CN101015557A - 窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的新组合以及含有它的药物组合物 - Google Patents
窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的新组合以及含有它的药物组合物 Download PDFInfo
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- CN101015557A CN101015557A CNA2006100643181A CN200610064318A CN101015557A CN 101015557 A CN101015557 A CN 101015557A CN A2006100643181 A CNA2006100643181 A CN A2006100643181A CN 200610064318 A CN200610064318 A CN 200610064318A CN 101015557 A CN101015557 A CN 101015557A
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- angiotensin converting
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的新组合以及含有它的药物细合物本发明涉及包含选择性和特异性窦房结If电流抑制剂、更特别是伊伐布雷定与血管紧张肽转化酶抑制剂的组合以及含有它的药物。
Description
技术领域
本发明涉及选择性和特异性窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的新组合。
发明内容
本发明涉及选择性和特异性窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的新组合。
更具体地,本发明涉及选择性和特异性窦房结If电流抑制剂、即式(I)的伊伐布雷定或3-{3-[{[(7S)-3,4-二甲氧基-二环[4.2.0]辛-1,3,5-三烯-7-基]甲基}(甲基)氨基]丙基}-7,8-二甲氧基-1,3,4,-四氢-2H-3-苯并氮杂-2-酮:
以及它的水合物和结晶形式和其与可药用酸的加成盐与血管紧张肽转化酶抑制剂的新组合。
选择性和特异性窦房结If电流抑制剂、更特别是伊伐布雷定以及它的水合物和结晶形式和其与可药用酸的加成盐、更特别是它的盐酸盐具有非常有价值的药理学和治疗学性质,特别是负性变时性质(降低心率),这使得这些化合物可用于治疗、预防和预后改善与心肌缺血有关的各种心血管疾病如心绞痛、心肌梗死和相关的节律紊乱,并且还可用于涉及节律紊乱、特别是室上性节律紊乱的各种病变以及慢性心力衰竭。
伊伐布雷定和其与可药用酸的加成盐、更特别是它的盐酸盐的制备和治疗用途已经在欧洲专利说明书EP0 534 859中有描述。
申请人现已令人惊奇地发现与血管紧张肽转化酶抑制剂组合使用的选择性和特异性窦房结If电流抑制剂、更特别是伊伐布雷定或3-{3-[{[(7S)-3,4-二甲氧基-二环[4.2.0]辛-1,3,5-三烯-7-基]甲基}(甲基)氨基]丙基}-7,8-二甲氧基-1,3,4,5-四氢-2H-3-苯并氮杂-2-酮具有有价值的性质,这使得它们可被组合用于治疗高血压。
高血压是一种静息性的隐袭疾病:尽管大多数时候高血压不伴随任何即发问题,但是如果不经治疗10至20年后它将会通过发生严重的血管、心脏或脑意外事件而显现出来。除了生物学参数被定义为超过专家所确定的特定水平以外,高血压还是发生心血管疾病的主要危险因素,这些心血管疾病是工业国家中人们生命的后三分之一期间最常见的死亡原因。
由于其在一般人群中的高发生率,这种健康“定时炸弹”造成了非常大的公众健康问题。从治疗角度看,保健-饮食措施总是必须的。这些措施使得有时可避免使用药物治疗,但是最常发生的是仅仅可延迟使用药物治疗。尽管药物种类非常多,但是常常仍不足以获得令人满意的动脉压控制。
已知动脉压(收缩压和舒张压)水平是发生脑血管意外事件或心肌梗死危险的非常重要的决定因素。大量临床试验已经表明降低动脉压可非常显著地减少高血压患者发生脑和心脏意外事件的危险。
已知个体对抗高血压治疗的反应不同,且难以预测。在大多数高血压患者中,获得最适宜的动脉压控制需要依靠多药物治疗(使用具有不同作用模式的药物)。
人们仍然一直在寻找针对对现有治疗有抗性均高血压具有活性的化合物。另外,也在寻找具有更长的作用持续时间或具有更少的临床或生物学副作用的药物。因此,开发新的可供选择的治疗目前仍是重要的,且将一直是必需的。
