葡萄糖—阿司匹林共价复合物的合成及体外释放研究
|
摘要
为了改善阿司匹林药效,降低其毒副作用。本文以葡萄糖和阿司匹林为原料,先将阿司匹林转化为相应的酰氯,然后在n (乙酰水杨酰氯) /n (葡萄糖)=5,吡啶为催化剂, 50℃下将二者进行成酯反应,合成了葡萄糖-阿司匹林共价复合物,采用FT-IR、1H-NMR对其结构进行了表征。并利用紫外可见分光光度法确定了此复合物的接枝率为54.9%,乙酰水杨酰氯的转化率为10.7%。对于此共价复合物在不同释放介质中的释放行为的考察中发现,在人工胃液或人工肠液的体外释放中均呈现零级缓慢释药且释药的开始阶段无爆释现象出现,人工胃液中随着胃液酸度的降低,零级释放时间随之增长,当PH=5时,零级释放时间达到25h;在人工肠液中该共价复合物的零级释放时间长达28h,与阿司匹林相比较,其作用时间有明显增长,有望大大减轻药物对胃粘膜的刺激作用。
本文还以水杨酸和二溴代烷为原料,在水溶液中100℃左右合成了五种水杨酸二醚类化合物,此反应具有合成条件温和、环境友好以及产率高等优点。并利用FT-IR、GC-MS以及1H-NMR对几种产物进行结构表征。在对该系列化合物进行体外释放时发现,此类化合物的水溶性较差,未能达到预期的效果。
For improving the drug effect of aspirin, reducing its side effect. In the paper, Glucose-aspirin conjugate was synthesized via a reaction of o-acetoxybenzoyl chloride and glucose in normal pressure, at 50℃, pyridine was used as catalyst in the reaction. Its structure was characterized by FTIR and 1HNMR. The drug-loading ratio was measured by UV spectrophotometry, its result was about 54.9%, and converting efficiency of o-acetoxybenzoyl chloride was 10.7%. In the different release medium, vitro release study showed that release rate of the conjugate was nearly zero order with no abrupt release. With the reduction of artificial gastric juice acidity, the release time of zero order grow. When PH=5, the release time of zero order was about 25h; the release time of zero order was about 28h in the artificial intestinal juice. It shows that the conjugate may lead to less side-effect and relieving stimulation of ASA on gastrointestinal tract.
In addition, five new salicylic acid compounds in ether derivatives are prepared by the reaction of the salicylic acid and dibromoalkane with tetrabutylammonium bromide in DMF and deioned water, under the condition of atmospheric pressure and hot reflux, and their yields are above ninety percents. Their structures are characterized by FT-IR、GC-MS、H-NMR. Vitro release study showed that water-solubility of these compounds was very lower.
本文还以水杨酸和二溴代烷为原料,在水溶液中100℃左右合成了五种水杨酸二醚类化合物,此反应具有合成条件温和、环境友好以及产率高等优点。并利用FT-IR、GC-MS以及1H-NMR对几种产物进行结构表征。在对该系列化合物进行体外释放时发现,此类化合物的水溶性较差,未能达到预期的效果。
For improving the drug effect of aspirin, reducing its side effect. In the paper, Glucose-aspirin conjugate was synthesized via a reaction of o-acetoxybenzoyl chloride and glucose in normal pressure, at 50℃, pyridine was used as catalyst in the reaction. Its structure was characterized by FTIR and 1HNMR. The drug-loading ratio was measured by UV spectrophotometry, its result was about 54.9%, and converting efficiency of o-acetoxybenzoyl chloride was 10.7%. In the different release medium, vitro release study showed that release rate of the conjugate was nearly zero order with no abrupt release. With the reduction of artificial gastric juice acidity, the release time of zero order grow. When PH=5, the release time of zero order was about 25h; the release time of zero order was about 28h in the artificial intestinal juice. It shows that the conjugate may lead to less side-effect and relieving stimulation of ASA on gastrointestinal tract.
In addition, five new salicylic acid compounds in ether derivatives are prepared by the reaction of the salicylic acid and dibromoalkane with tetrabutylammonium bromide in DMF and deioned water, under the condition of atmospheric pressure and hot reflux, and their yields are above ninety percents. Their structures are characterized by FT-IR、GC-MS、H-NMR. Vitro release study showed that water-solubility of these compounds was very lower.
