CN112494451B - 一种埃索美拉唑镁碳酸氢钠胶囊 - Google Patents
一种埃索美拉唑镁碳酸氢钠胶囊 Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及生物医药技术领域,具体涉及一种埃索美拉唑镁碳酸氢钠胶囊;该胶囊中为:埃索美拉唑镁、碳酸氢钠和辅料,其中该胶囊中:化合物Ⅰ重量百分比为大于0且小于等于0.50%;化合物Ⅱ重量百分含量为大于0且小于等于0.10%;化合物Ⅲ重量百分含量为大于等于0且小于等于0.10%;研究表明:本发明胶囊剂具有更好的稳定性以及较低的不良反应发生率,充分说明本发明胶囊的杂质控制具有重要意义。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种埃索美拉唑镁碳酸氢钠胶囊。
背景技术
质子泵抑制剂(proton pump inhibitors,PPIs)是一类无活性的前体药,能特异性地作用于胃粘膜壁细胞,降低壁细胞中H+/K+-ATP酶活性,从而显著抑制多种因素导致的酸生产,对基础、夜间胃酸和五肽胃泌素等刺激的胃酸分泌有极明显的抑制作用,是目前已发现的作用最强的一类胃酸分泌抑制剂。该类药物具有如选择性高、治疗好、副作用少,与抗生素配伍的复方制剂的明显优越性,是治疗胃溃疡类疾病的临床一线用药。奥美拉唑含有S-异构体和R-异构体,前者为埃索美拉唑,较奥美拉唑拥有更高的生物利用度和更优良的药代动力学,原研公司于2002年研发出埃索美拉唑,它相比于奥美拉唑的口服肝代谢率较低,血药浓度和生物利用度较高,且抑酸作用更强。埃索美拉唑疗效显著且用药量低,通过特异性抑制胃壁细胞质子泵减少胃酸分泌,临床实验和药物研究证实,其维持胃内pH>4的时间更长,治疗胃食管反流病(GERD),抑酸效率更高,疗效优于前两代PPI,个体差异小。
埃索美拉唑原料药在酸性和中性介质中不稳定,尤其在酸性环境中能够被迅速地降解,湿、热、有机溶剂以及某些程度上的光也会对该活性化合物的稳定性造成一定影响,特别是氧有一定的敏感性,经加速试验和影响因素试验表明氧化杂质是主要杂质。因此在临床用药时通过药物制剂技术使药物贮存于碱性环境下,同时避免湿、光、氧等环境因素对药物产生的不良影响。为保障产品在体内环境的稳定性,避免酸性胃液对药物的分解,在药物制剂方面多制备成肠溶剂型,阻断埃索美拉唑与胃液的直接接触,保证药物的临床治疗效果。
发明内容
为解决上述技术问题,申请人经过多次创造性研究发现,得到一种新的胶囊制剂,该胶囊中组成为埃索美拉唑镁、碳酸氢钠和辅料,其中该胶囊中:化合物Ⅰ重量百分比为大于0且小于等于0.50%;化合物Ⅱ重量百分含量为大于等于0且小于等于0.10%;化合物Ⅲ重量百分含量为大于0且小于等于0.10%;研究表明:本发明胶囊剂具有更好的稳定性以及不良反应的发生率,充分说明胶囊的杂质控制具有重要意义。
本发明通过下述技术方案实现的。
一种埃索美拉唑镁碳酸氢钠胶囊,该胶囊中为:埃索美拉唑镁、碳酸氢钠和辅料,其中该胶囊中:化合物Ⅰ重量百分比为大于0且小于等于0.50%;化合物Ⅱ重量百分含量为大于0且小于等于0.10%;化合物Ⅲ重量百分含量为大于等于0且小于等于0.10%;
所述的数值范围中0为痕量未检出数值。
其中埃索美拉唑镁与碳酸氢钠重量比22.3:1100。
其中埃索美拉唑镁的制备方法为:
