CN1116042C - 含有氯吡格雷和一种抗血栓形成药活性成分的组合物 - Google Patents
含有氯吡格雷和一种抗血栓形成药活性成分的组合物 Download PDFInfo
- Publication number
- CN1116042C CN1116042C CN97192393A CN97192393A CN1116042C CN 1116042 C CN1116042 C CN 1116042C CN 97192393 A CN97192393 A CN 97192393A CN 97192393 A CN97192393 A CN 97192393A CN 1116042 C CN1116042 C CN 1116042C
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- Prior art keywords
- aspirin
- clopidogrel
- active component
- pharmaceutical composition
- medicine
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- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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Abstract
本发明涉及一种包含活性成分组合的药物组合物，其中活性成分是氯吡格雷和阿司匹林，这两种成分以游离态或药学可接受盐的形式存在。
Description
发明领域
本发明的主题是一种由氯吡格雷和阿司匹林组成的具有抗血小板凝集活性的活性成分的新的组合，以及含有它们的药物组合物。
构成该组合物的活性成分以其游离态或其一种药学可接受盐的形式存在。
发明背景
在过去的十年里，人们对于血小板在与动脉粥样硬化相关疾病(心肌梗塞形成，绞痛，大脑疾病发作，外周动脉病，等等)的进展中所起的作用的研究显示出极大的兴趣。已经证明的血小板在动脉血栓形成中的作用使开发了几种抑制血小板这些功能的药物，而对于ADP在血栓形成过程中起基本作用的发现导致开发出了噻氯匹定，这是一种有潜力的抗血栓形成药物。这种噻吩并[3，2-c]吡啶衍生物公开于专利FR 73 03503。噻氯匹定选择性抑制ADP诱导的血小板凝集以及ADP介导的其它拮抗剂引起的血小板凝集[Feliste等，血栓研究(Thromb.Res.)，1987，48，403-415]。
在多中心双盲临床研究中，证明噻氯匹定在预防血管意外伤害高危患者大脑疾病发作中明显比阿司匹林或安慰剂更有效(Gent等，Lancet，1989，8649，1215-1220；Hass等，N.Eng.J.Med.，1989，321，501-507)。也证明其对于中心或外周血管意外伤害高危患者明显比安慰剂更有效(Janzon等，Scand.J.Int.Med.，1990，227，301-308)。
尽管至今已知阿司匹林和噻氯匹定通过两种不同的机理作用，进行了一些研究来比较这两种药物的有效性，但是只是最近一些研究建议与阿司匹林结合施用噻氯匹定以代替目前对于移植金属血管内膜修复患者不好的治疗效果在急性血栓形成方面特别令人感兴趣(Van Belle等，Cor.Art.Dis.，1995，6，341-345)。
专利FR 75 12084要求保护噻氯匹定和阿司匹林的组合作为赋予血动力学作用的抗血小板凝集的用途，其定性和定量上都比单独的噻氯匹定优越得多。这些结果借助于通过测定ADP或胶原诱导的血小板凝集进行的与血小板凝集抑制性质相关的药学研究被证明。获得的这些结果预计了噻氯匹定与阿司匹林的组合在尤其是在外科手术之后出现的一些类型的急性血栓形成中的治疗学上的重要性，但还不足以从中得出对动脉粥样硬化疾病或动脉内膜切除术或进行金属血管内膜修复术中的血管意外伤害的第二预防作用的指示法。
此外已知，抗血小板凝集剂的其它组合例如阿司匹林-双嘧达莫的组合，是在预防患者脑血管意外伤害或发生血管分路闭合的研究中针对于单独的双嘧达莫或阿司匹林的临床研究的主题。这些研究的结论是阿司匹林-双嘧达莫的组合在大脑动脉栓塞局部缺血或趋向于血栓形成的第二预防作用中不比用单独的双嘧达莫或单独的阿司匹林产生任何显著的改进作用(Acta..Neurol.Scand.，1987，76(6)，413-421；血栓(Thrombosis)，1994，AlertNo.12；血栓，1994，Alert No.9；血栓，1993，Alert No.9；血栓，1993，AlertNo.2)。
今天，冠状动脉和颈动脉水平上的金属血管内膜修复术可以被认为是预防和治疗中心和外周血管意外伤害中一个重要的治疗上的进展。然而因为其金属性质，这些修复术具有潜在的亲血栓形成作用，现在基本上借助于抗血栓剂和主要的抗血小板凝集剂来防止这种作用。
