CN100432057C - 盐酸伊伐布雷定的γd-晶形、其制备方法和含有它的药物组合物 - Google Patents
盐酸伊伐布雷定的γd-晶形、其制备方法和含有它的药物组合物 Download PDFInfo
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- CN100432057C CN100432057C CNB200610058077XA CN200610058077A CN100432057C CN 100432057 C CN100432057 C CN 100432057C CN B200610058077X A CNB200610058077X A CN B200610058077XA CN 200610058077 A CN200610058077 A CN 200610058077A CN 100432057 C CN100432057 C CN 100432057C
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Abstract
通式(I)的盐酸伊伐布雷定的γd-晶形：其特征在于其粉末X射线衍射图。药物。
Description
本发明涉及通式(I)的盐酸伊伐布雷定(ivabradine hydrochloride)的新γd-晶形、其制备方法和含有它的药物组合物：
伊伐布雷定及其与药学上可接受的酸形成的加成盐、更具体为其盐酸盐具有极为有价值的药理和治疗特性，尤其是减慢心律(bradycardic)特性，从而使得这些化合物用于治疗或预防心肌缺血的各种临床情况如心绞痛、心肌梗死和相关节律失常，以及涉及节律失常的各种病理情况、尤其是室上性节律失常，和心力衰竭。
欧洲专利说明书EP 0534 859中已经描述了伊伐布雷定及其与药学上可接受的酸形成的加成盐、更尤其是其盐酸盐的制备和治疗用途。
鉴于该化合物的药物价值，所以最重要的是获得具有极佳纯度的该化合物。另外重要的是能够通过一种易于转化成工业化规模的方法合成它，尤其是允许快速过滤和干燥的形式。最终，该晶形必须完全可再现，易于配制且足够稳定以便其长期贮存，而对温度、光或氧的水平没有特定的要求。
专利说明书EP 0534 859中描述了用于合成伊伐布雷定及其盐酸盐的方法。然而，该对比文献中未特别详述用于以可再现方式获得表现出那些特征的伊伐布雷定形式的条件。
本申请人目前已经发现，可以获得伊伐布雷定的特定盐即盐酸盐的一种晶体形式，该晶形得到充分定义并且表现出有价值的稳定性和加工性能的特征。
更具体而言，本发明涉及盐酸伊伐布雷定的γd-晶形，其特征在于如下粉末X射线衍射图，所述衍射图使用PANalytical X’Pert Pro衍射仪与X’Celerator检测器测定，并根据谱线位置(布拉格角2θ，以度表示)、谱线高度(以计数表示)、谱线面积(以计数×度表示)、半高处的谱线宽度(“FWHM”，以度表示)和晶面间距d(以
表示)表示：
本发明还涉及制备盐酸伊伐布雷定的γd-晶形的方法，其特征在于将盐酸伊伐布雷定和2-乙氧基乙醇的混合物、盐酸伊伐布雷定、2-乙氧基乙醇和水的混合物或盐酸伊伐布雷定、乙醇和水的混合物加热，直至溶解完全，然后冷却，直至结晶完全，并且通过过滤收集获得的晶体并脱水。
·在本发明的结晶方法中，能够使用通过任意方法获得的盐酸伊伐布雷定，例如通过专利说明书EP 0534 859中所述的制备方法获得的盐酸伊伐布雷定。
·可以在冷却步骤中有利地将该溶液种晶。
本发明还涉及药物组合物，包含作为活性成分的盐酸伊伐布雷定的γd-晶形以及一种或多种适宜的惰性无毒性赋形剂。在本发明的药物组合物中，更尤其可以提及的是适合于口服、胃肠外(静脉内或皮下)或鼻部给药的那些片剂或糖衣丸、舌下片、明胶胶囊、锭剂、栓剂、霜剂、软膏剂、皮肤凝胶、可注射制剂、可饮用的混悬液。
有用的剂量可以根据疾病的性质和严重程度、给药途径和患者的年龄和体重而改变。该剂量在1-500mg/天之间改变，分一次或多次给药。
下列实施例解释本发明。
在下列实验条件下测定X射线粉末衍射光谱：
-PANalytical X’Pert Pro衍射仪、X’Celerator检测器、温控室；
-电压45kV，电流40mA；
-上机(mounting)θ-θ；
-镍(Kβ)滤波器；
-入射线和衍射线索勒缝隙：0.04拉德；
-发散狭缝的固定角：1/8°；
-障板(mask)：10mm；
-防散射狭缝：1/4°；
-测定方式：从3°连续至30°，按0.017°递增；
-测定时间/步骤：19.7s；
-总时间：4min 32s
-测定速度：0.108°/s；
-测定温度：环境.
