CN101193656B - 甘油三酸酯降低剂 - Google Patents
甘油三酸酯降低剂 Download PDFInfo
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- CN101193656B CN101193656B CN2006800201019A CN200680020101A CN101193656B CN 101193656 B CN101193656 B CN 101193656B CN 2006800201019 A CN2006800201019 A CN 2006800201019A CN 200680020101 A CN200680020101 A CN 200680020101A CN 101193656 B CN101193656 B CN 101193656B
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- CN
- China
- Prior art keywords
- inhibitor
- hmg
- coa reductase
- pitavastatin
- reductase inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及一种含有HMG-CoA还原酶抑制剂和PDE3抑制剂的血中甘油三酸酯(TG)降低剂。
Description
技术领域
本发明涉及一种以HMG-CoA还原酶抑制剂及cAMP分解酶抑制剂为有效成分的甘油三酸酯降低剂。
背景技术
期待各种他汀类药物(HMG-CoA还原酶抑制剂)具有强的降胆固醇作用而给予高胆固醇患者。作为他汀类药物的附带作用,已知对甘油三酸酯(TG)有轻微的降低作用(文献:CE Rackley,Clin.Cardio1.,1996,19(9):683-9等),由于其作用不充分,因此提出与其它TG降低剂并用。因此TG降低作用强的贝特类药物与他汀类药物的并用是理想的,但以肾功能障碍患者为重点,常发生横纹肌溶解症等副作用,因此该组合应慎重给药。
磷酸二酯酶(PDE)是分解环核苷酸的磷酸二酯键的酶,目前已知有11种同位型(isotype)。PDE3是磷酸二酯酶的同位型之一,受环GMP(cGMP)抑制,是在心脏、支气管等组织细胞、脂肪细胞、血小板等中发现的酶。因此,PDE3抑制剂用作强心剂、血小板凝集抑制剂。
另外,关于PDE3抑制剂有以下报道:将西洛他唑给予糖尿病大鼠时,有降低TG的作用(学会発表:上原 二等,日本動 硬化学会冬季大会(1992)抄録、動 硬化1992,20:824),但将其给予正常大鼠时,降低TG的作用不确定(厚生劳动省2003,大塚制药关于西洛他唑预防脑梗塞发病后复发的效能扩大的申请概要),临床报告显示向患者给药4周时TG降低(文献:向原伸彦等,カレントフア一マシ一(Current Pharmacy)1990,8:618)、或者在给药24周时出现一过性上升后又回到前值(文献:百 修司等,新薬と臨床1996,45:1837),以及在大鼠静脉内给予米力农时,确认由于TG分解引起游离脂肪酸上升(文献:P Cheung等,Metabolism,2003,52:1496-50)等降低TG的作用,但是明确的作用效果尚不清楚。
PDE3抑制剂的主要作用是通过抑制PDE,即磷酸二酯酶的活性,提高环AMP(cAMP)的水平。即:通过给予PDE3抑制剂,使cAMP 上升,从而诱导、激活脂蛋白脂酶,这在约30年前就已经知道,已知cAMP及其稳定诱导体、cAMP合成酶(腺苷酸环化酶)激活剂及各种PDE抑制剂有脂质分解作用(文献:D Baum等,Proc.Soc.Exp.Bio1.Med.1976,151:244-8等)。现在已知,在使用脂肪组织及细胞的体外实验中,脂质分解作用强,但在使用动物的体内实验中,其效果不显著。
通常,高脂血症患者往往表现出高TG血浆的症状,开发了通过与作为高脂血症治疗剂的HMG-CoA还原酶抑制剂并用以减少副作用且有效促进TG降低作用的药物。
