CN101015556B - 窦房结If电流抑制剂与钙抑制剂的组合以及含有它的药物组合物 - Google Patents
窦房结If电流抑制剂与钙抑制剂的组合以及含有它的药物组合物 Download PDFInfo
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- CN101015556B CN101015556B CN2006100643177A CN200610064317A CN101015556B CN 101015556 B CN101015556 B CN 101015556B CN 2006100643177 A CN2006100643177 A CN 2006100643177A CN 200610064317 A CN200610064317 A CN 200610064317A CN 101015556 B CN101015556 B CN 101015556B
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Abstract
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钙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电流抑制剂与钙抑制剂的新组合。
发明内容
本发明涉及选择性和特异性窦房结If电流抑制剂与钙抑制剂的新组合。
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-1，3，4，5-四氢-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钙抑制剂、更特别是来自二氢吡啶类的钙抑制剂的新组合。
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EP 0 534 859中有描述。
申请人现已令人惊奇地发现与钙抑制剂、更特别是来自二氢吡啶类的钙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-酮具有非常有价值的性质，这使得它们可被组合用于治疗绞痛。
钙抑制剂是具有阻断细胞膜的某些通道对钙的通透性这一基本性质的化合物。它们防止电压依赖性通道的孔的打开并且因此对抗钙进入血管平滑肌纤维。它们降低细胞内游离钙的水平，结果是降低外周和冠状血管的平滑肌张力。因此，这些化合物且更特别是属于二氢吡啶类的那些特别适用于治疗绞痛，因为它们减少静脉血回流，从而减少左心室的工作负荷，并且它们一方面降低心肌耗氧量，另一方面利用它们对大的心外膜动脉的血管舒张作用来改善冠脉血流。二氢吡啶类的外周血管舒张作用的结果之一是导致反射性心动过速，其在被治疗心绞痛的患者中可持续存在。已知在心率增加与冠脉患者(coronary patient)的心血管死亡率之间存在密切关系。这已经被与报道的二氢吡啶类的心血管死亡率增加和心肌梗死的可能风险相关联。
二氢吡啶类最常出现的不良作用是心动过速、心悸、头痛和下肢水肿，这些不良作用具有剂量依赖性。
因此，确实需要使得可由这些化合物的正性作用受益同时又增加它们的安全限度、特别是它们的心血管安全限度的新疗法。
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不仅能增强钙抑制剂且更特别是属于二氢吡啶类的那些钙抑制剂的作用，而且其本身还显示出能极好地提高那些钙拮抗剂的安全性，且更特别是不良心脏作用、下肢水肿和头痛。这种双重作用使得考虑将本发明的组合用于治疗绞痛并且增加使用安全性成为可能。
本发明的组合中的选择性和特异性窦房结If电流抑制剂更特别地是伊伐布雷定、扎替雷定和西洛雷定，还有它们的水合物、结晶形式和与可药用的酸或碱的加成盐。
本发明的组合中的钙抑制剂更特别地是属于二氢吡啶类的那些。本发明的组合中的钙抑制剂是：氨氯地平、硝苯地平、非洛地平以及它们的水合物、结晶形式和与可药用的酸或碱的加成盐，且更特别是苯磺酸盐或马来酸盐，但这不表示任何限制。
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钙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。
本发明甚至更优选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氨氯地平或者它的水合物、结晶形式和与可药用酸的加成盐中的一种、更特别是它的苯磺酸盐或马来酸盐的组合。
