橙皮素和穿心莲内酯的增溶研究
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摘要
目前,临床上使用的药物当中有1／3以上为难溶性药物。由于难溶性药物溶出和吸收慢,导致体内生物利用度低,影响了其在临床上的应用。因此,如何提高提高难溶性药物的溶解度和溶出度是药剂学的一个难点问题。本文将固体分散用于橙皮素,β-环糊精(β-CD)及其衍生物羟丙基β-CD (HP-β-CD)、磺丁基醚β-CD (SBE-β-CD)包合用于穿心莲内酯研究难溶性药物增溶。
主要研究内容和结果如下：
(1)以PVPk30和Tween80为复合载体,采用溶剂法制备橙皮素的三元固体分散体,测定其溶出度,与相应比例的橙皮素-PVPk30制成的二元固体分散体进行比较,发现由橙皮素与PVPk30和Tween80制备的三元固体分散体明显提高了橙皮素溶出度。
用红外光谱法(FTIR)、差示扫描量热法(DSC)、X-射线粉末衍射法(XRD)鉴定橙皮素在三元固体分散体中的存在状态。结果表明橙皮素以非晶态分散在固体分散体中。
(2)分别考察β-CD及其两种衍生物HP-β-CD、SBE-β-CD与穿心莲内酯的相溶解度,判断包合类型并计算稳定常数。研究表明：β-CD、HP-β-CD和SBE-β-CD可与穿心莲内酯形成摩尔比为1：1的包合物,其包合类型分别为Bs型、AL型和AL型,前者在高浓度的β-CD溶液中环糊精羟基间所形成的分子间氢键使穿心莲内酯难以进入孔内,从而使穿心莲内酯溶解度下降；后二者随着HP-β-CD或SBE-β-CD溶液浓度的增加,穿心莲内酯的溶解度也增加。稳定常数表明用β-CD、HP-β-CD、SBE-β-CD包合后所形成的包合物均较稳定。
分别采用研磨法、超声法和共沉淀法制备穿心莲内酯的β-CD及其衍生物包合物,测定其溶出度,并与穿心莲内酯原药,以及穿心莲内酯与各种环糊精的物理混合物的溶出性能进行比较,发现包合后穿心莲内酯的溶出率显著增加。
用差示扫描量热法,X-射线衍射和红外光谱对穿心莲内酯进行物相鉴别。结果表明,用研磨法、超声波法和共沉淀法制备的穿心莲内酯-p-CD体系确实形成了包合物。
There are a lot of poorly water-soluble drugs in clinic. Those drugs are slowly absorbed, which lead to low bioavailability and effect their clinical application. In this paper, the solubility of poorly water-soluble drugs which was dispersed in the polymer carrier or inclused byβ-cyclodextrin (β-CD) and its two derivatives hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was studied.
The following contents were studied:
(1) Ternary solid dispersions consisting of hesperetin, PVPk30 and Polysorbate 80 were prepared in various weight ratios by solvent-evaporation method. Solid dispersions of hesperetin andin PVPk30 in corresponding weight ratios were also prepared for comparison. Dissolution test was performed to investigate the pharmaceutical performance of solid dispersions.
The fourier transformation-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffactionary (XRD) were used to identify the status of hesperetin in the ternary solid dispersions.
(2) The phase solubility profiles of andrographolide withβ-CD, HP-β-CD and SBE-β-CD were investigated to determine the inclusion types and calculate the stability constants. It was found that the inclusion type of andrographolide withβ-CD was BS and that with HP-β-CD and SBE-β-CD were AL. The solubility of andrographolide could be lower in higher concentration ofβ-CD which might be due to a steric hindrance of hydrophilic action between (3-CDs which prevented andrographolide from entering the CD cavity. The solubility of andrographolide was markedly enhanced by either HP-(3-CD or SBE-β-CD. It could be concluded that andrographolide could form stable complexes withβ-CDs according to the stability constants.
Various methods were employed to prepare the inclusion complexes of andrographolide with P-CDs. Then the dissolution profiles of the inclusion complexes were determined and compared with those of original andrographolide and physical mixtures. The results suggested that the inclusion complexes obviously enhanced the dissolution rate of andrographolide.
Binary systems of andrographolide withβ-CDs prepared by various methods were characterized by DSC, XRD and FTIR. It was confirmed that the inclusion complexes of andrographolide withβ-CDs prepared by all the various methods were formed.
主要研究内容和结果如下：
(1)以PVPk30和Tween80为复合载体,采用溶剂法制备橙皮素的三元固体分散体,测定其溶出度,与相应比例的橙皮素-PVPk30制成的二元固体分散体进行比较,发现由橙皮素与PVPk30和Tween80制备的三元固体分散体明显提高了橙皮素溶出度。
用红外光谱法(FTIR)、差示扫描量热法(DSC)、X-射线粉末衍射法(XRD)鉴定橙皮素在三元固体分散体中的存在状态。结果表明橙皮素以非晶态分散在固体分散体中。
(2)分别考察β-CD及其两种衍生物HP-β-CD、SBE-β-CD与穿心莲内酯的相溶解度,判断包合类型并计算稳定常数。研究表明：β-CD、HP-β-CD和SBE-β-CD可与穿心莲内酯形成摩尔比为1：1的包合物,其包合类型分别为Bs型、AL型和AL型,前者在高浓度的β-CD溶液中环糊精羟基间所形成的分子间氢键使穿心莲内酯难以进入孔内,从而使穿心莲内酯溶解度下降；后二者随着HP-β-CD或SBE-β-CD溶液浓度的增加,穿心莲内酯的溶解度也增加。稳定常数表明用β-CD、HP-β-CD、SBE-β-CD包合后所形成的包合物均较稳定。
分别采用研磨法、超声法和共沉淀法制备穿心莲内酯的β-CD及其衍生物包合物,测定其溶出度,并与穿心莲内酯原药,以及穿心莲内酯与各种环糊精的物理混合物的溶出性能进行比较,发现包合后穿心莲内酯的溶出率显著增加。
用差示扫描量热法,X-射线衍射和红外光谱对穿心莲内酯进行物相鉴别。结果表明,用研磨法、超声波法和共沉淀法制备的穿心莲内酯-p-CD体系确实形成了包合物。
There are a lot of poorly water-soluble drugs in clinic. Those drugs are slowly absorbed, which lead to low bioavailability and effect their clinical application. In this paper, the solubility of poorly water-soluble drugs which was dispersed in the polymer carrier or inclused byβ-cyclodextrin (β-CD) and its two derivatives hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) was studied.