发明内容
本发明人进行了专门研究,结果意外地发现将HMG-CoA还原酶抑制剂与PDE3抑制剂并用,显示出显著降低血中TG的作用,从而完成了本发明。
因此,本发明涉及一种含有HMG-CoA还原酶抑制剂和PDE3抑制剂以及药学上可接受载体的医药组合物,更具体而言涉及一种用于降低血中甘油三酸酯(TG)的医药组合物。另外,本发明提供一种含有HMG-CoA还原酶抑制剂和PDE3抑制剂以及药学上可接受的载体,将这些有效成分制成单一制剂给予需要的患者的医药组合物,更具体而言提供一种用于降低血中甘油三酸酯(TG)的医药组合物。此外,本发明提供一种含有有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂以及药学上可接受的载体,同时或间隔地分别给予需要的患者的医药组合物,更具体而言提供一种用于降低血中甘油三酸酯(TG)的医药组合物。
另外,本发明涉及一种含有HMG-CoA还原酶抑制剂和PDE3抑制剂的甘油三酸酯(TG)降低剂。另外,本发明提供一种含有HMG-CoA还原酶抑制剂和PDE3抑制剂以及药学上可接受的载体,将这些有效成分制成单一制剂给予需要的患者的甘油三酸酯(TG)降低剂。此外,本发明提供一种含有有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂以及药学上可接受的载体,同时或间隔地分别给予需要的患者的甘油三酸酯(TG)降低剂。
另外,本发明提供一种降低血中甘油三酸酯(TG)含量的方法或预 防血中甘油三酸酯(TG)含量上升的方法,其特征是将有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂同时或间隔地分别给予需要的患者。另外,本发明还提供一种降低血中甘油三酸酯(TG)含量的方法或预防血中甘油三酸酯(TG)含量上升的方法,其特征是将有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂这些有效成分制成单一制剂给予需要的患者。
另外,本发明提供一种HMG-CoA还原酶抑制剂和PDE3抑制剂的用途,用于制备含有有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂的用于降低血中甘油三酸酯(TG)的医药组合物。本发明提供一种HMG-CoA还原酶抑制剂和PDE3抑制剂的用途,用于制备将有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂制成单一制剂给药的甘油三酸酯(TG)降低剂。另外,本发明还提供一种HMG-CoA还原酶抑制剂和PDE3抑制剂的用途,用于制备将有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂同时或间隔地分别给药的甘油三酸酯(TG)降低剂。
此外,本发明提供一种预防或治疗高甘油三酸酯(TG)血症的方法,其特征是将有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂同时或间隔地分别给予需要的患者。另外,本发明还提供一种预防或治疗高甘油三酸酯(TG)血症的方法,其特征是将有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂这些有效成分制成单一制剂给予需要的患者。
附图说明
图1是表示匹伐他汀钙(记为匹伐他汀)与K-134或西洛他唑并用给药对血浆TG浓度的影响图。
具体实施方式
本发明人为了改善HMG-CoA还原酶抑制剂的甘油三酸酯(TG)降低作用,尝试了与各种药物并用。研究了通过各种药物组合对TG的降低作用,结果本发明人意外地发现,在HMG-CoA还原酶抑制剂与PDE3抑制剂组合时,显示出显著降低血中TG的作用。虽然报道各种PDE抑制剂具有脂质分解作用,但是体内实验表明其作用不显著,特别是关于 通过PDE3抑制剂降低TG的作用仍不明确,因此该结果令人感到意外。
