CN1268328C - 辅酶q与二十碳五烯酸(epa) - Google Patents
辅酶q与二十碳五烯酸(epa) Download PDFInfo
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- CN1268328C CN1268328C CNB028110110A CN02811011A CN1268328C CN 1268328 C CN1268328 C CN 1268328C CN B028110110 A CNB028110110 A CN B028110110A CN 02811011 A CN02811011 A CN 02811011A CN 1268328 C CN1268328 C CN 1268328C
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- epa
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- ubiquinone
- acid
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Classifications
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A61P13/04—Drugs for disorders of the urinary system for urolithiasis
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Abstract
泛醌(辅酶Q)与二十碳五烯酸的联合给药,其可用一或多种不饱和脂肪酸γ-亚麻酸、二高-γ-亚麻酸、花生四烯酸以及十八碳四烯酸补充或代替。脂肪酸二十二碳六烯酸以及亚油酸含量应少于10%。
Description
二十碳五烯酸(EPA,20:5n-3)是一种高度不饱和脂肪酸,对许多疾病有治疗作用。例如,因为它能降低甘油三酯水平,产生血管舒张作用并具有抗心率失常的效果,因此可用于心血管疾病。它在多种疾病中具有消炎效果,如类风湿性关节炎、骨关节炎以及炎性肠疾病。它对精神性以及神经性失调具有有益的效果,如精神分裂症、抑郁症以及亨廷顿氏疾病。它具有抗癌症效果,特别在减轻癌症恶病质(cancer cachexia)方面具有效果。
通常EPA异常地安全,除了轻度胃肠道失调以外没有很要紧的副作用。美国食品与药品管理局(FDA)已经确定,当存在于鱼油中剂量多达3g/天,对大众而言,EPA通常仍被认为是安全的(GRAS)。
尽管二十碳五烯酸通常以鱼或其他海洋生物油或以混合乙基酯的形式进行给药,其中其与许多其他脂肪酸包括二十二碳六烯酸(DHA)进行混合,本申请者及合作者最近发现制备的二十碳五烯酸或其衍生物制剂的纯度越高,其治疗效果显著增强。特别有效的制剂是那些其中二十二碳六烯酸或其衍生物含量低或非常低或没有的制剂(WO00/44361)。特别有价值的制剂是其中二十碳五烯酸水平高于90%或优选高于95%以及其中二十二碳六烯酸含量低于5%,以及优选低于1%的制剂。亚油酸会影响二十碳五烯酸的作用,因此当制剂中亚油酸含量低于5%以及优选低于1%也很有意义。
