注射用埃索美拉唑钠最新标准USP-MC Esomeprazole for Injection 2012.07.24
注射用埃索美拉唑纳

注射用埃索美拉唑纳商品名称:耐信注射剂通用名称:埃索美拉唑钠英文名称:Esomeprazole Sodium适应症:作为当口服疗法不适用时,胃食管反流病的替代疗法。
本品通常应短期用药(不超过7天),一旦可能就应转为口服治疗。
规格:40mg(以埃索美拉唑计)用法用量:对于不能口服用药的患者,推荐每日1次注射本品20-40 mg。
反流性食管炎患者应使用40mg,每日1次;对于反流疾病的症状治疗应使用20mg,每日1次。
给药方法注射用药:40mg和20mg配制的溶液均应在至少3分钟以上的时间内静脉注射。
滴注用药:40mg和20mg配制的溶液均应在10-30分钟的时间内静脉滴注。
使用指导:注射液的制备是通过加入5mL的0.9%氯化钠溶液至本品小瓶中供静脉使用。
滴注液的制备是通过将本品1支溶解至0.9%氯化钠溶液100 mL,供静脉使用。
配制后的注射用或滴注用液体均是无色至极微黄色的澄清溶液,应在12小时内使用,保存在30°C以下。
从微生物学的角度考虑最好立即使用。
配伍禁忌:配制溶液的降解对pH值的依赖性很强,因此药品必须按照使用指导应用。
本品只能溶于0.9%氯化钠中供静脉使用。
配制的溶液不应与其他药物混合或在同一输液装臵中合用。
不良反应:在埃索美拉唑口服或静脉给药的临床试验以及口服给药的上市后研究中,已确定或怀疑有下列不良反应。
这些反应按照发生次数分为以下几类(常见 - >1%,<10% ;偶见- >0.1%,<1% ;罕见 - >0.01%,<0.1% ;十分罕见 - <0.01%)。
眼睛:偶见视力模糊。
耳和迷路:偶见眩晕。
皮肤和皮下组织:偶见皮炎、瘙痒、皮疹、荨麻疹;罕见脱发、光过敏;十分罕见多形红斑、Stevens-Johnson综合征、中毒性表皮坏死溶解(TEN)。
骨骼肌、结缔组织和骨骼:罕见关节痛、肌痛;十分罕见肌无力。
呼吸、胸、纵隔:罕见支气管痉挛。
2013-Q3埃索美拉唑钠和注射用埃索美拉唑钠CTD

技术参数 5KW, 转 速
容 积 20L, 电 热 功 率 ~600rpm
O
OH OH
CH3OK
异丙苯基过氧化氢,C9H12O2
DIPEA
甲醇钾,CH3OK
CH3OHHຫໍສະໝຸດ CO CH3Ti[OCH(CH3)2]4
化学名:5- 甲氧基- 2- [ [ ( 4- 甲氧基- 3,5- 二甲基 - 2- 吡啶基)甲基]硫基]- 1H- 苯并咪唑 分子式:C17H19N3O2S 分子量:329.42
2.3.S.2.2 生产工艺和过程控制 ........................................................................................................ 2
2.3.S.2.3 物料控制 ................................................................................................. 4 2.3.S.2.4 关键步骤和中间体的控制 ..................................................................... 4 2.3.S.2.5 工艺验证和评价 ..................................................................................... 5 2.3.S.2.6 生产工艺的开发 ..................................................................................... 6 2.3.S.3 特性鉴定 ........................................................................................................ 11 2.3.S.3.1 杂质 ....................................................................................................... 13 2.3.S.4 原料药的质量控制 ........................................................................................ 15 2.3.S.4.1 质量标准 ............................................................................................... 15 2.3.S.4.2 分析方法 ............................................................................................... 17 2.3.S.4.3 分析方法的验证 ................................................................................... 19 2.3.S.4.4 批检验报告 ........................................................................................... 25 2.3.S.4.5 质量标准制定依据 ............................................................................... 25 2.3.S.5 对照品 ............................................................................................................ 29 2.3.S.6 包装材料和容器 ............................................................................................ 35 2.3.S.7 稳定性 ............................................................................................................ 35 2.3.S.7.1 稳定性总结 ........................................................................................... 35 2.3.S.7.2 上市后稳定性承诺和稳定性方案 ....................................................... 37 2.3.S.7.3 稳定性数据汇总 ................................................................................... 38
埃索美拉唑镁usp34

© 2010 USPC Official 5/1/11 - 7/31/11 USP Monographs: Esomeprazole ...
