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
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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。
注射用埃索美拉唑钠
注射用埃索美拉唑钠（耐信）Esomeprazole Sodium for Injection(Nexium)本品为埃索美拉唑钠的无菌冻干品。
含埃索美拉唑钠以埃索美拉唑（C17H19N3O3S）计算，应为标示量的97.0%～109.0%。
【性状】本品为白色或类白色的冻干块状物或粉末。
【鉴别】（1）取本品1瓶，加水5ml使溶解，作为供试品溶液。
取0.008%硫酸镍溶液1ml，加供试品溶液0.5ml，摇匀，加1mol/L 氨溶液1ml，摇匀，加1%丁二酮肟的乙醇溶液1ml，摇匀，放置1分钟，溶液应不显色或显微黄色。
另取0.03%乙二胺四醋酸二钠溶液与水各0.5ml，分别作为阳性对照溶液和空白溶液，同法操作。
阳性对照溶液应不显色或显微黄色，空白溶液应显粉红色。
（2）取奥美拉唑对照品10mg，精密称定，置100ml量瓶中，加磷酸盐缓冲液（pH11.4）（取磷酸钠6.8g和二水合磷酸氢二钠6.2g，加水适量使溶解并稀释至1000ml，摇匀，pH值应为11.3～11.6）15ml 使溶解，加水稀释至刻度，摇匀，精密量取5ml，置25ml量瓶中，加磷酸盐缓冲液（pH11）（取磷酸盐缓冲液（pH11.4）10ml，加水稀释至100ml）稀释至刻度，摇匀，作为对照品溶液；另取本品，加磷酸盐缓冲液（pH11）溶解并定量稀释制成每1ml中约含埃索美拉唑0.01mg的溶液，作为供试品溶液。
照高效液相色谱法（中国药典2005年版二部附录ⅤD）测定，采用手性色谱柱，以α1-酸性糖蛋白（α1-acidglycoprotein）键合硅胶为填充剂，以乙腈-磷酸盐缓冲液（pH6.2）（取磷酸二氢钠2.4g和二水合磷酸氢二钠0.45g，加水适量使溶解并稀释至1000ml，摇匀，pH值应为6.1～6.3）（75∶425）为流动相，检测波长为280nm。
精密量取对照品溶液与供试品溶液各20μl，分别注入液相色谱仪，记录色谱图，对照品溶液中第二个被洗脱峰为埃索美拉唑峰，保留时间约为4分钟，奥美拉唑两个对映体峰的分离度应符合要求。
注射用埃索美拉唑钠-分析方法
3.2.P.5 制剂的质量控制3.2.P.5.1 质量标准均没有发生明显的变化趋势，放行标准与货架期标准一致。
3.2.P.5.2 分析方法(1)订入标准的分析方法1 性状目检：本品为白色或类白色的冻干块状物或粉末。
2 鉴别2.1. 试药与试剂：硫酸镍、氨试液、丁二酮肟、乙醇、乙二胺四醋酸二钠2.2. 仪器与设备：电子分析天平（万分之一）、高效液相色谱仪。
2.3. 操作方法：a). 依地酸二钠的鉴别：取供试品1瓶，加水5ml使溶解，作为供试品溶液。
取0.008%硫酸镍溶液1ml，加供试品溶液0.5ml，摇匀，加1mol/L氨试液1ml，摇匀，加1%丁二酮肟乙醇溶液1ml，摇匀，放置1分钟，结果溶液应不显色或显微黄色。
另取0.03%乙二胺四醋酸二钠溶液与水各0.5 ml（0.5ml），分别作为阳性对照溶液和空白溶液，同法操作，结果空白溶液应显粉红色。
b). HPLC保留时间法：在含量测定项下记录的色谱图中，供试品溶液主峰的保留时间与对照品溶液主峰的保留时间一致。
3 碱度3.1. 试剂与试液：硼砂标准缓冲液、氢氧化钙标准缓冲液。
3.2. 仪器与用具：旋光仪、电子分析天平、容量瓶。
3.3. 操作方法：取供试品1瓶，加0.9%氯化钠注射液5.2 ml使溶解，照Q/SOP 08000033《pH值测定法操作规程》检测，即得。
3.4. 限度：pH值应为10.0～11.0。
4 溶液的澄清度4.1. 操作方法取可见异物项下的供试品溶液，照Q/SOP 08000043《溶液颜色检查法操作规程》与Q/SOP 08000031《澄清度检查法操作规程》检测。
结果：溶液应澄清无色；如显浑浊，与1号浊度标准液比较，照Q/SOP 08000031《澄清度检查法操作规程》检测比较。
结果：供试液浊度淡于1号浊度标准液5 有关物质5.1. 试剂与试液：乙腈、磷酸氢二钠、氢氧化钠、磷酸。
5.2. 仪器与用具：电子分析天平、移液管、容量瓶、十八烷基硅烷键合硅胶柱、高效液相色谱仪。
注射用埃索美拉唑钠CTD申报资料
C DE注射用埃索美拉唑钠 CTD 药学研究资料目 录3.2.P.1 剂型及产品组成 ........................................................................................... 33.2.P.2 产品开发 ....................................................................................................... 43.2.P.2.1 处方组成.................................................................................................... 43.2.P.2.1.1 原料药 .............................................................................................. 43.2.P.2.1.2 辅料 .................................................................................................. 43.2.P.2.2 制剂研究 ................................................................................................. 53.2.P.2.2.1 处方开发过程 .................................................................................. 53.2.P.2.2.2 制剂相关特性................................................................................ 113.2.P.2.3 生产工艺的开发................................................................................... 133.2.P.2.4 包装材料/容器...................................................................................... 253.2.P.2.5 相容性................................................................................................... 253.2.P.3 生产 ............................................................................................................. 263.2.P.3.1 生产商 ................................................................................................... 263.2.P.3.2 批处方 ................................................................................................... 263.2.P.3.3 生产工艺和工艺控制 ........................................................................... 273.2.P.3.4 关键步骤和中间体的控制 ................................................................... 293.2.P.3.5 工艺验证和评价 ................................................................................... 323.2.P.4 原辅料的控制 ............................................................................................. 343.2.P.5 制剂的质量控制 ......................................................................................... 353.2.P.5.1 质量标准 ............................................................................................... 353.2.P.5.2 分析方法 ............................................................................................... 363.2.P.5.3 分析方法的验证 ................................................................................... 453.2.P.5.4 批检验报告 ........................................................................................... 753.2.P.5.5 杂质分析 ............................................................................................... 