NZTD吸收机理研究及其缓释片的研制
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摘要
本课题的目的是以生物药剂学理论为指导，研制以NZTD为主药，能在体内缓慢释放12h的胃滞留型缓释片。
研究药物在胃肠道的吸收速率和吸收动力学可以为口服制剂的研制提供理论指导，所以在研制处方之前，建立了NZTD在大鼠胃肠道的原位灌注模型，对NZTD吸收动力学进行研究。分别建立了测定胃灌注液中NZTD浓度以及同时测定肠灌注液中NZTD和酚红浓度的高效液相色谱方法。对NZTD大鼠胃肠道吸收动力学研究的结果表明：NZTD在大鼠胃中吸收较好(高、中、低三个浓度的灌注液2h的平均吸收百分率为80.9±4.46％，在小肠各段都有吸收只是吸收较差。结合NZTD人体药物动力学数据(T_(max)约为1.2 h，T_(1／2)约为2h)以及NZTD普通片剂的临床给药方案(300 mg·d~(-1)或150 mg，b．i．d．ort．i．d．)，考虑将其制成能够缓慢释放12h的胃滞留型缓释片，以达到减小血药浓度波动，提高患者用药顺应性的目的。
初步建立了NZTD缓释片释放度的高效液相色谱测定方法，以释放度、颗粒流动性和片剂外观为指标，对NZTD缓释片进行处方工艺筛选。在基本处方的基础上选择主要骨架材料种类及用量，加入一定比例的崩解剂和表面活性剂以调整NZTD缓释片的释放行为，最终得到优化处方。按选定处方制备三批样品，测定释放度，结果表明：本课题研制的NZTD缓释片体外释放具有较好的重现性和均一性，体外释药特征符合缓释制剂的设计要求。
在NZTD缓释片的质量评价研究中，建立了NZTD缓释片的鉴别方法；确定了缓释片中NZTD的HPLC含量测定方法，并建立了NZTD缓释片的释放度测定方法，并把2、6、10小时的释放度限度初步定为标示量的20～30％、55～65％、80％以上；建立了NZTD缓释片有关物质的检查方法。对NZTD缓释片质量评价研究结果表明，NZTD缓释片质量研究方法科学合理，NZTD缓释片质量可控。同时对NZTD缓释片体外释放规律进行研究。研究结果表明：Higuchi模型为最佳拟合模型，Ritger-Peppas方程释放参数n=0.7529，0.45＜n＜0.89，说明NZTD缓释片中NZTD的释放机制是扩散和骨架溶蚀协同作用的结果。
稳定性影响因素实验表明，NZTD缓释片在光照条件下稳定，在高温和高湿条件下不稳定。在高温条件下，缓释片的外观、有关物质检查、释放度和含量测定均产生明显改变；在高湿条件下，NZTD缓释片的部分检查项目的检查结果发生了改变。提示NZTD缓释片成品应采用防潮包装，置阴凉干燥处保存。
本课题在生物药剂学理论的指导下，以NZTD的胃肠道吸收特征为基础进行制剂研制，减少了制剂开发的盲目性。本课题的研究结果为今后NZTD其它剂型设计的处方工艺、质量评价、稳定性研究等方面提供参考。
The objective of this study was to develop NZTD gastric retention sustained-release tablet which could steadily release drug in 12 hours in vivo, under the direction of biopharmaceutics.
Absorption kinetics of NZTD was studied by method of in situ perfusion of rat before NZTD formulation developed because the preparation of oral formulation could be guided by absorption rate and kinetics. HPLC methods were established respectively to determine the concentration of NZTD in gastric juice and the concentration of NZTD and phenolsulfnphthalein in the intestinal perfusate. The result indicates that NZTD can be well absorbed in stomach of rat and the average absoption rate of high, middle and low dose in 2 hours is 80.9±4.46%, and the absorption of NZTD in intestine of rat is poor. Considering of the pharmacokinetics data of NZTD(T_(max) is about 1.2h , T_(1/2) is about 2h) and its clinical dosage regimen (300 mg·d~(-1) or 150 mg, b.i.d, or t.i.d.), we prepared to design its sustained-release formulation, in order to diminish the fluctuation of blood concentration of NZTD and elevate the compliance of patients.