实施例1：盐酸伊伐布雷定的γd-晶形
将40ml 2-乙氧基乙醇预加热至80℃，然后分批加入按照专利说明书EP 0534859中所述方法获得的8.4g盐酸伊伐布雷定，同时搅拌，将该混合物在80℃加热，直至溶解完全。在返回到环境温度后，将该溶液贮存8天，然后通过过滤收集形成的结晶，并且用环己烷冲洗。
通过以5℃/分钟的速率逐步加热至达80℃的温度使由此获得的产物脱水。
X射线粉末衍射图：
通过下表中整理的重要谱线，给出了盐酸伊伐布雷定γd-晶形的X射线粉末衍射图谱(衍射角)：
实施例2：药物组合物
制备1000片各自含有5mg伊伐布雷定碱的片剂的配方：
实施例1的化合物 5.39g
玉米淀粉 20g
无水胶体二氧化硅 0.2g
甘露糖醇 63.91g
PVP 10g
硬脂酸镁 0.5g
Claims (8)
1.通式(I)的盐酸伊伐布雷定的γd-晶形：
其特征在于如下粉末X射线衍射图，所述衍射图使用PANalytical X’PertPro衍射仪与X’Celerator检测器测定，并根据谱线位置、谱线高度、谱线面积、半高处的谱线宽度和晶面间距d表示，其中所述的谱线位置以布拉格角2θ表示，单位为度，所述的谱线高度以计数表示，所述的谱线面积以计数×度表示，所述的半高处的谱线宽度以度表示，所述的晶面间距d以
表示：
2.制备根据权利要求1的盐酸伊伐布雷定的γd-晶形的方法，其特征在于将盐酸伊伐布雷定和2-乙氧基乙醇的混合物、盐酸伊伐布雷定、2-乙氧基乙醇和水的混合物或盐酸伊伐布雷定、乙醇和水的混合物加热，直至溶解完全，然后冷却，直至结晶完全，并且通过过滤收集获得的晶体并脱水。
3.根据权利要求2的方法，其特征在于在冷却步骤中将盐酸伊伐布雷定的溶液种晶。
4.药物组合物，包含作为活性成分的根据权利要求1的盐酸伊伐布雷定的γd-晶形以及一种或多种药学上可接受的惰性无毒性载体。
5.根据权利要求1的盐酸伊伐布雷定的γd-晶形在制备具有减慢心率药用途的药物中的用途。
6.根据权利要求1的盐酸伊伐布雷定的γd-晶形在制备药物中的用途，所述药物用于治疗或预防心肌缺血的各种临床情况，以及涉及节律失常的各种病理情况，和心力衰竭。
7.根据权利要求6的用途，其中所述的心肌缺血的临床情况是心绞痛、心肌梗死或相关节律失常。
8.根据权利要求6的用途，其中所述的涉及节律失常的病理情况是室上性节律失常。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0501990A FR2882556B1 (fr) | 2005-02-28 | 2005-02-28 | Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR0501990 | 2005-02-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1827601A CN1827601A (zh) | 2006-09-06 |
| CN100432057C true CN100432057C (zh) | 2008-11-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200610058077XA Active CN100432057C (zh) | 2005-02-28 | 2006-02-28 | 盐酸伊伐布雷定的γd-晶形、其制备方法和含有它的药物组合物 |
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Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2882554B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme critalline beta d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2882555B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2882556B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2882553B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2891826B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2891827B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline deltad du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2894825B1 (fr) * | 2005-12-21 | 2010-12-03 | Servier Lab | Nouvelle association d'un inhibiteur du courant if sinusal et d'un inhibiteur de l'enzyme de conversion et les compositions pharmaceutiques qui la contiennent |
| ES2381771T3 (es) | 2006-11-30 | 2012-05-31 | Cadila Healthcare Limited | Procedimiento para la preparación de hidrocloruro de ivabradina |
| CN101353325B (zh) * | 2007-07-27 | 2011-11-09 | 上海优拓医药科技有限公司 | 稳定型盐酸伊伐布雷定结晶及其制备方法 |
| RU2473544C2 (ru) | 2007-05-30 | 2013-01-27 | Инд-Свифт Лабораториз Лимитед | Способ получения ивабрадина гидрохлорида и его полиморфных модификаций |
| EP2367782B1 (en) | 2008-12-22 | 2013-02-13 | KRKA, D.D., Novo Mesto | Process for preparation of ivabradine |
| CN101774969B (zh) | 2009-01-13 | 2012-07-04 | 江苏恒瑞医药股份有限公司 | 硫酸伊伐布雷定及其i型结晶的制备方法 |
| EP2534135A2 (en) | 2010-02-12 | 2012-12-19 | KRKA, D.D., Novo Mesto | Novel forms of ivabradine hydrochloride |
| HUP1000245A2 (en) | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
| WO2012025940A1 (en) | 2010-08-25 | 2012-03-01 | Cadila Healthcare Limited | Polymorphic form of ivabradine hydrochloride and process for preparation thereof |