页码,Байду номын сангаас/7
prepared atomic absorption standard solution. [NOTE—Store the solution in a plastic bottle. ] Standard solution A: Transfer 10.0 mL of Standard stock solution to a 500-mL volumetric flask, add 50 mL of 1 N hydrochloric acid, and dilute with water to volume. Transfer 20.0 mL of this solution to a 200-mL volumetric flask, and dilute with water to volume. [NOTE —This solution contains 2 µg/mL of magnesium. ] Standard solution B: Combine 5.0 mL of Standard solution A and 4.0 mL of Lanthanum solution , and dilute with water to 100.0 mL (0.1 µg/mL). Standard solution C: Combine 10.0 mL of Standard solution A and 4.0 mL of Lanthanum solution , and dilute with water to 100.0 mL (0.2 µg/mL). Standard solution D: Combine 15.0 mL of Standard solution A and 4.0 mL of Lanthanum solution , and dilute with water to 100.0 mL (0.3 µg/mL). Standard solution E: Combine 20.0 mL of Standard solution A and 4.0 mL of Lanthanum solution , and dilute with water to 100.0 mL (0.4 µg/mL). Standard solution F: Combine 25.0 mL of Standard solution A and 4.0 mL of Lanthanum solution , and dilute with water to 100.0 mL (0.5 µg/mL). [NOTE— Concentrations of the Standard solutions and the Sample solution may be modified to fit the linear or working range of the instrument. When using instruments with a linear calibration graph, the number of Standard solutions can be reduced. ] Blank solution: Transfer 4.0 mL of Lanthanum solution to a 100-mL volumetric flask, and dilute with water to volume. Sample solution: Transfer 250 mg of Esomeprazole Magnesium to a 100-mL volumetric flask, add 20 mL of 1 N hydrochloric acid, swirl until dissolved, and dilute with water to volume. Allow to stand for 30 min. Transfer 10.0 mL of this solution to a 200-mL volumetric flask, and dilute with water to volume. Transfer 10.0 mL of the solution to another 100 -mL volumetric flask, add 4.0 mL of Lanthanum solution , and dilute with water to volume. Spectrometric conditions (See Spectrophotometry and Light-Scattering 851 .) Mode: Atomic absorption spectrophotometer Flame: Air–acetylene Analytical wavelength: 285.2 nm Analysis Samples: Standard solution B, Standard solution C, Standard solution D, Standard solution E , Standard solution F, Blank solution , and Sample solution Determine the concentration, C s , in µg/mL, of magnesium in the Sample solution using the calibration graph. Calculate the percentage of magnesium in the portion of Esomeprazole Magnesium taken:
注射用埃索美拉唑钠的研制及其稳定性考察

注射用埃索美拉唑钠的研制及其稳定性考察随着社会发展,环境变迁,人口结构以及人们生活方式的改变,吸烟、饮酒、情绪紧张、药物刺激等因素引起的消化性溃疡发病率逐渐增高,给患者带来极大的痛苦,且生活质量下降。
因此,消化性溃疡的治疗在临床上越来越受到关注。
基于以上原因,开发生产安全、有效的抗消化性溃疡药物已成为目前药物研究开发的重点和热点之一。