The following contents were studied:
(1) Ternary solid dispersions consisting of hesperetin, PVPk30 and Polysorbate 80 were prepared in various weight ratios by solvent-evaporation method. Solid dispersions of hesperetin andin PVPk30 in corresponding weight ratios were also prepared for comparison. Dissolution test was performed to investigate the pharmaceutical performance of solid dispersions.
The fourier transformation-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffactionary (XRD) were used to identify the status of hesperetin in the ternary solid dispersions.
(2) The phase solubility profiles of andrographolide withβ-CD, HP-β-CD and SBE-β-CD were investigated to determine the inclusion types and calculate the stability constants. It was found that the inclusion type of andrographolide withβ-CD was BS and that with HP-β-CD and SBE-β-CD were AL. The solubility of andrographolide could be lower in higher concentration ofβ-CD which might be due to a steric hindrance of hydrophilic action between (3-CDs which prevented andrographolide from entering the CD cavity. The solubility of andrographolide was markedly enhanced by either HP-(3-CD or SBE-β-CD. It could be concluded that andrographolide could form stable complexes withβ-CDs according to the stability constants.
Various methods were employed to prepare the inclusion complexes of andrographolide with P-CDs. Then the dissolution profiles of the inclusion complexes were determined and compared with those of original andrographolide and physical mixtures. The results suggested that the inclusion complexes obviously enhanced the dissolution rate of andrographolide.
Binary systems of andrographolide withβ-CDs prepared by various methods were characterized by DSC, XRD and FTIR. It was confirmed that the inclusion complexes of andrographolide withβ-CDs prepared by all the various methods were formed.
引文
1 Connors KA. The stability of cyclodextrin complexes in solution [J]. Chem Rev, 1997,97(5):1325-1358.
2 Rekharsky MV, Inoue Y. Complexation thermodynamics of cyclodextrin [J]. Chem Rev,1998,98(5):1875-1917.
3 Schneider HJ, Hacket F, Rudiger V, et al. NMR studies of cyclodextrins and cyclodextrin complexes [J]. Chem Rev,1998,98:1755-1785.
4 Savolainen J, Jarvinen K, Taipale H, et al.Co-administration of a water-soluble polymer increases the usefulness of cyclodextrin in solid oral dosageforms [J]. Pharm Res,1998,15(11):1696-1701.
5 Kaukonen AM, Kilpelainen I, Mannermaa JP. Water soluble βcyclodextrins in paediatric oral solutions of spironolactone:solubiliztion and stability of spironolactone in solutions of cyclodextrin derivatives [J]. Int J Pharm,1997, 159:159-170.
6 Formica JV, Regelson W. Review of the Biology of Quercetin and Related Bioflavonoids [J]. Food Chem. Toxicol,1995,33:1061-1080.
7 So FV, Guthrie N, Chambers AF, Carroll KK. Inhibition of Proliferation of Estrogen Receptor-positive MCF-7 Human Breast Cancer Cells by Flavonoids.in the Presence and Absence of Excess Estrogen [J]. Cancer lett,1997,112:127-133.
8 Rotelli AE, Guardia T, Juarez AO, et al. Comparative Study of Flavonoids in Experimental Models of Inflammation [J]. Pharmacol Res,2003,48:601-606.
9 Kim JY, Jung KJ, Choi JS, et al. Hesperetin:a Potent Antioxidant Against Peroxynitrite [J]. Free Radic Res,2004,38:761-769.
10 Kim HK, Jeong TS, Lee MK, et al. Lipid-lowing Efficacy of Hesperetin Metabolites in High-cholesterol Fed Rats [J]. Clin Chim Acta,2003,327: 129-137.
11 Liu LX, CHEN J. Solubility of hesperetin in various solvents from (288.2 to 323.2)K [J]. J Chem Eng Data 2008,53:1649-1650.
12刘文英.药物分析[M].北京：人民卫生出版社,2005,81.
13刘文英.药物分析[M].北京：人民卫生出版社,2005,80.
14中华人民共和国药典(二部)[S].2005：附录74-75.
15 Samy R P, Thwin MM, Gopalakrishnakone P. Phytochemistry, pharmacology and clinical use of Andrographis paniculata [J]. Nat Prod Commun.2007,2,607-618.
16 Singha PK, Roy S, Dey S. Protective activity of andrographolide and arabinogalactan proteins from Andrographis paniculata Nees. against ethanol-induced toxicity in mice [J]. J Ethnopharmacol.2007,111,13-21.
17 Poolsup N, Suthisisang C, Prathanturarug S, et al. Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials [J]. J Clin Pharm Ther.2004,29, 37-45.
18 Iruretagoyena MI, Tobar JA, Gonzalez PA et al. Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse [J]. J Pharmacol Exp Ther.2005,312,366-372.
