CN1245963C - 包括心动徐缓剂的药物组合物及其用途 - Google Patents
包括心动徐缓剂的药物组合物及其用途 Download PDFInfo
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- CN1245963C CN1245963C CNB018079598A CN01807959A CN1245963C CN 1245963 C CN1245963 C CN 1245963C CN B018079598 A CNB018079598 A CN B018079598A CN 01807959 A CN01807959 A CN 01807959A CN 1245963 C CN1245963 C CN 1245963C
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- pyridine
- bradley
- treatment
- hypertrophy
- lip river
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Abstract
本发明涉及一种心动徐缓物质，例如Ca++通道阻断剂、β-受体阻断剂或if通道阻断剂的新用途，if通道阻断剂是优选的，与用于心脏的物质任意混合，降低肥大型心肌病的退化，特别是用于人和家养动物原发性的肥大型心肌病的治疗。
Description
采用心动徐缓物质可以治疗上升的心率，特别是Ca++通道阻断剂例如地尔硫卓和维拉帕米，或β-受体阻断剂例如阿替洛尔、比索洛尔、卡维洛尔、美多洛尔或心得安，以及if通道阻断剂例如查特布拉啶(zatebradine)[1-(7，8-二甲氧基-1，3，4，5-四氢-2H-3-苯基氮杂-2-酮-3-基)-3-[N-甲基-N-(2-(3，4-二甲氧基-苯基)-乙基)丙烷](参阅EP-B-0 065 229)、3-[(N-(2-(3，4-二甲氧基-苯基)-乙基)-哌啶-3-基)-甲基]-(7，8-二甲氧基-1，3，4，5-四氢-2H-3-苯基氮杂-2-酮)(参阅EP-B-0 224 794)及其对映体西洛布拉啶(cilobradine)[(+)-3-[(N-(2-(3，4-二甲氧基-苯基)-乙基)-哌啶-3-(S)-基)-甲基](7，8-二甲氧基-1，3，4，5-四氢-2H-3-苯基氮杂-2-酮]或者烯丙尼啶[2-(N-烯丙基-2，6-二氯苯胺基)-2-咪唑烷，也可参阅美国专利No.3,708,485]，而且，还知道查特布拉啶对治疗心的机能不全也有适当的效果(参阅EP-B-0 471388)。
然而，还已知该心动徐缓物质，特别是上述化合物，其中if通道阻断剂例如查特布拉啶、西洛布拉啶或烯丙尼啶，其中，西洛布拉啶是特别优选的，对于肥大型心肌疾病的症状治疗有利，特别适于原发性肥大型心肌病(HCM)例如心肌梗塞后心肌残留肥大、缺血性心肌病、瓣膜缺损的心肌肥大以及毒性或医源性影响的心肌肥大的治疗。
目前，惊奇地发现，心动徐缓物质，其中if通道阻断剂例如查特布拉啶、西洛布拉啶或烯丙尼啶，特别是西洛布拉啶是优选的，它不仅对肥大型心肌病的临床症状有适当的治疗效果，而且，甚至导致这些严重心脏病的消退。
本发明涉及心动徐缓物质，特别是上述化合物的一种新的用途，其中，if通道阻断剂例如查特布拉啶、西洛布拉啶或烯丙尼啶，特别是西洛布拉啶是优选的，它们导致肥大型心肌病的消退，特别适于人类和家养动物的原发性肥大型心肌病的治疗。
为了达到本发明的上述效果，采用文献中对单个心动徐缓物质用于治疗提高心率所给出的剂量的心动徐缓物质是适宜的。例如，西洛布拉啶的一次剂量，口服为0.1至0.5mg/kg，优选是0.2至0.4mg/kg、每天1至3次，对查特布拉啶是0.2至1mg/kg、每天2次，对烯丙尼啶是0.5至5mg/kg、每天2次。
本发明心动徐缓物质的新用途，是采用if通道阻断剂-西洛布拉啶作为实施例的方法进行研究，采用下列方法：
得了严重肥大型心肌病(心率约200次/分钟)的猫，采用ST增强的心电图作为心肌缺血信号，在血中以及在超声图像中肌酸激酶活性的增加，随着心室容积和痰分的减少心室壁的巨大压缩表明，在用if通道阻断剂例如西洛布拉啶(0.3mg/kg口服，每天2次)治疗后，临床症状有很大的改进(痛苦消除，心电图正常，正常的生理活性图像恢复)。
在1年以及大约2年治疗后，研究惊人地表明心肌的肥大消退，并保持症状改善。