本发明人将匹伐他汀钙用作HMG-CoA还原酶抑制剂,此外,将K-134或西洛他唑用作PDE3抑制剂,从而确认本发明的并用作用。
即:关于这些药物并用时的作用,使用大鼠进行实验,结果在图1中示出。图1表示在14天内,将药物反复口服给予大鼠,从最后一天下午给药开始断食,22小时后采血,测定血浆中的TG的结果。图1的纵轴表示血浆中甘油三酸酯(TG)的浓度(mg/dL)。从图1的左侧起,分别表示对照组、匹伐他汀钙(记为匹伐他汀)单独给药组、K-134单独给药组、西洛他唑单独给药组、匹伐他汀钙(记为匹伐他汀)与K-134并用给药组,右侧表示匹伐他汀钙(记为匹伐他汀)与西洛他唑并用给药组。
正如所预料的那样,该结果表明PDE3抑制剂K-134和西洛他唑在生物体内几乎没有TG降低作用,另外还表明HMG-CoA还原酶抑制剂匹伐他汀的TG降低作用也非常弱。但是,虽然任一药物单独给药时几乎不显示降低甘油三酸酯(TG)的作用,但当这些药物并用时,尽管断食下也显示约30~40%这样非常显著的甘油三酸酯(TG)降低作用。
这样,本发明首次阐明了HMG-CoA还原酶抑制剂与PDE3抑制剂并用具有各药物单独使用无法发现的显著的甘油三酸酯(TG)降低作用。
作为本发明中并用的PDE3抑制剂,只要是具有能在生物体内抑制PDE3活性作用的物质即可,具体地说,可以列举例如依诺昔酮、伊马唑旦、匹罗昔酮、伊索马唑、利沙齐农(リキサジノン)、吲哚利旦、西洛他唑、K-134((-)-6-[3[3-环丙基-3-[(1R,2R)-2-羟基环己基]脲基]-丙氧基]-2-(1H)-喹啉酮)(日本专利第2964029号、美国专利第6,143,763号、欧洲专利第796248号)、匹莫苯、氨力农、米力农、维司力农(OPC-8212)、利沙齐农(リクサジオン)、曲喹辛及西洛酰胺等,其中特别优选西洛他唑和K-134。如果制剂学上需要,这些药物也可以作为盐及溶剂化物使用。本发明中的PDE3抑制剂可以使用选自上述PDE抑制剂中的1种或2种以上的药物。
另外,作为本发明中并用的HMG-CoA还原酶抑制剂,是具有能在生 物体内抑制HMG-CoA还原酶活性作用的物质,具体地说,可以列举例如以下化合物。
洛伐他汀(化学名:(S)-2-甲基丁酸-(+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-六氢-3,7-二甲基-8-[2-[(2R,4R)-四氢-4-羟基-6-氧代-2H-吡喃-2-基]乙基]-1-萘酯(参照美国专利第4,231,938号));
辛伐他汀(化学名:2,2-二甲基丁酸-(+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-六氢-3,7-二甲基-8-[2-[(2R,4R)-四氢-4-羟基-6-氧代-2H-吡喃-2-基]乙基]-1-萘酯(参照美国专利第4,444,784号));
普伐他汀(化学名:(+)-(3R,5R)-3,5-二羟基-7-[(1S,2S,6S,8S,8aR)-6-羟基-2-甲基-8-[(S)-2-甲基丁酰氧基]-1,2,6,7,8,8a-六氢-1-萘基]庚酸(参照美国专利第4,346,227号));
氟伐他汀(化学名:(3RS,5SR,6E)-7-[3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基]-3,5-二羟基-6-庚烯酸(参照美国专利第5,354,772号));
阿托伐他汀(化学名:(3R,5R)-7-[2-(4-氟苯基)-5-异丙基-3-苯基-4-苯基氨基甲酰基-1H-吡咯-1-基]-3,5-二羟基庚酸(参照美国专利第5,273,995号));
西立伐他汀(化学名:(3R,5S)-赤-(E)-7-[4-(4-氟苯基)-2,6-二异丙基-5-甲氧基甲基-吡啶-3-基]-3,5-二羟基-6-庚烯酸(参照美国专利第5,177,080号));
美伐他汀(化学名:(S)-2-甲基丁酸-(+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-六氢-7-甲基-8-[2-[(2R,4R)-四氢-4-羟基-6-氧代-2H-吡喃-2-基]乙基]-1-萘酯(参照美国专利第3,983,140号));