The HPLC method was established for the content determination of NZTD in the NZTD sustained-release tablet. The formulation and preparation technology was filtrated by the index of dissolution, granule fluidity and appearance of tablet. Based on the basic formulation , the type and usage amount of main backbone materials was chosen and a certain proportion of disintegrating agent and surfactant was added to adjust the dissolution behavior of the sustained-release tablet. The dissolution profile of 3 bathes of tablet indicate that the dissolution of NZTD sustained-release tablet had well reproducibility and homogenicity and accorded with demond of sustained-release formulation.
The identification methods and the HPLC method for the content determination of NZTD were set up in the quality study of the NZTD sustained-release tablet. The dissolution rate at 2 h, 6 h, 10 h was 20～30%、55～65% and above 80% respectively in regulation . The examining method of the correlated material was founded. The studying results according to items of the quality evaluating showed the evaluating method was reasonable and the quality of the NZTD sustained-release tablet was under the control. The release mechanism was studied, the Higuchi equation was the best one. The release parameter of n of Ritger-Peppas equation equals to 0.7529,0.45＜n＜0.89, it means that the release mechanism is the synergism of diffusion and matrix erosion.
The stability showed that light had not abvious effect on the NZTD sustained-release tablet but high temperature and high humidity influenced its stability. The result suggested that it should be packed in moistureproof material and stored in dry, cool and shady place.
The NZTD sustained-release tablet was prepared based on the absorption kinetics of NZTD in stomach and intestine under the direction of biopharmaceutics. The research result of this study could to be reference of the other dosage form of NZTD.
研究药物在胃肠道的吸收速率和吸收动力学可以为口服制剂的研制提供理论指导，所以在研制处方之前，建立了NZTD在大鼠胃肠道的原位灌注模型，对NZTD吸收动力学进行研究。分别建立了测定胃灌注液中NZTD浓度以及同时测定肠灌注液中NZTD和酚红浓度的高效液相色谱方法。对NZTD大鼠胃肠道吸收动力学研究的结果表明：NZTD在大鼠胃中吸收较好(高、中、低三个浓度的灌注液2h的平均吸收百分率为80.9±4.46％，在小肠各段都有吸收只是吸收较差。结合NZTD人体药物动力学数据(T_(max)约为1.2 h，T_(1／2)约为2h)以及NZTD普通片剂的临床给药方案(300 mg·d~(-1)或150 mg，b．i．d．ort．i．d．)，考虑将其制成能够缓慢释放12h的胃滞留型缓释片，以达到减小血药浓度波动，提高患者用药顺应性的目的。
初步建立了NZTD缓释片释放度的高效液相色谱测定方法，以释放度、颗粒流动性和片剂外观为指标，对NZTD缓释片进行处方工艺筛选。在基本处方的基础上选择主要骨架材料种类及用量，加入一定比例的崩解剂和表面活性剂以调整NZTD缓释片的释放行为，最终得到优化处方。按选定处方制备三批样品，测定释放度，结果表明：本课题研制的NZTD缓释片体外释放具有较好的重现性和均一性，体外释药特征符合缓释制剂的设计要求。
在NZTD缓释片的质量评价研究中，建立了NZTD缓释片的鉴别方法；确定了缓释片中NZTD的HPLC含量测定方法，并建立了NZTD缓释片的释放度测定方法，并把2、6、10小时的释放度限度初步定为标示量的20～30％、55～65％、80％以上；建立了NZTD缓释片有关物质的检查方法。对NZTD缓释片质量评价研究结果表明，NZTD缓释片质量研究方法科学合理，NZTD缓释片质量可控。同时对NZTD缓释片体外释放规律进行研究。研究结果表明：Higuchi模型为最佳拟合模型，Ritger-Peppas方程释放参数n=0.7529，0.45＜n＜0.89，说明NZTD缓释片中NZTD的释放机制是扩散和骨架溶蚀协同作用的结果。
稳定性影响因素实验表明，NZTD缓释片在光照条件下稳定，在高温和高湿条件下不稳定。在高温条件下，缓释片的外观、有关物质检查、释放度和含量测定均产生明显改变；在高湿条件下，NZTD缓释片的部分检查项目的检查结果发生了改变。提示NZTD缓释片成品应采用防潮包装，置阴凉干燥处保存。
本课题在生物药剂学理论的指导下，以NZTD的胃肠道吸收特征为基础进行制剂研制，减少了制剂开发的盲目性。本课题的研究结果为今后NZTD其它剂型设计的处方工艺、质量评价、稳定性研究等方面提供参考。
The objective of this study was to develop NZTD gastric retention sustained-release tablet which could steadily release drug in 12 hours in vivo, under the direction of biopharmaceutics.