作为另一种噻吩并吡啶衍生物的公开于EP 099802的氯吡格雷也被证实是一种有潜力的抗凝血剂，其作用机理与噻氯匹定相同(Savi等，J.Pharmacol.Exp.Ther.，1994，269，772-777；Herbert等，新血管药物研究(Cardiovasc.Drug Rev.)，1993，11，180-198)。
其应用对于一些病态例如心血管和脑血管系统的疾病是有益的，所述疾病例如与动脉粥样硬化或与糖尿病相关的血栓栓塞疾病，例如不稳定性绞痛，大脑疾病发作，血管成形术后的再狭窄，动脉内膜切除术或金属动脉内膜修复术，与栓塞后的再栓塞，与梗塞形成，与局部缺血起源的痴呆，与外周动脉疾病，与血渗析，与心房纤维性颤动相关的或与应用血管修复术或主动脉冠状动脉分流术期间相关的，或与稳定的或不稳定的绞痛相关的血栓栓塞疾病。
根据使用的凝集剂，氯吡格雷在动物和人体内的功效比噻氯匹定高大约10-50倍。而且与后者不一样，氯吡格雷实际上具有即刻抗凝集活性，其在给药后15分钟内出现抗凝集活性，而噻氯匹定为了达到功效，需要以高得多的剂量至少3天延长给药。而且与噻氯匹定不同，氯吡格雷可以静脉途径给药，而且通过该途径具有与通过口服途径获得的效果完全相等的抗凝集作用(Herbert等，心血管药物研究，1993，11，180-198)。而只能通过口服途径给药的噻氯匹定却未产生这种情况。
发明内容
令人非常吃惊和出人意料的是，证明本发明氯吡格雷-阿司匹林组合产生这两种活性成分的协同作用。该作用与兔血小板与胶原的凝集有关，其特征在于ADP和花生四烯酸的新陈代谢机制，胶原由于其连接依赖性而是唯一的可以使用的凝集剂。
此外，关于在兔的连接颈动脉和颈静脉的导管中植入的形成血栓的表面(丝线)的植入所诱导的形成动脉源血栓发现了类似的协同作用。
本发明组合物不会由于放血时间延长而增大出血的可能性，而且毒性很低。其毒性与其作为治疗这些疾病和治疗上述血栓源疾病的药物的用途相适应。
本发明组合物可以配制成用于对包括人在内的哺乳动物给药的药物组合物，用于治疗上述疾病。
根据本发明，可以以药学可接受盐的形式施用氯吡格雷和阿司匹林。
这些盐是药学上常用的盐，例如乙酸盐，苯甲酸盐，富马酸盐，马来酸盐，柠檬酸盐，酒石酸盐，2，5-二羟基苯甲酸盐，甲磺酸盐，乙磺酸盐，苯磺酸盐，月桂基磺酸盐，氢醌磺酸盐和对甲苯磺酸盐。
在下文中，氯吡格雷的量和阿司匹林的量以等量的没有成盐的游离形式的氯吡格雷和阿司匹林表示。
有益的是，本发明组合物含有的氯吡格雷和阿司匹林的摩尔比(阿司匹林/氯吡格雷)在2.5和11.5之间，优选在5和9之间，更优选在7和8之间。
本发明组合物可以以要治疗的哺乳动物的每千克体重0.1-100mg氯吡格雷或阿司匹林的日剂量使用。
对于人来说，根据要治疗的对象的年龄和治疗的类型：预防或治愈，各成分的日剂量可以在每天1-500mg范围内变化。
因此本发明的目的是含有氯吡格雷和阿司匹林的组合为活性成分的药物组合物，其中的活性成分被配制成每单位剂量含有0.1-500mg所述活性成分的剂量单位，这两种成分均以游离状态或药学上可接受盐的形式存在。优选制备可通过口服或肠胃外途径给药的组合物。
在用于口服，舌下，皮下，肌内，静脉内，皮内，局部或直肠给药的本发明药物组合物中，活性成分可以以与常规药物载体混合的用于给药的单位形式对动物和对人给药。合适的给药单位形式包括用于口服给药的形式，例如片剂，明胶胶囊，粉剂，粒剂和口服溶液或悬浮液，用于舌下或口腔含化给药的形式，用于皮下，肌内，静脉内，鼻内或眼内给药的形式和用于直肠给药的形式。
当制备片剂形式的固体组合物时，主要活性成分与例如明胶，淀粉，乳糖，硬脂酸镁，滑石粉，阿拉伯胶等这样的药物赋形剂混合。片剂可以用蔗糖或其它合适的材料包衣，或者可以处理片剂使其具有缓释活性，使其持续释放预定量的活性成分。
明胶胶囊形式的制剂通过将活性成分与一种稀释剂混合和通过将得到的混合物倒入软的或硬明胶胶囊中来获得。
糖浆或酏剂形式的制剂可以含有活性成分和一种优选没有热量的甜味剂，作为防腐剂的对羟基苯甲酸甲酯或对羟基苯甲酸丙酯，以及味觉增强剂和合适的着色剂。
水可分散的粒剂或粉剂可以含有与分散剂或湿润剂，或悬浮剂，例如聚乙烯吡咯烷酮，以及甜味剂或矫味剂混合的活性成分。
对于直肠给药，采用由在直肠温度下融化的粘合剂，例如可可脂或聚乙二醇制备的栓剂。
对于肠胃外，鼻内或眼内给药，使用水悬浮液，等渗盐水溶液，灭菌和可注射溶液，其中含有药学相容的分散剂和/或湿润剂，例如聚乙二醇或丁二醇。
活性成分也可以视具体情况而定与一种或几种载体或添加剂配制成微胶囊形式。
组合的活性成分也可以以与环糊精例如α-，β-或γ-环糊精，2-羟基丙基-β-环糊精或甲基-β-环糊精复合的形式存在。
当本发明组合物通过肠胃外和/或口服途径对人给药时，优选氯吡格雷的日剂量是50-100mg，阿司匹林的日剂量是100-500mg。
注意，根据本发明，氯吡格雷和阿司匹林二者都可以通过口服途径给药，或者二者都通过肠胃外途径给药，或者一种通过口服途径给药(优选阿司匹林)，另一种通过肠胃外途径给药(优选氯吡格雷)。