773.2.P.5.6 质量标准制订依据 (80)C DE3.2.P.6 对照品 ......................................................................................................... 833.2.P.7 稳定性 ......................................................................................................... 883.2.P.7.1 稳定性总结 ........................................................................................... 883.2.P.7.2上市后稳定性承诺和稳定性方案 ...................................................... 1023.2.P.7.3 稳定性数据 (103)附件目录：附件一 注射用埃索美拉唑钠处方研究图谱附件二 注射用埃索美拉唑钠工艺验证方案 附件三 注射用埃索美拉唑钠工艺验证报告附件四 注射用埃索美拉唑钠原辅料来源及证明性文件 附件五 注射用埃索美拉唑钠质量研究图谱 附件六 注射用埃索美拉唑钠杂质F 结构解析图谱附件七 注射用埃索美拉唑钠稳定性试验图谱正文3.2.P.1 剂型及产品组成(1) 本品为注射用无菌粉末，规格有20mg和40mg（以埃索美拉唑计）两种，其单位剂量产品的处方组成分别如下表：规格20mg（以埃索美拉唑计）：【注2】主药用量根据埃索美拉唑钠与埃索美拉唑的分子量折算，灌装时增加4%装量以抵消复溶时的损失，即每瓶20.8mg（以埃索美拉唑计）；【注3】原料药同期申报，为申报生产企业标准。
注射用埃索美拉唑钠CTD案例点评分析整理稿
注射用埃索美拉唑钠CTD案例点评分析整理稿3.2.P.1 剂型及产品组成1.标明了辅料种类、作用及执行标准。
2.灌装时增加4%装量以抵消复溶时的损失。
3.说明了包装材料及容器。
4.不足：建议列出辅料型号和百分比。
3.2.P.2.1 处方组成1.考察了原料药的溶解性与稳定性，列出FDA公布的耐信处方，进行了原辅料相容性试验。
2.不足：产品开发目标缺失；埃索美拉唑钠的吸湿性？埃索美拉唑钠溶液稳定性——温度的影响？问号处内容缺失。
3.2.P.2.2 制剂研究1.在处方开发过程中，考察了甘露醇用量、依地酸二钠/依地酸钠钙、依地酸二钠的用量（0.10mg、0.15mg），pH=11.0相关内容，以性状、有关物质、水分、复溶后性状为考察指标，同时用两个批次对照药品进行比对。
2.本品小试、注册批的处方一致，不存在过量投料。
3.本品与耐信质量对比—等同。
4.制剂相关特性研究方面，结合对照药品，考察了碱度（5.2ml 0.9%氯化钠注射液复溶）、临床使用时的渗透压、复溶（澄清度、复溶时间）、有关物质、对映异构体等，项目比较齐全。
不足：5.在P.2.1.1中说明埃索美拉唑钠遇光易变色，试验发现本品光照10天后性状变为淡绿色，原研产品光照10天后是否与本品发生相同变化？—数据？这些均应考察。
6.不同用量依地酸二钠处方各项指标没有差异，没有说明为什么要加依地酸二钠？配伍后输液中金属离子可能会使药物产生不溶性微粒，继而发生沉淀，故需加依地酸二钠来控制金属离子水平，此项应在配伍后考察，检查项目应为不溶性微粒水平。
7.潜在的降解产物没有考察，配伍后室温放置下形成的杂质？8.原研产品两批生产日期仅相差3个月，刚出厂与接近有效期的批次比较更能说明问题。
3.2.P.2.3 生产工艺的开发1.选择常规冻干工艺，进行工艺研究，包括：a.药液配制，考察了药液pH值控制、药液的温度、是否需要氮气保护、活性炭用量、原辅料的加入顺序等；b.除菌过滤，考察了滤材选择；c.冷冻干燥，考察了预冻方式和温度、升华升温速率和温度、真空度、解析干燥的温度上限等；d.包装，提供了小试工艺和放大生产工艺，总结了生产工艺和生产设备的变化，随批量规模增加，生产地点、生产设备随之改变。
阿斯利康公司埃索美拉唑钠最新原版英文说明书
HIGHLIGHTS OF PRESCRIBING INFORMATION •Hypomagnesemia has been reported rarely with prolonged treatmentThese highlights do not include all the information needed to use NEXIUM I.V. safely and effectively. See full prescribing information for NEXIUM I.V.NEXIUM® I.V. (esomeprazole sodium) for Injection, for intravenous use Initial US Approval: 2005---------------------------RECENT MAJOR CHANGES-----------------------Warnings and Precautions, Interaction with Clopidogrel (5.4) 10/2012 Warnings and Precautions, Clostridium difficile associated 09/2012 diarrhea (5.3)Warnings and Precautions, Concomitant use of NEXIUMwith Methotrexate (5.9) 01/2012-------------------------INDICATIONS AND USAGE--------------------------NEXIUM I.V. is a proton pump inhibitor indicated for the treatment of Gastroesophageal Reflux Disease (GERD) with erosive esophagitis (EE) in adults and pediatric patients greater than one month of age, when oral therapy is not possible or appropriate. (1.1)-----------------------DOSAGE AND ADMINISTRATION-------------------GERD – with Erosive Esophagitis• Adults: Dose is either 20 mg or 40 mg esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion(10 minutes to 30 minutes). (2.1)• Pediatric: Give the following doses once daily as an intravenous infusion over 10 minutes to 30 minutes• 1 year to 17 years: (2.1)o Body weight less than 55 kg: 10 mgo Body weight 55 kg or greater: 20 mg• 1 month to less than 1 year of age: 0.5 mg/kg (2.1)---------------------DOSAGE FORMS AND STRENGTHS------------------NEXIUM I.V. for Injection is supplied as a freeze-dried powder containing 20 mg or 40 mg of esomeprazole per single-use vial. (3)----------------------------CONTRAINDICATIONS-----------------------------Patients with known hypersensitivity to any component of the formulation or to substituted benzimidazoles (angioedema and anaphylaxis have occurred).(4)-----------------------WARNINGS AND PRECAUTIONS--------------------• Symptomatic response to therapy with NEXIUM does not preclude the presence of gastric malignancy. (5.1)• Atrophic gastritis has been noted with long-term omeprazole therapy.(5.2)• PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.3)• Avoid concomitant use of NEXIUM I.V. with clopidogrel. (5.4)• Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.5)with PPIs (5.6)• Avoid concomitant use of NEXIUM with St John’s Wort or rifampin due to the potential reduction in esomeprazole levels (5.7, 7.2)• Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. (5.8, 12.2)-----------------------------ADVERSE REACTIONS----------------------------Most common adverse reactions (≥1%):• Headache, flatulence, nausea, abdominal pain, injection site reaction, diarrhea, dry mouth, dizziness/vertigo, constipation and pruritus (6.1)To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or /medwatch. ---------------------------------DRUG INTERACTIONS------------------------• NEXIUM I.V. inhibits gastric acid secretion and may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g. ketoconazole, iron salts, erlotinib, and digoxin).Patients treated with NEXIUM and digoxin may need to be monitored for digoxin toxicity. (7)• Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.