Absorption kinetics of NZTD was studied by method of in situ perfusion of rat before NZTD formulation developed because the preparation of oral formulation could be guided by absorption rate and kinetics. HPLC methods were established respectively to determine the concentration of NZTD in gastric juice and the concentration of NZTD and phenolsulfnphthalein in the intestinal perfusate. The result indicates that NZTD can be well absorbed in stomach of rat and the average absoption rate of high, middle and low dose in 2 hours is 80.9±4.46%, and the absorption of NZTD in intestine of rat is poor. Considering of the pharmacokinetics data of NZTD(T_(max) is about 1.2h , T_(1/2) is about 2h) and its clinical dosage regimen (300 mg·d~(-1) or 150 mg, b.i.d, or t.i.d.), we prepared to design its sustained-release formulation, in order to diminish the fluctuation of blood concentration of NZTD and elevate the compliance of patients.
The HPLC method was established for the content determination of NZTD in the NZTD sustained-release tablet. The formulation and preparation technology was filtrated by the index of dissolution, granule fluidity and appearance of tablet. Based on the basic formulation , the type and usage amount of main backbone materials was chosen and a certain proportion of disintegrating agent and surfactant was added to adjust the dissolution behavior of the sustained-release tablet. The dissolution profile of 3 bathes of tablet indicate that the dissolution of NZTD sustained-release tablet had well reproducibility and homogenicity and accorded with demond of sustained-release formulation.
The identification methods and the HPLC method for the content determination of NZTD were set up in the quality study of the NZTD sustained-release tablet. The dissolution rate at 2 h, 6 h, 10 h was 20～30%、55～65% and above 80% respectively in regulation . The examining method of the correlated material was founded. The studying results according to items of the quality evaluating showed the evaluating method was reasonable and the quality of the NZTD sustained-release tablet was under the control. The release mechanism was studied, the Higuchi equation was the best one. The release parameter of n of Ritger-Peppas equation equals to 0.7529,0.45＜n＜0.89, it means that the release mechanism is the synergism of diffusion and matrix erosion.
The stability showed that light had not abvious effect on the NZTD sustained-release tablet but high temperature and high humidity influenced its stability. The result suggested that it should be packed in moistureproof material and stored in dry, cool and shady place.
The NZTD sustained-release tablet was prepared based on the absorption kinetics of NZTD in stomach and intestine under the direction of biopharmaceutics. The research result of this study could to be reference of the other dosage form of NZTD.
引文
[1] 南天平，郭广炎，潘伯荣．新型H_2受体阻滞剂尼扎替丁．国外医药——合成药、生化药、制剂分册，1990，11(3)：162-164．
[2] 高宗武，李荣成，杨国友．尼扎替丁在十二指肠溃疡中的应用[J]．现代中西医结合杂质，1999，8(12)：2057-2058．
[3] Abdel-Rahman, Susan M., Johnson, et al. Developmental Pharrnacokinetics and Pharmacodynamics of Nizatidine [J]. Journal of Pediatric Gastroenterology and Nutrition, 2004, 38(4): 442-451
[4] XUE S, KATA PO, BANERJEE P, et al. Bedtime H_2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors[J]. Aliment Pharmacol Ther, 2001, 15(9): 1351-1356.
[5] DAJANI EZ, KLAMUT MJ. Novel therapeutic approaches to gastic and duodenal ulcers: an update[J]. Expert Opin Invest Drugs, 2000, 9(7): 1537-1544.