根据一个优选的实施方案，通过肠胃外和/或口服途径对人给药的氯吡格雷的日剂量在65-100mg之间，在65-85mg之间更好，通过肠胃外途径给药的阿司匹林的日剂量在200-400mg之间，在315-335mg之间更好。
优选的是，在这种情况下氯吡格雷的剂量是每天75mg，阿司匹林的剂量是每天325mg。
具体实施方式
本发明活性成分的组合是药物研究的主题。如上所述，针对用胶原凝集兔血小板的试验进行研究(Born等，J.Physiol.，1963，168，178-95)。简要地说，通过口服途径用噻氯匹定(100mg/kg/天)对2.5-3kg新西兰兔治疗3天，或者通过静脉内途径用氯吡格雷(10mg/kg)治疗。最后一次给药后1小时，用阿司匹林(1mg/kg)静脉内途径处理动物。
给药阿司匹林5分钟后，用乙醚麻醉动物，并且从耳中动脉采取2ml血样，并与0.2ml 3.8％柠檬酸钠水溶液混合。将血样在15℃以500g离心10分钟，获得富血小板血浆。然后借助于通过将抗凝血样离心(3000g，15分钟)获得的低血小板的血浆，将血小板数目调节至106细胞/μl。
根据Born的方法(Born等，J.Physiol.，1963，168，178-95)借助于双道凝集测试仪(Chrono Log)，在37℃，搅拌下(900rpm)，测定血小板的凝集作用。血小板的凝集作用是胶原(12.5μg/ml)诱发的。
根据Umetsu等所述(Thromb.Haemostas.，1978，39，74-83)，关于在兔的颈动脉和颈静脉之间植入的动静脉分路中存在的丝线上的血栓形成，测定氯吡格雷或噻氯匹定与阿司匹林组合的抗血栓作用。简要地说，通过口服途径用噻氯匹定(100mg/kg/d)对2.5-3kg新西兰兔治疗3天，或者通过静脉内途径用氯吡格雷(10mg/kg)治疗。
通过皮下给予戊巴比妥钠(30mg/kg)麻醉动物。在右颈动脉和左颈静脉之间放入含有5cm长丝线的与6cm长中心部分(内径：0.9mm)连接的12cm长(内径：0.6mm；外径：0.9mm)的两个聚乙烯管。最后给药噻氯匹定或氯吡格雷1小时后用阿司匹林(1mg/kg)静脉内途径处理动物。然后放入分路的中心部分，然后在血液在分路中循环20分钟后去除。然后测定丝线上存在的血栓的重量。
表1所示的结果表明，通过静脉内途径对兔给予单一剂量的氯吡格雷(10mg/kg)或阿司匹林(1mg/kg)，抑制胶原诱发的血小板凝集。对于胶原诱发的血小板凝集，口服途径给药噻氯匹定(100mg/kg/天)三天，也显示出显著的抑制效果。
在所有的情况下，对于胶原诱发的血小板凝集，氯吡格雷和阿司匹林的结合给药都产生显著的协同作用。也就是说，当组合给药这些产品时，获得的抗凝集效果总是大于两种试验产品分别获得的效果的简单加和。
与获得的噻氯匹定和阿司匹林的抗凝集效果之间所发现的简单加和效果相比，以及与专利FR73 03503中所要求保护的效果相比，该活性完全是新的和意料之外的。
以相同的方式，氯吡格雷的抗血栓活性通过与阿司匹林的组合而加强。在这些条件下，关于胶原诱发的血小板凝集，发现了显著的协同作用(表2)。
表1
单独或组合产品对胶原诱发的兔血小板凝集的作用
| 活性成分 | 剂量 | 抑制百分率 |
| 噻氯匹定 | 100mg/kg/天-3天 | 35±3％ |
| 氯吡格雷 | 10mg/kg | 42±6％ |
| 阿司匹林 | 1mg/kg | 21±2％ |
| 噻氯匹定+阿司匹林 | 100+1mg/kg | 52±6％ |
| 氯吡格雷+阿司匹林 | 10+1mg/kg | 98±1％ |
表中给出的值是5个试验±标准误差的平均值(n＝5)。
表2
单独或组合产品对兔动静脉分路中植入的丝线上动脉血栓形成的作用
| 活性成分 | 剂量 | 抑制百分率 |
| 噻氯匹定 | 100mg/kg/天-3天 | 25±9％ |
| 氯吡格雷 | 10mg/kg | 34±4％ |
| 阿司匹林 | 1mg/kg | 19±5％ |
| 噻氯匹定+阿司匹林 | 100+1mg/kg | 45±3％ |
| 氯吡格雷+阿司匹林 | 10+1mg/kg | 82±1％ |
表中给出的值是5个试验±标准误差的平均值(n＝5)。
Claims (7)
1.含有活性成分协同组合的药物组合物，其中的活性成分为氯吡格雷和阿司匹林，其被配制成每单位剂量含有0.1-500mg所述活性成分的剂量单位，这两种成分均以游离状态或药学上可接受盐的形式存在。
2.含有活性成分协同组合的药物组合物，其中的活性成分为氯吡格雷和阿司匹林，并且这两种成分均以游离状态或药学上可接受盐的形式存在，氯吡格雷和阿司匹林以阿司匹林/氯吡格雷的摩尔比为2.5-11.5存在。
3.权利要求2的药物组合物，其特征在于氯吡格雷和阿司匹林以阿司匹林/氯吡格雷的摩尔比为5-9存在。
4.含有权利要求1-3任一项所述组合物以及至少一种药学上可接受赋形剂的药物组合物。
