CN104254321A - 稳定性提高的药物制剂 - Google Patents
稳定性提高的药物制剂 Download PDFInfo
- Publication number
- CN104254321A CN104254321A CN201280069949.6A CN201280069949A CN104254321A CN 104254321 A CN104254321 A CN 104254321A CN 201280069949 A CN201280069949 A CN 201280069949A CN 104254321 A CN104254321 A CN 104254321A
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- CN
- China
- Prior art keywords
- ramipril
- pharmaceutical preparation
- stability
- amlodipine
- enhanced
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960003401 ramipril Drugs 0.000 claims abstract description 84
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- 238000002360 preparation method Methods 0.000 claims description 27
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 24
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Abstract
本发明涉及一种稳定性提高的含雷米普利药物制剂,其包含用粘合剂直接制粒的雷米普利和崩解剂。
Description
发明领域
本发明涉及稳定性提高的含雷米普利[化学名:(2S,3aS,6aS)-1-[(S)-N-[(S)-1-羧基-3苯基丙基]丙氨酰]-八氢环戊烷-[B]吡咯-2-羧酸-1-乙基酯]的药物制剂及其制备方法。
更特别地,本发明涉及一种稳定的药物制剂,其包含直接与粘合剂一起配制成颗粒形式的雷米普利和超级崩解剂。
发明背景
雷米普利是一种已知的药物活性成分,它被用于治疗高血压、心功能不全和肾病的疗法,增强血管再生,减少心血管疾病和事件的风险,特别是中风或心肌梗塞的风险,并降低心血管死亡率的风险。雷米普利主要通过其活性代谢物雷米普利拉发挥作用,它是一种特别有效的血管紧张肽转化酶(ACE)抑制剂。
与雷米普利结构类似的化合物已在欧洲专利No.50800中首次被公开。雷米普利的化学结构已在欧洲专利No.79022中首次被公开。
雷米普利是一种对热和湿敏感的、容易分解的药物活性成分。在分解过程中,发生了会产生与活性代谢物具有相同化学结构的杂质的酯基水解(欧洲药典:杂质E)。在雷米普利另一个重要的分解反应中,生成了雷米普利二酮哌嗪(欧洲药典:杂质D)。例如,根据美国专利No.5442008,在将干法制粒的2.5毫克强度的雷米普利片经受40℃温度下储存六个月的情况中,二酮哌嗪分解产物的浓度可以达到22.8%。在具有相同强度的雷米普利胶囊于相同条件下储存的情况中,二酮哌嗪分解产物的浓度可达到6.4%。根据已公布的国际专利申请WO2005041940,除上述的分解反应方法外,雷米普利在空气存在下的氧化分解可能导致不希望的变色。
现有技术中有几种已知的用来防止雷米普利分解的方法。这些方法中有一些是基于分离出药物制剂或其环境中存在的会促进雷米普利分解的物质。其它的方法依赖于使用适合用于有效稳定雷米普利的成分的制剂。