引文
[1]唐星.口服缓控释制剂[M].北京:人民卫生出版社, 2007. 15-16.
[2]张健泓.药物制剂技术实训教程[M].北京:化学工业出版社, 2007. 28
[3]梁文权.生物药剂学与药物动力学(第三版)[M].北京:人民卫生出版社, 2007. 21-23.
[4]孙进.口服药物吸收与转动[M].北京:人民卫生出版社, 2007. 56.
[5]刘俊田.药理学[M].郑州:郑州大学出版社, 2007. 173.
[6] Nishakawa Y, Yoshimoto K, et al. Chemical and biochemical studies on carbohydrate esters Antitumor activity of unsaturated-fatty acids and their ester derivatives against chrlich ascites carcinoma[J].Chem. Pyarm.Bull.,1976,24(4):756.
[7]彭司勋.药物化学进展(2)[M].北京:化学工业出版社, 2003.
[8]郭振楚.糖类化学[M].北京:化学工业出版社, 2005.
[9]耿洪业,王少华.实用治疗药物学(第二版) [M].北京:人民卫生出版社, 2003. 430-437.
[10]张克义,赵乃才.临床药物不良反应大典[M].南昌:二十一世纪出版社, 2001. 91-97.
[11] J.R. Vane, R.M. Botting. The mechanism of action of aspirin[J]. Thrombosis Research. 2003, (110):255–258
[12]高文霞.右旋糖酐改性阿司匹林及体外释药研究[D].合肥:合肥工业大学,2005.
[13] Wallace JL, Ignarro LJ, Fiorucci.S. Potential cardio protective action of no-releasing aspirin[ J ]. Nature Review, Drug Discovery, 2002, (1):375 - 382.
[14] Gilmer JF, Moriarty LM, McCafferty DF, et al. Synthesis, hydrolysis kinetics and anti-platelet effects of sosorbide mononitrate derivatives of aspirin[J]. European Journal of Pharmaceutical Sciences, 2001, (14):221-227.
[15] Patrono C. Aspirin as an anti-platelet drug[ J ]. New England Journal of Medicine, 1994, 330 (18) : 1287 - 1294.
[16] Meht SS, Silver RJ., Aaronson A, et al. Comparison of Aspirin Resistance in Tape 1 Versus Tape 2 Diabetes Mellitus[J]. Am. J. Cardiol., 2006, (97): 567-570 .
[17]陈新谦,金有豫,汤光.新编药物学(第十五版)[M].北京:人民卫生出版社, 2005. 180.
[18]李瑞芳.药物化学教程[M].北京:化学工业出版社, 2006. 137-138.
[19]张进玉.类风湿性关节炎(第二版) [M].北京:人民卫生出版社, 1999. 361.
[20]李殊响.药理学歌诀[M].北京:科学出版社, 2005. 43-44.
[21] Pui-Yin Lee, Wai-Hong Chen, William Ng, et al. Low-dose aspirin increase aspirin resistance in patients with coronary artery disease [J]. The American Journal of Medicine. 2005, (118):723-727.
[22] Christopher B. Granger, Philippe Gabriel Steg, Eric Peterson, et al. Medication performance measures and mortality following acute coronary syndromes [J]. The American Journal of Medicine. 2005, (118):858-865.
[23] Yibing Yan, David R Phillips. Aspirin response and failure in diabetic patients with cardiovascular disease [J]. Current Opinion in Pharmacology . 2005, (5):190-197.
[24] Sheena S. Mehta, Robert J. Silver, Arthur Aaronson, et al. Comparison of aspirin resistance in type 1 versus type 2 diabetes mellitus [J]. The American Journal of Cardiology. 2006, 567-570.
[25] N. R. Jana. NSAIDs and apoptosis [J]. Cellular and Molecular Life Sciences . 2008. 1-7.
[26] J. Y. Park·K. H. Park·S. Bang. Expression of nonsteroidal anti-inXammatory drug-activated gene-1 (NAG-1) inversely correlates with tumor progression in gastric adenomas and carcinomas [J]. J Cancer Res Clin Oncol. 2008.1-7.