5.权利要求1所述的组合物用于制备治疗因血小板凝集诱导的病症的药物的用途，所述的病症包括稳定或不稳定绞痛和心血管系统疾病。
6.权利要求5所述的制备药物的用途，所述的药物用来治疗不稳定绞痛、大脑疾病发作、血管成形术、动脉内膜切除术或金属动脉内膜修复术后的再狭窄。
7.权利要求5所述的制备药物的用途，所述的药物用来治疗与栓塞后的再栓塞相关的血栓栓塞疾病，与梗塞形成、局部缺血起源的痴呆、外周动脉疾病、血渗析、心房纤维性颤动相关的血栓栓塞疾病或与应用血管修复术或主动脉冠状动脉分流术期间相关的血栓栓塞疾病。
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| EP (1) | EP0881901B1 (zh) |
| JP (1) | JP3662028B2 (zh) |
| KR (1) | KR100295345B1 (zh) |
| CN (1) | CN1116042C (zh) |
| AT (1) | ATE218870T1 (zh) |
| AU (1) | AU715655B2 (zh) |
| BR (1) | BR9707556A (zh) |
| CA (1) | CA2246289C (zh) |
| CZ (1) | CZ292363B6 (zh) |
| DE (2) | DE69713287T2 (zh) |
| DK (1) | DK0881901T3 (zh) |
| EE (1) | EE03513B1 (zh) |
| ES (1) | ES2176684T3 (zh) |
| FR (1) | FR2744918B1 (zh) |
| HK (1) | HK1017850A1 (zh) |
| HU (1) | HU225036B1 (zh) |
| IL (1) | IL125848A (zh) |
| IS (1) | IS1892B (zh) |
| NO (2) | NO317747B3 (zh) |
| NZ (1) | NZ331444A (zh) |
| PL (1) | PL187292B1 (zh) |
| PT (1) | PT881901E (zh) |
| RU (1) | RU2184547C2 (zh) |
| SI (1) | SI0881901T1 (zh) |
| SK (1) | SK284285B6 (zh) |
| TR (1) | TR199801608T2 (zh) |
| UA (1) | UA51695C2 (zh) |
| WO (1) | WO1997029753A1 (zh) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2322824A1 (en) * | 1998-03-13 | 1999-09-16 | Merck & Co., Inc. | Combination therapy and composition for acute coronary ischemic syndrome and related conditions |
| WO1999065500A1 (en) | 1998-06-17 | 1999-12-23 | Bristol-Myers Squibb Company | Preventing cerebral infarction through administration of adp-receptor antiplatelet and antihypertensive drugs in combination |
| US6509348B1 (en) | 1998-11-03 | 2003-01-21 | Bristol-Myers Squibb Company | Combination of an ADP-receptor blocking antiplatelet drug and a thromboxane A2 receptor antagonist and a method for inhibiting thrombus formation employing such combination |
| FR2792836B3 (fr) | 1999-04-30 | 2001-07-27 | Sanofi Sa | Composition pharmaceutique sous forme unitaire contenant de l'aspirine et de l'hydrogenosulfate de clopidogrel |