以猫的肥大型心肌病作为模型对人体相应疾病进行研究(Kittleson等人，Circulation 91，3172-3180(1999))。
用if通道阻断剂西洛布拉啶不仅导致症状改善，而且疾病消退。
本发明还涉及药物组合物，其中含有至少一种心动徐缓物质，特别是一种上述化合物，优选是if通道阻断剂，和至少一种作用于心脏的物质，例如心糖苷如甲基地高辛或洋地黄毒苷；血管舒扩张剂如硝酸甘油；ACE抑制剂如卡托普利或依那普利；血管紧张素-II拮抗剂如洛沙丹(losartan)或替蜜沙丹(telmisartan)，该组合物对于肥大型心肌病的治疗也是适合的，特别适于原发性肥大型心肌病(HCM)的治疗，通过将它们与心动徐缓物质组合，可以防止心率上升。
为了达到本发明的效果，一般使用由文献中已知的单一的心动徐缓物质用于治疗心率上升的剂量，以及文献中已知的作用于心脏物质所用的剂量。
为了这个目的，心动徐缓物质，既可独立地用它们，也可与其他的作用于心脏的化合物组合使用，与一种或多种常用的惰性载体及/或稀释剂，例如与玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、聚乙烯基吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/丙三醇、水/山梨醇、水/聚乙二醇、丙二醇、硬脂醇、羧甲基纤维素或脂类物质例如硬脂防或其适当的混合物配制，以制成常用的药物制剂例如普通片剂、糖衣片剂、胶囊、粉剂、悬浮剂、液剂、喷雾剂或栓剂。
因此，例如，由西洛布拉啶和作用于心脏的化合物形成的组合物，一般每次口服含有0.1至0.5mg/kg，优选0.2至0.4mg/kg的西洛布拉啶，加上0.01至1mg的甲基地高辛，每天1至2次；0.01至1mg地高辛，每天1次；0.1至2mg的硝酸甘油，每天2至3次；10至100mg的卡托普利，每天1至2次；2至20mg的依那普利，每天1次；10至200mg的洛沙丹，每天2次；或20至80mg的替蜜沙丹，每天1次。
作为在药物组合物中if通道阻断剂的配偶体另外作用在单独的生物体系，并且，if通道阻断剂抑制心率的反射增加，它在与上述混合配偶体组合时可能产生，这些具有协同效应。
通过下列实施例说明本发明，但本发明不受其局限。
实施例1
含有1.25mg西洛布拉啶的胶囊
组成：
1胶囊含有：
乳糖一水合物 82.75mg
玉米淀粉 55.3mg
制造方法
把活性物质、乳糖一水合物和玉米淀粉加以混合，填充至4号胶囊中。
实施例2
含10mg西洛布拉啶的胶囊。
组成：
1胶囊含有：
乳糖一水合物 77.6mg
玉米淀粉 51.7mg
制造方法
把活性物质、乳糖一水合物和玉米淀粉加以混合，填充至4号胶囊中。
实施例3
含7.5mg西洛布拉啶的片剂
组成：
1片剂含有：
活性物质 7.5mg
玉米淀粉 59.5mg
乳糖 48.0mg
聚乙烯吡咯烷酮 4.0mg
硬脂酸镁 1.0mg
合计 120.0mg
制造方法
把活性物质、玉米淀粉、乳糖和聚乙烯吡咯烷酮进行混合，用水湿润。对湿润的混合物迫使通过1.5目细筛，并于45℃干燥。使干燥的颗粒通过1.0目细筛并与硬脂酸镁混合。把最终的混合物用配有分开槽的7mm直径的冲模的压片机压制成片剂，形成片。
每片重量：120mg
实施例4
含5mg西洛布拉啶的糖衣片剂
1片剂芯含有：
活性物质 5.0mg
玉米淀粉 41.5mg
乳糖 30.0mg
聚乙烯吡咯烷酮 3.0mg
硬脂酸镁 0.5mg
合计 80.0mg
制造方法
把活性物质、玉米淀粉、乳糖和聚乙烯吡咯烷酮均匀混合，用水湿润。对湿润的物质迫使通过1.0mm细筛并于45℃干燥，然后，使颗粒物通过同样的细筛。在与硬脂酸镁混合后，用压片机压制成直径6mm的凸状片芯。把这样制成的片芯，用已知的方法，用含有主要是蔗糖和滑石的涂层液进行涂布。用蜡抛光最终的糖衣片剂。
糖衣片剂重量：130mg
实施例5
含5mg西洛布拉啶的安瓿
1安瓿含有：
活性物质 5.0mg
山梨醇 50.0mg
注射用水 2.0mg
制造方法
在适当的混合容器内使活性物质溶于注射用水中，用山梨醇使该溶液等渗。
通过膜式过滤器过滤后，在氮气氛中把溶液注入经过洗涤和灭菌的安瓿中，并且在水蒸汽汽流中高压灭菌20分钟。
实施例6
含10mg西洛布拉啶的栓剂
1栓剂含有：
活性物质 0.010g
硬脂肪(例如，Witepsol H 19和W 45) 1.690g
合计 1.700g
制造方法