[6] 陈勇川，何菊英，唐敏等．尼扎替丁片在健康人体的药代动力学及生物等效性研究[J]．第三军医大学学报，2005，27(2)：133-135．
[1] 国家药典委员会．中华人民共和国药典[S]．二部．北京：化学工业出版社．2005．
[2] 梁文权．生物药剂学与药物动力学[M]．第一版，北京：人民卫生出版社．2000．
[3] 陆彬．药剂学实验[M]．第一版．北京：人民卫生出版社，1994，131-135．
[4] 丁全福．药理实验教程[M]．第一版，北京：人民卫生出版社，1996，19-21．
[5] 沈凯．药物肠吸收实验研究方法进展．中国新药杂志[J]．2003，12(12)：988．
[6] 李高，方超．药物肠道吸收的生物学研究方法．中国药学杂志[J]．2002，37(10)：726-729．
[7] 聂淑芳．对大鼠在体肠单向灌流技术中重量法的评价．中国新药杂志[J]．2005，14(10)：1176-1179．
[8] 张莉，陈大为，李芳久等．法莫替丁大鼠在体小肠吸收动力学研究．沈阳药科大学学报[J]．2001，18(3)：170-172．
[9] 冯亮，蒋学华，周静．三七皂苷R_1和人参皂苷Rg_1的大鼠在体肠吸收动力学研究[J]．中国药学杂志，2006，41(14)：1099-1099．
[10] 杨星刚，张立波，潘卫三．芍药苷大鼠在体肠吸收动力学的研究[J]．中国药学杂志，2006，41(11)：856-856．
[11] Sofia Bergren,Janet Hoogstraate, Urban Fagerholm. etc. Characterization of jejunal absorption and apical effiux of ropivacaine, lidocatine and buqivacaine in the rat using in situ and in vitro absorption models. European Journal of Pharmaceutical Sciences[J]. 2004, 21: 553-560.
[12] Kenjiro Koga, Susumu Kawashima, Masahiro Murakami. In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on trasport of cephalexin and cefoperazone by rat intesine. European Journal of Pharmaceutical Sciences[J]. 2002, 54: 311-318.
[13] 陈勇川，何菊英，唐敏等．尼扎替丁片在健康人体的药代动力学及生物等效性研究[J]．第三军医大学学报，2005，27(2)：133-135．
[1] 国家药典委员会．中华人民共和国药典[S]．二部，北京：化学工业出版社．2005．
[2] 平其能．现代药剂学[M]．第一版，北京：中国医药科技出版社．1998，756．
[3] Hypromellose, USP28-NF23: 989.
[4] Nizatidine, European Pharmacopiea 5th. Edition, monograph 1453.
[5] 张蓉琴，李铜铃，程强等．尼扎替丁的含量及有关物质测定方法的改进．华西药学杂志[J]．2004，19(3)：217-218．
[6] A. T. M. Serajuddin. A. B. Thakur. et. al. Selection of Solid Dosage Form Composition through Drug-Excipient Compatibility Testing. J. Pharmaceu. Sci. 88(1999): 696-704.
[7] T. Selzer, M. Radau, J. Kreuter. The use of isothermal heat conduction microcalorimetry to evaluate drug stability in tablets. Inter. J. Pharmaceutics. 184(1999)199-206.
[8] SFDA．药品研究技术知道原则2005版．
[9] 曾环想，潘卫三，陈济民等．法莫替丁缓释片的制备工艺及其体外释放特点的研究．中国药学杂质[J]．1997，32(4)：213-216．
[10] 陈珊珊，徐榕青，曹剑虹等．法莫替丁胃内滞留型漂浮缓释片的制备及体外释放度[J]．中国医院药学杂质，2002，22(4)：197-200．
[1] 国家药典委员会．中华人民共和国药典[S]．二部，北京：化学工业出版社．2005．
[2] 张蓉琴，李铜铃，程强等．尼扎替丁的含量及有关物质测定方法的改进．华西药学杂志[J]．2004，19(3)：217-218．
[3] 梁文权．生物药剂学与药物动力学[M]．第一版，北京：人民卫生出版社．2000．
[4] T. O' Hara, A. Dunne, J. Butler, J. Devane. A review of methods used to compare dissolution profile data. Pharmaceutical Science and Technology Today[J]. 1998, 1(5): 214-223.
[5] P. Costa, J. Manuel Sousa Lobo, Modeling and comparison of dissolution profiles. Europea Journal of Pharmaceutical Sciences[J]. 2000, 209: 57-67.
[1] 国家药典委员会．中华人民共和国药典2005版附录XIX C原料药与药物制剂稳定性试验指导原则．
[2] 药品研究技术指导原则2005版．
[1] GOMOLLON F. SICILIA B. Helicobacter pylori, strategies for treatment[J]. Expert Opin Invest Drugs, 2001, 10(7): 1231-1241.
[2] 姚永莉，张万岱．幽门螺杆菌致病因子研究进展[J]．世界华人消化杂志，2002，10(4)：455-458．
[3] ZHEN G PY, HUA J, YEOH KG, et al. Association of peptic ulcer with increased expression of lewis antigens but not cagA, ice A and vacA in Helicobacter pylori isolates in an asian population[J]. Gut, 2000, 47(1): 18-22.