| FR2797400A1 (fr) * | 1999-08-11 | 2001-02-16 | Sanofi Synthelabo | Associations a activite anti-thrombotique constituees de l'hydrogenosulfate de clopidogrel et d'un antagoniste des recepteurs gpiib/iiia et les compositions pharmaceutiques les contenant |
| PL206138B1 (pl) * | 2000-12-25 | 2010-07-30 | Daiichi Sankyo Company Limiteddaiichi Sankyo Company Limited | Kompozycja farmaceutyczna zawierająca aspirynę oraz zestaw i zastosowanie składników kompozycji |
| SE0101932D0 (sv) * | 2001-05-31 | 2001-05-31 | Astrazeneca Ab | Pharmaceutical combinations |
| FR2832929A1 (fr) * | 2001-12-05 | 2003-06-06 | Sanofi Synthelabo | Compositions pharmaceutiques contenant un agent antithrombotique et un derive d'amines cycliques |
| AU2003270861A1 (en) * | 2002-10-02 | 2004-04-23 | Bristol-Myers Squibb Company | Novel combination of a factor xa inhibitor and clopidogrel |
| US20070243632A1 (en) * | 2003-07-08 | 2007-10-18 | Coller Barry S | Methods for measuring platelet reactivity of patients that have received drug eluting stents |
| ATE536889T1 (de) | 2003-07-08 | 2011-12-15 | Accumetrics Inc | Kontrollierte thrombozyten-aktivierung zur überwachung der behandlung von adp-antagonisten |
| HUP0400982A2 (en) * | 2004-05-17 | 2006-08-28 | Chemor Kutato | New veterinary product for honeybees |
| US20060222640A1 (en) * | 2005-03-29 | 2006-10-05 | Boehringer Ingelheim International Gmbh | New pharmaceutical compositions for treatment of thrombosis |
| EP1926736A4 (en) * | 2005-09-21 | 2010-08-25 | Chong Kun Dang Pharm Corp | NEW RESINATE COMPLEX OF S-CLOPIDOGREL AND METHOD FOR THE PRODUCTION THEREOF |
| WO2008048083A1 (es) * | 2006-10-17 | 2008-04-24 | Espinosa Abdala Leopoldo De Je | Composiciones farmacéuticas para el tratamiento de enfermedades tromboembólicas |
| DE102006051625A1 (de) | 2006-11-02 | 2008-05-08 | Bayer Materialscience Ag | Kombinationstherapie substituierter Oxazolidinone |
| KR20160033792A (ko) | 2007-04-27 | 2016-03-28 | 사이덱스 파마슈티칼스, 인크. | 클로피도그렐 및 설포알킬 에테르 사이클로덱스트린을 함유하는 제형 및 사용 방법 |
| KR100949273B1 (ko) * | 2008-02-22 | 2010-03-25 | 한올제약주식회사 | 복합제제 |
| DE102008032361A1 (de) * | 2008-07-10 | 2010-01-21 | Csl Behring Gmbh | Der Einsatz von Faktor VIII und vWF bzw. vWF-enthaltenden Konzentraten zur Therapie der durch Thrombocyten-Inhibitoren induzierte Koagulopathie |
