CN101507726B - 窦房结If电流抑制剂和β-阻滞剂的组合 - Google Patents
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Abstract
窦房结If电流抑制剂和β-阻滞剂的组合和包含它的药物组合物。
Description
本发明涉及窦房结If电流抑制剂和beta阻滞剂或β-阻滞剂的固定组合和包含它们的药物组合物。
更具体地，本发明涉及其为式(I)的伊伐布雷定或3-{3-[{[(7S)-3，4-二甲氧基双环[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、或其水合物、结晶形式或与药物可接受酸的任何加成盐之一和β-阻滞剂的固定组合。
本发明优选地涉及在心脏选择性类型的β-阻滞剂、更特别地阿替洛尔或其水合物、结晶形式或其与药物可接受酸的任何加成盐之一和作为窦房结If电流抑制剂伊伐布雷定或其水合物或结晶形式之一之间的固定组合。
窦房结If电流抑制剂，更具体地伊伐布雷定及其水合物和结晶形式及其与药物可接受酸的加成盐，更特别地盐酸盐，具有非常有价值的药理学和治疗学性质，特别是阴性变时(negative chronotropic)性质(心率的降低)，这些性质使这些化合物用于心肌缺血诸如心绞痛、心肌梗塞和相关的心律紊乱的各种临床情况的治疗或预防中，并且还用于涉及心律紊乱的各种病理，特别是室上性心律紊乱和心衰。
伊伐布雷定及其与药物可接受酸的加成盐更特别地其盐酸盐的制备及治疗用途，已在欧洲专利说明书EP 0534859中进行了描述。
β-阻滞剂(β-blockers)或β-阻滞剂(β-blocking agents)，是抑制β-肾上腺素能受体的化合物。β-阻滞剂具有通过降低去极化斜率、降低心脏的工作负荷和减少氧的需求而使心脏减慢的作用。因此，β-阻滞剂被用于心绞痛的治疗、特别是心脏病发作的预防中。β-阻滞剂以表面上矛盾的方式用于心衰治疗。
根据本发明的β-阻滞剂优选地是心脏选择性β-阻滞剂，也就是说它们优先地阻断β1心脏受体。它们的心脏选择性特性使其可能降低继发作用，特别是外周血管收缩和支气管收缩。心脏选择性β-阻滞剂更特别地选自以下药物：醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、艾司洛尔、美托洛尔和奈比洛尔。
心血管障碍领域中的文献与舆论导向人一般得出这样的结论：在稳定性心绞痛的治疗中证实包含β-阻滞剂加另一类抗心绞痛化合物的组合比β-阻滞剂单一疗法的优越性是困难的。
本发明令人惊异地证实，窦房结If电流抑制剂，且更特别地，伊伐布雷定能够使β-阻滞剂具有提高锻炼能力的作用。因此，锻炼能力的提高与活性剂即窦房结If电流抑制剂和β-阻滞剂之间的协同作用相关。
在根据本发明的药物组合物中，窦房结If电流抑制剂和β-阻滞剂的用量与这些活性剂的性质相匹配，且它们的相对比例是随着所述活性剂的功能相应地变化的。
根据本发明的药物组合物具有活性剂总重比例1.6％至80％的窦房结If电流抑制剂，活性剂总重比例20％至98％的β-阻滞剂。
当窦房结If电流抑制剂为盐酸盐形式的伊伐布雷定，且β-阻滞剂为阿替洛尔时，组合优选的百分数是盐酸盐形式的伊伐布雷定约25％，相对的阿替洛尔为75％。
本发明还涉及药物组合物，其包含作为活性剂的一种任选地以药物可接受盐的形式存在的窦房结If电流抑制剂和β-阻滞剂的组合，独自或连同一种或多种适当的、惰性的、非毒性的载体或赋形剂而存在。
在根据本发明的药物组合物中，活性剂的重量比例(活性剂的重量对组合物的总重量)优先地为从5至50％。
至于药物可接受的赋形剂，无需任何限制地可提及的有：粘合剂、稀释剂、崩解剂、稳定剂、防腐剂、润滑剂、香料、芳香剂或甜味剂。
以非限制性实例的方式可提及的有：
-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、硬脂酸及其镁盐和钙盐、聚乙二醇；
-作为粘合剂：硅酸镁铝、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。
在根据本发明的药物组合物中，将更特别地选自适于通过口服、肠胃外且特别是静脉、经皮或透皮、鼻内、直肠、舌下、眼部或呼吸途径施用的那些，更具体地为片剂或糖衣丸剂、舌下片剂、硬明胶胶囊剂、glossettes、胶囊剂、锭剂、可注射制剂、气雾剂、滴眼剂、滴鼻剂、栓剂、乳膏剂、软膏剂或皮肤用凝胶剂。
优选的施用途径是口服途径，且相应的药物组合物可允许活性剂的即刻或延期释放。
优选的药物组合物为片剂。
剂量可根据障碍的性质与严重程度、施用途径以及患者的年龄与体重而变化。在根据本发明的组合物中，其每24小时以一次或多次施用的剂量范围，β-阻滞剂为从25至150mg，对窦房结If电流抑制剂为从2.5至30mg。优选地，当窦房结If电流抑制剂为伊伐布雷定，施用剂量为每天两次(b.i.d.)从5至7.5mg。当β-阻滞剂为阿替洛尔时，每日施用剂量优选地为一次施用50mg。
最后，根据本发明的药物组合物用于制备治疗心绞痛、心肌缺血和心衰的药物。
以下组合物的实施例是以非限制性实施例的方式给出的。
伊伐布雷定/阿替洛尔片：
实施例1：
临床试验：
选择用于临床试验的患者是患心绞痛至少3个月、且使用诸如阿替洛尔(50mg o.d.)或任何其他的相当剂量的β-阻滞剂至少3个月的、年龄在18至75岁的男人和女人。尽管接受治疗，但这些患者运动耐力试验(ETT)仍为阳性，且每日有心绞痛的症状。
该双盲、平行组、国际临床试验是在889名患者中进行的。患者全部正在接受阿替洛尔，被随机化至两组：
-除了β-阻滞剂以外，第一组以每日两次5mg的剂量给予伊伐布雷定(盐酸盐)两个月，并以每日两次7.Smg的剂量再给予两个月；
-除了β-阻滞剂以外，第二组给予安慰剂4个月。
患者在被施用伊伐布雷定之前(即只接受β-阻滞剂时)按照Bruce方案接受跑台运动耐力试验(ETT)，并且在用伊伐布雷定与阿替洛尔之间的组合治疗4个月以后。在运动试验的过程中测定的主要参数是：
-总的运动持续时间(TED)-TED包括开始至结束跑台运动(即从患者请求停止运动开始的约10秒钟的时间)的时间；
-至“心绞痛”疼痛使得患者停止运动(TLA)的时间；
-至“心绞痛”疼痛发作(TAO)的时间；