埃索美拉唑是奥美拉唑的S-异构体,是全球首个异构体质子泵抑制剂(proton pump inhibitors,PPI),通过特异性的靶向作用机制减少胃酸分泌,是壁细胞中质子泵的特异性抑制剂,埃索美拉唑较奥美拉唑具有更高的生物利用度和更好的药代动力学性质[1~2]。
埃索美拉唑为弱碱,在壁细胞泌酸微管的高酸环境浓集并转化为活性形式,从而抑制该部位的H+/K+-ATP酶(质子泵),对基础胃酸分泌和刺激的胃酸分泌均产生抑制[3~8]。
埃索美拉唑钠是埃索美拉唑的钠盐,其水溶性较好,但pH依赖性较强,且溶液状态下不太稳定,适合开发成冻干制剂。
其适用于口服不适用的急性胃或十二指肠溃疡出血的低危患者,我们以上市药品“注射用埃索美拉唑钠”为参比制剂,进行仿制研究,开发出适应大生产的处方工艺等,现将研究结果报道如下。
1 仪器与试药仪器:Agilent 1200高效液相色谱仪(美国安捷伦公司);pHS-3C型酸度计(上海雷磁仪器厂);XP204电子天平(***** TOLEDO公司);聚丙烯过滤器(0.2μm,Millipore公司);YB-2型澄明度检测仪(天津大学精密仪器厂);Lyo-5冷冻干燥机(上海东富龙科技有限公司);V20型卡尔费休水分测定仪(***** TOLEDO公司)。
试药:埃索美拉唑钠原料药(江苏正大丰海制药有限公司,批号:***-*****);依地酸二钠(湖南尔康制药有限公司,批号:***-*****);依地酸钙钠(湖南尔康制药有限公司,批号:***-*****);奥美拉唑对照品(中国食品药品检定研究院,批号:*****-*****,含量100.0%);耐信(阿斯利康制药有限公司,批号:PANG(分:***-*****);其他试剂均为市售分析纯。
埃索美拉唑钠

埃索美拉唑钠(征求意见稿)AisuomeilazuonaEsomeprazole SodiumNa+C17H18N3O3SNa 367.4本品为S-5-甲氧基-2-{[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]亚磺酰基] }-1H-苯并咪唑钠盐。
按无水物计,含C17H18N3O3SNa不得少于98.0%。
【性状】本品为白色或类白色粉末。
本品在乙醇中易溶。
【鉴别】(1)本品的红外光吸收图谱应与埃索美拉唑钠对照品的图谱一致(中国药典2010年版二部附录Ⅳ C)。
(2)取本品约195mg,精密称定,置200ml量瓶中,加水溶解并稀释至刻度,摇匀,精密量取10ml,置100ml量瓶中,加3.8%氯化钾溶液10ml,用水稀释至刻度,摇匀,作为供试品溶液;另精密量取标准钠溶液(每1ml相当于1.0mg的Na)1ml,置25ml量瓶中,用水稀释至刻度,摇匀,精密量取15ml,置100ml量瓶中,加3.8%氯化钾溶液10ml,用水稀释至刻度,摇匀,作为对照品溶液。
取对照品溶液与供试品溶液,照原子吸收分光光度法(中国药典2010年版二部附录Ⅳ D),在589.0nm的波长处测定,供试品溶液的吸光度应与对照品溶液的吸光度基本一致。
【检查】 R-对映体取本品适量,精密称定,加磷酸盐缓冲液(pH11.0)(含磷酸钠0.028mol/L和磷酸氢二钠0.011mol/L)溶解并定量稀释制成每1ml中约含0.32mg的溶液,精密量取2ml,置20ml量瓶中,用水稀释至刻度,摇匀,作为供试品溶液;精密量取适量,用水稀释制成每1ml中约含0.16μg的溶液,作为对照溶液。
照高效液相色谱法(中国药典2010年版二部附录Ⅴ D)测定,用α1-酸性糖蛋白键合硅胶为填充剂;以磷酸盐缓冲液(pH6.0)(含磷酸二氢钠0.0175mol/L和磷酸氢二钠0.0025mol/L)-乙腈(85∶15)为流动相,检测波长为302nm。
取奥美拉唑约18mg,置100ml量瓶中,加甲醇5ml使溶解,用磷酸盐缓冲液(pH11.0)稀释至刻度,摇匀,精密量取2ml,置100ml量瓶中,用水稀释至刻度,摇匀,取20µl注入液相色谱仪,出峰顺序依次为R-对映体峰和埃索美拉唑峰,埃索美拉唑峰的保留时间应为4~5分钟,两峰之间的分离度应不小于3。
埃索美拉唑钠及注射用埃索美拉唑钠

埃索美拉唑钠及注射用埃索美拉唑钠江苏奥赛康药业股份有限公司唐建华一、一般情况品名:注射用埃索美拉唑钠规格:40mg(以埃索美拉唑计)适应症:胃食管反流性疾病(GERD)-糜烂性反流性食管炎的治疗-已经治愈的食管炎患者防止复发的长期维持治疗-胃食管反流性疾病(GERD)的症状控制与适当的抗菌疗法联合用药根除幽门螺杆菌,并且-愈合与幽门螺杆菌感染相关的十二指肠溃疡-防止与幽门螺杆菌相关的消化性溃疡复发。
二、基本介绍埃索美拉唑是奥美拉唑的S-旋光异构体, 是全球首个异构体质子泵抑制剂(PPI), 通过特异性抑制胃壁细胞质子泵减少胃酸分泌。
经大量临床实验和药物研究证实: 其维持胃内pH>4的时间更长, 抑酸效率更高, 疗效优于前两代PPI,个体差异小。
作为新一代PPI, 现已广泛应用于临床治疗诸多酸相关疾病。
质子泵抑制剂(PPI)是治疗消化性溃疡、胃食管反流病等酸相关疾病的首选药物。
目前临床上常用的PPI 有奥美拉唑、兰索拉唑、雷贝拉唑、泮托拉唑和埃索美拉唑5种。
奥美拉唑作为第一种PPI药物,其治疗酸相关疾病的疗效得到了一致认可。
埃索美拉唑,商品名耐信(Nexium),是奥美拉唑的单一异构体,即(S)-异构体。
由于具有代谢优势,埃索美拉唑较奥美拉唑具有更高的生物利用度和更一致的药代动力学,使到达质子泵的药物增加,抑酸效果优于其他PPI。
虽然口服埃索美拉唑能获得良好临床效果,但是在某些患者,如吞咽困难、呕吐、急性上消化道出血及外科大手术恢复期患者,口服成为一种不可行的给药途径时,静脉给药途径就成为必然的选择。
因此,注射用埃索美拉唑钠适用于需要使用PPI却无法口服给药的患者。
现就埃索美拉唑的药理学研究、药代动力学、药效动力学及临床应用作一综述:1、药理学研究埃索美拉唑是奥美拉唑的S-异构体,通过特异性的耙向作用机制减少胃酸分泌,为壁细胞中质子泵的特异性抑制剂。
作用部位和机理:埃索美拉唑为一弱碱,在壁细胞泌酸微管的高酸环境中浓集并转化为活性形式,从而抑制该部位的H+/k+-ATP(质子泵),对基础胃酸分泌和刺激的胃酸分泌均产生抑制。
埃索美拉唑镁标准-EP7.0

CHARACTERS Appearance: white or slightly coloured powder, slightly hygroscopic. Solubility : slightly soluble in water, soluble in methanol, practically insoluble in heptane.