本发明解决了当EPA以高剂量以及提纯形式使用的时候的迄今为止还不为人所知的可能的副作用,并提供了一种减轻这种副作用的方法。本发明不仅发现了EPA的应用,而且还包括其他有治疗意义的基本脂肪酸的应用,尤其是二十碳五烯酸前体,十八碳四烯酸(stearidonic acid,18:4n-3)以及ω-6脂肪酸γ-亚麻酸(gamma-linolenic acid,18:3n-6)、二高-γ-亚麻酸(dihomo-gamma-linolenic acid,20:3n-6)以及花生四烯酸(20:4n-6)。
不饱和基本脂肪酸(EFAs)的代谢途径显示在图1中。EFAs与维生素类似,是人和动物代谢所必需的,但是不能由哺乳动物体内合成。有两类EFAs:n-6(或ω-6)以及n-3(或ω-3)。n-6系列亚油酸(LA)以及n-3系列的α-亚麻酸(ALA)母体化合物是食物中发现的主要化合物。但是,要对人体有用,这些母体化合物必需转化成图1中显示的所谓的衍生基本脂肪酸。这些衍生的EFAs在所有的细胞内膜和细胞外膜的结构中发挥重要作用。它们也在许多不同类型的细胞激活后从这些细胞膜中释放出来,所述的细胞激活将磷脂酶A2、C以及D转化成活化形式并直接或间接地导致游离酸从磷脂膜中释放出来。
本发明提供了泛醌(辅酶Q)与EPA的联合给药。通过将泛醌与EPA掺入到制剂中可以极其方便地实现。本发明提供了药用或营养用途的制剂,所述制剂包含二十碳五烯酸(EPA)以及任何合适的可吸收形式的泛醌。
这些制剂明确地不含任何形式的抗坏血酸或抗坏血酸盐,本发明者发现后者将使二十碳五烯酸制剂不稳定。此外,本制剂不包含任何其他的降三甘油酯药物,如潘特生,因为当使用提纯的二十碳五烯酸的时候,所述药物的甘油酯下降效果也许会不适当地变大。不饱和酸本身有降低三甘油酯效果。此外,本发明不涉及下列制剂,其中脂肪酸制剂以相同的剂量或同样的包装与下列酶抑制剂进行的组合制剂,酶抑制剂选自COX-1和/或COX-2抑制剂、LOX抑制剂以及一或多种FACL酶抑制剂。
本发明也提供了泛醌(辅酶Q)以及EPA在制备治疗患者疾病的药物中的用途,所述疾病为常规用EPA治疗的任何失调,并且本发明还提供了一种通过联合施用泛醌(辅酶Q)以及EPA治疗或预防所述失调的方法。所述失调包括心血管以及脑血管疾病;炎症在其中发挥作用的疾病,包括类风湿关节炎以及骨关节炎、炎性肠失调、子宫内膜异位以及哮喘;异常和疼痛性肌肉痉挛性失调,包括过敏性肠或膀胱综合征、痛经或骨骼肌痉挛(spasms);中枢以及外周神经系统机能失调,包括精神性以及神经失调;癌症以及癌症相关综合征,包括恶病质。
优选地,EPA与泛醌的比例介于2000∶1和1∶1之间,以及更优选介于200∶1和3∶1之间。
EPA可为游离酸、钠、钾、锂或其他盐、任何酯的形式,包括乙基酯或胆固醇酯、酰胺、磷脂或三-、二-或单甘油酯。也可使用可增加血液或组织中脂肪酸水平的其他衍生物。优选的EPA形式为乙基酯或三甘油酯。这些形式特别为胃肠道良好地耐受。
二十碳五烯酸或衍生物应该具有一定的纯度水平,这样可以降低其他脂肪酸或脂肪酸衍生物对生物作用关键点的干扰作用。在本发明制剂的二十碳五烯酸制剂中二十碳五烯酸或衍生物应该至少为70%的纯度以及优选至少80%的纯度。特别优选二十碳五烯酸或衍生物为90%或95%的纯度。特别地,通常在油中发现以及并干扰脂肪酸治疗作用的两种基本脂肪酸:二十二碳六烯酸以及亚油酸。必要的条件是用于本发明制剂的任何脂肪酸或脂肪酸衍生物制剂中,二十二碳六烯酸或衍生物以及亚油酸或衍生物存在的量各少于10%,优选少于5%以及特别优选少于1%。
有利的是EPA每日剂量介于100mg和100g之间,并且泛醌每日剂量介于10mg和2000mg之间。优选地,EPA每日剂量介于0.5g和20g之间,并且泛醌的每日剂量介于50mg和500mg之间。