[4] 程晔，吕籽兰，张萍艳．吸烟与消化性溃疡[J]．中华消化内镜杂志，1996，13(3)：157
[5] 刘高金，金铃，莫爱勤．心理杜会因素与儿童消化性溃疡病的相关性研究[J]．中国行为医学科学，1996，16(2)：241．
[6] NISHIKWA K, SUGIYAMA T, KATO M, et al. Non-Helicobecter pylori and non-NSAID peptic ulcer disease in the Japanese population[J]. Eur J Gastroenterol Hepatol, 2000, 12(6): 635-640
[7] MEUCCI G, DI BATTISTA R, ABBIATI C, et al. Prevalence and risk factors of Helicobacter pylori-negative peptic ulcer: a multicenter study[J]. J Clin Gastrenterol. 2000, 31(1): 42-47.
[8] 陈士葆．遗传与消化呼吸系统疾病．第1版[M]．北京：科学出版社，1990．42-46，52-57．
[9] 王润华．消化性溃疡的药物治疗[M]．广西：健康生活杂志社，2000，7．42-42．
[10] KAUSHAL S, MIDHA V, SOOD A, et al. A comparative study of the effects of famotidine and sucralfate in prevention of upper gastro-intestinal bleeding in patients of head injury[J]. Indian J Pharmacol, 2000, 32(3): 246-249.
[11] XUE S, KATA PO, BANERJEE P, et al. Bedtime H_2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors[J]. Aliment Pharmacol Ther, 2001, 15(9): 1351-1356.
[12] DAJANI EZ, KLAMUT MJ. Novel therapeutic approaches to gastic and duodenal ulcers: an update[J]. Expert Opin Invest Drags, 2000, 9(7): 1537-1544.
[13] 姚光弼．质子泵抑制剂的新成员—埃索美拉唑[J]．中华消化杂志，2002，22(4)：233-235．
[14] LAINEL, FENNERTY MB, OSATO M, et al. Esomeprazol-based Helicobacter pylori eradication therapy and the effect of antibiotic resistance: results of three US multicenter, double-blind trials[J]. Am J Gastroenterol, 2000, 95(12): 3393-3398.
[15] 陈沛书．消化性溃疡现行治疗策略分析[J]．中国基层医药，2002，9(1)：37-37
[16] 匡邵忠，逢德堂．常用抗Hp抗菌药物的应用进展与评价[J]．青岛医药卫生，2005，37(4)：273-274．
[17] 郑松柏，项平，曹秀英，等．国产克拉霉素的短程三联疗法根除幽门螺杆菌感染的疗效[J]．中国新药与临床杂志，2000，19(4)：259-261．
[18] BARDHAN KD, MORTON D, PERRY MJ, et al. Ranitidine bismuth citrate with clarithromycin alone or with metronidazole for the eradication of Helicobacter pylori[J]. Aliment Pharmacol Ther, 2001, 15(8): 1199-1204.
[19] ZULLO A, HASSAN C, CAMEO SM, et al. A triple therapy regimen after failed Helicobacter pylori treatment[J]. Aliment pharmacol ther, 2001, 15(8): 1193-1197.
[20] 郑松柏．项平，徐富星．四联疗法作为二线方案根除幽门螺杆菌感染的疗效[J]．中国 新药与临床杂志，2002，21(3)：146-148．
[21] ADACHI K, ISHIHARAS S, HASHIMOTO T, et al. Efficacy of ecabet sodium for Helicobecter pylori eradication triple therapy in comparison with a lansoprazol-based regimen[J]. Aliment Pharmacol Ther, 2001, 18(5): 919-922.