[27] A. R. Amina, M. G. Attura, M. Pillingera,b and S. B. Abramsona, The pleiotropic functions of aspirin: mechanisms of action [J] , Cellular and Molecular Life Sciences, 1999,(56) 305–312
[28] Kenneth K. Wu,Novel mechanisms of aspirin pharmacologicactions: A model for studying herbal natural products [J]. Thrombosis Research . 2005, (117), 61-64
[29] Vane J. R. and Botting R. M. Anti-inflammatory drugs and their mechanism of action[J] Inflamm. Res. 1998. (47):S78–87.
[30] Daniel J. Rader, Alan Daugherty. Translating molecular discoveries into new therapies for atherosclerosis [J]. Nature. 2008, (451):904-913.
[31] Stephane Siberman, Catherine Neukich-Stoop, Philippe Gabriel Steg. Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting [J]. The American Journal of Cardiology . 2005, (95):509-510.
[32]张进玉.类风湿性关节炎(第二版) [M].北京:人民卫生出版社, 1999. 365.
[33] Banoob D W, Mc Closkey W W, Webster W. Risk of gastric injury withenteric-versus nonenteric-coated aspirin [J]. Ann Pharmacother. 2002 , 36(1):163-166.
[34] Kelly J P, Kaufman D W, Jurgelon J M, et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product [J]. Lancet. 1996, 348(9039):1413-14166.
[35]李晓芳,洪慧,何琳.阿司匹林胃漂浮微球的制备[J].广东药学院学报. 2006, 22(1):13-15.
[36]史振祺,蒋新国.胃漂浮片的研究进展[J].中国医药工业杂志. 2003, 34(4): 199-202.
[37] Xu G, Groves M J. Effect of FITC-dextran mo1ecu1ar weight on its re1ease from f1oating cety1 a1coho1 and HPMC tab1ets [J]. J Pharm Pharmaco1. 2001, 53(1):49-56.
[38] Svetlana Ibri?, Milica Jovanovi?, Zorica Djuri?, et al. Artificial Neural Networks in the Modeling and Optimization of Aspirin Extended Release Tablets With Eudragit L 100 as Matrix Substance[J] . AAPS PharmSciTech 2003, 4(1):1-9.
[39] Mohammad A. Chowdhury, David J. T. Hill, Andrew K. Whittaker. NMR Imaging of the Diffusion of Water at 37°C into poly(2-hydroxyethyl methacrylate) Containing Aspirin or vitamin B12[J]. Biomacromolecules. 2004, (5):971-976.
[40] Takanori Fukahori, Minako Kondo, Sadakatsu Nishikawa. Dynamic Study of Interaction between a-Cyclodextrin and Aspirin by the Ultrasonic Relaxation Method[J]. J. Phys. Chem. B 2006, (110): 4487-4491.
[41]张晓云,乔华,倪京满.阿司匹林β-环糊精包合物的实验研究[J].兰州大学学报(医学版). 2005, 31(2):17-19.
[42] Je′ro?me Mulhbacher, Pompilia Ispas-Szabo, Vincent Lenaerts, et al. Cross-linked high amylose starch derivatives as matrices for controlled release of high drug loadings [J]. Journal of Controlled Release . 2001, (76):51–58.
[43] Hong Wen, Tonglei Li, Kenneth R. Morris, et al. Dissolution Study on Aspirin and r-Glycine Crystals [J]. J. Phys. Chem. B. 2004, (108):11219-11227.
[44] J.A. Ko, H.J. Park, S.J. Hwang, et al. Preparation and characterization of chitosan microparticles intended for controlled drug delivery [J]. International Journal of Pharmaceutics. 2002, (249):165-174.
[45] Steven J. Siegel, Jonathan B. Kahn, Kayla Metzger, et al. Effect of drug type on the degradation rate of PLGA matrices [J]. European Journal of Pharmaceuticsand Biopharmaceutics. 2006, (64):287–293.
[46] Leon Shargel, Susanna Wu-Pong, Aandrew B.C.Yu著,李安良,吴艳芬译.应用生物药剂学与药物动力学[M].北京:化学工业出版社. 2006,275.303.
[47] Barry, B. W.. Is transdermal drug delivery research still important today [J]. DDT. 2001, (60):967-971.