本发明制剂优选地制备成适合口服给药或经肠给药。其也可制备成适合局部、阴道或直肠给药,或适合通过静脉内、肌内或皮下途径进行肠胃外给药。
尽管当使用非常高剂量的EPA的时候,这种联合给药可能特别有价值,任何剂量的EPA也有用于降低任何副作用以及也有助于保护EPA抵抗体内氧化的风险。
泛醌,也为辅酶Q,是一种在人体大多数细胞中可以发现的分子(LErnster & G Dallner,Biochimica Biophysica Acta 1995;1271:195-204)。其结构为:
泛醌50
该分子由苯醌环和聚异戊二烯侧链组成。侧链中异戊二烯单元是可变的,但每一物种具有特定的数字,人类中为10。泛醌在机体中有两种主要的明确作用。首先它是线粒体中呼吸链的成分,是正常电子传递以及正常能量产生所必须的。其次,它具有很强的抗氧化特性,并因此可有助于预防从高度不饱和脂肪酸如EPA产生潜在有害的自由基。
其他的高度不饱和脂肪酸也可用于治疗,可能产生自由基,理论上可能带来副作用。所述脂肪酸尤其包括ω-6脂肪酸,γ-亚麻酸、二高-γ-亚麻酸以及花生四烯酸,以及二十碳五烯酸前体,十八碳四烯酸。
本发明另一方面提供了这些脂肪酸或衍生物的制剂,其包含辅酶Q,以及涉及联合施用辅酶Q以及上述的任何脂肪酸或衍生物治疗或预防失调的方法。在任何的本发明上述制剂中的EPA可用一种或多种高度不饱和脂肪酸补充或替代,所述的脂肪酸选自γ-亚麻酸、二高-γ-亚麻酸、花生四烯酸以及十八碳四烯酸。当用EPA的时候,用于制备本发明制剂的脂肪酸制剂应该包含多于70%的特定脂肪酸,优选多余80%或90%,以及更优选多余95%。脂肪酸制剂也包含少于10,%优选少于5%以及更优选少于1%的二十二碳六烯酸或亚油酸。
也可有下述情况,其中合适地将一种含70%或更高的一种脂肪酸的制剂与含70%或更高的另一种脂肪酸的制剂进行组合。例如,在下述情况下,合适地将n-3系列的脂肪酸与一种n-6系列进行组合,EPA和/或SA制剂可与GLA和/或DGLA或AA制剂组合,从而制备最终的产物。
EPA以及其他脂肪酸可以任何可吸收形式进行提供,这样将导致在血浆或红细胞膜或制剂直接使用(如对皮肤)的组织中的EPA或其他脂肪酸浓度升高。EPA或其他脂肪酸浓度的这种变化可很方便地用标准技术如用标准脂质萃取后进行的脂质级分的气相色谱进行。在进行气相色谱之前,脂质萃取可任选接着使用薄层色谱或高压液相色谱进行脂质类别的分离。EPA或其他脂肪酸可以游离脂肪酸、盐、酯如乙基酯、酰胺、磷脂,三-、二-或单-甘油酯或以任何其他的可吸收形式进行提供。
EPA或其他脂肪酸的每日剂量可为100mg~100g,但优选在0.5g~20g的范围内。EPA或其他脂肪酸在为所述制剂提供的含EPA物质中的浓度可高于70%的任何浓度,但优选高于80%或90%以及更优选高于95%。
制剂中泛醌的每日剂量可为10mg~2000mg每天,但优选为50mg~500mg每天。EPA或其他脂肪酸与泛醌的比例可为2000∶1~1∶1,但优选为200∶1~3∶1。
EPA/其他脂肪酸制剂以及泛醌可掺入到任何合适的制剂或溶媒中,用于口服给药、经肠给药,通过静脉内、肌内或皮下途径进行肠胃外给药,或通过皮肤进行局部给药或通过栓剂或阴道栓进行直肠或阴道给药。