[22] ADACHI K, ISHIHARAS S, HASHIMOTO T, et al. Efficacy of ecabet sodium for Helicobecter pylori eradication triple therapy in comparison with a lansoprazol-based regimen[J]. Aliment Pharmacol Ther, 2001, 18(5): 1187-1101
[23] 钱国新．消化性溃疡药物的进展及临床应用[J]．继续医药教育，1995，9(4)：33-35．
[24] 陈士葆，沈云芳，陈惠君，等．硫糖铝混悬液治疗消化性溃疡[J]．新药与临床，1996，15(1)：11-13．
[25] 王霄华，马应杰，胡世亮．醋氨己酸锌治疗幽门螺杆菌阳性的十二指肠溃疡[J]．中国新药与临床杂志，2000，19(5)：389-391．
[26] 彭铁立，王小虎，吴清明，等．醋氨己酸锌治疗肝硬化合并笑话性溃疡[J]．中国新药与临床杂志，2002，21(2)：104-106．
[27] 胡伏莲，钱可大，袁爱力，等．醋氨己酸锌对提高消化性溃疡愈合质量的作用[J]．中华消化杂志，2001，21(11)：703-704．
[28] 胡伏莲，张希金，贾博琪，等．醋氨己酸锌在消化性溃疡中的治疗作用[J]．中国临床药理学杂志，1996，12(2)：65-70．
[29] 谢宜奎，马新，冯宁．醋氨己酸锌治疗溃疡的作用机制的探讨[J]．中国新药与临床杂志，2003，22(8)：481-483．
[30] 张凯，陶玉莲．米索前列醇与西咪替丁对胃及十二指肠黏膜保护作用比较[J]．内蒙古医学杂志，2005，37(4)，373-373．
[31] 谢宜奎，张淑芹，张云甫．替普瑞酮加奥美拉唑和阿莫西林治疗胃溃疡73例[J]．中国新药与临床杂志，1999，18(5)：283-284．
[32] KUSU GAMI K, INA K, HOSOKAWAT, et al. Troxipide, a novel antiulcer compound, has inhibitory effects on human neutrophil migration and activation induced by various stimulates[J]. Dig Liver Dis, 2000, 32(4): 305-311.
[2] 高宗武，李荣成，杨国友．尼扎替丁在十二指肠溃疡中的应用[J]．现代中西医结合杂质，1999，8(12)：2057-2058．
[3] Abdel-Rahman, Susan M., Johnson, et al. Developmental Pharrnacokinetics and Pharmacodynamics of Nizatidine [J]. Journal of Pediatric Gastroenterology and Nutrition, 2004, 38(4): 442-451
[4] XUE S, KATA PO, BANERJEE P, et al. Bedtime H_2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors[J]. Aliment Pharmacol Ther, 2001, 15(9): 1351-1356.
[5] DAJANI EZ, KLAMUT MJ. Novel therapeutic approaches to gastic and duodenal ulcers: an update[J]. Expert Opin Invest Drugs, 2000, 9(7): 1537-1544.
[6] 陈勇川，何菊英，唐敏等．尼扎替丁片在健康人体的药代动力学及生物等效性研究[J]．第三军医大学学报，2005，27(2)：133-135．
[1] 国家药典委员会．中华人民共和国药典[S]．二部．北京：化学工业出版社．2005．
[2] 梁文权．生物药剂学与药物动力学[M]．第一版，北京：人民卫生出版社．2000．
[3] 陆彬．药剂学实验[M]．第一版．北京：人民卫生出版社，1994，131-135．
[4] 丁全福．药理实验教程[M]．第一版，北京：人民卫生出版社，1996，19-21．
[5] 沈凯．药物肠吸收实验研究方法进展．中国新药杂志[J]．2003，12(12)：988．
[6] 李高，方超．药物肠道吸收的生物学研究方法．中国药学杂志[J]．2002，37(10)：726-729．
[7] 聂淑芳．对大鼠在体肠单向灌流技术中重量法的评价．中国新药杂志[J]．2005，14(10)：1176-1179．
[8] 张莉，陈大为，李芳久等．法莫替丁大鼠在体小肠吸收动力学研究．沈阳药科大学学报[J]．2001，18(3)：170-172．
[9] 冯亮，蒋学华，周静．三七皂苷R_1和人参皂苷Rg_1的大鼠在体肠吸收动力学研究[J]．中国药学杂志，2006，41(14)：1099-1099．
[10] 杨星刚，张立波，潘卫三．芍药苷大鼠在体肠吸收动力学的研究[J]．中国药学杂志，2006，41(11)：856-856．
[11] Sofia Bergren,Janet Hoogstraate, Urban Fagerholm. etc. Characterization of jejunal absorption and apical effiux of ropivacaine, lidocatine and buqivacaine in the rat using in situ and in vitro absorption models. European Journal of Pharmaceutical Sciences[J]. 2004, 21: 553-560.
[12] Kenjiro Koga, Susumu Kawashima, Masahiro Murakami. In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on trasport of cephalexin and cefoperazone by rat intesine. European Journal of Pharmaceutical Sciences[J]. 2002, 54: 311-318.