把硬脂肪熔融。于38℃，把碾碎的活性物质均匀分散在熔融物中。冷却至35℃，注入稍为冷却的栓剂模中。
实施例7
含10mg西洛布拉啶的滴剂
100ml溶液中含有：
活性物质 0.2g
羟乙基纤维素 0.15g
酒石酸 0.1g
山梨醇溶液，70％干重 30.0g
丙三醇 10.0g
苯甲酸 0.15g
蒸馏水 加至100ml
制造方法
把蒸馏水加热至70℃。在搅拌下把羟乙基纤维素、苯甲酸和酒石酸溶于其中。把溶液冷却至室温，在搅拌下添加丙三醇和山梨醇溶液。在室温下添加活性物质，搅拌该混合物使完全溶解。然后，搅拌下抽真空以从糖浆中除去空气。
Claims (3)
1.西洛布拉啶在制备用于治疗肥大型心肌病的药物组合物中的用途。
2.权利要求1的用途，特征在于所述的药物组合物还包括其他作用于心脏的化合物。
3.权利要求1的用途，特征在于所述的药物组合物还含有作为另一种作用于心脏的化合物的心糖苷、血管舒张剂、ACE-抑制剂或血管紧张素-II拮抗物。
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| ES2211846T3 (es) * | 2002-07-25 | 2004-07-16 | BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG | Uso de cilobradina o sus sales farmaceuticamente aceptables para el tratamiento o la prevencion de la insuficiencia cardiaca. |
| US20040138306A1 (en) * | 2002-07-25 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of a specific cyclic amine derivative or the pharmaceutically acceptable salts thereof for the treatment or prevention of heart failure |
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| TR200100062T2 (tr) * | 1998-07-10 | 2001-06-21 | Novartis Ag | Valsartan ve kalsiyum kanalı bloklayıcısının anti-hipertensif kombinasyonu |
| 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 |
| CA2435526A1 (en) | 2002-07-25 | 2004-01-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of cyclic amine derivatives or the pharmaceutically acceptable salts thereof for the treatment or prevention of heart failure |
| US20040138306A1 (en) * | 2002-07-25 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of a specific cyclic amine derivative or the pharmaceutically acceptable salts thereof for the treatment or prevention of heart failure |
| EP1762179A1 (en) * | 2005-09-07 | 2007-03-14 | Boehringer Ingelheim Vetmedica Gmbh | Method for improving diagnostic quality in echocardiography |
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2000
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