[48] Kattan A.E., Asbill C S, Haidar S. Transdermal testing: practical aspects and methods[J]. Pharmaceutical Science and Technology Today. 2000, (3):426-430.
[49]刘蜀宝.药剂学[M].郑州:郑州大学出版社. 2004, 540-555.
[50] H.O. Ammara, M. Ghorab , S.A. El-Nahhas, et al. Design of a transdermal delivery system for aspirin as an antithrombotic drug [J]. International Journal of Pharmaceutics. 2006, (327):81-88.
[51] Minja Gerber , Jaco C. Breytenbach , Jonathan Hadgraft , et al. Synthesis and transdermal properties of acetylsalicylic acid and selected esters[J]. International Journal of Pharmaceutics. 2006, (310):31–36.
[52]陈新谦,金有豫,汤光.新编药物学(第十五版)[M].北京:人民卫生出版社, 2005. 181-184.
[53] S.B. Etcheverry , P.A.M. Williams, D.A. Barrio, et al, Synthesis, characterization and bioactivity of a new VO2+/ Aspirin complex[J]. Journal of Inorganic Biochemistry. 2000, (80):169–171.
[54] Anne Spasojevic′-de Bire′, Nouzha Bouhmaida, Aleksandar Kremenovic′,et al. Experimental Electron Density and Electrostatic Potential Analysis of Zinc(aspirinate)2(H2O)2 Complex: A 3d10 Metal Bonding to a Drug Ligand[J]. J. Phys. Chem. A. 2002(106):12170-12177.
[55] John F. Gilmer , Louise M. Moriarty , Dermot F. McCafferty ,et al. Synthesis, hydrolysis kinetics and anti-platelet effects of isosorbide mononitrate derivatives of aspirin[J]. European Journal of Pharmaceutical Sciences. 2001, (14):221–227.
[56] Elliott S N, Wallace J L. Nitric oxide:A regulator of mucosal defense and injure [J]. J. Gastroenterology. 1998, 33(6):792-806.
[57] Kato S, Kitamura M, Korolkiewicz R P, et al. Role of nitric oxide in regulation of gastric acid secretion in rats:effects of NO donors and NO syntheses inhibitors. Br. J. Pharmacol.. 1998, 123(5):839-846.
[58] Ichikawa T, Ishihara K, Saigenji K, et al. Lafutidine-induced stimulation of mucin biosynthesis mediated by nitric oxide is limited to the surface mucous cells of rat gastric oxyntic mucosa [J]. Lif. Sci.. 1998, 62(16):PL259-264.
[59] Kurose I, Kubes P, Wolf R, et al. Inhibition of nitric oxide production:Mechanisms of vascular albumin leakage [J]. Circ. Res.. 1993, 73(1):164-171.
[60] Elliott S N, Mcknight W, Cirino G, et al. A nitric oxide releasing nonsteroidal anti-inflammatory drug accelerate gastric ulcer healing in rats [J]. Gastroenterology, 1995, 109(2):524-530.
[61] Tam S W, Saha J K, Garvey D S. Nitrosothiol-based NO donors inhibit the gastrointestinal mucosal damaging actions of NSAIDs [J]. Inflammopharmacology. 2000, 8(1):81-88.
[62] Katsuyama, Ryosuke. Asapirin with little gastric damage.Action mechanism of NO-releasing aspirin [J]. Farumashia. 2001, 37(5):429-430.
[63] Wallace John L, Del Soldato Piero, Cirino Giuseppe. Nitric oxide-releasing NSAIDs:GI-safe antithrombotics [J]. IDrugs. 1999, 2(4):321-326.
[64] Kimihito Tashima, Akinobu Fujita, Masakazu Umeda, et al. Lack of gastric toxicity of nitric oxide-releasing aspirin,NCX-4016, in the stomach of diabetic rats[J]. Life Sciences . 2000, (67):1639-1652.
[65] Galen M. Pieper, Wolfgang Siebeneich, Cara L. Olds, et al. Vascular Protective Actions of A Nitric Oxide Aspirin Analog in Both in Vitro and in Vivo Models of Diabetes Mellitus [J]. Free Radical Biology & Medicine. 2002, 32(11): 1143–1156.