根据基于第一原理的方法,雷米普利颗粒被提供为具有排除促进分解的水和空气且存在辅料的包衣。或者,药物剂型以这样的方式提供,其中雷米普利和不太相容的辅料或进一步的活性成分位于制剂空间上分离的隔室中,其与含雷米普利的隔室仅接触很少的表面积。
根据美国专利No.5442008,所提供的雷米普利颗粒具有聚合物包衣,由此被稳定的活性成分被用于随后的配制工序中,任选地用于压片。对于包衣,可将羟丙基纤维素、羟丙基甲基纤维素、邻苯二甲酸酯、羟乙基纤维素、乙基纤维素、纤维素乙酸酯邻苯二甲酸酯、聚乙烯吡咯烷酮或甲基丙烯酸酯型,或进一步类型的药学上可接受的包衣材料转移到雷米普利颗粒的表面。
已公开的国际专利申请No.WO2006050533涉及具有稳定包衣的雷米普利颗粒,其中避免了包衣操作前的聚集,并且每个颗粒具有单独的包衣。作为优选的包衣剂,使用羟丙基甲基纤维素。包衣过程通过流化进行。
根据进一步的方法,在稳定赋形剂的存在下配制活性成分,并避免使用与雷米普利不相容的普遍适用的赋形剂。
根据英国专利申请No.2394660的发明人,具有高比表面积和酸性性质的赋形剂与雷米普利是不相容的,因此在配制过程中应避免使用它们。这一组赋形剂包括制药技术操作中广泛使用的胶体二氧化硅(Aerosil)。
欧洲专利申请No.1734931涉及含硫酸钙二水合物赋形剂的稳定雷米普利制剂。使用该赋形剂制备的制剂在40℃的温度和75%相对湿度储存6个月后,含有0.478-1.06%雷米普利二酮哌嗪杂质,这比市售产品的情况低得多。
已公开的国际专利申请WO2007056907的发明人同时使用了碳酸氢钠和硫酸钙稳定雷米普利,由此实现了雷米普利杂质浓度的降低。类似的方法已在公开的美国专利申请No.20030215526中被披露。
已公开的国际专利申请WO2005041940披露了一种制剂,其中尝试通过使用葡甲胺和任选的低取代羟丙基纤维素稳定ACE抑制剂或雷米普利。该产品在60℃下储存15天后含有0.75-1.59%的杂质。该组合物的缺点是即使在升高的温度下短暂储存,都会导致显著分解。
已公开的国际专利申请WO2005002548涉及一种稳定的药物制剂,包含除其他任选赋形剂外的ACE抑制剂和有效量药物润滑剂的紧密混合物。作为润滑剂,任何现有技术中已知的这类试剂都可以使用。然而,根据该现有技术的制剂甚至在48小时后,就含有与那些市售产品相似量的分解产物。
在公开的美国专利申请20070232680和公开的国际专利申请WO2008000040中,氧化镁被用来稳定雷米普利。已公开国际专利申请WO2008132756的发明人使用氧化镁和乳酸用于相同的目的。然而,在这些申请中没有披露稳定性试验的结果。
已公开的国际专利申请WO2007120930涉及稳定的药物制剂,包含雷米普利和稳定赋形剂。在填充到硬明胶胶囊内含雷米普利(1.25毫克)、凝胶化淀粉(23.35毫克)、乳糖(25.0毫克)和硬脂酰富马酸钠(0.4毫克)的组合物的稳定性研究期间,发明入发现在40℃温度和75%相对湿度下储存3个月后,雷米普利二酮哌嗪杂质的浓度达到3.5%。在原ALTACE产品的情况中,在相同的储存条件和相同的存储时间下,相同杂质的浓度为4.9%。
在含有几种药物活性成分的联合制剂的情况中,还必须考虑活性成分的不相容性。已公开的国际专利申请WO2008021875披露了一种作为片剂的联合药物剂型,其中活性成分位于多层片空间分离的层中,由此含活性成分的层仅以最小的表面接触。
已公开的国际专利申请WO2008095263涉及一种联合药物剂型,其中各活性成分作为不同的物理剂型(例如粉剂、颗粒剂、丸剂、颗粒剂、小片、片剂)存在,以便最大限度地减少活性成分之间的相互作用。因此,例如已生产了片剂剂型,其中活性成分盐酸氟西汀作为粉末混合物的一种成分存在,而奥氮平存在于小片中。