| US8236782B2 (en) * | 2009-05-13 | 2012-08-07 | Cydex Pharmaceuticals, Inc. | Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same |
| EA021588B1 (ru) | 2009-06-25 | 2015-07-30 | Тетра Сиа | Бетаиновые соли ацетилсалициловой кислоты |
| US8563574B2 (en) | 2009-12-07 | 2013-10-22 | Academic Pharmaceuticals, Inc. | Parenteral formulation of clopidogrel |
| CN102389436A (zh) * | 2011-09-09 | 2012-03-28 | 北京阜康仁生物制药科技有限公司 | 一种抗血小板聚集的药物组合物 |
| KR101675501B1 (ko) * | 2011-11-02 | 2016-11-14 | 한국유나이티드제약 주식회사 | 클로피도그렐 및 아스피린의 복합제제 |
| US8513278B2 (en) | 2011-11-26 | 2013-08-20 | Academic Pharmaceuticals, Inc. | Parenteral dextrose formulation of clopidogrel |
| CN102406938A (zh) * | 2011-11-29 | 2012-04-11 | 北京阜康仁生物制药科技有限公司 | 一种抗血栓的药物组合物 |
| WO2013133620A1 (en) * | 2012-03-09 | 2013-09-12 | Yuhan Corporation | Pharmaceutical composition comprising clopidogrel and aspirin and process for preparing the same |
| CN103720700A (zh) * | 2012-10-10 | 2014-04-16 | 江苏威凯尔医药科技有限公司 | 含有阿斯匹林和维卡格雷的药用组合物 |
| EP2796145B1 (en) | 2013-04-22 | 2017-11-01 | CSL Ltd. | A covalent complex of von willebrand factor and faktor viii linked by a disulphide bridge |
| KR101502588B1 (ko) | 2013-05-01 | 2015-03-16 | 한국유나이티드제약 주식회사 | 클로피도그렐 및 아스피린의 복합제제 |
| WO2015015062A1 (fr) * | 2013-08-02 | 2015-02-05 | Sanofi | Comprime pharmaceutique comprenant de l'acide acetylsalicylique et du clopidogrel |
| HUP1400294A2 (hu) | 2014-06-13 | 2015-12-28 | Skillpharm Kft | Clopidogrel új alkalmazása |
| CN107698620A (zh) * | 2015-06-23 | 2018-02-16 | 江苏天士力帝益药业有限公司 | 一种氘代噻吩并哌啶衍生物、制备方法及其应用 |
| RU2745774C1 (ru) * | 2020-08-14 | 2021-03-31 | Алексей Викторович Марочков | Способ лечения пациентов с новой коронавирусной инфекцией (covid-19) |
| US20230059869A1 (en) | 2021-08-03 | 2023-02-23 | Liqmeds Worldwide Limited | Oral pharmaceutical solution of clopidogrel |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2307538A1 (fr) * | 1975-04-18 | 1976-11-12 | Centre Etd Ind Pharma | Nouveau medicament anti-agregant plaquettaire |
