,罗虹嘉,王欢,固体分散体在缓释制剂中的应用,中国药业,2002,11(11),72-73
(61)刘善奎,钟延强,孙其荣,盐酸尼卡地平缓释固体分散体的研究,中国医药工业杂志,2000,31(3),107-110
(62)肖玉秀,耿灏,张凯,阿司匹林固体分散物的研究,中国现代应用药学杂志,1999,16(5),20-22
(63)李国栋,周全,赵长文,青蒿素固体分散物的制备及体外溶出研究,中国药学杂志,1999,34(1),26-28
(64)王展,韩立炜,任天池,葛根素-聚乙二醇6000固体分散体的制备及其溶解性能的研究,北京中医药大学学报,2007,30(5),346-349
(65)王烈群,王宏宇,萘普生-聚乙烯吡咯烷酮固体分散体的制备及溶出速率测定,内蒙古医学院学报,1998,20(1),27-31
(66)赵红,环孢素固体分散物一些物性的研究,药学学报,1997 ,32(10),777-781
(67) H?rter,D.; Dressman,J.B. Influence of Physicochemical Properties on Dissolution of Drugs in the Gastrointestinal Tract. Adv. Drug Deliv. Rev. 2001, 46, 75–87.
(68) Bai,T.C.; Yan,G.B.; Hu,J.; Zhang,H.L.; Huang,C.G.. Solubility of silybin in aqueous poly(ethylene glycol) solution. Int. J. Pharm. 2006, 308, 100–106.
(69) Vasconcelos,T; Sarmento,B;Costa, P. Solid Dispersions as Strategy to Improve Oral Bioavailability of Poor Water Soluble Drugs. Drug Discovery Today 2007, 12, 1068-1075.
(70) Yao,W.W.; Bai,T.C.; Sun, J. P.; Zhu,C.W.;Hu,J.; Zhang, H. Li. Thermodynamic Properties for the System of Silybin and Poly(ethylene glycol) 6000. Thermochim. Acta 2005, 437, 17–20.
(71) Naima, Z.; Siro, T.; Juan-Manuel, G. D.; Chantal, C.; René, C.; Jerome, D. Interactions Between Carbamazepine and Polyethylene Glycol (PEG) 6000: Characterisations of the Physical, Solid Dispersed and Eutectic Mixtures. Eur. J. Pharm. Sci. 2001, 12, 395–404.
(72) Damian, F.; Blaton, N.; Naesens, L.; Balzarini, J.; Kinget, R.; Augustijns, P.; Van den Mooter, G.Physicochemical Characterization of Solid Dispersions of the Antiviral Agent UC-781 with Polyethylene Glycol 6000 and Gelucire 44/14. Eur. J. Pharm. Sci. 2000, 10, 311–322.
(73) Verheyen, S.; Augustijins, P.; Kinget, R.; Van den Mooter, G. Melting Behavior of Pure Polyethylene Glycol 6000 and Polyethylene Glycol 6000 in Solid Dispersions Containing Diazepam or Temazepam: a DSC Study, Thermochim. Acta, 2001, 380, 153-164.
(74) Vanden Mooter, G., Augustijins. P., Blaton, N., Kinget, R., Physicochemical Chara-cterization of Solid Dispersions of Temazepam with Polyethylene Glycol 6000 and PVP K30. Int. J. Pharm. 1998, 164, 67-80.
(75) Wagner, H.; Selingman, O.; Lotter, H. Flavonoids and Bioflavonoids; Elsevier: Amsterdam, 1986.
(76) Lee,D.Y.-W.; Liu,Y. Molecular Structure and Stereochemistry of Silybin A, Silybin B, Isosilybin A, and Isosilybin B, Isolated from Silybum marianum (Milk Thistle) J. Nat. Prod 2003, 66, 1171-1174.
(77) Lee,J.I.; Narayan,M.; Barrett,J.S. Analysis and Comparison of Active Constituents in Commercial Standardized Silymarin Extracts by Liquid Chromatography– Electrospray Ionization Mass Spectrometry. J. Chromatogr. B 2007, 845, 95–103.
(78) Kvasnicka, F.; Bíba, B.; ?ev?ík, R.; Vold?ich, M.; Krátká, J. Analysis of the Active Components of Silymarin, J.Chromatogr. A 2003, 990, 239–245.
(79) Ga?ák, R.; Walterová, D.; K?en, V. Silybin and Silymarins– New and Emerging Applications in Medicine. Curr. Med. Chem. 2007, 14, 315.
(80) Wellington, K.; Jarvis, B. Silymarin: A Review of Its Clinical Properties in the Management of Hepatic Disorders. Biodrugs 2001, 15, 465-489.
(81) Saller, R.; Meier, R.; Brignoli, R. The Use of Silymarin in the Treatment of Liver Diseases. Drugs 2001, 61, 2035-2063.
(82) El-Samaligy, M. S.; Afifi, N. N.; Mahmoud, E. A. Increasing Bioavailability of Silymarin Using A Buccal Liposomal Delivery System: Preparation and Experimental Design Investigation, Int. J. Pharm.2006, 308, 140–148.
(83) Nair, L. M.; Konkel, J.; Thomas, M.; Koberda, M. Comparison of Electrospray Ionization Mass Spectrometry and Evaporative Light Scattering Detections for the Determination of Poloxamer 188 in Itraconazole Injectable Formulation. J. Pharm. Biomed. Anal. 2006, 41, 725–730.
(84) Harting, M. T.; Jimenez, F.; Kozar, R. A.; Moore, F. A.; Mercer, D. W.; Hunter, R. L.; Cox, C. S.; Gonzalez, E. A.; Effects of Poloxamer 188 on Human PMN Cells, Surgery, 2008, 144, 198-203.
(85) Mustafi, D.; Smith, C. M.; Makinen, M. W.; Lee, R. C. Multi-block Poloxamer Surfactants Suppress Aggregation of Denatured Proteins, Biochim. Biophys. Acta, 2008, 1780, 7–15.
(86) Woodle, M. C., Newman, M. S., Martin, F. J., Liposome Leakage and Blood Circulation: Comparison of Adsorbed Block Copolymers with Covalent Attachment of PEG. Int. J. Pharm. 1992, 88, 327–334.
(87) Castile, J. D.; Taylor, K. M. G.; Buckton, G. The Influence of Incubation Temperature and Surfactant Concentration on the Interaction between Dimyristoylphosphatidylcholine Liposomes and Poloxamer Surfactants. Int. J. Pharm. 2001, 221, 197–209.
(88) Jamil, A.; Kousksou, T.; Zeraouli, Y.; Dumas, J.-P. Liquidus Temperatures Determination of the Dispersed Binary System. Thermochim. Acta. 2008, 471, 1–6.
(89) Acree, W. E. Thermodynamic Properties of Nonelectrolyte Solutions; Academic Press Inc.: 1984.
(90) Bondi, A. vander Waals Volumes and Radii. J. Phys. Chem. 1964, 68, 441-451.