ห้องสมุดไป่ตู้
TESTS
A. pXe=ntNa-nCoHl,3: 1-[(2-chlorophenyl)(methylimino)methyl]cycloC. X = O : (2-chlorophenyl)(1-hydroxycyclopentyl)methanone,
B. (2RS)-2-(2-chlorophenyl)-2-hydroxycyclohexanone,
identification CRS and the chromatogram obtained with reference solution (b) to identify the peak due to impurity E ; — use the chromatogram obtained with reference solution (a) to identify the peak due to impurity D. Relative retention with reference to esomeprazole (retention time = about 9 min) : impurity E = about 0.6 ; impurity D = about 0.8. System suitability : reference solution (a) : — resolution : minimum 3.0 between the peaks due to impurity D and omeprazole. If necessary, adjust the pH of the aqueous part of the mobile phase or its proportion of acetonitrile ; an increase in the pH will improve the resolution. Limits : — impurity D : maximum 0.2 per cent ; — impurity E : maximum 0.1 per cent; — unspecified impurities : for each impurity, maximum 0.10 per cent ; — total : maximum 0.5 per cent ; — disregard limit : 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (c) (0.05 per cent).
埃索美拉唑钠的微生物限度方法研究

埃索美拉唑钠的微生物限度方法研究作者:郑露来源:《中国民族民间医药·上半月》2017年第06期【摘要】目的:建立通过验证的埃索美拉唑钠的微生物限度检测方法。
方法:用薄膜过滤加200mL pH70的无菌氯化钠蛋白胨缓冲液冲洗的方法检查该品需氧菌总数,用常规培养法检查该品霉菌和酵母菌总数;直接薄膜过滤法检查控制菌大肠埃希菌。
结果:对埃索美拉唑钠进行微生物限度检查可用薄膜过滤法。
结论:应优先采用薄膜过滤法,以去除埃索美拉唑钠的抑菌效力,为其微生物检验方法的确立提供了实验室检测根据。
【关键词】埃索美拉唑钠;微生物限度;方法学验证【中图分类号】R975+2【文献标志码】 A【文章编号】1007-8517(2017)11-0022-03Validation of Microbial Limit Study of Esomeprazole SodiumZHENG LuChongqing Institute for Food and Drug Control,Chongqing 401121,ChinaObjective To validate the microbial limit tests of Esomeprazole sodium. Methods Compare studing with the conventional method, membrane-filter procedure, membrane-filter procedure and washing methods. Results Membrane-filter procedure and washing 200mL with pH 70 method can be used to examin total amount of aerobe, conventional culture method can be used to check the mold and yeast, direct membrane-filter procedure can be used to examin mould and saccharomycetes and Escherichia coli count. Conclusion Membrane- filter procedure should be considered preferentially in performing microbial limit test for Esomeprazole sodium.Esomeprazole Sodium; Microbial Limit; Method Validation埃索美拉唑钠是治疗胃食管反流病等酸相关疾病的首选药物,抑酸效率很高且持续时间长,有可能有一定的抑菌作用[1],按照2015年版《中国药典》四部[2]规定,对其微生物限度检查时要有必要的方法进行适用性试验。
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Esomeprazole for Injection
For Comment Version 0.2
DEFINITION Esomeprazole for Injection contains an amount of esomeprazole sodium (C17H19N3NaO3S) equivalent to NLT 95.0% and NMT 105.0% of the labeled amount of esomeprazole (C17H19N3O3S).