根据已公开的国际专利申请WO2008065485,通过混合活性成分并将制剂的pH值调节到大于6.0的数值,制备了一种含氨氯地平和ACE-抑制剂的药物制剂。这种作用是通过将苯磺酸氨氯地平、微晶纤维素、碳酸镁和着色剂混合,通过湿法制粒将由此得到的混合物转化成微丸,并将所述微丸填充到胶囊中实现的。
已公开的国际专利申请WO2011104588披露了一种含雷米普利和氨氯地平的药物剂型,其中使用了包衣的雷米普利颗粒。
市售产品TRITACE的组合物除活性成分雷米普利外,还含有硬脂酰富马酸钠、羟丙甲纤维素、微晶纤维素、冷溶胀淀粉,以及在某些强度情形下的着色剂。根据该产品的使用说明,其应储存在不超过25℃的温度中。因此,可以预料该组合物在较高的温度/相对湿度下会迅速分解。
发明概述
负责颁布药品上市许可的卫生主管部门对药品的活性成分含量、稳定性和纯度提出了严格要求。为了满足这些要求,就需要含雷米普利的药物制剂可以在延长的时期内储存,并且它们的质量不会恶化,活性成分的浓度不会减少到低于规定限度,以及分解产物的浓度不会增加到限度之上。
虽然有几种稳定雷米普利的解决办法在本领域是已知的,但是在大多数情况下,没有提供有关所述方法的效果和稳定日期、组合物的保质期和杂质性质的数据。
因此,我们研究开发工作的目的是开发一种含有雷米普利的制剂,其可用作单组分制剂以及联合制剂中的含雷米普利组分,其与最常使用的药物赋形剂和最常与雷米普利联合应用的药物活性成分相容,其能以低成本、均匀的质量制造,并且能够储存较长的时间周期,而不会质量变差以及分解产物的浓度显著增加。开发的另一个目的是配制能在氨氯地平-雷米普利联合产品中使用的含雷米普利组合物。
上述目的根据本发明得以解决。
当将雷米普利与通常在制药技术中作为超级崩解剂的赋形剂混合,并用合适的粘合剂对所得混合物制粒时,我们出人意料地发现含雷米普利的药物制剂能以稳定性提高的颗粒或微丸形式获得。在由此得到的制剂中,雷米普利的分解速率,特别是雷米普利拉分解产物的生成速率,进行得明显比现有技术中已知的其它药物组合物要慢,并且杂质的总和也较低。认识到这一点是非常令人惊奇的,因为现有技术没有提到这样的技术解决方案,其中ACE抑制剂特别是雷米普利的稳定是由现有技术中表征为超级崩解剂的赋形剂来实现的。
发明详述
本发明用粘合剂直接制粒的含活性成分雷米普利、超级崩解剂的新制剂适合用于压片或者作为胶囊填充物,或者作为压片混合物、胶囊填充物的组分,例如与其它赋形剂的混合物或与含其它活性成分的匀浆的混合物。我们已发现,用根据本发明的颗粒生产的匀浆显示出特别好的含量均匀度,从而允许制备质量一致的药品。
本发明的制剂优选以微丸或颗粒的形式生产,其基本上是粒径为约0.2-2毫米的球形颗粒,其可提供为具有可控制药物活性成分释放的一层或多层,并且其可以被填装到硬明胶胶囊中,或者可以被压片。该制剂给药后在胃中分散成单个的微丸或颗粒,与胃内容物混合好并以统一的方式从胃排出。
在制备本发明的药物制剂时,可以使用现有技术中已知的超级崩解剂。超级崩解剂是接触湿气后体积大幅度增加(“溶胀”),并且这种体积改变导致剂型崩解的药物辅料。这种超级崩解剂有例如:某些改性淀粉衍生物,如羧基乙酸淀粉钠;某些纤维素衍生物,如低取代的羟丙基纤维素,交联羧甲基纤维素钠;以及交联聚维酮。根据本发明,使用不同等级的交联聚维酮是特别有利的。不论是美国药典,还是任何其它代表现有技术的文献,都没有提到超级崩解剂的稳定效果或以上提及的其优选代表的稳定效果。
根据本发明的另一个方面,提供了一种稳定性提高的含雷米普利药物制剂的制备方法,其包括:将雷米普利和超级崩解剂用合适粘合剂的水溶液制粒,优选水溶性聚合物,并将混合物转化为微丸或颗粒。该制粒操作可使用现有技术中已知的制药技术方法进行(pl.Isaac Ghebre-Sellassie:PharmaceuticalPelletization Technology,Marcel Dekker,Inc.,New York,Basel,1989)。