19 Pekthong D, Martin H, Abadie C, et al. Differential inhibition of rat and human hepatic cytochrorne P450 by Andrographis paniculata extract and andrographolide [J]. J Ethnopharmacol.2008,115,432-440.
20 Zhao F, He EQ, Wang L, et al. Anti-tumor activities of andrographolide, a diterpene from Andrographis paniculata, by inducing apoptosis and inhibiting VEGF level [J]. J Asian Nat Prod Res.2008,10,473-479.
21 Yu, BC, Hung CR, Chen WC, et al. Antihyperglycemic effect of andrographolide in streptozotocin-induced diabetic rats [J]. Planta Med.2003,69,1075-1079.
22 Mohsen-Nia M, Modarress H, Razzaghi D. Solubility of 1,3,5-trioxane in methanol, ethanol, and 2-propanol [J]. J Chem Eng Data.2004,49,1613-1614.
23 Wang LH, Cheng YY. Solubility of puerarin in water, ethanol, and acetone from (288.2 to 328.2) K [J]. J Chem Eng Data.2005,50,1375-1376.
24 Shi LX, Zhang BH, Song SQ, et al. Solubility of 1-H-tetrazole-l-acetic acid in different solvents between 283 K and 323 K [J]. J Chem Eng Data.2007,52, 1856-1857.
25 Del Valle EMM. Cyclodextrins and their uses:a review [J]. Process Biochem. 2004,39,1033-1046.
26 Higuchi T, Connors KA. Phase-solubility techniques.Adv Anal Chem Instrum 1965,4:117-210.
27陆彬.药物新剂型与新技术[M],北京：人民卫生出版社,2002,40-46.
28谷福根,高永良,崔福德.磺丁基醚-β-环糊精及其在药剂学中的应用[J].中国新药杂志,2004,13(1)：16-19.
29 Brewster ME, Vandecruys R, Peeters J, et al. Comparative interaction of 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin with itraconazole:Phase-solubility behavior and stabilization of supersaturated drug solutions [J]. Eur J Pharm Sci,2008,34:94-103.
30 Fukuda M, Miller DA, Peppas NA, et al. Influence of sulfobutyl ether (3-cyclodextrin (Captisol(?)) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion [J]. Int J Pharm,2008,350: 188-196.
31 Jain AC, Adeyeye MC. Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether β-cyclodextrins (SBE) and danazol-SBE inclusion complexes [J]. Int J Pharm,2001,212 (2):177-186.
1 Barker S A, Yap S P, Yuen K H, et al. An investigation into the structure and bioavailability of a-tocopherol dispersions in Gelucire 44/14 [J]. J Control Rel, 2003,91 (3):477-488.
2 Kim J S, Kim M S, Park H J. Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process [J]. Int J Pharm,2008,359:211-219.
3 Qian F, Tao J, Desikan S, et al. Mechanistic Investigation of Pluronic Based Nano-crystalline Drug-polymer Solid Dispersions [J]. Pharm Res,2007,24 (8): 1551-1560.
4 Van D J, Hinrichs W L, Dickhoff D H, et al.Spray freeze drying to produce a stable Δ9-tetrahydrocannabinol containing inulin-based solid dispersion powder suitable for inhalation [J]. Eur J Pharm Sci,2005,26 (2):231-240.
5 Nakanfidfi K, Nakano T, Yasuura H, et al. The role of the kneading paddie and the effects of screw revolutions and water content on the preparation of lide dispersions using an extruder [J]. J Pharm Sci,2002,241 (2):203-211.
6李慧,唐星.热熔挤出法制备联苯双酯固体分散体的工艺[J].沈阳药科大学学报,2008,25(7)：515-518.
7陆彬主编.药物新剂型与新技术[M].北京：人民卫生出版社,1998,7.
8 Serajuddin AT, Sheen PC, Mufson D, et al. Effect of vehicle amphiphilicity on the dissolution and bioavailability of a pooly water soluble drug from solid dispersions [J]. J Pharm Sci,1988,77 (5):414.
9陈洁,邱利焱.多烯紫杉醇固体分散体的制备和体内外研究[J].中国药学杂志,2007,42(22)：1717-1722.
10黄静琳,陆锦芳,郭圣荣.生物粘附性聚丙烯酸类高分子材料在药剂学中的应用[J].中国医药工业杂志,2001,32(2)：90-93.
11 Ozeki T, Yuasa H. Controlled release from solid dispersion composed of poly(ethylene oxide)-carbopol interpolymer complex with various cross-linking degrees of carbopol [J]. J Control Rel,2000,63 (3):287-295.
12 Najib N, Suleiman M S. The kinedcs of drug release from ethylcellulose solid dispersions [J]. Drug Dev Ind Pharm,1985,11 (12):2169.
13陈桂兰,周秋峰,杨晓凤,等.水溶性药物控释制剂的一种制备方法[J].中国医药工业杂志,1996,27(2)：65-69.
14 Hasegawa A, Nakagawa H, Sugimoto I. Application of solid dispersions of nifedipine with enteric coating agent to prepare asustained-release dosage form [J]. Chem Pharm Bull,1985,33 (4):1615.
15刘善奎,钟延强,孙其荣,等.盐酸尼卡地平缓释固体分散体的研究[J].中国医药工业杂志,2000,31(3)：107.
16 Kohri N, Yamayoshi Y, Xie H, et al. Improving the oral bioavailability of albendazole in rubbits by the solid dispersion technique [J]. Pharm Pharmacol, 1999,51(2):159.
17 Yukinao K, Hitoshi K, Yasuyusi B, et al. Controlled release of lidocaine hydrochloride from buccal mucosa-adhesive films with solid dispersion [J]. Int J Pharm,1997,158:147-155.