[13] 陈勇川，何菊英，唐敏等．尼扎替丁片在健康人体的药代动力学及生物等效性研究[J]．第三军医大学学报，2005，27(2)：133-135．
[1] 国家药典委员会．中华人民共和国药典[S]．二部，北京：化学工业出版社．2005．
[2] 平其能．现代药剂学[M]．第一版，北京：中国医药科技出版社．1998，756．
[3] Hypromellose, USP28-NF23: 989.
[4] Nizatidine, European Pharmacopiea 5th. Edition, monograph 1453.
[5] 张蓉琴，李铜铃，程强等．尼扎替丁的含量及有关物质测定方法的改进．华西药学杂志[J]．2004，19(3)：217-218．
[6] A. T. M. Serajuddin. A. B. Thakur. et. al. Selection of Solid Dosage Form Composition through Drug-Excipient Compatibility Testing. J. Pharmaceu. Sci. 88(1999): 696-704.
[7] T. Selzer, M. Radau, J. Kreuter. The use of isothermal heat conduction microcalorimetry to evaluate drug stability in tablets. Inter. J. Pharmaceutics. 184(1999)199-206.
[8] SFDA．药品研究技术知道原则2005版．
[9] 曾环想，潘卫三，陈济民等．法莫替丁缓释片的制备工艺及其体外释放特点的研究．中国药学杂质[J]．1997，32(4)：213-216．
[10] 陈珊珊，徐榕青，曹剑虹等．法莫替丁胃内滞留型漂浮缓释片的制备及体外释放度[J]．中国医院药学杂质，2002，22(4)：197-200．
[1] 国家药典委员会．中华人民共和国药典[S]．二部，北京：化学工业出版社．2005．
[2] 张蓉琴，李铜铃，程强等．尼扎替丁的含量及有关物质测定方法的改进．华西药学杂志[J]．2004，19(3)：217-218．
[3] 梁文权．生物药剂学与药物动力学[M]．第一版，北京：人民卫生出版社．2000．
[4] T. O' Hara, A. Dunne, J. Butler, J. Devane. A review of methods used to compare dissolution profile data. Pharmaceutical Science and Technology Today[J]. 1998, 1(5): 214-223.
[5] P. Costa, J. Manuel Sousa Lobo, Modeling and comparison of dissolution profiles. Europea Journal of Pharmaceutical Sciences[J]. 2000, 209: 57-67.
[1] 国家药典委员会．中华人民共和国药典2005版附录XIX C原料药与药物制剂稳定性试验指导原则．
[2] 药品研究技术指导原则2005版．
[1] GOMOLLON F. SICILIA B. Helicobacter pylori, strategies for treatment[J]. Expert Opin Invest Drugs, 2001, 10(7): 1231-1241.
[2] 姚永莉，张万岱．幽门螺杆菌致病因子研究进展[J]．世界华人消化杂志，2002，10(4)：455-458．
[3] ZHEN G PY, HUA J, YEOH KG, et al. Association of peptic ulcer with increased expression of lewis antigens but not cagA, ice A and vacA in Helicobacter pylori isolates in an asian population[J]. Gut, 2000, 47(1): 18-22.
[4] 程晔，吕籽兰，张萍艳．吸烟与消化性溃疡[J]．中华消化内镜杂志，1996，13(3)：157
[5] 刘高金，金铃，莫爱勤．心理杜会因素与儿童消化性溃疡病的相关性研究[J]．中国行为医学科学，1996，16(2)：241．
[6] NISHIKWA K, SUGIYAMA T, KATO M, et al. Non-Helicobecter pylori and non-NSAID peptic ulcer disease in the Japanese population[J]. Eur J Gastroenterol Hepatol, 2000, 12(6): 635-640
[7] MEUCCI G, DI BATTISTA R, ABBIATI C, et al. Prevalence and risk factors of Helicobacter pylori-negative peptic ulcer: a multicenter study[J]. J Clin Gastrenterol. 2000, 31(1): 42-47.
[8] 陈士葆．遗传与消化呼吸系统疾病．第1版[M]．北京：科学出版社，1990．42-46，52-57．
[9] 王润华．消化性溃疡的药物治疗[M]．广西：健康生活杂志社，2000，7．42-42．
[10] KAUSHAL S, MIDHA V, SOOD A, et al. A comparative study of the effects of famotidine and sucralfate in prevention of upper gastro-intestinal bleeding in patients of head injury[J]. Indian J Pharmacol, 2000, 32(3): 246-249.