本发明还涉及包含选择性和特异性窦房结If电流抑制剂与钙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、结晶形式或与可药用酸的加成盐、更特别是它的盐酸盐与钙抑制剂、更特别是来自二氢吡啶类的钙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。
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电流抑制剂和钙抑制剂以外，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15至20mg，还优选每天5至15mg。钙抑制剂的剂量可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10mg伊伐布雷定和5mg氨氯地平的片剂的处方：
伊伐布雷定盐酸盐.......................................10g
氨氯地平苯磺酸盐.......................................5g
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 |
| 氨氯地平 | 5 |
实施例2
| 组分 | 量(mg) |
| 伊伐布雷定 | 15 |
| 氨氯地平 | 5 |
实施例3
| 组分 | 量(mg) |
| 伊伐布雷定 | 10 |
| 氨氯地平 | 10 |
实施例4
| 组分 | 量(mg) |
| 伊伐布雷定 | 15 |
| 氨氯地平 | 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(相当于高血压且超过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5mg氨氯地平，以片剂形式施用。
临床研究：
·在正在用二氢吡啶类钙拮抗剂进行治疗、仍然具有疼痛性心绞痛发作(尽管使用了钙拮抗剂)的患者中进行的两项临床研究已经表明用伊伐布雷定进行伴随治疗可很大幅度地(约60％)减少这些发作。
表1：
入选时正在施用二氢吡啶类且已经施用伊伐布雷定1年的患者绞痛发作次数的变
化
n＝患者数
·另外，令人惊奇的是，伊伐布雷定与氨氯地平的组合导致氨氯地平的安全性和可接受性提高。在伊伐布雷定用于治疗心绞痛的临床研发过程中，与氨氯地平单一药物治疗或氨氯地平与伊伐布雷定的组合相比，对伊伐布雷定的可接受性进行了研究。结果显示当伊伐布雷定与氨氯地平组合时，后者的使用安全性、特别是其心脏安全性增加：
表2：
每100病人-年暴露(patient-year of exposure)单独使用氨氯地平或使用氨氯地平+
伊伐布雷定组合进行治疗的冠脉患者的不良事件
| 伊伐布雷定+钙拮抗剂 n＝686 病人-年：262.6 | 单独的氨氯地平 n＝401 病人-年：94.8 | |
| 不良心脏事件 | 40.0 | 58.0 |
| -心律失常 | 28.6 | 35.9 |
| -不稳定型心绞痛 | 2.3 | 5.3 |
| -心肌梗死 | 1.9 | 3.2 |
| -冠心病恶化 | 0.4 | 2.1 |
| -心悸 | 1.1 | 3.1 |
| 下肢水肿 | 22.9 | 33.5 |
| 头痛 | 3.8 | 9.5 |
n＝患者数
当将伊伐布雷定与氨氯地平进行加合时，可以清楚地看出不良事件水平更低，特别是心律失常类和冠脉缺血事件类(不稳定型心绞痛、心肌梗死和冠心病恶化)心脏事件。重要的是应当注意到当加入伊伐布雷定时下肢水肿的发生率非常明显地降低(下肢水肿是氨氯地平最常见的不良作用且接近10％的病例为此原因停止治疗)，头痛的情况也是如此。
Claims (8)
1.选择性和特异性窦房结If电流抑制剂伊伐布雷定或其与可药用酸的加成盐与钙抑制剂氨氯地平或其与可药用酸的加成盐的组合。
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盐酸盐。
3.权利要求1的组合，其中钙抑制剂是氨氯地平苯磺酸盐。
4.权利要求1的组合，其包含伊伐布雷定盐酸盐和氨氯地平苯磺酸盐。
5.药物组合物，其仅包含作为活性成分的权利要求1至4中任意一项的选择性和特异性窦房结If电流抑制剂伊伐布雷定或其与可药用酸的加成盐和钙抑制剂氨氯地平或其与可药用酸的加成盐，或者还包含一种或多种可药用赋形剂。
6.权利要求5的药物组合物，其仅包含作为活性成分的伊伐布雷定盐酸盐与氨氯地平苯磺酸盐的组合，或者还包含一种或多种可药用赋形剂。
7.权利要求5和6中任意一项的药物组合物，其用于制备治疗绞痛的药物。
8.权利要求1至4中任意一项的组合在获得用于治疗绞痛的药物组合物中的用途。
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