(7)• NEXIUM I.V. may reduce the plasma levels of atazanavir, nelfinavir, and saquinavir. (7)• Concomitant treatment with a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. (7)• May increase systemic exposure of cilostazol and an active metabolite.Consider dose reduction (7)• Clopidogrel: NEXIUM I.V. decreases exposure to the active metabolite of clopidogrel. (7)• Tacrolimus: NEXIUM may increase serum levels of tacrolimus (7.2)• Methotrexate: NEXIUM may increase serum levels of methotrexate(7.3)------------------------USE IN SPECIFIC POPULATIONS-------------------• Pregnancy: Based on animal data, may cause fetal harm. Limited human data. (8.1)• Nursing Mothers: Caution should be exercised when administered to a nursing woman. (8.3)• Hepatic Insufficiency: For patients with severe liver impairment (Child Pugh Class C), a dose of 20 mg of NEXIUM should not be exceeded. (2,8.6, 12.3)See 17 for PATIENT COUNSELING INFORMATIONRevised: 10/2012_______________________________________________________________________________FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE1.1 Treatment of Gastroesophageal Reflux Disease (GERD) withErosive Esophagitis2 DOSAGE AND ADMINISTRATION2.1 GERD with Erosive Esophagitis2.2 Preparations for Use and Administration3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Risk of Concomitant Gastric Malignancy5.2 Atrophic Gastritis5.3. Clostridium difficile associated diarrhea5.4 Interaction with Clopidogrel5.5 Bone Fracture5.6 Hypomagnesemia5.7 Concomitant use of NEXIUM with St John's Wort or Rifampin5.8 Interactions with Investigations for Neuroendocrine Tumors5.9 Concomitant use of NEXIUM with Methotrexate6 ADVERSE REACTIONS6.1 Clinical Trials Experience with Intravenous NEXIUM6.2 Clinical Trials Experience with Oral NEXIUM6.3 Postmarketing Experience7 DRUG INTERACTIONS7.1 Interactions With Investigations of Neuroendocrine Tumors7.2 Tacrolimus7.3 Methotrexate8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics12.4 Microbiology13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES14.1 Acid Suppression in Gastroesophageal Reflux Disease(GERD)16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed.________________________________________________________________________2 FULL PRESCRIBING INFORMATION1. INDICATIONS AND USAGE1.1 Treatment of Gastroesophageal Reflux Disease(GERD) with Erosive EsophagitisNEXIUM I.V. for Injection is indicated for the short-termtreatment of GERD with erosive esophagitis in adults andpediatric patients 1 month to 17 years, inclusively as analternative to oral therapy when oral NEXIUM is not possibleor appropriate.DOSAGE AND ADMINISTRATIONNEXIUM I.V. for Injection should not be administeredconcomitantly with any other medications through the sameintravenous site and or tubing. The intravenous line shouldalways be flushed with either 0.9% Sodium ChlorideInjection, USP, Lactated Ringer’s Injection, USP or 5%Dextrose Injection, USP both prior to and after administrationof NEXIUM I.V. for Injection.The admixture should be stored at room temperature up to30°C (86°F) and should be administered within the designatedtime period as listed in the Table 1 below. No refrigeration isrequired.Table 1Diluent Administer within:0.9% Sodium Chloride 12 hoursInjection, USPLactated Ringer’sInjection, USP12 hours5% Dextrose 6 hoursInjection, USPParenteral drug products should be inspected visually forparticulate matter and discoloration prior to administration,whenever solution and container permit.As soon as oral therapy is possible or appropriate, intravenoustherapy with NEXIUM I.V. for Injection should bediscontinued and the therapy should be continued orally.Special PopulationsHepatic Insufficiency: No dosage adjustment is necessary inpatients with mild to moderate liver impairment (Child PughClasses A and B). For patients with severe liver impairment(Child Pugh Class C), a dose of 20 mg of NEXIUM shouldnot be exceeded [see Use in Specific Populations (8.6) andClinical Pharmacology, Pharmacokinetics (12.3)].2.1 GERD with Erosive EsophagitisAdultsThe recommended adult dose is either 20 mg or 40 mgesomeprazole given once daily by intravenous injection (noless than 3 minutes) or