rU = response of each impurity in the Sample solution rS = response of each appropriate USP Impurity RS from the Standard solution. [Note—If no USP Impurity RSs are available, use the response of esomeprazole.] CS = concentration of standard material in the Standard solution esomeprazole sodium in the Sample solution CU = nominal concentration of esomeprazole sodium in the Sample solution Acceptance criteria Any individual impurity: NMT 0.2%
Analysis Samples: Standard solution and Sample solution Calculate the percentage of the labeled amount of esomeprazole (C17H19N3O3S) in the Sample solution:
IMPURITIES • ELEMENTAL IMPURITIES <232>: Proceed as directed in the chapter. • RESIDUAL SOLVENTS <467>: Proceed as directed in the chapter.
• ORGANIC IMPURITIES Standard solution: USP Esomeprazole Sodium CRM and all appropriate USP Impurity RSs, at concentrations corresponding to the Acceptance criteria of the impurity, in an appropriate diluent Sample solution: Dilute a portion of constituted Injection in an appropriate diluent to obtain a concentration approximately the same as that of the Standard solution. Analytical system: Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>.
SPECIFIC TESTS • BACTERIAL ENDOTOXINS TEST <85>: Proceed as directed in the chapter.
• INJECTIONS <1>: Proceed as directed in the chapter.
ADDITIONAL REQUIREMENTS • REFERENCE STANDARDS <11>
1,3-Dimethyl-9-methoxy-12-thioxopyrido[1’,2’:3,4] imidazo[1,2-a] benzimidazol-2(12H)-one. USP Omeprazole Impurity I RS
Omeprazole sulfone N-oxide, 4-methoxy-2-[[(5-methoxy-1H-benzimidazol-2-yl)sulphonyl]methyl]-3,5-dimethylpyridine 1-oxide. USP R-Omeprazole RS
Table 1
Time (min)
Solution A (%)
Solution B (%)
0
60
40
30
45
55
35
30
70
45
30
70
47
60
40
50
60
40
System suitability solution: 0.01 mg/mL each of USP Esomeprazole Sodium CRM and USP Omeprazole Impurity A RS in methanol Standard solution: 0.2 mg/mL of USP Esomeprazole Sodium CRM in methanol Sample solution: Constitute the content of the vial in methanol, and dilute quantitatively with methanol to obtain a nominal esomeprazole concentration of 0.2 mg/mL. Chromatographic system
5-Methoxy-2-[(R)-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole.
REFERENCE PROCEDURES (This section provides detailed descriptions of procedures that may be used for the evaluation of the material under test. These procedures have been fully validated, and the data is available on the MC website.)
Mr1 = molecular weight of esomeprazole, 345.42 Mr2 = molecular weight of esomeprazole sodium, 368.41 Acceptance criteria: 95.0%–105.0%
PERFORMANCE TESTS • UNIFORMITY OFrequirements
Omeprazole N-oxide, 4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulphinyl]methyl]-3,5-dimethylpyridine 1-oxide. USP Omeprazole Impurity F RS
1,3-Dimethyl-8-methoxy-12-thioxopyrido[1’,2’:3,4] imidazo[1,2-a] benzimidazol-2(12H)-one. USP Omeprazole Impurity G RS
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
rU = response from the Sample solution rS = response from the Standard solution CS = concentration of USP Esomeprazole Sodium CRM in the Standard solution CU = nominal concentration of esomeprazole in the Sample solution
Standard solution: USP Esomeprazole Sodium CRM in an appropriate diluent Sample solution: Dilute a portion of constituted Injection in an appropriate diluent to obtain a concentration approximately the same as that of the Standard solution. Analytical system: Use a procedure validated as described in MC general chapter Assessing Validation Parameters for Reference and Acceptable Procedures <10>.
System performance requirements Precision: Meets the requirements for 98.0%–102.0% Accuracy: Meets the requirements for 98.0%–102.0% Specificity: Meets the requirements Range: Meets the requirements
USP Esomeprazole Sodium CRM USP Omeprazole Impurity A RS
Omeprazole sulfone, 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfonyl]-1H-benzimidazole. USP Omeprazole Impurity E RS