[66] Clara Cena, Marco L. Lolli, Loretta Lazzarato, et al. Antiinflammatory, Gastrosparing and Antiplatelet Properties of New NO-Donor Esters of Aspirin [J]. J. Med. Chem.. 2003, (46):747-754.
[67]俞耀庭.生物医用材料[M].天津:天津大学出版社. 2000, 173-180.
[68] H.van de Waterbeemd, H. Lennernas, P. Artursson著,何仲贵,钟大放,等译.药物生物利用度[M].北京:化学工业出版社. 2007, 6.
[69]缪立德.药物化学(第二版)[M].北京:中国医药科技出版社. 2005, 336.
[70]蔡孟深,李中军.糖化学[M].北京:化学工业出版社. 2007, 324.
[71] Min Ge, Zhong Chen, H. Russell Onishi, et al. Vancomycin Derivatives That Inhibit Peptidoglycan Biosynthesis Without Binding D-Ala-D-Ala [J]. science . 1999, 284(5413): 507-511.
[72] a.郭振楚.糖类化学[M].北京:化学工业出版社. 2005, 284-286. b.郭振楚.糖类化学[M].北京:化学工业出版社. 2005, 269-278.
[73]刘蜀宝.药剂学[M].郑州:郑州大学出版社. 2004, 530.
[74]阮建明,邹俭鹏,黄伯云.生物材料学[M].北京:科学出版社. 2006, 366.
[75]刘昌孝.药物评价学[M].北京:化学工业出版社. 2006, 119-122.
[76]中华人民共和国药典委员会.中华人民共和国药典(2005年版).北京:化学工业出版社. 2005,附录XD.
[77]夏锦辉,刘昌孝.固体药物制剂的体外溶出度的统计学评价分析[J].中国药学杂志. 2000, 35(2):130-131.
[78]胡乔生,王建国,范小林,等.葡萄糖-阿司匹林偶联物的合成[J].现代生物医学进展. 2007, 7(7):1086-1088.
[79]王瑞,孙铁民.药物化学实验[M].沈阳:沈阳药科大学药物化学教研室. 2004, 3.
[80]盛龙生,何丽一,徐连连,等.药物分析[M].北京:化学工业出版社. 2003, 472
[81]李玉宝.生物医学材料[M].北京:化学工业出版社. 2003, 46.
[2]张健泓.药物制剂技术实训教程[M].北京:化学工业出版社, 2007. 28
[3]梁文权.生物药剂学与药物动力学(第三版)[M].北京:人民卫生出版社, 2007. 21-23.
[4]孙进.口服药物吸收与转动[M].北京:人民卫生出版社, 2007. 56.
[5]刘俊田.药理学[M].郑州:郑州大学出版社, 2007. 173.
[6] Nishakawa Y, Yoshimoto K, et al. Chemical and biochemical studies on carbohydrate esters Antitumor activity of unsaturated-fatty acids and their ester derivatives against chrlich ascites carcinoma[J].Chem. Pyarm.Bull.,1976,24(4):756.
[7]彭司勋.药物化学进展(2)[M].北京:化学工业出版社, 2003.
[8]郭振楚.糖类化学[M].北京:化学工业出版社, 2005.
[9]耿洪业,王少华.实用治疗药物学(第二版) [M].北京:人民卫生出版社, 2003. 430-437.
[10]张克义,赵乃才.临床药物不良反应大典[M].南昌:二十一世纪出版社, 2001. 91-97.
[11] J.R. Vane, R.M. Botting. The mechanism of action of aspirin[J]. Thrombosis Research. 2003, (110):255–258
[12]高文霞.右旋糖酐改性阿司匹林及体外释药研究[D].合肥:合肥工业大学,2005.
[13] Wallace JL, Ignarro LJ, Fiorucci.S. Potential cardio protective action of no-releasing aspirin[ J ]. Nature Review, Drug Discovery, 2002, (1):375 - 382.
[14] Gilmer JF, Moriarty LM, McCafferty DF, et al. Synthesis, hydrolysis kinetics and anti-platelet effects of sosorbide mononitrate derivatives of aspirin[J]. European Journal of Pharmaceutical Sciences, 2001, (14):221-227.
[15] Patrono C. Aspirin as an anti-platelet drug[ J ]. New England Journal of Medicine, 1994, 330 (18) : 1287 - 1294.