广泛用于治疗高血压的一个治疗类别包括血管紧张肽转化酶抑制剂(ACE抑制剂)。在高血压的治疗中,血管紧张肽转化酶抑制剂是主要治疗类别之一。它们主要通过抑制血管紧张肽II的合成和通过阻断缓激肽的分解发挥作用。它们的血液动力学作用基本包括通过小动脉血管舒张作用降低总外周阻力,这导致动脉压降低,但不发生交感神经刺激和水/钠滞留。它们对各种类型的高血压都有效。除了降低动脉压以外,还已经证明它们可改善高血压患者、糖尿病患者和具有原有(preexisting)冠心病的患者的发病率(心肌梗死、脑血管意外事件)和心血管死亡率。除了在一些患者中发生干咳(一旦停止治疗该干咳是可逆的)以外,一般而言它们的耐受性非常好。
申请人现已令人惊奇地发现选择性和特异性窦房结If电流抑制剂、更特别是伊伐布雷定能增强血管紧张肽转化酶抑制剂的作用。这种作用是无法因选择性和特异性窦房结If电流抑制剂所属治疗类别这一事实而被预见的,其使得考虑将本发明的组合用于治疗高血压成为可能,并且更特别的是这种增强作用使得在用常规治疗组合无法控制的患者的治疗中使用本发明的组合成为可能。
可用于本发明的ACE抑制剂有:培哚普利、卡托普利、依那普利、赖诺普利、地拉普利、福辛普利、喹那普利、雷米普利、螺拉普利、咪哒普利、群多普利、贝那普利、西拉普利和替莫普利以及它们的水合物、结晶形式和与可药用的酸或碱的加成盐,但这不表示任何限制。
优选的ACE抑制剂有培哚普利、卡托普利、依那普利、雷米普利、赖诺普利、贝那普利、喹那普利和地拉普利以及它们的水合物、结晶形式和与可药用的酸或碱的加成盐,并且更尤其是培哚普利或者它的水合物、结晶形式和与可药用的酸或碱的加成盐中的一种,更特别是它的叔丁胺盐或精氨酸盐。
选择性和特异性窦房结If电流抑制剂是伊伐布雷定和来自Astellas的YM758以及它们的水合物、结晶形式和与可药用的酸或碱的加成盐。
本发明更特别地涉及伊伐布雷定或者它的水合物、结晶形式和与可药用酸的加成盐中的一种、更特别是它的盐酸盐与血管紧张肽转化酶抑制剂或者它的水合物、结晶形式和与可药用酸的加成盐中的一种的组合。
本发明更特别地涉及伊伐布雷定或者它的水合物、结晶形式和与可药用酸的加成盐中的一种、更特别是它的盐酸盐与培哚普利或者它的水合物、结晶形式和与可药用碱的加成盐中的一种、更特别是它的精氨酸盐或叔丁胺盐的组合。
本发明还涉及包含选择性和特异性窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的组合以及一种或多种可药用赋形剂的药物组合物。
本发明更特别地涉及包含选择性和特异性窦房结If电流抑制剂伊伐布雷定或者它的水合物、结晶形式和与可药用酸的加成盐、更特别是它的盐酸盐与血管紧张肽转化酶抑制剂或者它的水合物、结晶形式和与可药用酸的加成盐中的一种的组合以及一种或多种可药用赋形剂的药物组合物。
本发明优选涉及包含选择性和特异性窦房结If电流抑制剂伊伐布雷定或者它的水合物、结晶形式和与可药用酸的加成盐、更特别是它的盐酸盐与血管紧张肽转化酶抑制剂培哚普利或者它的水合物、结晶形式和与可药用碱的加成盐中的一种、更特别是它的精氨酸盐或叔丁胺盐的组合以及一种或多种可药用赋形剂的药物组合物。
在本发明的药物组合物中,可以更特别地提及的是适于口服、胃肠外或鼻施用的那些、片剂、糖锭剂(dragée)、舌下片、胶囊剂、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶剂等以及具有程序化释放(programmed release)、延迟释放、延长释放或延期释放(deferred release)性质的药物组合物。
除了选择性和特异性窦房结If电流抑制剂和血管紧张肽转化酶抑制剂以外,本发明的药物组合物还包含一种或多种选自稀释剂、润滑剂、粘合剂、崩解剂、吸收剂、着色剂、甜味剂等的赋形剂或载体。
可以以非限制性举例的方式提及的有:
◆作为稀释剂:乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素、甘油,
◆作为润滑剂:二氧化硅、滑石粉、硬脂酸及其镁和钙盐、聚乙二醇,
◆作为粘合剂:硅酸铝和硅酸镁、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮,
◆作为崩解剂:琼脂、海藻酸及其钠盐、泡腾混合物。
有效剂量随患者的性别、年龄和体重、施用途径、病症和任何联合治疗的性质而变化,伊伐布雷定的有效剂量为每24小时1至500mg,更优选每天10至15mg,还优选每天5至15mg。血管紧张肽转化酶抑制剂的剂量可以低于其单独施用时所用的剂量。
具体实施方式
以下实施例用于阐述本发明,但不以任何方式限制本发明。
药物组合物:
制备1000片每片含有7.5mg伊伐布雷定和2mg培哚普利的片剂的处方:
伊伐布雷定盐酸盐......................................7.5g
培哚普利叔丁胺盐......................................2g