| EP2726462B1 (en) * | 2011-08-02 | 2017-03-22 | Sandoz AG | Acetone solvate of ivabradine hydrochloride |
| EP2773621B1 (en) | 2011-11-04 | 2015-12-30 | Synthon BV | A process for making crystalline delta-form of ivabradine hydrochloride |
| EP2589594A1 (en) * | 2011-11-04 | 2013-05-08 | Urquima S.A. | Ivabradine hydrochloride Form IV |
| WO2013102919A1 (en) | 2011-11-14 | 2013-07-11 | Cadila Healthcare Limited | Polymorphic forms of ivabradine hydrochloride |
| EP2948432B1 (en) | 2013-01-24 | 2018-09-19 | Synthon BV | Process for making ivabradine |
| CZ305096B6 (cs) | 2013-10-02 | 2015-04-29 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (S)-mandlové kyseliny a její farmaceutická kompozice |
| MX363389B (es) | 2013-12-12 | 2019-03-20 | Synthon Bv | Composicion farmaceutica que comprende ivabradina amorfa. |
| EP2774606B1 (en) | 2014-02-14 | 2019-01-30 | Synthon B.V. | Pharmaceutical composition comprising ivabradine hydrochloride polymorph IV |
| CZ305436B6 (cs) | 2014-07-10 | 2015-09-16 | Zentiva, K.S. | Pevná forma Ivabradin hydrochloridu a (R)-mandlové kyseliny a její farmaceutická kompozice |
| TWI598360B (zh) * | 2016-12-19 | 2017-09-11 | 義守大學 | Ｆｓｂｍ重組蛋白及其用途 |
| EP3366282A1 (en) | 2017-02-28 | 2018-08-29 | Sanovel Ilac Sanayi ve Ticaret A.S. | Solid oral pharmaceutical compositions of ivabradine |
| TR201703066A2 (tr) | 2017-02-28 | 2018-09-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | İvabradi̇ni̇n kati oral farmasöti̇k kompozi̇syonlari |
| IT202000025312A1 (it) | 2020-10-26 | 2022-04-26 | Cambrex Profarmaco Milano S R L | Processi per la preparazione di polimorfi di ivabradina hcl |
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| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US534859A (en) * | 1895-02-26 | Condenser for ice-machines | ||
| DE3119874A1 (de) * | 1981-05-19 | 1982-12-09 | Dr. Karl Thomae Gmbh, 7950 Biberach | "benzazepinderivate, ihre herstellung und ihre verwendung als arzneimittel" |
| DE3418270A1 (de) * | 1984-05-17 | 1985-11-21 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue aminotetralinderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| AU647528B2 (en) | 1990-08-29 | 1994-03-24 | Humanetics Corporation | Treatment process for promoting weight loss employing a substituted delta5-androstene |
| FR2818552B1 (fr) | 2000-12-26 | 2003-02-07 | Servier Lab | Compositions pharmaceutique solide thermoformable pour la liberation controlee d'ivabradine |
| FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2882554B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme critalline beta d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2882553B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline beta du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2882555B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2882556B1 (fr) * | 2005-02-28 | 2007-05-04 | Servier Lab | Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2891827B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline deltad du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| FR2891826B1 (fr) * | 2005-10-11 | 2007-12-28 | Servier Lab | Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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