罗苏伐他汀(化学名:7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰基氨基嘧啶)-5-基]-(3R,5S)-二羟基-(E)-6-庚烯酸(参照美国专利第5,260,440号、日本专利第2648897号));
匹伐他汀((3R,5S,6E)-7-[2-环丙基-4-(4-氟苯基)-3-喹啉基]-3,5-二羟基-6-庚烯酸(参照美国专利第5,856,336号、日本专利第2569746号))
这些药物如果制剂学上需要,也可以盐及溶剂化物的形式使用。特 别优选的抑制剂是匹伐他汀。作为本发明中的HMG-CoA还原酶抑制剂,可以使用选自上述HMG-CoA还原酶抑制剂中的1种或2种以上的药物。
本发明使用的HMG-CoA还原酶抑制剂及PDE3抑制剂,可以将其通过公知方法或以下所示方法等分别单独进行制剂化后同时或间隔地并用给予而使用。也可以将各有效量按适当的配合比制成单一的剂型使用。
作为这些制剂,本领域技术人员可以根据公知的制剂方法,混合药学上可接受的载体,制备成口服制剂或非口服制剂,例如口服剂、注射剂、栓剂、软膏剂、贴剂等适于给药形式的组合物。另外,本发明中的HMG-CoA还原酶抑制剂及PDE3抑制剂也可以使用其制药上可接受的盐、其水合物、或其制药上可接受的盐的水合物,该制药上可接受的盐及其水合物可以按常规方法制备。其中,作为制药上可接受的盐,例如形成酸加成盐的酸,可以列举盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸等无机酸;醋酸、乳酸、琥珀酸、酒石酸、苹果酸、马来酸、富马酸、柠檬酸、抗坏血酸、甲磺酸、苯磺酸、甲苯磺酸等有机酸等。本发明的HMG-CoA还原酶抑制剂及PDE3抑制剂,可以将其中1种作为有效成分使用,也可以将其中的2种以上混合作为有效成分使用。
在配制口服固体制剂时,例如,可以在HMG-CoA还原酶抑制剂及PDE3抑制剂或其制药上可接受的盐或其水合物中,添加赋形剂、根据需要的粘合剂、崩解剂、润滑剂、着色剂、矫味剂、矫臭剂等后,按照常规方法制备片剂、包衣片剂、颗粒剂、散剂、胶囊剂等。作为该添加剂,可以是本领域中通常使用的添加剂,例如,作为赋形剂,可以乳糖、白糖、氯化钠、葡萄糖、淀粉、碳酸钙、高岭土、微晶纤维素、硅酸等为例;作为粘合剂,可以水、乙醇、丙醇、单糖浆、葡萄糖液、淀粉液、明胶液、羧甲基纤维素、羟丙基纤维素、羟丙基淀粉、甲基纤维素、乙基纤维素、紫胶、磷酸钙、聚乙烯吡咯烷酮等为例;作为崩解剂,可以干燥淀粉、褐藻酸钠、琼脂末、碳酸氢钠、碳酸钙、十二烷基硫酸钠、单硬脂酸甘油酯、乳糖等为例;作为润滑剂,可以以精制滑石、硬脂酸盐、硼砂、聚乙二醇等为例;作为矫味剂,可以白糖、橙皮、柠檬酸、酒石酸等为例。
在配制口服液体制剂时,例如可以在HMG-CoA还原酶抑制剂及 PDE3抑制剂或其制药上可接受的盐或其水合物中,根据需要添加矫味剂、缓冲剂、稳定剂、矫臭剂等,按照常规方法制备内服液剂、糖浆剂、酏剂等。在这种情况下,作为矫味剂可为上述列举的矫味剂;作为缓冲剂可以柠檬酸钠等为例;作为稳定剂可以黄芪胶、阿拉伯胶、明胶等为例。
在配制注射剂时,例如可以根据需要添加pH调节剂、缓冲剂、稳定剂、等渗剂、局部麻醉剂等,按照常规方法制备皮下、肌肉及静脉内注射剂。在这种情况下,作为pH调节剂及缓冲剂,可以柠檬酸钠、醋酸钠、磷酸钠等为例。作为稳定剂,可以焦亚硫酸钠、EDTA、巯基乙酸、硫代乳酸等为例。作为局部麻醉剂,可以盐酸普鲁卡因、盐酸利多卡因等为例。作为等渗剂,可以氯化钠、葡萄糖等为例。
其它剂型也可以根据公知的方法同样进行制剂化。
另外,也可以将该制剂化的医药品制剂分别包装,在给药时分别从各包装中取出各医药品制剂使用。另外,也可以将各医药品制剂以适于每一次并用给药的形式包装。