18 Sandrien J, Hector NA, Jean PR, et al. The use of a new hydrophilic polymer, Kollicoat IR, in the formulation of solid dispersions of Itraconazole [J]. Eur J Pharm Sci,2007,30:288-294.
19 Huang JJ, Wigent RJ, Bentzley CM, et al. Nifedipine solid dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend for controlled drug delivery effect of drug loading on release kinetics [J]. Int J Pharm,2006,319:44-54.
20 Hemant NJ, Ravindra WT, Martha D, et al. Bioavailability enhancement of poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture [J]. Int J Pharm,2004,269:251.
21 Guan QX, Lin TM, Liu JY, et al. Peparetion of nimodipine solid dispersion [J]. J Jilin Univ,2003,29 (1):72-75.
22 Newa M, Bhandari KH, Li DX. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188 [J]. Int J Pharm,2007,343:228-237.
23 Naveen A, Om PK, Bhupinder S. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers [J]. Eur J Pharm Biopharm,2007,65:26-38.
24 Sandrien J, Hector N, Clive JR, et al. Characterization of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5 [J]. J Pharm Sci,2008,97 (6): 2110-2120.
25 Kanaze FI, Kokkalou E, Niopas I, et al. Thermal analysis study of flavonoid solid dispersions having enhanced solubility [J]. J Therm Anal Calorim,2006,83 (2): 283-290.
26 Higuchi T, Connors KA. Phase-solubility techniques.Adv Anal Chem Instrum 1965,4:117-210.
27陆彬主编.药物新剂型与新技术[M].北京：人民卫生出版社,1998,23.
28孙伟张,曾仁杰,于波涛,等.伊曲康唑固体分散体制备及体外溶出试验[J].中国医院药学杂志,2004,24(10)：617-619.
29 Najib N, Suleiman MS. Characterisation of a diflusinal polyethylene glycol solid dispersion system [J]. Int J Pharm,1989,51:225-232.
30 Lloyd GR, Craig DQM, Smith A. An investigation into the melting behaviour of binary mixes and solid dispersions of paracetamol and PEG 4000 [J]. J Pharm Sci, 1997,86:991-996.
31 Newa M, Bhandari KH, Li DX, et al. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188 [J]. Int J Pharm.2007,343:228-237.
32闫月荣,王保安,郑军伟.拉曼光谱研究水飞蓟宾在载体中的分散形式及分子间的作用[J].焦作师范高等专科学校学报.2007,23(4)：72-73.
33 Fini A, Cavallari C, Ospitali F. Raman and thermal analysis of indomethacin/PVP solid dispersion enteric microparticles [J]. Eur J Pharm,2008,70:409-420.
34 Kanaze FI, Kokkalou E, Niopas I, et al. Dissolution enhancement of flavonoids by solid dispersion in PVP and PEG matrixes:a comparative study [J]. J Appl Polym Sci,2006,102:460-471.
35柳晨,朱赛杰.环孢素-PVP固体分散体的体外研究[J].中国药学杂志,2007,42(10)：761-764.
36陈国广,张柯萍,李学明等.灯盏花素缓释固体分散体的制备及溶出度的研究[J].华西药学杂志,2007,22(2)：169-171.
37钟延强,王春燕.新型非甾体抗炎药—氯比洛芬制剂学研究进展[J].药学实践杂志,1999,17(2)：97-101.
38 lrie T, Uekama K. Pharmaceutical applications of cyclodextrins. Ⅲ. Toxicological issues and safety evaluation [J]. J Pharm Sci,1997,86 (2):147-162.
39陆彬.药物新剂型与新技术[M],北京：人民卫生出版社,2002,40-46.
40谷福根,高永良,崔福德.磺丁基醚-β-环糊精及其在药剂学中的应用[J].中国新药杂志,2004,13(1)：16-19.
41 Brewster ME, Vandecruys R, Peeters J, et al. Comparative interaction of 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin with itraconazole:Phase-solubility behavior and stabilization of supersaturated drug solutions [J]. Eur J Pharm Sci,2008,34:94-103.
42 Fukuda M, Miller DA, Peppas NA, et al. Influence of sulfobutyl ether β-cyclodextrin (Captisol(?)) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion [J]. Int J Pharm,2008,350: 188-196.
43 Jain AC, Adeyeye MC. Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether β-cyclodextrins (SBE) and danazol-SBE inclusion complexes [J]. Int J Pharm,2001,212 (2):177-186.
44 Lockwood SF, O'Malley S, Mosher GL, et al. Improved aqueous solubility of crystalline astaxanthin (3,3'-dihydroxy-β,β-carotene-4,4'-dione) by captisol(?) (sulfobutyl etherβ-cyclodextrin) [J]. J Pharm Sci,2003,92:922-926.
45 Liu LX, Zhu SY. Preparation and characterization of inclusion complexes of prazosin hydrochloride with β-cyclodextrin and hydroxypropyl-β-cyclodextrin [J]. J Pharm Biomed Anal,2006,40 (1):122-127.
46 Bayomi MA, Abanumay KA, Al-Angary AA. Effect of inclusion complexation with cyclodextrins on photostability of nifedipine in solid state [J]. Int J Pharm, 2002,243:107-117.
47 Fernandes CM, Vieira MT, Veiga FJB. Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds [J]. Eur J Pharm Sci,2002,15:79-88.
48 Mura P, Faucci MT, Parrini PL, et al. Influence of the preparation method on the physicochemical properties of ketoprofen-cyclodextrin binary systems [J]. Int J Pharm,1999,197:117-128.
49 Wen X, Tan F, Jing Z, et al. Preparation and study the 1:2 inclusion complex of carvedilol with β-cyclodextrin [J]. J Pharm Biomed Anal,2004,34 (3):517-523.