作为粘合剂,可使用现有技术已知的任何相容性粘合剂,优选水溶性聚合物,例如改性纤维素衍生物,最有利的是羟丙基甲基纤维素。
现有技术中有几种适合生产微丸或颗粒的方法,它们来自以下三种基本方法:
1.层积法(layering method),
2.挤出滚圆法,
3.堆造制粒(building-up granulation)。
根据层积法,由活性成分颗粒和具有较小粒径的辅料组成的混合物被沉积到较大的、基本上等径的芯材上,它可以是惰性的芯,也可以是活性成分的颗粒。这种沉积可以在糖果生产容器、离心造粒装置或流化喷雾没备中进行。在某些情况下,可以将活性成分作为溶液喷涂到惰性颗粒的表面。
在挤出滚圆工艺中,将活性成分和辅料混合并用液体捏合,使用具有约1mm直径开口的工具将湿团挤出,并使用转板球化装置将所得挤出团转化成近球形。
在堆造法中,将活性成分和辅料的混合物在搅拌装置、离心造粒设备或流化床造粒装置中搅拌,直到粉末混合物的颗粒彼此粘结并依靠剪切和研磨力转化成球形。
根据本发明的药物制剂有利地可通过堆造法制备。
填装到胶囊内的颗粒或微丸的适宜粒径为0.5至1.0毫米,而用来压制成片的微丸的优选粒径为0.3至0.6毫米。
在制备本发明稳定性提高的药物制剂过程中,特别出人意料的是,尽管体积的增加较大,但超级崩解剂与水制粒是可行的,并且尽管湿法制粒的工艺过程以及膨胀的湿超级崩解剂中存在湿气,但在造粒或干燥颗粒的过程中没有出现水和热敏感雷米普利的分解。在根据本发明的湿法制粒过程中,颗粒的密度由于超级崩解剂膨胀而降低。然而,在干燥步骤中,膨胀逐渐减少,颗粒的密度恢复到通常的操作范围。
由于雷米普利是热敏感的活性成分,所以制粒过程在低于65℃,优选低于50℃,最优选低于45℃的温度下进行。
本发明稳定性提高的药物制剂中关于雷米普利的浓度没有限制。根据所生产剂型成品的需要,雷米普利的浓度可选自例如1至80重量%,优选5至50重量%,最优选10至40重量%。
如有需要,含雷米普利的、稳定性提高的药物制剂在制粒后,可使用进一步的药学上可接受的辅料转化为不同的药物组合物,所述辅料例如填充剂,粘合剂,润滑剂,助流剂,崩解剂和溶解度改良剂,缓冲剂,表面活性剂。因此,最终的剂型可以包含例如,填充剂,如硫酸钙,磷酸氢钙,乳糖,甘露糖醇,蔗糖,淀粉,微晶纤维素;粘合剂,如明胶,羟丙基纤维素,羟丙基甲基纤维素,甲基纤维素,聚乙烯吡咯烷酮,蔗糖,淀粉;润滑剂,如硬脂酸钙,氢化植物油,硬脂酸镁,矿物油,硬脂酸钠。
最终的剂型可以进一步含有助流剂,如高岭土,滑石粉或二氧化硅,溶解促进剂的崩解剂,如海藻酸盐,羧甲基纤维素钠,交联聚维酮,淀粉,预凝胶化淀粉,羧甲基淀粉钠;缓冲剂(如柠檬酸盐,磷酸盐,碳酸盐或碳酸氢盐),表面活性剂(如聚山梨酯,十二烷基硫酸钠)。合适助流利的例子是胶体二氧化硅,硬脂酸镁,滑石粉或淀粉。
本发明稳定性提高的含雷米普利药物制剂还可转化为控释制剂。为实现该目的,任何现有技术中已知的方法都适用于此目的,例如可以应用包衣。在包衣操作中,作为成膜剂,可以使用水溶性(例如羟丙基甲基纤维素,聚乙烯醇),水不溶性(例如乙基纤维素,丙烯酸乙酯-甲基丙烯酸甲酯共聚物,聚醋酸乙烯酯)的成膜剂,具有pH依赖性溶解度的成膜剂的成膜聚合物(如醋酸纤维素邻苯二甲酸,乙酸琥珀酸羟丙基甲基纤维素,丙烯酸乙酯甲基丙烯酸共聚物)。包衣可以通过使用水溶液,或成膜剂溶于有机溶剂制备的溶液,或使用其水分散体进行。根据包衣的溶解特性,可以制备立即释放的(水溶性包衣),缓释的(水不溶性包衣)或控释的(pH依赖的溶解性)制剂。包衣辅料的质量和数量应根据所需的溶出性质,即溶解程度的时间依赖性来确定。