-1mm ST段衰退(TST)至出现在心电图记录上的时间，这反映了心肌缺血与相应的心肌疼痛的电信号。
这些测定是在活性剂组合的谷活性时，即在活性剂施用后的12±1小时和24±2小时测定的。
根据来自依从性总结的数据，根据本发明的伊伐布雷定/β-阻滞剂的组合确保了良好的接受性和良好的使用安全性。
患者平均年龄为60±8岁。在进入本研究中时，患者在休息时的平均收缩/舒张动脉压与心率分别为：127±12/78±7mmHg/67±7次每分钟。在使用该组合治疗4个月后，心率已降低9±10bpm(β-阻滞剂+安慰剂1±10bpm)。
将在跑台运动试验期间测定的开始使用伊伐布雷定治疗前与治疗期结束时测定的数值之间的各种参数的平均改善情况，排列下表中：
| β-阻滞剂+伊伐布雷定(n＝441) | β-阻滞剂+安慰剂(n＝434) | p-值 | |
| TED | 24±65 | 8±64 | P＜0.001 |
| TAO | 49±83 | 23±79 | P＜0.001 |
| TLA | 26±66 | 9±64 | P＜0.001 |
| TST | 46±93 | 15±87 | P＜0.001 |
参数的改善(以秒表示，均值±SD)
本研究显示伊伐布雷定能够改善已经接受标准剂量的β-阻滞剂的患者的运动耐力。
高水平的依从性(接受伊伐布雷定患者中的99％)和严重不良事件的低百分率显示了伊伐布雷定加β-阻滞剂与单一疗法中的β-阻滞剂相比的接受性与安全性。
Claims (6)
1.窦房结If电流抑制剂和β-阻滞剂的组合产品，其中窦房结If电流抑制剂为伊伐布雷定或其与药物可接受酸的加成盐，β-阻滞剂为阿替洛尔或比索洛尔，或其与药物可接受酸的加成盐。
2.根据权利要求1的组合产品，其特征在于窦房结If电流抑制剂为伊伐布雷定盐酸盐。
3.药物组合物，其包含作为活性成分的独自或与一种或多种药物可接受的赋形剂组合的根据权利要求1或2的组合产品。
4.用于制备治疗心绞痛、心肌缺血和心衰的药物的根据权利要求3的药物组合物。
5.根据权利要求1或2的组合产品在制备治疗心绞痛、心肌缺血和心衰的药物中的用途。
6.根据权利要求3或4的药物组合物在制备治疗心绞痛、心肌缺血和心衰的药物中的用途。
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| FR0800800A FR2927538B1 (fr) | 2008-02-14 | 2008-02-14 | Association d'un inhibiteur du courant if sinusal et d'un beta-bloquant. |
| FR08/00800 | 2008-02-14 |
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| US9674435B1 (en) * | 2016-07-06 | 2017-06-06 | Lawrence Maxwell Monari | Virtual reality platforms for capturing content for virtual reality displays |
| KR20190001340A (ko) * | 2017-06-27 | 2019-01-04 | 에리슨제약(주) | 이바브라딘을 포함하는 서방성 약제학적 조성물 및 이의 제조방법 |
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| CN101015557A (zh) * | 2005-12-21 | 2007-08-15 | 瑟维尔实验室 | 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 |
| CN101015556A (zh) * | 2005-12-21 | 2007-08-15 | 瑟维尔实验室 | 窦房结If电流抑制剂与钙抑制剂的新组合以及含有它的药物组合物 |
| CN101095682A (zh) * | 2007-07-23 | 2008-01-02 | 北京本草天源药物研究院 | 一种伊伐布雷定或其药用盐的口服制剂 |
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| EP0519925A1 (en) * | 1989-11-21 | 1992-12-30 | Sepracor, Inc. | Use of optically pure s(-) atenolol for the treatment of cardiovascular disorders |
| FR2681862B1 (fr) | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
| US20040242565A1 (en) * | 2001-09-11 | 2004-12-02 | Yoshinori Toshima | Medicinal composition for prevention of or treatment for cerebrovascular disorder and cardiopathy |
| 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 |
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| CN101015557A (zh) * | 2005-12-21 | 2007-08-15 | 瑟维尔实验室 | 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 |
| CN101015556A (zh) * | 2005-12-21 | 2007-08-15 | 瑟维尔实验室 | 窦房结If电流抑制剂与钙抑制剂的新组合以及含有它的药物组合物 |
| CN101095682A (zh) * | 2007-07-23 | 2008-01-02 | 北京本草天源药物研究院 | 一种伊伐布雷定或其药用盐的口服制剂 |
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