[16] Meht SS, Silver RJ., Aaronson A, et al. Comparison of Aspirin Resistance in Tape 1 Versus Tape 2 Diabetes Mellitus[J]. Am. J. Cardiol., 2006, (97): 567-570 .
[17]陈新谦,金有豫,汤光.新编药物学(第十五版)[M].北京:人民卫生出版社, 2005. 180.
[18]李瑞芳.药物化学教程[M].北京:化学工业出版社, 2006. 137-138.
[19]张进玉.类风湿性关节炎(第二版) [M].北京:人民卫生出版社, 1999. 361.
[20]李殊响.药理学歌诀[M].北京:科学出版社, 2005. 43-44.
[21] Pui-Yin Lee, Wai-Hong Chen, William Ng, et al. Low-dose aspirin increase aspirin resistance in patients with coronary artery disease [J]. The American Journal of Medicine. 2005, (118):723-727.
[22] Christopher B. Granger, Philippe Gabriel Steg, Eric Peterson, et al. Medication performance measures and mortality following acute coronary syndromes [J]. The American Journal of Medicine. 2005, (118):858-865.
[23] Yibing Yan, David R Phillips. Aspirin response and failure in diabetic patients with cardiovascular disease [J]. Current Opinion in Pharmacology . 2005, (5):190-197.
[24] Sheena S. Mehta, Robert J. Silver, Arthur Aaronson, et al. Comparison of aspirin resistance in type 1 versus type 2 diabetes mellitus [J]. The American Journal of Cardiology. 2006, 567-570.
[25] N. R. Jana. NSAIDs and apoptosis [J]. Cellular and Molecular Life Sciences . 2008. 1-7.
[26] J. Y. Park·K. H. Park·S. Bang. Expression of nonsteroidal anti-inXammatory drug-activated gene-1 (NAG-1) inversely correlates with tumor progression in gastric adenomas and carcinomas [J]. J Cancer Res Clin Oncol. 2008.1-7.
[27] A. R. Amina, M. G. Attura, M. Pillingera,b and S. B. Abramsona, The pleiotropic functions of aspirin: mechanisms of action [J] , Cellular and Molecular Life Sciences, 1999,(56) 305–312
[28] Kenneth K. Wu,Novel mechanisms of aspirin pharmacologicactions: A model for studying herbal natural products [J]. Thrombosis Research . 2005, (117), 61-64
[29] Vane J. R. and Botting R. M. Anti-inflammatory drugs and their mechanism of action[J] Inflamm. Res. 1998. (47):S78–87.
[30] Daniel J. Rader, Alan Daugherty. Translating molecular discoveries into new therapies for atherosclerosis [J]. Nature. 2008, (451):904-913.
[31] Stephane Siberman, Catherine Neukich-Stoop, Philippe Gabriel Steg. Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting [J]. The American Journal of Cardiology . 2005, (95):509-510.
[32]张进玉.类风湿性关节炎(第二版) [M].北京:人民卫生出版社, 1999. 365.
[33] Banoob D W, Mc Closkey W W, Webster W. Risk of gastric injury withenteric-versus nonenteric-coated aspirin [J]. Ann Pharmacother. 2002 , 36(1):163-166.
[34] Kelly J P, Kaufman D W, Jurgelon J M, et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product [J]. Lancet. 1996, 348(9039):1413-14166.
[35]李晓芳,洪慧,何琳.阿司匹林胃漂浮微球的制备[J].广东药学院学报. 2006, 22(1):13-15.
[36]史振祺,蒋新国.胃漂浮片的研究进展[J].中国医药工业杂志. 2003, 34(4): 199-202.
[37] Xu G, Groves M J. Effect of FITC-dextran mo1ecu1ar weight on its re1ease from f1oating cety1 a1coho1 and HPMC tab1ets [J]. J Pharm Pharmaco1. 2001, 53(1):49-56.
[38] Svetlana Ibri?, Milica Jovanovi?, Zorica Djuri?, et al. Artificial Neural Networks in the Modeling and Optimization of Aspirin Extended Release Tablets With Eudragit L 100 as Matrix Substance[J] . AAPS PharmSciTech 2003, 4(1):1-9.