含微丸化或颗粒化活性成分的药物制剂通常以剂量单位提供。微丸或颗粒制备过程中活性成分的浓度通过单个剂量单位中存在的单剂量活性成分确定,使得含单剂量活性成分的颗粒或微丸的重量在50至1500毫克,优选100至700毫克。
本发明稳定形式的含雷米普利药物制剂本身适合用来制备剂型成品。但是,所述的制剂还适合作为联用药品的含雷米普利组分。在这种情况中,本发明的药物制剂通过使用进一步的活性成分和任选地使用进一步的赋形剂,被转化成联合剂型成品。
当想要配制第二种或进一步的药物活性成分时,进一步的活性成分有利地可以预混形式应用,其中活性成分与赋形剂,例如微晶纤维素和任选地进一步的药物赋形剂是混匀的。如果使用微晶纤维素作为赋形剂,对于其质量没有限制,可以自由使用不同的等级、不同的粒径和比重。
使用本发明的药物制剂,可以制备雷米普利与利尿剂,如氢氯噻嗪;钙通道阻断剂,如氨氯地平,非洛地平或硝苯地平;β-受体阻滞剂,降低胆固醇的活性成分,如辛伐他汀或贝特类,α-肾上腺素阻滞剂,例如多沙唑嗪,或血小板聚集抑制药物的联合制备物。
本发明稳定性提高的含雷米普利药物制剂特别有利地可用来制备含雷米普利和氨氯地平的联合剂型。氨氯地平是一种易分解的化合物,具有较差的压片适应性。氨氯地平以苯磺酸盐用于药物组合物中。
由公开的国际专利申请WO2010038091已知,在联合制剂中,氨氯地平会与另外的活性成分相互作用,可导致不希望的分解反应。
制备稳定的含氨氯地平药物剂型是一个相对不同的任务。在欧洲专利说明书No.1458384中,披露了含苯磺酸氨氯地平的片剂。
由于苯磺酸氨氯地平在水分存在下会水解,可以预期因此形成的酸性微环境会导致雷米普利快速分解。在本发明稳定性提高的制剂使用雷米普利的情况中,可将苯磺酸氨氯地平与赋形剂优选微晶纤维素,以及润滑剂优选硬脂酸镁的简单匀浆添加到制剂中。我们发现,在含有本发明雷米普利颗粒或微丸以及上述所得苯磺酸氨氯地平的混合物中,雷米普利和氨氯地平都具有优良的稳定性。
根据本发明的另一个方面,提供了一种含有雷米普利和氨氯地平的药物剂型,其中所含的雷米普利是与超级崩解剂和粘合剂优选水溶性聚合物直接制粒的形式,苯磺酸氨氯地平是与药学上可接受的赋形剂和任选润滑剂的粉末混合物。作为超级崩解剂,优选使用交联聚维酮。优选的药学上可接受的赋形剂是微晶纤维素。
根据本发明的另一个方面,提供了一种稳定的含雷米普利和氨氯地平药物剂型的制备方法,其包括对雷米普利和超级崩解剂的混合物用粘合剂,优选水溶性聚合物制粒,所得的颗粒与含苯磺酸氨氯地平、药学上可接受的赋形剂和任选的润滑剂的匀浆均匀混合。
实施例4的对比稳定性结果表明,在根据实施例3的联合剂型中,雷米普利特分解产物的浓度以及杂质的总和(分别是雷米普利二酸,杂质E;雷米普利杂质D和杂质E的浓度之和)比对比实施例的制剂所得到的更有利,尽管根据实施例3的剂型含有除雷米普利外的苯磺酸氨氯地平,并且不存在对比实施例中的稳定剂碳酸氢钠。此外,从稳定性试验中得出结论,容易分解的苯磺酸氨氯地平直到6个月的稳定性测试期结束时仍然保持稳定。
本发明的另一方面通过以下的实施例示范,而不会将本发明仅限制为实施例。
对比实施例
对已公布的国际专利申请WO2007120930中披露的药物制剂组成进行重现,其改进是组合物中补充了现有技术中已知作为稳定剂的碳酸氢钠。
药物剂型的组成为:雷米普利3.85%,碳酸氢钠3.85%,乳糖74.3%,交联羧甲基纤维素钠2.00%,预胶化淀粉15%,硬脂酰富马酸钠1%。
为制备20000片2.5毫克强度的片剂,将3.1千克乳糖一水合物、50克雷米普利、50克碳酸氢钠、80克交联羧甲基纤维素钠和600克预胶化淀粉混合,过筛,并用1600克96%(v/v)乙醇和水1∶1(v/v)的混合物制粒。颗粒过筛,在40至50℃的温度下干燥,直到含水量为1.7%。将颗粒与40克过筛的硬脂酰富马酸钠混合,并用旋转冲压片机压片。配制在空气相对含水量低于40%的环境中进行。
实施例1.雷米普利颗粒