其中将埃索美拉唑钾加入到甲醇中,加入七水硫酸镁,搅拌2-4小时后过滤,滤饼用甲醇洗涤,将滤液浓缩,加入丙酮,搅拌1-3小时,过滤,滤饼用丙酮和水洗涤,将滤饼加入到水中,35℃搅拌2-4小时,过滤,滤饼用水洗涤,将滤饼于35℃真空干燥36-60小时,得埃索美拉唑镁。
其中该胶囊由下述重量份原辅料制备而成:埃索美拉唑镁:22.3份、碳酸氢钠:1100份、交联羧甲基纤维素钠:15-20份;硬脂富马酸钠:5-7份。该胶囊在制备治疗胃食管反流病药物中的应用。
该胶囊与抗菌药在制备根除幽门螺杆菌药物中应用。
本发明所述的原辅料均购自于隆誉翼尧(北京)科技有限公司。
本发明的有益效果为:
本发明通过新的制备方法,得到一种稳定性好的埃索美拉唑镁原料,从而进一步控制胶囊的杂质的含量,具有更好的安全性,有利于患者,在临床应用中,可以降低头痛、腹痛、腹泻、腹胀、恶心、呕吐等不良反应的发生率,进一步也降低:中枢和外周神经系统:感觉异常,嗜睡,失眠,眩晕。可逆性精神错乱,激动,易攻击,抑郁和幻觉,主要存在于严重疾病患者。内分:男子女性型乳房。胃肠道:口腔炎和胃肠道念珠菌病。血液学:白细胞减少症,血小板减少症,粒细胞缺乏症,全血细胞减少症。肝脏:脑病(先前有严重肝病者);黄疸或非黄疸性肝炎;肝衰竭。肌肉骨骼:关节痛,肌无力和肌痛。皮肤:皮疹,光过敏,多形性红斑,史蒂文斯-约翰逊综合征,中毒性上皮坏死,脱发。其他:不适。过敏反应,如:发热,支气管痉挛,间质性肾炎。多汗,外周水肿,视力模糊,味觉障碍和低钠血症等不良反应的发生率。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
其中下述埃索美拉唑镁的制备方法如下:其中将埃索美拉唑钾(7千克)加入到甲醇(14千克)中,加入七水硫酸镁(4.5千克),搅拌3小时后过滤,滤饼用甲醇(3.5千克)洗涤,将滤液浓缩至10千克,加入丙酮(35千克),搅拌2小时,过滤,滤饼用丙酮(3.5千克)和水(3.5千克)洗涤。将滤饼加入到水(70千克)中,35℃搅拌3小时,过滤,滤饼用水洗涤。将滤饼于35℃真空干燥48小时得埃索美拉唑镁。
实施例1
一种埃索美拉唑镁碳酸氢钠胶囊
原辅料按重量份计的包括:埃索美拉唑镁:22.3份、碳酸氢钠:1100份、交联羧甲基纤维素钠:15份、硬脂富马酸钠:5份、去离子水20份。
制备方法包括以下步骤:
(1)将交联羧甲基纤维素钠、硬脂富马酸钠溶于水后得到混合溶液,然后加入埃索美拉唑镁和碳酸氢钠,混合均匀后,制成软材;
(2)将软材经过制粒、干燥、过24目筛后得到干颗粒,装入胶囊即得。
实施例2
一种埃索美拉唑镁碳酸氢钠胶囊
原辅料按重量份计的包括:埃索美拉唑镁:22.3份、碳酸氢钠:1100份、交联羧甲基纤维素钠:20份、硬脂富马酸钠:7份、去离子水25份。
制备方法包括以下步骤:
(1)将交联羧甲基纤维素钠、硬脂富马酸钠溶于水后得到混合溶液,然后加入埃索美拉唑镁和碳酸氢钠,混合均匀后,制成软材;
(2)将软材经过制粒、干燥、过24目筛后得到干颗粒,装入胶囊即得。
实施例3
一种埃索美拉唑镁碳酸氢钠胶囊
原辅料按重量份计的包括:埃索美拉唑镁:22.3份、碳酸氢钠:1100份、交联羧甲基纤维素钠:17.5份、硬脂富马酸钠:6份、去离子水22份。
制备方法包括以下步骤:
(1)将交联羧甲基纤维素钠、硬脂富马酸钠溶于水后得到混合溶液,然后加入埃索美拉唑镁和碳酸氢钠,混合均匀后,制成软材;
(2)将软材经过制粒、干燥、过24目筛后得到干颗粒,装入胶囊即得。
对比例1
一种埃索美拉唑碳酸氢钠胶囊