50 Lu R, Wang H, Tong L. Spectroscopic studies on inclusion complexes of MAQO and MPQO with cyclodextrins [J]. Mat Sci Eng C-Bio S,1999,10:7-11.
51 Crisma M, Fornasier R, Marcuzzi F. The crystal structure of the 1:1 inclusion complex of β-cyclodextrin with squaric acid [J]. Carbohydr Res,2001,333: 145-151.
52 Aree T, Chaichit N. Crystal structure of β-cyclodextrin-dimethylsufoxide inclusion complex [J]. Carbohydr Res,2002,337:2487-2494.
53 Zerrouk N, Gine's Dorado JM, Arnaud P, et al. Physical characteristics of inclusion compounds of 5-AS A in a and p cyclodextrins [J]. Int J Pharm,1998, 171:19-29.
54 Jullian C, Moyano L Yanez C. Complexation of quercetin with three kinds of cyclodextrins:An antioxidant study [J]. Spectrochimi Acta A,2007,67:230-234.
55刘龙孝,朱素燕.羟丙基-β-环糊精包合对盐酸哌唑嗪的增溶作用研究[J].中国药学杂志,2006,41(2)：122-125.
56 Rawat S, Jain SK. Solubility enhancement of celecoxib using β-cyclodextrin inclusion complexes [J]. Eur J Pharm Biopharm,2004,57:263-267.
57 Bernini A, Spiga O, Ciutti A, et al. NMR studies of the inclusion complex between P-cyclodextrin and paroxetine [J]. Eur J Pharm Sci,2004,22:445-450.
58 Oh I, Lee MY, Lee YB, et al. spectroscopic characterization of ibuprofen/2-hydroxypropyl-β-cyclodextrin inclusion complex [J]. Int J Pharm, 1998,175:215-233.
59何华,汤瑶,孙成,等.光谱法及热动力学法研究环糊精与三氟氯氰菊酯的包合作用[J].化学学报,2006,64(2)：175-181.
60 Calabro ML, Tommasini S, Donato P, et al. The rutin/β-cyclodextrin interactions in fully aqueous solution:spectroscopic studies and biological assays [J]. J Pharm Biomed Anal,2005,36 (5):1019-1027.
61 Shen Y, Yang S, Wu L, et al. Study on structure and characterization of inclusion complex of gossypol/β cyclodextrin [J]. Spectrochim Acta A,2005,61: 1025-1028.
62曹书霞,苏玉倩,陈晓岚,等.βCD与蛋白质非共价复合物的电喷雾质谱研究[J].分析测试学报,2004,23(5)：76-79.
63 Connors KA. The stability of cyclodextrin complexes in solution [J]. Chem Rev, 1997,97 (5):1325-1358.
64 Rekharsky MV, Inoue Y. Complexation thermodynamics of cyclodextrin [J]. Chem Rev,1998,98 (5):1875-1917.
65 Schneider HJ, Hacket F, Riidiger V, et al. NMR studies of cyclodextrins and cyclodextrin complexes [J]. Chem Rev,1998,98:1755-1785.
66宋乐新,周桃玉,郭子建.环糊精及其衍生物的超分子晶体结构研究进展[J].无机化学学报,2001,17(1)：9-16.
67 Harata K. Structural aspects of stereodifferentiation in the solid state [J]. Chem Rev,1998,98:1803-1827.
68雍国平,李光水,郑飞,等.β-环糊精包合物的结构研究[J].高等学校化学学报,2000,21(7)：1124-1126.
69 Stejtli J. Cyclodextrin Techology (1st Ed) [M]. Kluwer, Dordrecht,1988:79-81.
70 Jogun KH, Stezowski JJ. Metastable crystals of β-cyclodextrin complexes and the membrane diffusion model [J]. Nature,1979,278:667-668.
71 Hamilton JA, Chen L. Crystal structure of an inclusion complex of β-cyclodextrin with racemic fenoprofen:direct evidence for chiral recognition [J]. J Am Chem Soc,1988,110:5833-5836.
2 Rekharsky MV, Inoue Y. Complexation thermodynamics of cyclodextrin [J]. Chem Rev,1998,98(5):1875-1917.
3 Schneider HJ, Hacket F, Rudiger V, et al. NMR studies of cyclodextrins and cyclodextrin complexes [J]. Chem Rev,1998,98:1755-1785.
4 Savolainen J, Jarvinen K, Taipale H, et al.Co-administration of a water-soluble polymer increases the usefulness of cyclodextrin in solid oral dosageforms [J]. Pharm Res,1998,15(11):1696-1701.
5 Kaukonen AM, Kilpelainen I, Mannermaa JP. Water soluble βcyclodextrins in paediatric oral solutions of spironolactone:solubiliztion and stability of spironolactone in solutions of cyclodextrin derivatives [J]. Int J Pharm,1997, 159:159-170.
6 Formica JV, Regelson W. Review of the Biology of Quercetin and Related Bioflavonoids [J]. Food Chem. Toxicol,1995,33:1061-1080.
7 So FV, Guthrie N, Chambers AF, Carroll KK. Inhibition of Proliferation of Estrogen Receptor-positive MCF-7 Human Breast Cancer Cells by Flavonoids.in the Presence and Absence of Excess Estrogen [J]. Cancer lett,1997,112:127-133.
8 Rotelli AE, Guardia T, Juarez AO, et al. Comparative Study of Flavonoids in Experimental Models of Inflammation [J]. Pharmacol Res,2003,48:601-606.
9 Kim JY, Jung KJ, Choi JS, et al. Hesperetin:a Potent Antioxidant Against Peroxynitrite [J]. Free Radic Res,2004,38:761-769.