[39] Mohammad A. Chowdhury, David J. T. Hill, Andrew K. Whittaker. NMR Imaging of the Diffusion of Water at 37°C into poly(2-hydroxyethyl methacrylate) Containing Aspirin or vitamin B12[J]. Biomacromolecules. 2004, (5):971-976.
[40] Takanori Fukahori, Minako Kondo, Sadakatsu Nishikawa. Dynamic Study of Interaction between a-Cyclodextrin and Aspirin by the Ultrasonic Relaxation Method[J]. J. Phys. Chem. B 2006, (110): 4487-4491.
[41]张晓云,乔华,倪京满.阿司匹林β-环糊精包合物的实验研究[J].兰州大学学报(医学版). 2005, 31(2):17-19.
[42] Je′ro?me Mulhbacher, Pompilia Ispas-Szabo, Vincent Lenaerts, et al. Cross-linked high amylose starch derivatives as matrices for controlled release of high drug loadings [J]. Journal of Controlled Release . 2001, (76):51–58.
[43] Hong Wen, Tonglei Li, Kenneth R. Morris, et al. Dissolution Study on Aspirin and r-Glycine Crystals [J]. J. Phys. Chem. B. 2004, (108):11219-11227.
[44] J.A. Ko, H.J. Park, S.J. Hwang, et al. Preparation and characterization of chitosan microparticles intended for controlled drug delivery [J]. International Journal of Pharmaceutics. 2002, (249):165-174.
[45] Steven J. Siegel, Jonathan B. Kahn, Kayla Metzger, et al. Effect of drug type on the degradation rate of PLGA matrices [J]. European Journal of Pharmaceuticsand Biopharmaceutics. 2006, (64):287–293.
[46] Leon Shargel, Susanna Wu-Pong, Aandrew B.C.Yu著,李安良,吴艳芬译.应用生物药剂学与药物动力学[M].北京:化学工业出版社. 2006,275.303.
[47] Barry, B. W.. Is transdermal drug delivery research still important today [J]. DDT. 2001, (60):967-971.
[48] Kattan A.E., Asbill C S, Haidar S. Transdermal testing: practical aspects and methods[J]. Pharmaceutical Science and Technology Today. 2000, (3):426-430.
[49]刘蜀宝.药剂学[M].郑州:郑州大学出版社. 2004, 540-555.
[50] H.O. Ammara, M. Ghorab , S.A. El-Nahhas, et al. Design of a transdermal delivery system for aspirin as an antithrombotic drug [J]. International Journal of Pharmaceutics. 2006, (327):81-88.
[51] Minja Gerber , Jaco C. Breytenbach , Jonathan Hadgraft , et al. Synthesis and transdermal properties of acetylsalicylic acid and selected esters[J]. International Journal of Pharmaceutics. 2006, (310):31–36.
[52]陈新谦,金有豫,汤光.新编药物学(第十五版)[M].北京:人民卫生出版社, 2005. 181-184.
[53] S.B. Etcheverry , P.A.M. Williams, D.A. Barrio, et al, Synthesis, characterization and bioactivity of a new VO2+/ Aspirin complex[J]. Journal of Inorganic Biochemistry. 2000, (80):169–171.
[54] Anne Spasojevic′-de Bire′, Nouzha Bouhmaida, Aleksandar Kremenovic′,et al. Experimental Electron Density and Electrostatic Potential Analysis of Zinc(aspirinate)2(H2O)2 Complex: A 3d10 Metal Bonding to a Drug Ligand[J]. J. Phys. Chem. A. 2002(106):12170-12177.
[55] John F. Gilmer , Louise M. Moriarty , Dermot F. McCafferty ,et al. Synthesis, hydrolysis kinetics and anti-platelet effects of isosorbide mononitrate derivatives of aspirin[J]. European Journal of Pharmaceutical Sciences. 2001, (14):221–227.
[56] Elliott S N, Wallace J L. Nitric oxide:A regulator of mucosal defense and injure [J]. J. Gastroenterology. 1998, 33(6):792-806.
[57] Kato S, Kitamura M, Korolkiewicz R P, et al. Role of nitric oxide in regulation of gastric acid secretion in rats:effects of NO donors and NO syntheses inhibitors. Br. J. Pharmacol.. 1998, 123(5):839-846.