研究表明应用基本脂肪酸(EFAs),包括二十碳五烯酸,在许多疾病的治疗中具有治疗有益的效果。因此本发明的优点非常广泛。下列给出的研究病例,但基于目前以及未来的有关EFAs应用的有关知识,其应用预期是广泛的。证明这些脂肪酸在许多疾病中具有广泛的用途的已经授权专利实例为下述美国专利:US4,826,877;5,847,000;5,457,130;4,302,447;4,681,896;5,198,468;5,922,345。
本发明所述制剂适于治疗任何形式的癌症以及癌症恶病质,并且本发明进一步提供了这种治疗,以及脂肪酸制剂与泛醌的组合在用于治疗癌症或癌症恶病质的药物的制备方法中的用途。
本发明进一步提供了异常心率以及节律的治疗或控制,以及脂肪酸制剂与泛醌的组合在用于治疗或控制异常心率和节律的药物的制备方法中的用途。
所述制剂也适于治疗任何形式的精神性疾病,包括精神分裂症、分裂情感性失调(schizoaffective disorder)、分裂型精神性疾病(schizotypy)、抑郁症、焦虑症、两极失调(bipolar disorder)、躁狂症、边缘型个性失调(borderlinepersonality disorder)、酒精中毒以及注意力不足极度活跃失调(attention deficitheperactivity disorder)或任何其他的精神性疾病,并且本发明提供了这种治疗以及脂肪酸制剂与泛醌的组合在用于治疗任何一种所述精神性疾病的药物的制备方法中的用途。
所述制剂可用于治疗任何形式的神经或神经退行性疾病,包括帕金森氏疾病、阿尔茨海默氏疾病、肌萎缩外侧硬化症、亨廷顿氏疾病以及其他″三联重复″(triplet-repeat)疾病、中风、多发性梗塞(multi-infarct)以及其他形式的痴呆、多发性硬化症、慢性疲劳以及癫痫症,并且本发明提供了这种治疗以及脂肪酸制剂与泛醌的组合在用于治疗任何一种所述神经或神经退行性疾病的药物的制备方法中的用途。
所述制剂适于治疗任何形式的炎性疾病,包括任何形式的关节炎,任何形式的炎性皮肤疾病,包括牛皮癣以及湿疹、哮喘,任何形式的炎性胃肠道疾病,包括溃疡性结肠炎以及局限性回肠病,以及任何其他的器官包括肾、生殖系统、眼以及脑的任何炎性疾病,并且本发明提供了这种治疗以及脂肪酸制剂与泛醌的组合在用于治疗任何一种所述炎性疾病的药物的制备方法中的用途。
所述制剂可用于治疗任何形式的心血管或脑血管疾病,并且本发明提供了这种治疗以及脂肪酸制剂与泛醌组合在制备用于治疗任何心血管或脑血管疾病的药物的方法中的用途。
所述制剂可用于治疗任何形式的呼吸疾病,包括哮喘或慢性阻塞性肺部疾病,并且本发明提供了这种治疗以及脂肪酸制剂与泛醌的组合在用于治疗任何呼吸疾病,包括哮喘或慢性阻塞性肺部疾病的药物的制备方法中的用途。
所述制剂可用于治疗任何形式的代谢疾病,包括糖尿病、综合征X、以及任何钙代谢紊乱包括骨质疏松症、尿石病、或尿道结石形成,并且本发明提供了所述的治疗以及脂肪酸制剂与泛醌的组合在制备用于治疗任何一种所述代谢疾病药物的方法中的用途。
所述制剂可用于治疗任何形式的肾或尿道疾病,并且本发明提供了所述治疗以及脂肪酸制剂与泛醌的组合在制备用于治疗任何肾或尿道疾病的药物的方法中的用途。
所述制剂可用于治疗任何形式的生殖系统或月经周期疾病或失调,包括乳房疼痛、经期前综合征、痛经或子宫内膜异位,并且本发明提供所述治疗以及脂肪酸制剂与泛醌的组合在用于治疗所述生殖系统或月经周期疾病或失调,包括乳房疼痛、经期前综合征、痛经或子宫内膜异位的药物的制备方法中的用途。