10 Kim HK, Jeong TS, Lee MK, et al. Lipid-lowing Efficacy of Hesperetin Metabolites in High-cholesterol Fed Rats [J]. Clin Chim Acta,2003,327: 129-137.
11 Liu LX, CHEN J. Solubility of hesperetin in various solvents from (288.2 to 323.2)K [J]. J Chem Eng Data 2008,53:1649-1650.
12刘文英.药物分析[M].北京：人民卫生出版社,2005,81.
13刘文英.药物分析[M].北京：人民卫生出版社,2005,80.
14中华人民共和国药典(二部)[S].2005：附录74-75.
15 Samy R P, Thwin MM, Gopalakrishnakone P. Phytochemistry, pharmacology and clinical use of Andrographis paniculata [J]. Nat Prod Commun.2007,2,607-618.
16 Singha PK, Roy S, Dey S. Protective activity of andrographolide and arabinogalactan proteins from Andrographis paniculata Nees. against ethanol-induced toxicity in mice [J]. J Ethnopharmacol.2007,111,13-21.
17 Poolsup N, Suthisisang C, Prathanturarug S, et al. Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials [J]. J Clin Pharm Ther.2004,29, 37-45.
18 Iruretagoyena MI, Tobar JA, Gonzalez PA et al. Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse [J]. J Pharmacol Exp Ther.2005,312,366-372.
19 Pekthong D, Martin H, Abadie C, et al. Differential inhibition of rat and human hepatic cytochrorne P450 by Andrographis paniculata extract and andrographolide [J]. J Ethnopharmacol.2008,115,432-440.
20 Zhao F, He EQ, Wang L, et al. Anti-tumor activities of andrographolide, a diterpene from Andrographis paniculata, by inducing apoptosis and inhibiting VEGF level [J]. J Asian Nat Prod Res.2008,10,473-479.
21 Yu, BC, Hung CR, Chen WC, et al. Antihyperglycemic effect of andrographolide in streptozotocin-induced diabetic rats [J]. Planta Med.2003,69,1075-1079.
22 Mohsen-Nia M, Modarress H, Razzaghi D. Solubility of 1,3,5-trioxane in methanol, ethanol, and 2-propanol [J]. J Chem Eng Data.2004,49,1613-1614.
23 Wang LH, Cheng YY. Solubility of puerarin in water, ethanol, and acetone from (288.2 to 328.2) K [J]. J Chem Eng Data.2005,50,1375-1376.
24 Shi LX, Zhang BH, Song SQ, et al. Solubility of 1-H-tetrazole-l-acetic acid in different solvents between 283 K and 323 K [J]. J Chem Eng Data.2007,52, 1856-1857.
25 Del Valle EMM. Cyclodextrins and their uses:a review [J]. Process Biochem. 2004,39,1033-1046.
26 Higuchi T, Connors KA. Phase-solubility techniques.Adv Anal Chem Instrum 1965,4:117-210.
27陆彬.药物新剂型与新技术[M],北京：人民卫生出版社,2002,40-46.
28谷福根,高永良,崔福德.磺丁基醚-β-环糊精及其在药剂学中的应用[J].中国新药杂志,2004,13(1)：16-19.
29 Brewster ME, Vandecruys R, Peeters J, et al. Comparative interaction of 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin with itraconazole:Phase-solubility behavior and stabilization of supersaturated drug solutions [J]. Eur J Pharm Sci,2008,34:94-103.
30 Fukuda M, Miller DA, Peppas NA, et al. Influence of sulfobutyl ether (3-cyclodextrin (Captisol(?)) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion [J]. Int J Pharm,2008,350: 188-196.
31 Jain AC, Adeyeye MC. Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether β-cyclodextrins (SBE) and danazol-SBE inclusion complexes [J]. Int J Pharm,2001,212 (2):177-186.
1 Barker S A, Yap S P, Yuen K H, et al. An investigation into the structure and bioavailability of a-tocopherol dispersions in Gelucire 44/14 [J]. J Control Rel, 2003,91 (3):477-488.
2 Kim J S, Kim M S, Park H J. Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process [J]. Int J Pharm,2008,359:211-219.
3 Qian F, Tao J, Desikan S, et al. Mechanistic Investigation of Pluronic Based Nano-crystalline Drug-polymer Solid Dispersions [J]. Pharm Res,2007,24 (8): 1551-1560.
4 Van D J, Hinrichs W L, Dickhoff D H, et al.Spray freeze drying to produce a stable Δ9-tetrahydrocannabinol containing inulin-based solid dispersion powder suitable for inhalation [J]. Eur J Pharm Sci,2005,26 (2):231-240.
5 Nakanfidfi K, Nakano T, Yasuura H, et al. The role of the kneading paddie and the effects of screw revolutions and water content on the preparation of lide dispersions using an extruder [J]. J Pharm Sci,2002,241 (2):203-211.
6李慧,唐星.热熔挤出法制备联苯双酯固体分散体的工艺[J].沈阳药科大学学报,2008,25(7)：515-518.
7陆彬主编.药物新剂型与新技术[M].北京：人民卫生出版社,1998,7.
8 Serajuddin AT, Sheen PC, Mufson D, et al. Effect of vehicle amphiphilicity on the dissolution and bioavailability of a pooly water soluble drug from solid dispersions [J]. J Pharm Sci,1988,77 (5):414.
9陈洁,邱利焱.多烯紫杉醇固体分散体的制备和体内外研究[J].中国药学杂志,2007,42(22)：1717-1722.
10黄静琳,陆锦芳,郭圣荣.生物粘附性聚丙烯酸类高分子材料在药剂学中的应用[J].中国医药工业杂志,2001,32(2)：90-93.