乳糖一水合物..........................................62g
硬脂酸镁..............................................1.3g
聚乙烯吡咯烷酮........................................9g
无水胶态二氧化硅......................................0.3g
羟乙酸纤维素钠(cellulose sodium glycolate)............30g
硬脂酸................................................2.6g
下文给出了本发明的药物组合物的其它实例,但不表示任何限制:
实施例1
组分 | 量(mg) |
伊伐布雷定 | 10 |
培哚普利叔丁胺盐 | 4 |
实施例2
组分 | 量(mg) |
伊伐布雷定 | 10 |
培哚普利叔丁胺盐 | 8 |
实施例3
组分 | 量(mg) |
伊伐布雷定 | 15 |
培哚普利叔丁胺盐 | 4 |
实施例4
组分 | 量(mg) |
伊伐布雷定 | 15 |
培哚普利叔丁胺盐 | 8 |
实施例5
组分 | 量(mg) |
伊伐布雷定 | 10 |
培哚普利精氨酸盐 | 5 |
实施例6
组分 | 量(mg) |
伊伐布雷定 | 10 |
培哚普利精氨酸盐 | 10 |
实施例7
组分 | 量(mg) |
伊伐布雷定 | 15 |
培哚普利精氨酸盐 | 5 |
实施例8
组分 | 量(mg) |
伊伐布雷定 | 15 |
培哚普利精氨酸盐 | 10 |
上述药物组合物的给药是每24小时口服施用1片。
在有危险的人群(相当于超过75岁的患者)中,通过口服途径施用的初始临界剂量是每24小时5mg伊伐布雷定和2mg培哚普利叔丁胺盐或者5mg伊伐布雷定和2.5mg培哚普利精氨酸盐,以片剂形式施用。
临床研究no.1:
在患有已经正在用血管紧张肽转化酶抑制剂(培哚普利n=3,雷米普利n=2,依那普利n=1,赖诺普利n=1,福辛普利n=1)进行治疗的高血压和按照NYHA分类为1或2类的轻度至中度心力衰竭的8名患者中进行临床研究。对这些患者中的7名患者以7.5mg的剂量每天两次施用伊伐布雷定,对1名患者以5mg的剂量每天两次施用伊伐布雷定。治疗2个月(认为该持续时间足以达到两种治疗的最大作用)后,平均卧位动脉收缩压和动脉舒张压分别降低了7.5mmHg和7.3mmHg。
此外,将那些在入选研究时用血管紧张肽转化酶抑制剂无法良好控制动脉压的患者、也就是说那些仍然具有≥140mmHg的动脉收缩压和/或≥90mmHg的动脉舒张压的患者考虑在内,该组中动脉压的降低为:动脉收缩压降低10mmHg,动脉舒张压降低8mmHg。
表1:
入选时与用ACE抑制剂和伊伐布雷定治疗2个月后卧位动脉压的变化
入选时 | 2个月后 | |
SAP(mmHg) | 149.5 | 141.8 |
DAP(mmHg) | 81.7 | 74.4 |
SAP:动脉收缩压,卧位
DAP:动脉舒张压,卧位
表2:
进入试验时动脉压未被控制的患者入选时与治疗2个月后卧位动脉压的变化
入选时 | 2个月后 | |
SAP(mmHg ) | 159 | 149 |
DAP(mmHg) | 85 | 77 |
SAP:动脉收缩压,卧位
DAP:动脉舒张压,卧位
当将伊伐布雷定与血管紧张肽转化酶抑制剂进行加合时,相应地观察到动脉压的大幅度降低。这种动脉压降低是出乎意料的,因为在用伊伐布雷定进行的临床试验中所产生的平均降低一般为:动脉舒张压降低1-2mmHg数量级,实际上还伴有动脉收缩压的数量级为1mmHg的轻微增加。这种降低是重要的,因为已知在高血压患者中4-5mmHg的降低会很大幅度地(30%)减少心脏和神经系统意外事件的发生。
临床研究no.2:
在患有高血压和按照NYHA分类为3类的重度心力衰竭(相当于引起明显体力活动限制且仅在静止状态感觉舒适的心脏病)的患者中进行了补充临床研究。对患者治疗6周,该持续时间被认为足以清楚地观察到治疗的作用。患者通过口服施用接受下列治疗:
-以2.5mg的剂量每天两次施用伊伐布雷定,施用2周;然后
-在按下来的2周中,以5mg的剂量每天两次施用伊伐布雷定,除非患者表现出不耐受该产品,如过度的心动过缓或与明显的心动过缓有关的临床症状;然后
-在最后2周中,以7.5mg的剂量每天两次施用伊伐布雷定,除非患者表现出不耐受该产品,如过度的心动过缓或与明显的心动过缓有关的临床症状。40名已经正在用血管紧张肽转化酶抑制剂如培哚普利、雷米普利、依那普利、赖诺普利或福辛普利进行治疗的患者接受了上述治疗。平均卧位动脉收缩压和动脉舒张压分别降低了2.5mmHg和3.8mmHg。
表3:
入选时与用ACE抑制剂和伊伐布雷定治疗6周后卧位动脉压的变化