intravenous infusion (10 minutes to30 minutes).Safety and efficacy of NEXIUM I.V. for Injection as atreatment of GERD patients with erosive esophagitis for morethan 10 days have not been demonstrated.PediatricThe recommended doses for children ages 1 month to 17years, inclusive, are provided below. Dose should be infusedover 10 minutes to 30 minutes.1 year to 17 years:Body weight less than 55 kg: 10 mgBody weight 55 kg or greater: 20 mg1 month to less than 1 year of age: 0.5 mg/kg2.2 Preparations for Use and AdministrationAdultsIntravenous Injection (20 mg or 40 mg vial) over no less than3 minutesThe freeze-dried powder should be reconstituted with5 mL of 0.9% Sodium Chloride Injection, USP.Withdraw 5 mL of the reconstituted solution andadminister an intravenous injection over no less than 3minutes.Intravenous Infusion (20 mg or 40 mg) over 10 minutes to 30 minutesA solution for intravenous infusion is prepared by firstreconstituting the contents of one vial with 5 mL of 0.9% Sodium Chloride Injection, USP, Lactated Ringer’s Injection, USP or 5% Dextrose Injection, USP and further diluting the resulting solution to a final volume of 50 mL.The solution (admixture) should be administered as an intravenous infusion over a period of 10 minutes to 30 minutes.The reconstituted solution should be stored at room temperature up to 30°C (86°F) and administered within 12 hours after reconstitution. No refrigeration is required. Pediatric PopulationIntravenous Infusion over 10 minutes to 30 minutes (0.5mg/kg) for patients ages 1 month to less than 1 year of ageA solution for intravenous infusion is prepared by firstreconstituting the contents of one vial with 5 mL of 0.9%Sodium Chloride Injection, USP and further diluting theresulting solution to a final volume of 50 mL. Theresultant concentration after diluting to a final volume of50 mL is as follows:40 mg vial: 0.8 mg/mL20 mg vial: 0.4 mg/mLWithdraw appropriate amount of volume for desired dose(0.5 mg/kg) and administer as an intravenous infusion over10 minutes to 30 minutesIntravenous Infusion (10 mg and 20 mg) over 10 minutes to 30 minutes for Pediatric Patients, ages 1 year to 17 years of age40 mg vialA solution for intravenous infusion is prepared by firstreconstituting the contents of one vial with 5 mL of 0.9%Sodium Chloride Injection, USP and further diluting theresulting solution to a final volume of 50 mL. Theresultant concentration after diluting to a final volume of50 mL is 0.8 mg/mL.20 mg dose: Withdraw 25 mL of the final solution andadminister as an intravenous infusion over 10 minutes to30 minutes10 mg dose: Withdraw 12.5 mL of the final solution andadminister as an intravenous infusion over 10 minutes to30 minutes20 mg vialA solution for intravenous infusion is prepared by firstreconstituting the contents of one vial with 5 mL of 0.9%Sodium Chloride Injection, USP and further diluting theresulting solution to a final volume of 50 ml. The resultantconcentration after diluting to a final volume of 50 mL is0.4 mg/mL.20 mg dose: Administer the final solution (50 mL) as anintravenous infusion over 10 minutes to 30 minutes10 mg dose: Withdraw 25 mL of the final solution andadminister as an intravenous infusion over 10 minutes to30 minutes3 DOSAGE FORMS AND STRENGTHSNEXIUM I.V. for Injection is supplied as a freeze-dried whiteto off-white powder containing 20 mg or 40 mg ofesomeprazole per single-use vial.4 CONTRAINDICATIONSPatients with known hypersensitivity to any component of theformulation or to substituted benzimidazoles (angioedema andanaphylaxis have occurred).5 WARNINGS AND PRECAUTIONS5.1 Risk of Concomitant Gastric MalignancySymptomatic response to therapy with NEXIUM does notpreclude the presence of gastric malignancy.5.2 Atrophic GastritisAtrophic gastritis has been noted occasionally in gastriccorpus biopsies from patients treated long-term withomeprazole, of which esomeprazole is an enantiomer.5.3 Clostridium difficile associated diarrheaPublished observational studies suggest that PPI therapy likeNEXIUM may be associated with an increased risk ofClostridium difficile associated diarrhea, especially inhospitalized patients. This diagnosis should be considered fordiarrhea that does not improve [see Adverse Reactions (6.2)].5.4 5.5 5.6 5.7 Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Interactions with ClopidogrelAvoid concomitant use of NEXIUM I.V. with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using NEXIUM I.V. consider alternative anti-platelet therapy. [see Drug Interactions (7 and Pharmacokinetics (12.3)]Bone FractureSeveral