11 Ozeki T, Yuasa H. Controlled release from solid dispersion composed of poly(ethylene oxide)-carbopol interpolymer complex with various cross-linking degrees of carbopol [J]. J Control Rel,2000,63 (3):287-295.
12 Najib N, Suleiman M S. The kinedcs of drug release from ethylcellulose solid dispersions [J]. Drug Dev Ind Pharm,1985,11 (12):2169.
13陈桂兰,周秋峰,杨晓凤,等.水溶性药物控释制剂的一种制备方法[J].中国医药工业杂志,1996,27(2)：65-69.
14 Hasegawa A, Nakagawa H, Sugimoto I. Application of solid dispersions of nifedipine with enteric coating agent to prepare asustained-release dosage form [J]. Chem Pharm Bull,1985,33 (4):1615.
15刘善奎,钟延强,孙其荣,等.盐酸尼卡地平缓释固体分散体的研究[J].中国医药工业杂志,2000,31(3)：107.
16 Kohri N, Yamayoshi Y, Xie H, et al. Improving the oral bioavailability of albendazole in rubbits by the solid dispersion technique [J]. Pharm Pharmacol, 1999,51(2):159.
17 Yukinao K, Hitoshi K, Yasuyusi B, et al. Controlled release of lidocaine hydrochloride from buccal mucosa-adhesive films with solid dispersion [J]. Int J Pharm,1997,158:147-155.
18 Sandrien J, Hector NA, Jean PR, et al. The use of a new hydrophilic polymer, Kollicoat IR, in the formulation of solid dispersions of Itraconazole [J]. Eur J Pharm Sci,2007,30:288-294.
19 Huang JJ, Wigent RJ, Bentzley CM, et al. Nifedipine solid dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend for controlled drug delivery effect of drug loading on release kinetics [J]. Int J Pharm,2006,319:44-54.
20 Hemant NJ, Ravindra WT, Martha D, et al. Bioavailability enhancement of poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture [J]. Int J Pharm,2004,269:251.
21 Guan QX, Lin TM, Liu JY, et al. Peparetion of nimodipine solid dispersion [J]. J Jilin Univ,2003,29 (1):72-75.
22 Newa M, Bhandari KH, Li DX. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188 [J]. Int J Pharm,2007,343:228-237.
23 Naveen A, Om PK, Bhupinder S. Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers [J]. Eur J Pharm Biopharm,2007,65:26-38.
24 Sandrien J, Hector N, Clive JR, et al. Characterization of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5 [J]. J Pharm Sci,2008,97 (6): 2110-2120.
25 Kanaze FI, Kokkalou E, Niopas I, et al. Thermal analysis study of flavonoid solid dispersions having enhanced solubility [J]. J Therm Anal Calorim,2006,83 (2): 283-290.
26 Higuchi T, Connors KA. Phase-solubility techniques.Adv Anal Chem Instrum 1965,4:117-210.
27陆彬主编.药物新剂型与新技术[M].北京：人民卫生出版社,1998,23.
28孙伟张,曾仁杰,于波涛,等.伊曲康唑固体分散体制备及体外溶出试验[J].中国医院药学杂志,2004,24(10)：617-619.
29 Najib N, Suleiman MS. Characterisation of a diflusinal polyethylene glycol solid dispersion system [J]. Int J Pharm,1989,51:225-232.
30 Lloyd GR, Craig DQM, Smith A. An investigation into the melting behaviour of binary mixes and solid dispersions of paracetamol and PEG 4000 [J]. J Pharm Sci, 1997,86:991-996.
31 Newa M, Bhandari KH, Li DX, et al. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188 [J]. Int J Pharm.2007,343:228-237.
32闫月荣,王保安,郑军伟.拉曼光谱研究水飞蓟宾在载体中的分散形式及分子间的作用[J].焦作师范高等专科学校学报.2007,23(4)：72-73.
33 Fini A, Cavallari C, Ospitali F. Raman and thermal analysis of indomethacin/PVP solid dispersion enteric microparticles [J]. Eur J Pharm,2008,70:409-420.
34 Kanaze FI, Kokkalou E, Niopas I, et al. Dissolution enhancement of flavonoids by solid dispersion in PVP and PEG matrixes:a comparative study [J]. J Appl Polym Sci,2006,102:460-471.
35柳晨,朱赛杰.环孢素-PVP固体分散体的体外研究[J].中国药学杂志,2007,42(10)：761-764.
36陈国广,张柯萍,李学明等.灯盏花素缓释固体分散体的制备及溶出度的研究[J].华西药学杂志,2007,22(2)：169-171.
37钟延强,王春燕.新型非甾体抗炎药—氯比洛芬制剂学研究进展[J].药学实践杂志,1999,17(2)：97-101.
38 lrie T, Uekama K. Pharmaceutical applications of cyclodextrins. Ⅲ. Toxicological issues and safety evaluation [J]. J Pharm Sci,1997,86 (2):147-162.
39陆彬.药物新剂型与新技术[M],北京：人民卫生出版社,2002,40-46.
40谷福根,高永良,崔福德.磺丁基醚-β-环糊精及其在药剂学中的应用[J].中国新药杂志,2004,13(1)：16-19.
41 Brewster ME, Vandecruys R, Peeters J, et al. Comparative interaction of 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin with itraconazole:Phase-solubility behavior and stabilization of supersaturated drug solutions [J]. Eur J Pharm Sci,2008,34:94-103.
42 Fukuda M, Miller DA, Peppas NA, et al. Influence of sulfobutyl ether β-cyclodextrin (Captisol(?)) on the dissolution properties of a poorly soluble drug from extrudates prepared by hot-melt extrusion [J]. Int J Pharm,2008,350: 188-196.