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1996
- 1996-02-19 FR FR9602027A patent/FR2744918B1/fr not_active Expired - Fee Related
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1997
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- 1997-02-17 HU HU9901144A patent/HU225036B1/hu active Protection Beyond IP Right Term
- 1997-02-17 IL IL12584897A patent/IL125848A/xx not_active IP Right Cessation
- 1997-02-17 WO PCT/FR1997/000296 patent/WO1997029753A1/fr active IP Right Grant
- 1997-02-17 CA CA002246289A patent/CA2246289C/fr not_active Expired - Lifetime
- 1997-02-17 JP JP52906097A patent/JP3662028B2/ja not_active Expired - Lifetime
- 1997-02-17 RU RU98117511/14A patent/RU2184547C2/ru active
- 1997-02-17 SK SK1105-98A patent/SK284285B6/sk not_active IP Right Cessation
- 1997-02-17 PL PL97327923A patent/PL187292B1/pl unknown
- 1997-02-17 NZ NZ331444A patent/NZ331444A/en not_active IP Right Cessation
- 1997-02-17 AT AT97905218T patent/ATE218870T1/de active
- 1997-02-17 SI SI9730355T patent/SI0881901T1/xx unknown
- 1997-02-17 CZ CZ19982499A patent/CZ292363B6/cs not_active IP Right Cessation
- 1997-02-17 UA UA98094800A patent/UA51695C2/uk unknown
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- 1997-02-17 CN CN97192393A patent/CN1116042C/zh not_active Expired - Lifetime
- 1997-02-17 DK DK97905218T patent/DK0881901T3/da active
- 1997-02-17 KR KR1019980706556A patent/KR100295345B1/ko not_active IP Right Cessation
- 1997-02-17 AU AU18844/97A patent/AU715655B2/en not_active Revoked
- 1997-02-17 DE DE201012000030 patent/DE122010000030I2/de active Active
- 1997-02-17 EP EP97905218A patent/EP0881901B1/fr not_active Expired - Lifetime
- 1997-02-17 BR BR9707556A patent/BR9707556A/pt not_active IP Right Cessation
- 1997-02-17 PT PT97905218T patent/PT881901E/pt unknown
- 1997-02-17 US US09/117,904 patent/US5989578A/en not_active Expired - Lifetime
- 1997-02-17 TR TR1998/01608T patent/TR199801608T2/xx unknown
- 1997-02-17 ES ES97905218T patent/ES2176684T3/es not_active Expired - Lifetime
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1998
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