由此得到的本发明的具有甘油三酸酯(TG)降低作用的医药组合物,不仅作为高甘油三酸酯(TG)血症等的预防药及/或治疗药有效,还具有作为HMG-CoA还原酶抑制剂及PDE3抑制剂的作用,因此,作为高胆固醇血症、动脉硬化症、末梢循环功能不全、动静脉血栓症、糖尿病及其并发症、高血压症及其并发症、代谢异常综合征(代谢综合征)等的预防药及/或治疗药也有效。
本发明具有降低甘油三酸酯(TG)作用的医药组合物的给药量,因患者体重、年龄、性别、症状、给药形式及给药次数等而不同,通常对于成人,作为HMG-CoA还原酶抑制剂,一日为0.01~1000mg、优选为0.1~100mg,另外,作为PDE3抑制剂,一日为0.01~5000mg、优选为0.1~500mg,将其1次或分数次,作为单独制剂或将各制剂并用地口服或非口服给药。在使用匹伐他汀作为HMG-CoA还原酶抑制剂时,优选1日1次,晚餐后口服1~2mg。在将HMG-CoA还原酶抑制剂及PDE3抑制剂分别以单独制剂使用时,这些制剂可以同时给药,也可以间隔15分 钟至6小时给药。
实施例
下面通过实施例具体地说明本发明,但是本发明并不受这些实施例的任何限制。
实施例1
匹伐他汀钙与K-134或西洛他唑并用给药时降低血浆TG的作用
按下述1~4所述的方法测定匹伐他汀钙与K-134或西洛他唑并用给药时降低血浆TG的作用。
1.供试动物及饲养环境
7周龄Wistar系雄性大鼠(日本クレア株式会社),实验期间,在维持明暗周期(通过室内光照明的时间:上午7点~下午7点)、温度23±3℃、湿度55±15%的饲养室内饲养,自由摄取固体饲料(日本クレア株式会社)及自来水。
2.药物配制
将匹伐他汀钙、K-134以及西洛他唑分别悬浮在1.0%(质量百分浓度)的羟丙基甲基纤维素(信越化学(株))水溶液中,配制成给药量1mL/kg。悬浮液在避光瓶中冷藏(4℃)保存,每7天配制一次。
3.试验方法
将36只大鼠分为以下6组(每组6例),即:(1)对照组、(2)匹伐他汀钙单独(10mg/kg)组、(3)K-134单独(100mg/kg)组、(4)西洛他唑单独(100mg/kg)组、(5)匹伐他汀钙(10mg/kg)及K-134(100mg/kg)并用组以及(6)匹伐他汀钙(10mg/kg)及西洛他唑(100mg/kg)并用组。
将匹伐他汀以1日1次(下午4点)反复口服给药14天,K-134或西洛他唑以1日2次(上午9点及下午4点)反复口服给药14天。对照组口服给予1.0%(质量百分浓度)的羟丙基甲基纤维素钠水溶液1mL/kg,1日1次(下午4点)。每一组均从最后一天下午给药开始断食,22小时后采血,测定血浆中的TG。
4.数据处理法
结果用各组的平均值±标准偏差表示。
试验的结果在图1中示出。
如图1(匹伐他汀钙记为匹伐他汀)所示,在将各药物单独给药时,血浆TG值几乎没有变化,而通过将匹伐他汀与K-134及匹伐他汀与西洛他唑并用给药,血浆TG值会显著降低。
因此确认将匹伐他汀与K-134或西洛他唑并用给药,与单独给予各药物相比,有显著降低血浆TG的作用。
工业实用性
本发明涉及通过将HMG-CoA还原酶抑制剂与PDE3抑制剂并用而显著降低血中TG的作用,不发生现有的HMG-CoA还原酶抑制剂及贝特类药物并用时常发生的横纹肌溶解症等严重副作用,而且显示出充分的降低甘油三酸酯的作用。本发明的药物作为治疗和预防各种高甘油三酸酯血浆、特别是伴有高脂血症的高甘油三酸酯血浆的药物,在工业上非常有用。
Claims (4)
1.一种含有HMG-CoA还原酶抑制剂和PDE3抑制剂以及药学上可接受载体的用于降低甘油三酸酯的医药组合物,其中所述HMG-CoA还原酶抑制剂是匹伐他汀或匹伐他汀的盐,所述PDE3抑制剂为K-134或西洛他唑。
2.如权利要求1所述的医药组合物,其中所述匹伐他汀的盐为匹伐他汀钙。
3.一种HMG-CoA还原酶抑制剂和PDE3抑制剂的用途,用于制备含有有效量的HMG-CoA还原酶抑制剂和有效量的PDE3抑制剂的用于降低甘油三酸酯的医药组合物,其中所述HMG-CoA还原酶抑制剂是匹伐他汀或匹伐他汀的盐,所述PDE3抑制剂为K-134或西洛他唑。
4.如权利要求3所述的用途,其中所述匹伐他汀的盐为匹伐他汀钙。