43 Jain AC, Adeyeye MC. Hygroscopicity, phase solubility and dissolution of various substituted sulfobutylether β-cyclodextrins (SBE) and danazol-SBE inclusion complexes [J]. Int J Pharm,2001,212 (2):177-186.
44 Lockwood SF, O'Malley S, Mosher GL, et al. Improved aqueous solubility of crystalline astaxanthin (3,3'-dihydroxy-β,β-carotene-4,4'-dione) by captisol(?) (sulfobutyl etherβ-cyclodextrin) [J]. J Pharm Sci,2003,92:922-926.
45 Liu LX, Zhu SY. Preparation and characterization of inclusion complexes of prazosin hydrochloride with β-cyclodextrin and hydroxypropyl-β-cyclodextrin [J]. J Pharm Biomed Anal,2006,40 (1):122-127.
46 Bayomi MA, Abanumay KA, Al-Angary AA. Effect of inclusion complexation with cyclodextrins on photostability of nifedipine in solid state [J]. Int J Pharm, 2002,243:107-117.
47 Fernandes CM, Vieira MT, Veiga FJB. Physicochemical characterization and in vitro dissolution behavior of nicardipine-cyclodextrins inclusion compounds [J]. Eur J Pharm Sci,2002,15:79-88.
48 Mura P, Faucci MT, Parrini PL, et al. Influence of the preparation method on the physicochemical properties of ketoprofen-cyclodextrin binary systems [J]. Int J Pharm,1999,197:117-128.
49 Wen X, Tan F, Jing Z, et al. Preparation and study the 1:2 inclusion complex of carvedilol with β-cyclodextrin [J]. J Pharm Biomed Anal,2004,34 (3):517-523.
50 Lu R, Wang H, Tong L. Spectroscopic studies on inclusion complexes of MAQO and MPQO with cyclodextrins [J]. Mat Sci Eng C-Bio S,1999,10:7-11.
51 Crisma M, Fornasier R, Marcuzzi F. The crystal structure of the 1:1 inclusion complex of β-cyclodextrin with squaric acid [J]. Carbohydr Res,2001,333: 145-151.
52 Aree T, Chaichit N. Crystal structure of β-cyclodextrin-dimethylsufoxide inclusion complex [J]. Carbohydr Res,2002,337:2487-2494.
53 Zerrouk N, Gine's Dorado JM, Arnaud P, et al. Physical characteristics of inclusion compounds of 5-AS A in a and p cyclodextrins [J]. Int J Pharm,1998, 171:19-29.
54 Jullian C, Moyano L Yanez C. Complexation of quercetin with three kinds of cyclodextrins:An antioxidant study [J]. Spectrochimi Acta A,2007,67:230-234.
55刘龙孝,朱素燕.羟丙基-β-环糊精包合对盐酸哌唑嗪的增溶作用研究[J].中国药学杂志,2006,41(2)：122-125.
56 Rawat S, Jain SK. Solubility enhancement of celecoxib using β-cyclodextrin inclusion complexes [J]. Eur J Pharm Biopharm,2004,57:263-267.
57 Bernini A, Spiga O, Ciutti A, et al. NMR studies of the inclusion complex between P-cyclodextrin and paroxetine [J]. Eur J Pharm Sci,2004,22:445-450.
58 Oh I, Lee MY, Lee YB, et al. spectroscopic characterization of ibuprofen/2-hydroxypropyl-β-cyclodextrin inclusion complex [J]. Int J Pharm, 1998,175:215-233.
59何华,汤瑶,孙成,等.光谱法及热动力学法研究环糊精与三氟氯氰菊酯的包合作用[J].化学学报,2006,64(2)：175-181.
60 Calabro ML, Tommasini S, Donato P, et al. The rutin/β-cyclodextrin interactions in fully aqueous solution:spectroscopic studies and biological assays [J]. J Pharm Biomed Anal,2005,36 (5):1019-1027.
61 Shen Y, Yang S, Wu L, et al. Study on structure and characterization of inclusion complex of gossypol/β cyclodextrin [J]. Spectrochim Acta A,2005,61: 1025-1028.
62曹书霞,苏玉倩,陈晓岚,等.βCD与蛋白质非共价复合物的电喷雾质谱研究[J].分析测试学报,2004,23(5)：76-79.
63 Connors KA. The stability of cyclodextrin complexes in solution [J]. Chem Rev, 1997,97 (5):1325-1358.
64 Rekharsky MV, Inoue Y. Complexation thermodynamics of cyclodextrin [J]. Chem Rev,1998,98 (5):1875-1917.
65 Schneider HJ, Hacket F, Riidiger V, et al. NMR studies of cyclodextrins and cyclodextrin complexes [J]. Chem Rev,1998,98:1755-1785.
66宋乐新,周桃玉,郭子建.环糊精及其衍生物的超分子晶体结构研究进展[J].无机化学学报,2001,17(1)：9-16.
67 Harata K. Structural aspects of stereodifferentiation in the solid state [J]. Chem Rev,1998,98:1803-1827.
68雍国平,李光水,郑飞,等.β-环糊精包合物的结构研究[J].高等学校化学学报,2000,21(7)：1124-1126.
69 Stejtli J. Cyclodextrin Techology (1st Ed) [M]. Kluwer, Dordrecht,1988:79-81.
70 Jogun KH, Stezowski JJ. Metastable crystals of β-cyclodextrin complexes and the membrane diffusion model [J]. Nature,1979,278:667-668.
71 Hamilton JA, Chen L. Crystal structure of an inclusion complex of β-cyclodextrin with racemic fenoprofen:direct evidence for chiral recognition [J]. J Am Chem Soc,1988,110:5833-5836.