入选时 | 6周后 | |
SAP(mmHg) | 126.3 | 123.8 |
DAP(mmHg) | 78.4 | 74.6 |
SAP:动脉收缩压,卧位
DAP:动脉舒张压,卧位
此外,11名患者接受了上述治疗,这些患者在入选研究时用血管紧张肽转化酶抑制剂无法良好控制动脉压,也就是说这些患者仍然具有≥140mmHg的动脉收缩压和/或≥90mmHg的动脉舒张压,在该组中观察到的动脉压降低为:动脉收缩压降低10.7mmHg,动脉舒张压降低8.6mmHg。
表4:
在入选时动脉压未被控制的患者入选时与用ACE抑制剂和伊伐布雷定治疗6周后卧位动脉压的变化
入选时 | 6周后 | |
SAP(mmHg) | 142.1 | 131.4 |
DAP(mmHg) | 87.4 | 78.8 |
SAP:动脉收缩压,卧位
DAP:动脉舒张压,卧位
已经正在用培哚普利作为特定血管紧张肽转化酶抑制剂进行治疗的一组6名患者接受了上述治疗。在6周治疗结束时观察到了动脉压的显著降低:动脉收缩压降低17.5mmHg,动脉舒张压降低7.7mmHg。与前述临床研究的结论一致,考虑到在高血压患者中4-5mmHg的降低可很大幅度地(30%)减少心脏和神经系统意外事件的发生这一事实,这被认为是非常大的动脉收缩压和动脉舒张压降低。
表5:
入选时与用培哚普利和伊伐布雷定治疗6周后卧位动脉压的变化
入选时 | 6周后 | |
SAP(mmHg) | 127 | 109.5 |
DAP(mmHg) | 77.5 | 69.8 |
SAP:动脉收缩压,卧位
DAP:动脉舒张压,卧位
Claims (10)
1.选择性和特异性窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的组合。
2.权利要求1的组合,其中选择性和特异性窦房结If电流抑制剂是伊伐布雷定或3-{3-[{[(7S)-3,4-二甲氧基二环[4.2.0]辛-1,3,5-三烯-7-基]甲基}(甲基)氨基]丙基}-7,8-二甲氧基-1,3,4,5-四氢-2H-3-苯并氮杂-2-酮或者它的水合物、结晶形式或与可药用酸的加成盐中的一种。
3.权利要求1的组合,其中选择性和特异性窦房结If电流抑制剂是伊伐布雷定盐酸盐或者它的水合物或结晶形式中的一种。
4.权利要求1的组合,其中血管紧张肽转化酶抑制剂是培哚普利或者它的水合物、结晶形式或与可药用碱的加成盐中的一种。
5.权利要求1的组合,其中血管紧张肽转化酶抑制剂是培哚普利叔丁胺盐或精氨酸盐或者其水合物或结晶形式中的一种。
6.权利要求1的组合,其中选择性和特异性窦房结If电流抑制剂是伊伐布雷定盐酸盐或者它的水合物或结晶形式中的一种,血管紧张肽转化酶抑制剂是培哚普利叔丁胺盐或精氨酸盐或者其水合物或结晶形式中的一种。
7.药物组合物,其仅包含作为活性成分的权利要求1至6中任意一项的选择性和特异性窦房结If电流抑制剂与血管紧张肽转化酶抑制剂的组合,或者还包含一种或多种可药用赋形剂。
8.权利要求7的药物组合物,其包括作为活性成分的伊伐布雷定盐酸盐或者它的水合物或结晶形式中的一种和培哚普利叔丁胺盐或精氨酸盐或者其水合物或结晶形式中的一种。
9.权利要求7和8中任意一项的药物组合物,其用于制备治疗高血压的药物。
10.权利要求1至6中任意一项的组合在获得用于治疗高血压的药物组合物中的用途。
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CN101564394B (zh) * | 2008-04-21 | 2010-12-15 | 鲁南制药集团股份有限公司 | 含有伊伐布雷定和曲美他嗪的药物组合物 |
CN101507726B (zh) * | 2008-02-14 | 2012-03-28 | 瑟维尔实验室 | 窦房结If电流抑制剂和β-阻滞剂的组合 |
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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 |
FR2920772B1 (fr) * | 2007-09-11 | 2009-10-23 | Servier Lab | Association entre un anti-atherothrombotique et un inhibiteur de l'enzyme de conversion de l'angiotensine |
FR2961105B1 (fr) * | 2010-06-15 | 2013-02-08 | Servier Lab | Utilisation de l'association d'un inhibiteur du courant if sinusal et d'un inhibiteur de l'enzyme de conversion de l'angiotensine pour le traitement de l'insuffisance cardiaque |