为制备10.5千克的雷米普利颗粒,在Hüttlin Pilotmix涡流造粒装置中装入2000克雷米普利和8000克交联聚维酮(Poliplasdone XL-10GAF),并将混合物在15转/分均化2分钟。
在实际进行制备的前一天,将470克羟丙甲纤维素(Pharmacoat 603)溶于7.7kg纯净水,并将由此得到的粒化溶液过滤。
将3670克部分的粒化溶液喷雾到粉末混合物中,混合器为30至50转/分,切碎机为1000至1400转/分,喷雾压力设定为1.5巴。喷雾后,将混合物再捏合5分钟。
湿产品过筛,并使用0.8毫米网筛的Glatt OR5030振荡再造粒装置再造粒。
将预制粒的混合物转移到Hüttlin Pilotlab流化造粒装置的容器内,并通过将剩余部分的粒化溶液喷雾到其上来进一步制粒。在流化造粒的操作中,流化空气的体积流量为800立方米/小时。空气温度为50℃,喷雾过程中粒化溶液的质量流为0.2千克/分钟,喷雾压力为0.7巴。当造粒完成后,颗粒在温度不超过50℃的流化造粒装置中干燥,直到含水量为2至3.5%,产物用具有0.8毫米网筛的Glatt振荡再造粒装置再次造粒。
实施例2.雷米普利胶囊
将根据实施例1方法制备的含雷米普利为活性成分的颗粒1047克与1671克微晶纤维素(Vivapur 200)均化。
使用0.8毫米的网筛孔径对混合物过筛,之后加入3000克微晶纤维素(Vivapur 200),在圆筒均质器(drum homogenizer)中均化10分钟。
将82克甘油二山嵛酸酯(Compritol 888)和200克微晶纤维素混合,并使用0.8毫米的网筛孔径过筛。将该混合物加入到含雷米普利的混合物中,并在圆筒中均化2分钟。由此得到的产物每30毫克混合物中含有1毫克雷米普利。
实施例3.含雷米普利和氨氯地平的匀浆
将1390克苯磺酸氨氯地平和1964克微晶纤维素(Vivapur 200)混合,并使用0.8毫米的网筛过筛。由此得到的混合物与5236克根据实施例1制备的雷米普利颗粒以及5000克微晶纤维素(Vivapur 200)在圆筒均质器中均化10分钟。
均化产物使用0.8毫米网筛的Glatt OR5030振荡再造粒装置过筛,在加入15千克微晶纤维素(Vivapur 200)后,再次均化10分钟。
将410克甘油二山嵛酸酯(Compritol 888)和1000克微晶纤维素混合,并使用0.8毫米的网筛过筛,由此得到的润滑混合物与苯磺酸氨氯地平以及含雷米普利的混合物均化,并在圆筒均质器中均化2分钟。由此得到的产物每30毫克含有1毫克雷米普利和1毫克氨氯地平,并且可直接用来填装胶囊。
实施例4.稳定性试验
分别在25℃/60%相对湿度和40℃/75%相对湿度的条件下进行6个月的稳定性研究,测定根据对比实施例和实施例3制备的组合物中雷米普利二酮哌嗪杂质(欧洲药典杂质D)和雷米普利二酸(欧洲药典杂质E,雷米普利拉)的浓度。使用现有技术中已知的分析方法测定杂质的浓度。
稳定性结果-雷米普利(r.h.:相对湿度)
苯磺酸氨氯地平的主要分解产物(3-乙基-5-甲基-2-[(2-氨基乙氧基)甲基〕-4(2-氯苯基)-6-甲基吡啶-3,5-二羧酸(欧洲药典:杂质D)的浓度不超过在任何储存条件下6个月稳定测试期浓度的0.05%。
Claims (8)
1.稳定性提高的含雷米普利药物制剂,其包括用粘合剂直接制粒的雷米普利和超级崩解剂。
2.根据权利要求1所述的药物制剂,其中超级崩解剂选自淀粉衍生物、纤维素衍生物或交联聚维酮。
3.根据权利要求1所述的药物制剂,其中超级崩解剂选自羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠或交联聚维酮。
4.根据权利要求1所述的药物制剂,其中粘合剂是水溶性聚合物,优选是改性纤维素衍生物,最有利的是羟丙基甲基纤维素。