其制备方法基本同实施例3,与实施例3的差别在于:埃索美拉唑镁:埃索美拉唑镁:22.3份、碳酸氢钠:1100份、低取代羟丙基纤维素:24.4份、硬脂富马酸钠:6份、去离子水22份。其中埃索美拉唑镁为市售,购自湖北大仝生物化工科技有限公司,含量为100.1%,总杂质含量0.59%。
制备方法包括以下步骤:
(1)将低取代羟丙基纤维素、硬脂富马酸钠溶于水后得到混合溶液,然后加入埃索美拉唑镁和碳酸氢钠,混合均匀后,制成软材;
(2)将软材经过制粒、干燥、过24目筛后得到干颗粒,装入胶囊即得。
试验例1稳定性试验
分别取实施例3和对比例1的样品,进行稳定性实验高温(温度60℃±2℃)、高湿(RH75%)、光照(照度4500±500LX)进行试验。影响因素试验结果如表2和表3所示:
【埃索美拉唑镁含量测定】
照高效液相色谱法(中国药典2015年版四部通则0512)测定。
色谱条件与系统适用性试验用辛烷基硅烷键合硅胶为填充剂(4.6mm×150mm,5μm或效能相当的色谱柱);以乙腈-磷酸盐缓冲液[(pH7.6)(每1L中含磷酸二氢钠0.0052mol和磷酸氢二钠0.032mol的溶液)](25:75)为流动相;检测波长为302nm。取奥美拉唑对照品和杂质Ⅰ对照品各适量,加磷酸盐缓冲液(pH7.6)溶解并稀释制成每1ml中均约含0.02mg的混合溶液,精密量取20μl注入液相色谱仪,奥美拉唑峰与杂质Ⅰ峰的分离度应不小于2.5。
测定法取装量差异项下内容物,混合均匀,精密称取适量(约相当于埃索美拉唑40mg),置200ml量瓶中,加甲醇10ml,磷酸盐缓冲液(pH11.0)10ml,超声使溶解,用水稀释至刻度,摇匀,滤过;精密量取续滤液5ml,置20ml量瓶,用水稀释至刻度;精密量取20μl,注入液相色谱仪,记录色谱图;另取奥美拉唑对照品,同法测定。按外标法以峰面积计算,即得。
【碳酸氢钠含量测定】
取装量差异项下内容物,混合均匀,精密称取适量(约相当于碳酸氢钠2g),置100ml量瓶中,加水适量,振摇使碳酸氢钠溶解,并用水稀释至刻度,摇匀,滤过;精密量取续滤液50ml,加甲基红-溴甲酚绿混合指示液适量,用盐酸滴定液(0.5mol/L)滴定至溶液由绿色变为紫红色,煮沸2分钟,放冷,继续滴定至溶液由绿色变为暗紫色。每1ml盐酸滴定液(0.5mol/L)相当于42.00mg的NaHCO3。
【有关物质】
避光操作。临用新制。取本品内容物细粉适量(约相当于埃索美拉唑20mg),置100ml量瓶中,加流动相A溶解并稀释至刻度,摇匀,滤过,取续滤液作为供试品溶液;精密量取适量,用流动相A定量稀释制成每1ml中约含0.2μg的溶液,作为对照溶液;另取奥美拉唑对照品和化合物Ⅰ对照品各适量,加流动相A溶解并稀释制成每1ml中均约含0.02mg的混合溶液,作为系统适用性溶液。照高效液相色谱法(中国药典2015年版四部通则0512)测定。用十八烷基硅烷键合硅胶为填充剂;以乙腈-磷酸盐缓冲液(pH7.6)-水(10:10:80)为流动相A,以乙腈-磷酸盐缓冲液(pH7.6)-水(80:1:19)为流动相B,照下表进行线性梯度洗脱;检测波长为302nm。取系统适用性溶液20μl注入液相色谱仪,奥美拉唑峰的保留时间应为14~19分钟;奥美拉唑峰与化合物Ⅰ峰(相对保留时间约为0.9)的分离度应大于2.5。取对照溶液20μl注入液相色谱仪,调节检测灵敏度,使主成分色谱峰的峰高约为满量程的10%,再精密量取供试品溶液与对照溶液各20μl,分别注入液相色谱仪,记录色谱图。