WO2013116738A1 (en) * | 2012-02-03 | 2013-08-08 | Cardeus Pharmaceuticals, Inc. | Drug formulations |
FR3050380B1 (fr) | 2016-04-20 | 2020-07-10 | Les Laboratoires Servier | Composition pharmaceutique comprenant un betabloquant, un inhibiteur de l'enzyme de conversion et un antihypertenseur ou un ains. |
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US4508729A (en) * | 1979-12-07 | 1985-04-02 | Adir | Substituted iminodiacids, their preparation and pharmaceutical compositions containing them |
DE3736866A1 (de) * | 1987-10-30 | 1989-05-11 | Thomae Gmbh Dr K | Mittel zur behandlung des bluthochdrucks und der herzinsuffizienz |
FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
DE10018401A1 (de) * | 2000-04-13 | 2001-10-25 | Boehringer Ingelheim Pharma | Verwendung von Bradycardica bei der Behandlung von mit Hypertrophie einhergehenden Myocarderkrankungen und neue Arzneimittelkombinationen |
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US20040242565A1 (en) * | 2001-09-11 | 2004-12-02 | Yoshinori Toshima | Medicinal composition for prevention of or treatment for cerebrovascular disorder and cardiopathy |
FR2834896B1 (fr) * | 2002-01-23 | 2004-02-27 | Servier Lab | Composition pharmaceutique orodispersible d'ivabradine |
FR2838648B1 (fr) * | 2002-04-18 | 2004-05-21 | Servier Lab | Nouveau sel de perindopril et les compositions pharmaceutiques qui le contiennent |
DE60200160T2 (de) * | 2002-07-25 | 2004-11-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Cilobradine oder pharmazeutisch akzeptablen Salze zur Behandlung oder Prävention von Herzversagen |
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 |
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 |
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CN101507726B (zh) * | 2008-02-14 | 2012-03-28 | 瑟维尔实验室 | 窦房结If电流抑制剂和β-阻滞剂的组合 |
CN101564394B (zh) * | 2008-04-21 | 2010-12-15 | 鲁南制药集团股份有限公司 | 含有伊伐布雷定和曲美他嗪的药物组合物 |
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