5.稳定性提高的雷米普利药物制剂,其包括用羟丙基甲基纤维素直接制粒的雷米普利和交联聚维酮。
6.包含根据权利要求1至5任一项所述的稳定性提高的含雷米普利药物制剂和进一步药物成分,例如利尿剂、钙通道阻滞剂、β受体阻滞剂、降低胆固醇的活性成分、α-受体阻滞剂或血小板聚集抑制剂的药物制备物。
7.含氨氯地平和雷米普利的药物制备物,其包括根据权利要求1至5任一项所述的稳定性提高的雷米普利药物制剂和氨氯地平,优选苯磺酸氨氯地平的形式。
8.含氨氯地平和雷米普利的药物制备物,其包括稳定性提高的雷米普利药物制剂,该制剂由与苯磺酸氨氯地平、微晶纤维素和任选的润滑剂混合、用羟丙基甲基纤维素直接制粒的雷米普利和交联聚维酮构成。
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EP2814465B1 (en) | 2012-02-17 | 2019-07-03 | Egis Gyógyszergyár Zrt. | Pharmaceutical formulation having improved stability |
HUP1300496A2 (hu) | 2013-08-16 | 2015-03-02 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Stabil kombinációs gyógyszerkészítmény |
EP3886817A1 (en) | 2018-11-27 | 2021-10-06 | Zaklady Farmaceutyczne Polpharma S.A. | Pharmaceutical composition comprising ramipril and indapamide |
CN114748436B (zh) * | 2022-05-30 | 2023-05-16 | 迪沙药业集团有限公司 | 一种硝苯地平组合物及其制备方法 |
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MX2014009871A (es) | 2015-03-19 |
ZA201405925B (en) | 2015-11-25 |
MX370647B (es) | 2019-12-19 |
BR112014020184A2 (zh) | 2017-06-20 |
CA2864456A1 (en) | 2013-08-22 |
BR112014020184B1 (pt) | 2021-11-30 |
EA201491510A1 (ru) | 2014-11-28 |
EP2814465B1 (en) | 2019-07-03 |
EP3501501A1 (en) | 2019-06-26 |
HK1205683A1 (zh) | 2015-12-24 |
EP2814465A1 (en) | 2014-12-24 |
BR112014020184A8 (pt) | 2017-07-11 |
AU2012369903A1 (en) | 2014-09-04 |
HUE046229T2 (hu) | 2020-02-28 |
PH12014501840A1 (en) | 2014-11-10 |
PL2814465T3 (pl) | 2020-01-31 |
CN107441495A (zh) | 2017-12-08 |
EA030466B1 (ru) | 2018-08-31 |
AU2016203463A1 (en) | 2016-07-07 |
US20150094345A1 (en) | 2015-04-02 |
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