表1梯度
附已知杂质信息
化合物Ⅰ:H168/66
5-甲氧基-2-{[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]磺酰基}-1H-苯并咪唑
化合物Ⅱ:H431/41
1,4-二氢-1-(5-甲氧基-1H-苯并咪唑-2-基)-3,5-二甲基-4-氧-2-吡啶羧酸
化合物Ⅲ:H153/73
奥美拉唑氮氧化物
表2-实施例3
注:N.D代表痕量,未检出。
表3-对比例1
试验结论:通过实验资料表明,根据本品影响因素试验考察结果,样品外观没有改变,测定各指标无明显变化,在高温、高湿、光照条件下放置10天,除有关物质稍有增加外,其他各指标均无明显变化。本发明的埃索美拉唑镁胶囊及其制备方法,产品质量稳定、杂质含量低,组方简便、工艺通顺,也保障了产品质量和临床治疗效果,能够取得显著的社会效益和经济效益。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。另外,各个实施例之间的技术方案可以相互结合,但是必须是以本领域普通技术人员能够实现为基础;当技术方案的结合出现相互矛盾或无法实现时应当认为这种技术方案的结合不存在,也不在本发明要求的保护范围之内。
Claims (3)
1.一种埃索美拉唑镁碳酸氢钠胶囊的制备方法,其特征在于所述制备方法包括以下步骤:
(1)将交联羧甲基纤维素钠、硬脂富马酸钠溶于水后得到混合溶液,然后加入埃索美拉唑镁和碳酸氢钠,混合均匀后,制成软材;
(2)将软材经过制粒、干燥、过24目筛后得到干颗粒,装入胶囊即得;
其中,所述胶囊由下述重量份原辅料制备而成:埃索美拉唑镁22.3份、碳酸氢钠1100份、交联羧甲基纤维素钠15-20份和硬脂富马酸钠5-7份;
所述埃索美拉唑镁的制备方法为:其中将埃索美拉唑钾加入到甲醇中,加入七水硫酸镁,搅拌2-4小时后过滤,滤饼用甲醇洗涤,将滤液浓缩,加入丙酮,搅拌1-3小时,过滤,滤饼用丙酮和水洗涤,将滤饼加入到水中,35℃搅拌2-4小时,过滤,滤饼用水洗涤,将滤饼于35℃真空干燥36-60小时,得埃索美拉唑镁;
且所述胶囊中:化合物Ⅰ重量百分比为大于0且小于等于0.50%;化合物Ⅱ重量百分含量为大于0且小于等于0.10%;化合物Ⅲ重量百分含量为大于等于0且小于等于0.10%;
2.根据权利要求1所述的制备方法得到的埃索美拉唑镁碳酸氢钠胶囊。
3.根据权利要求2所述的埃索美拉唑镁碳酸氢钠胶囊在制备治疗胃食管反流病药物中的应用。
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Denomination of invention: A type of esomeprazole magnesium bicarbonate capsule Effective date of registration: 20231226 Granted publication date: 20220301 Pledgee: China Construction Bank Co.,Ltd. Changchun Science and Technology Sub branch Pledgor: CHANGCHUN HAIYUE PHARMACEUTICAL Co.,Ltd. Registration number: Y2023220000149 |