published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. [see Dosage and Administration (2) and Adverse Reactions (6.3)] HypomagnesemiaHypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See Adverse Reactions (6.3)]Concomitant use of NEXIUM with St John’s Wort or RifampinDrugs which induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampin) can substantially decrease esomeprazole concentrations [see Drug Interactions (7)]. Avoid concomitant use of NEXIUM with St John’s Wort or rifampin.5.8 5.96 6.1 Interactions with Investigations for Neuroendocrine TumorsSerum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.Concomitant use of NEXIUM with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients. [see Drug Interactions (7.3)] ADVERSE REACTIONSClinical Trials Experience with Intravenous NEXIUM Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.AdultsThe safety of intravenous esomeprazole is based on results from clinical trials conducted in three different populations including patients having symptomatic GERD with or without a history of erosive esophagitis (n=199), patients with erosive esophagitis (n=160), and healthy subjects (n=204). Adverse experiences occurring in >1% of patients treated with intravenous esomeprazole (n=359) in trials are listed below by body system:Symptomatic GERD and Erosive Esophagitis TrialsThe data described below reflect exposure to NEXIUM I.V for Injection in 359 patients. NEXIUM I.V. for Injection was studied only in actively-controlled trials. The population was 18 to 77 years of age; 45% Male, 52% Caucasian, 17% Black, 3% Asian, 28% Other, and had either erosive reflux esophagitis (44%) or GERD (56%). Most patients received doses of either 20 or 40 mg either as an infusion or an injection.Table 2Adverse reactions occurring at an incidence≥ 1% in the NEXIUM I.V. group% of patientsEsomeprazoleIntravenous Adverse Reactions (n=359)Headache 10.9Flatulence 10.3Nausea 6.4Abdominal pain 5.8Diarrhea 3.9Mouth dry 3.9Dizziness/vertigo 2.8Constipation 2.5Injection site reaction 1.7Pruritus 1.1Intravenous treatment with esomeprazole 20 and 40 mgadministered as an injection or as an infusion was found tohave a safety profile similar to that of oral administration ofesomeprazole.PediatricIn a randomized, open-label, multi-national study to evaluatethe pharmacokinetics of repeated intravenous doses of oncedaily esomeprazole, esomeprazole was well tolerated inpediatric patients 1 month to 17 years old, inclusive. Thesafety results are consistent with the known safety profile ofesomeprazole and no unexpected safety signals wereidentified. [See Clinical Pharmacology (12.3)]6.2 Clinical Trials Experience with Oral NEXIUMAdultThe safety of oral NEXIUM was evaluated in over 15,000patients (aged 18 to 84 years) in clinical trials worldwideincluding over 8,500 patients in the United States and over6,500 patients in Europe and Canada. Over 2,900 patientswere treated in long-term studies for up to 6-12 months. Ingeneral, NEXIUM was well tolerated in both short and long-term clinical trials.The safety in the treatment of healing of erosive esophagitiswas assessed in four randomized comparative clinical trials,which included 1,240 patients on NEXIUM 20 mg, 2,434patients on NEXIUM 40 mg, and 3,008 patients onomeprazole 20 mg daily. The most frequently occurringadverse events (≥1%) in all three groups were headache (5.5, 5.0, and 3.8, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking NEXIUM or omeprazole.Additional adverse events that were reported as possibly or probably related to NEXIUM with an incidence <1% are listed below by body system:Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, chest pain substernal, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors; Cardiovascular: flushing, hypertension, tachycardia; Endocrine: goiter; Gastrointestinal: bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting; Hearing: earache, tinnitus; Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased; Infections and Infestations: Clostridium difficile associated diarrhea; Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica; Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect; Reproductive: dysmenorrhea, menstrual disorder, vaginitis; Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis; Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria; Special Senses: otitis media, parosmia, taste loss, taste perversion; Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria; Visual: conjunctivitis, vision abnormal.Endoscopic findings that were reported as adverse eventsinclude: duodenitis, esophagitis, esophageal stricture,esophageal ulceration, esophageal varices, gastric ulcer,gastritis, hernia, benign polyps or nodules, Barrett’sesophagus, and mucosal discoloration.The incidence of treatment-related adverse events during 6month maintenance treatment was similar to placebo. Therewere no differences in types of related adverse events seenduring maintenance treatment up to 12 months compared toshort-term treatment.Two placebo-controlled studies were conducted in 710patients for the treatment of symptomatic gastroesophagealreflux disease. The most common adverse events that werereported as possibly or probably related to NEXIUM werediarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%).The following potentially clinically significant laboratorychanges in clinical trials, irrespective of relationship toNEXIUM, were reported in ≤ 1% of patients: increasedcreatinine, uric acid, total bilirubin, alkaline phosphatase,ALT, AST, hemoglobin, white blood cell count, platelets,serum gastrin, potassium, sodium, thyroxine and thyroidstimulating hormone [see Clinical Pharmacology, EndocrineEffects (12.2) for further information on thyroid effects].Decreases were seen in hemoglobin, white blood cellcount,platelets, potassium, sodium, and thyroxine.PediatricThe safety of oral NEXIUM was evaluated in 316 pediatricand adolescent patients aged 1 to 17 years in four clinicaltrials for the treatment of symptomatic GERD [see ClinicalStudies (14.2)]. In 109 pediatric patients aged 1 to 11 years,the most frequently reported (at least 1%) treatment-relatedadverse reactions in these patients were diarrhea (2.8%),headache (1.9%) and somnolence (1.9%). In 149 pediatricpatients aged 12 to 17 years the most frequently reported (atleast 2%) treatment-related adverse reactions in these patientswere headache (8.1%), abdominal pain (2.7%), diarrhea (2%),and nausea (2%). No new safety concerns were identified inpediatric patients.6.3 Postmarketing ExperienceThe following adverse reactions have been identified duringpost-approval use of NEXIUM. Because these reactions arereported voluntarily from a population of uncertain size, it isnot always possible to reliably estimate their frequency orestablish a causal relationship to drug exposure.Postmarketing Reports -There have been spontaneous reportsof adverse events with postmarketing use of esomeprazole.These reports occurred rarely and are listed below by bodysystem:Blood And Lymphatic System Disorders: agranulocytosis,pancytopenia; Eye Disorders: blurred vision; GastrointestinalDisorders: pancreatitis; stomatitis; microscopic colitis;Hepatobiliary Disorders: hepatic failure, hepatitis with orwithout jaundice; Immune System Disorders: anaphylacticreaction/shock; Infections and Infestations: GI candidiasis;Metabolism and nutritional disorders: hypomagnesemia;Musculoskeletal And Connective Tissue Disorders: muscularweakness, myalgia, bone fracture; Nervous System Disorders:hepatic encephalopathy, taste disturbance; PsychiatricDisorders: aggression, agitation, depression, hallucination;Renal and Urinary Disorders: interstitial nephritis;Reproductive System and Breast Disorders: gynecomastia;Respiratory, Thoracic and Mediastinal Disorders:bronchospasm; Skin and Subcutaneous Tissue Disorders:alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermalnecrolysis (TEN, some fatal).Other adverse events not observed with NEXIUM, butoccurring with omeprazole can be found in the omeprazolepackage insert, ADVERSE REACTIONS section.7 DRUG INTERACTIONSEsomeprazole is extensively metabolized in the liver byCYP2C19 and CYP3A4.In vitro and in vivo studies have shown that esomeprazole isnot likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4.No clinically relevant interactions with drugs metabolized bythese CYP enzymes would be expected. Drug interactionstudies have shown that esomeprazole does not have anyclinically significant interactions with phenytoin, warfarin,quinidine, clarithromycin or amoxicillin. Post-marketingreports of changes in prothrombin measures have beenreceived among patients on concomitant warfarin andesomeprazole therapy. Increases in INR and prothrombin timemay lead to abnormal bleeding and even death. Patientstreated with proton pump inhibitors and warfarinconcomitantly may need to be monitored for increases in INRand prothrombin time.Esomeprazole may potentially interfere with CYP2C19, themajor esomeprazole metabolizing enzyme. Coadministrationof esomeprazole 30 mg and diazepam, a CYP2C19 substrate,resulted in a 45% decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after dosing and onwards. However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance. ClopidogrelClopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of NEXIUM I.V. with clopidogrel. When using NEXIUM I.V., consider use of alternative anti-platelet [see Pharmacokinetics (12.3)]. Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max and AUC of cilostazol by 18% and 26%, respectively. C max and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore, a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required for the recommended doses. However, in patients who may require higher doses, dose adjustment may be considered.Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. John’s wort, an inducer of CYP3A4. In a cross-over study in 12 healthy male subjects, St John’s wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C max and AUC decreased by37.5% and 37.9%, respectively) and extensive metabolizers(C max and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with NEXIUM.。
埃索美拉唑镁肠溶胶囊USP质量标准Esomeprazole Magnesium Delayed-Release Capsules
Add the following:Esomeprazole Magnesium Delayed-Release CapsulesDEFINITIONEsomeprazole Magnesium Delayed-Release Capsules contain an amount of Esomeprazole Magnesium equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of esomeprazole(C17H19N3O3S).IDENTIFICATION• A.Buffer: Prepare a pH 6.0 phosphate buffer containing 26.6 g/L of dibasic sodium phosphatedihydrate and 55.2 g/L of monobasic sodium phosphate monohydrate in water.Diluent: Prepare a pH 11.0 diluent as follows. Dissolve 5.24 g of tribasic sodium phosphatedodecahydrate in water. Add 110 mL of 0.5 M dibasic sodium phosphate solution, and dilute with water to 1000 mL.Mobile phase: Transfer 150 mL of acetonitrile and 85 mL of the Buffer to a 1000-mL volumetric flask, and dilute with water to volume.Standard stock solution: Prepare a solution containing 0.2 mg/mL of USP Omeprazole RS by dissolving a suitable amount first in alcohol, using 20% of the final volume, and then diluting with Diluent to volume.Standard solution: 0.02 mg/mL of USP Omeprazole RS from the Standard stock solution inwaterSample stock solution: Transfer a portion of the Capsule content, equivalent to 20 mg ofesomeprazole, to a 200-mL volumetric flask, add 120 mL of Diluent, and shake for 20 min to dissolve the pellets. Sonicate for a few min, if needed, to completely dissolve. Add 40 mL ofalcohol, and sonicate for a few min. Cool, and dilute with Diluent to volume. Pass a portion of the solution through a filter of 1-µm pore size.Sample solution: 0.01 mg/mL of esomeprazole from the Sample stock solution in waterChromatographic systemChromatography 621, System SuitabilityMode: LCDetector: UV 302 nmColumn: 4.0-mm × 10-cm; 5-µm packing L41Flow rate: 1 mL/minInjection size: 20 µLSystem suitabilitySample: Standard solution[Note—The elution order is the R-enantiomer, followed by the esomeprazole peak, which is the S-enantiomer. ]Suitability requirementsResolution: NLT 1.0 between the enantiomer peaksAnalysisSamples: Standard solution and Sample solutionCalculate the ratio of the retention times of the esomeprazole peak in the Standard solutionand the Sample solution:Result = (tU/tS)tU== retention time of esomeprazole from the SamplesolutiontS== retention time of esomeprazole from the StandardsolutionAcceptance criteria: 0.98–1.02ASSAY• ProcedureBuffer: Prepare a pH 7.3 phosphate buffer by mixing 10.5 mL of 1.0 M monobasic sodiumphosphate buffer and 60 mL of 0.5 M dibasic sodium phosphate buffer, and diluting with water to 1000 mL.Diluent: Prepare as directed in Identification test A.Mobile phase: Mix 350 mL of acetonitrile and 500 mL of the Buffer. Dilute with water to 1000 mL.Standard solution: Transfer 10 mg of USP Omeprazole RS to a 250-mL volumetric flask, and dissolve in about 10 mL of methanol. Add 40 mL of Diluent, and dilute with water to volume. This solution contains 0.04 mg/mL of USP Omeprazole RS.Sample stock solution: Mix the contents of NLT 20 Capsules. Transfer a portion of the Capsule content, equivalent to 20 mg of esomeprazole, to a 100-mL volumetric flask, add 60 mL ofDiluent, and shake for 20 min to dissolve the pellets. Sonicate for a few min, if needed, tocompletely dissolve. Add 20 mL of alcohol, and sonicate for a few min. Cool, and dilute withDiluent to volume. Pass a portion of the solution through a filter of 1-µm pore size.Sample solution: 0.04 mg/mL of esomeprazole from the Sample stock solution in water. Store this solution protected from light.Chromatographic systemChromatography 621, System SuitabilityMode: LCDetector: UV 302 nmColumn: 4.6-mm × 15-cm; 5-µm packing L1Flow rate: 1 mL/minInjection size: 20 µLSystem suitabilitySample: Standard solutionSuitability requirementsRelative standard deviation: NMT 2.0%AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of the labeled amount of esomeprazole (C17H19N3O3S) in theportion of the Capsules taken:Result = (rU/rS) × (CS/CU) × 100rU== peak response from the Sample solutionrS== peak response from the Standard solutionCS== concentration of USP Omeprazole RS in theStandard solution (mg/mL)CU== nominal concentration of esomeprazole in theSample solution (mg/mL)Acceptance criteria: 90.0%–110.0%PERFORMANCE TESTSDissolution 711Medium: 0.1 N hydrochloric acid; 300 mL. After 2 h, continue with a pH 6.8 phosphate buffer as follows. To the vessel, add 700 mL of 0.086 M dibasic sodium phosphate, and adjust with 2 N hydrochloric acid or 2 N sodium, if necessary, to a pH of 6.8 ± 0.05.Apparatus 2: 100 rpmTime: 30 min in a pH 6.8 phosphate bufferStandard solution: Prepare a solution containing 2 mg/mL of USP Omeprazole RS in alcohol.Dilute this solution with pH 6.8 phosphate buffer to obtain a solution containing (L/1000) mg/mL, where L is the label claim, in mg/Capsule. Immediately add 2.0 mL of 0.25 M sodium hydroxide to 10.0 mL of this solution, and mix. [Note—Do not allow the solution to stand before adding the sodium hydroxide solution. ]Sample solution: After 30 min in pH 6.8 phosphate buffer, pass a portion of the solution undertest through a suitable filter. Transfer 5.0 mL of the filtrate to a suitable glassware containing 1.0 mL of 0.25 M sodium hydroxide. Mix well. Protect from light.Buffer, Diluent, Mobile phase, System suitability, and Chromatographic system: Proceed asdirected in the Assay.AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of esomeprazole (C17H19N3O3S) dissolved:Result = (rU/rS) × (CS/L) × V × 100rU== peak response from the Sample solutionrS== peak response from the Standard solutionCS== concentration of the Standard solution (mg/mL)L== label claim (mg/Capsule)V== volume of Medium, 1000 mLTolerances: NLT 75% (Q) of the labeled amount of esomeprazole (C17H19N3O3S) isdissolved.Uniformity of Dosage Units 905: Meet the requirementsIMPURITIES• Organic ImpuritiesBuffer: Prepare a pH 7.6 phosphate buffer by mixing 5.2 mL of 1.0 M monobasic sodiumphosphate buffer and 63 mL of 0.5 M dibasic sodium phosphate buffer, and diluting with water to 1000 mL.Solution A: Mix 100 mL of acetonitrile and 100 mL of the Buffer. Dilute with water to 1000 mL.Solution B: Mix 800 mL of acetonitrile and 10 mL of the Buffer. Dilute with water to 1000 mL.Table 1Time (min)Solution A(%)Solution B(%)01000108020300100311000451000Diluent: Prepare as directed in Identification test A.System suitability stock solution: 1 mg/mL each of USP Omeprazole RS and USP OmeprazoleRelated Compound A RS in methanolSystem suitability solution: 1 µg/mL each of USP Omeprazole RS and USP Omeprazole Related Compound A RS from System suitability stock solution, in a mixture of Diluent and water (1:4)Sample solution: Transfer a portion of the powdered pellets, from the Capsule content, equivalent to 80–90 mg of esomeprazole, to a 200-mL volumetric flask, add 20 mL of methanol, and shake for 30 s. Add 40 mL of Diluent, shake for 30 s by hand, and sonicate for a few min. Cool, and dilute with water to volume. Pass a portion of the solution through a filter of 0.45-µm pore size. [Note—The solution is stable for 3 h if stored protected from light. ] Chromatographic systemChromatography 621, System SuitabilityMode: LCDetector: UV 302 nmColumn: 4.6-mm × 10-cm; 3-µm packing L1Flow rate: 1 mL/minInjection size: 20 µLSystem suitabilitySample: System suitability solutionSuitability requirementsResolution: NLT 2.5 between omeprazole related compound A and omeprazoleAnalysisSample: Sample solutionCalculate the percentage of any individual impurity in the portion of the Capsules taken:Result = (rU/rT) × 100rU== peak response for each impurityrT== sum of all peak responsesTable 2NameRelativeRetentionTimeAcceptanceCriteria,NMT (%)Omeprazole sulfone a0.930.5 Omeprazole 1.00—Any other individual impurity—0.2Total impurities—2ADDITIONAL REQUIREMENTS• Packaging and Storage: Preserve in tight containers. Store at room temperature.USP Reference Standards11USP Omeprazole RSUSP Omeprazole Related Compound A RSOmeprazole sulfone; 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole.C17H19N3O4S 361.421S (USP35)711。
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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