[58] Ichikawa T, Ishihara K, Saigenji K, et al. Lafutidine-induced stimulation of mucin biosynthesis mediated by nitric oxide is limited to the surface mucous cells of rat gastric oxyntic mucosa [J]. Lif. Sci.. 1998, 62(16):PL259-264.
[59] Kurose I, Kubes P, Wolf R, et al. Inhibition of nitric oxide production:Mechanisms of vascular albumin leakage [J]. Circ. Res.. 1993, 73(1):164-171.
[60] Elliott S N, Mcknight W, Cirino G, et al. A nitric oxide releasing nonsteroidal anti-inflammatory drug accelerate gastric ulcer healing in rats [J]. Gastroenterology, 1995, 109(2):524-530.
[61] Tam S W, Saha J K, Garvey D S. Nitrosothiol-based NO donors inhibit the gastrointestinal mucosal damaging actions of NSAIDs [J]. Inflammopharmacology. 2000, 8(1):81-88.
[62] Katsuyama, Ryosuke. Asapirin with little gastric damage.Action mechanism of NO-releasing aspirin [J]. Farumashia. 2001, 37(5):429-430.
[63] Wallace John L, Del Soldato Piero, Cirino Giuseppe. Nitric oxide-releasing NSAIDs:GI-safe antithrombotics [J]. IDrugs. 1999, 2(4):321-326.
[64] Kimihito Tashima, Akinobu Fujita, Masakazu Umeda, et al. Lack of gastric toxicity of nitric oxide-releasing aspirin,NCX-4016, in the stomach of diabetic rats[J]. Life Sciences . 2000, (67):1639-1652.
[65] Galen M. Pieper, Wolfgang Siebeneich, Cara L. Olds, et al. Vascular Protective Actions of A Nitric Oxide Aspirin Analog in Both in Vitro and in Vivo Models of Diabetes Mellitus [J]. Free Radical Biology & Medicine. 2002, 32(11): 1143–1156.
[66] Clara Cena, Marco L. Lolli, Loretta Lazzarato, et al. Antiinflammatory, Gastrosparing and Antiplatelet Properties of New NO-Donor Esters of Aspirin [J]. J. Med. Chem.. 2003, (46):747-754.
[67]俞耀庭.生物医用材料[M].天津:天津大学出版社. 2000, 173-180.
[68] H.van de Waterbeemd, H. Lennernas, P. Artursson著,何仲贵,钟大放,等译.药物生物利用度[M].北京:化学工业出版社. 2007, 6.
[69]缪立德.药物化学(第二版)[M].北京:中国医药科技出版社. 2005, 336.
[70]蔡孟深,李中军.糖化学[M].北京:化学工业出版社. 2007, 324.
[71] Min Ge, Zhong Chen, H. Russell Onishi, et al. Vancomycin Derivatives That Inhibit Peptidoglycan Biosynthesis Without Binding D-Ala-D-Ala [J]. science . 1999, 284(5413): 507-511.
[72] a.郭振楚.糖类化学[M].北京:化学工业出版社. 2005, 284-286. b.郭振楚.糖类化学[M].北京:化学工业出版社. 2005, 269-278.
[73]刘蜀宝.药剂学[M].郑州:郑州大学出版社. 2004, 530.
[74]阮建明,邹俭鹏,黄伯云.生物材料学[M].北京:科学出版社. 2006, 366.
[75]刘昌孝.药物评价学[M].北京:化学工业出版社. 2006, 119-122.
[76]中华人民共和国药典委员会.中华人民共和国药典(2005年版).北京:化学工业出版社. 2005,附录XD.
[77]夏锦辉,刘昌孝.固体药物制剂的体外溶出度的统计学评价分析[J].中国药学杂志. 2000, 35(2):130-131.
[78]胡乔生,王建国,范小林,等.葡萄糖-阿司匹林偶联物的合成[J].现代生物医学进展. 2007, 7(7):1086-1088.
[79]王瑞,孙铁民.药物化学实验[M].沈阳:沈阳药科大学药物化学教研室. 2004, 3.
[80]盛龙生,何丽一,徐连连,等.药物分析[M].北京:化学工业出版社. 2003, 472
[81]李玉宝.生物医学材料[M].北京:化学工业出版社. 2003, 46.