[11] XUE S, KATA PO, BANERJEE P, et al. Bedtime H_2 blockers improve nocturnal gastric acid control in GERD patients on proton pump inhibitors[J]. Aliment Pharmacol Ther, 2001, 15(9): 1351-1356.
[12] DAJANI EZ, KLAMUT MJ. Novel therapeutic approaches to gastic and duodenal ulcers: an update[J]. Expert Opin Invest Drags, 2000, 9(7): 1537-1544.
[13] 姚光弼．质子泵抑制剂的新成员—埃索美拉唑[J]．中华消化杂志，2002，22(4)：233-235．
[14] LAINEL, FENNERTY MB, OSATO M, et al. Esomeprazol-based Helicobacter pylori eradication therapy and the effect of antibiotic resistance: results of three US multicenter, double-blind trials[J]. Am J Gastroenterol, 2000, 95(12): 3393-3398.
[15] 陈沛书．消化性溃疡现行治疗策略分析[J]．中国基层医药，2002，9(1)：37-37
[16] 匡邵忠，逢德堂．常用抗Hp抗菌药物的应用进展与评价[J]．青岛医药卫生，2005，37(4)：273-274．
[17] 郑松柏，项平，曹秀英，等．国产克拉霉素的短程三联疗法根除幽门螺杆菌感染的疗效[J]．中国新药与临床杂志，2000，19(4)：259-261．
[18] BARDHAN KD, MORTON D, PERRY MJ, et al. Ranitidine bismuth citrate with clarithromycin alone or with metronidazole for the eradication of Helicobacter pylori[J]. Aliment Pharmacol Ther, 2001, 15(8): 1199-1204.
[19] ZULLO A, HASSAN C, CAMEO SM, et al. A triple therapy regimen after failed Helicobacter pylori treatment[J]. Aliment pharmacol ther, 2001, 15(8): 1193-1197.
[20] 郑松柏．项平，徐富星．四联疗法作为二线方案根除幽门螺杆菌感染的疗效[J]．中国 新药与临床杂志，2002，21(3)：146-148．
[21] ADACHI K, ISHIHARAS S, HASHIMOTO T, et al. Efficacy of ecabet sodium for Helicobecter pylori eradication triple therapy in comparison with a lansoprazol-based regimen[J]. Aliment Pharmacol Ther, 2001, 18(5): 919-922.
[22] ADACHI K, ISHIHARAS S, HASHIMOTO T, et al. Efficacy of ecabet sodium for Helicobecter pylori eradication triple therapy in comparison with a lansoprazol-based regimen[J]. Aliment Pharmacol Ther, 2001, 18(5): 1187-1101
[23] 钱国新．消化性溃疡药物的进展及临床应用[J]．继续医药教育，1995，9(4)：33-35．
[24] 陈士葆，沈云芳，陈惠君，等．硫糖铝混悬液治疗消化性溃疡[J]．新药与临床，1996，15(1)：11-13．
[25] 王霄华，马应杰，胡世亮．醋氨己酸锌治疗幽门螺杆菌阳性的十二指肠溃疡[J]．中国新药与临床杂志，2000，19(5)：389-391．
[26] 彭铁立，王小虎，吴清明，等．醋氨己酸锌治疗肝硬化合并笑话性溃疡[J]．中国新药与临床杂志，2002，21(2)：104-106．
[27] 胡伏莲，钱可大，袁爱力，等．醋氨己酸锌对提高消化性溃疡愈合质量的作用[J]．中华消化杂志，2001，21(11)：703-704．
[28] 胡伏莲，张希金，贾博琪，等．醋氨己酸锌在消化性溃疡中的治疗作用[J]．中国临床药理学杂志，1996，12(2)：65-70．
[29] 谢宜奎，马新，冯宁．醋氨己酸锌治疗溃疡的作用机制的探讨[J]．中国新药与临床杂志，2003，22(8)：481-483．
[30] 张凯，陶玉莲．米索前列醇与西咪替丁对胃及十二指肠黏膜保护作用比较[J]．内蒙古医学杂志，2005，37(4)，373-373．
[31] 谢宜奎，张淑芹，张云甫．替普瑞酮加奥美拉唑和阿莫西林治疗胃溃疡73例[J]．中国新药与临床杂志，1999，18(5)：283-284．
[32] KUSU GAMI K, INA K, HOSOKAWAT, et al. Troxipide, a novel antiulcer compound, has inhibitory effects on human neutrophil migration and activation induced by various stimulates[J]. Dig Liver Dis, 2000, 32(4): 305-311.