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US68837905P | 2005-06-08 | 2005-06-08 | |
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PCT/JP2006/310440 WO2006132091A1 (ja) | 2005-06-08 | 2006-05-25 | 新規なトリグリセリド低下剤 |
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EP2359826B1 (en) | 2006-07-05 | 2013-10-30 | Takeda GmbH | Combination of HMG-COA reductase inhibitor rosuvastatin with a phosphodiesterase 4 inhibitor, such as roflumilast, roflumilast-N-oxide for the treatment of inflammatory pulmonary diseases |
US20120108651A1 (en) * | 2010-11-02 | 2012-05-03 | Leiden University Medical Center (LUMC) Acting on Behalf of Academic Hospital Leiden (AZL) | Genetic polymorphisms associated with venous thrombosis and statin response, methods of detection and uses thereof |
US20150031769A1 (en) | 2013-07-25 | 2015-01-29 | Medicinova, Inc. | Methods for reducing triglyceride, total cholesterol and low density lipoprotein blood levels |
KR101920307B1 (ko) * | 2017-04-28 | 2018-11-20 | 가톨릭대학교 산학협력단 | 고정용량의 실로스타졸 서방출 및 스타틴 일반방출 미니정제를 포함하는 1일 1회 경구복용 복합 캡슐제 및 이의 제조방법 |
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ES2362534T3 (es) | 2011-07-07 |
EP1894576A4 (en) | 2010-04-21 |
PL1894576T3 (pl) | 2011-10-31 |
CN101193656A (zh) | 2008-06-04 |
US20090227610A1 (en) | 2009-09-10 |
PT1894576E (pt) | 2011-07-29 |
CY1111768T1 (el) | 2015-10-07 |
KR101258422B1 (ko) | 2013-04-26 |
EP1894576B1 (en) | 2011-05-25 |
WO2006132091A1 (ja) | 2006-12-14 |
EP1894576A1 (en) | 2008-03-05 |
US20150272944A1 (en) | 2015-10-01 |
JP4892477B2 (ja) | 2012-03-07 |
JPWO2006132091A1 (ja) | 2009-01-08 |
KR20080015789A (ko) | 2008-02-20 |
HK1111632A1 (en) | 2008-08-15 |
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