所述制剂可用于治疗任何形式的以异常和疼痛性肌肉痉挛为特征疾病或的失调,包括过敏性肠(irritable bowel)或膀胱综合征或骨骼肌痉挛,并且本发明提供了这种治疗和脂肪酸制剂与泛醌的组合在用于治疗以异常和疼痛性肌肉痉挛为特征的疾病,包括过敏性肠或膀胱综合征或骨骼肌痉挛药物的制备方法中的用途。
二十碳五烯酸被认为是具有抗癌潜力的脂肪酸。S S Palakurthi等(癌症研究2000;60:2919-25)报道了EPA能抑制癌症细胞的生长并报道了描述了类似的发现的在前文献。然而无论是Palakurthi等人,还是在前文献都没有提供任何关于如何将这些实验发现转化成用于人癌症治疗的信息。授权欧洲专利(EPO464084)描述了EPA在治疗癌症关联的体重减轻中的用途,但是没有讨论EPA用于治疗潜在癌症本身的可能性。
下列实施例报道了已患癌症个体以1g/天的常规剂量服用乙基-EPA的情况。该个体在过去的3年内也同时按2g/天的剂量服用EPA,但是癌症仍然发展。因此可以总结出2g/天或更低剂量的EPA可能在癌症控制方面无效。但是,当EPA的剂量增加到10g/天,在一定的时间内,癌症大小显著减小。这因此表明EPA本身的10g/天剂量具有直接的抗癌症效果。3g/天~30g/天的剂量,以及优选5g/天或20g/天的剂量因此将可用于癌症治疗。EPA可以任何可吸收形式进行提供。但是,三甘油酯形式以及乙基-酯形式对胃肠道相对地无刺激作用,因此为这种大剂量经口给药的优选形式,尽管其他形式可用于静脉内给药途径。口服给药的EPA应该为尽可能的纯净形式,至少70%纯度,优选80-90%纯度,以及更优选95%或更纯。二十二碳六烯酸以及亚油酸各自应该少于5%以及优选少于1%。EPA可配制成胶囊、液体或乳剂,为合适地用于或静脉内给药所必须的形式。
实施例中也描述了当施用高剂量EPA的时候,会有心律不齐的情况,心律不齐可通过联合使用辅酶Q得到成功的控制。但是当施用高剂量的EPA的时候,所述的心律不齐并不是总是出现,因此我们要求保护EPA本身以3g/天或更高的高剂量给药用于癌症治疗的用途。
实施例
一位61岁男性病人,按1g/天的剂量服用二十碳五烯酸乙酯,作为发展非Hodgkin氏淋巴瘤形式的普通健康原因的补充剂,该疾病也称为包膜细胞淋巴瘤。该疾病的特征为称为细胞周期蛋白D1的细胞周期控制因子的过表达。细胞周期蛋白D1似乎使细胞不断地分裂。已有报道称在体外以及在癌症动物模型中,EPA能抑制细胞周期蛋白D1的合成(S S Palakurthi等,癌症研究2000;60:2919-25)。但是,需要高剂量才能在癌症组织中得到所需要的水平。
因此决定给病人按10g/天服用96%纯度的二十碳五烯酸乙酯,含少于1%二十二碳六烯酸以及不能检测到的亚油酸。在给药的第6天,病人的可触知的肿瘤开始消退,显示出EPA具有有益的作用。在EPA治疗中,在病人身上没有观察到重要的副作用。但是,在第10天,他的心率变得明显地没规律,体现在心率以及节律上:从约60/分的低值到约150/分的高值之间振荡并表现出明显的无规律。
没有确定异常节律的可靠原因。一种可能性是由于EPA的高摄入引起的。非常高剂量的EPA理论上增加氧化的代谢物,后者会扰乱心脏节律。低剂量的EPA似乎具有强的抗心律不齐的作用,已知许多抗心律不齐药在一定的剂量的时候具有诱导心律不齐(pro-arrhythmic)的作用。
泛醌对心脏节律有有利的效果(RBSingh等,心血管药物及治疗1998;12:347-353)。按120mg/天对服用高剂量EPA的病人进行给药。在第二天心律以及节律恢复到正常,节律均匀以及休息时的心率振荡范围为65-75/分。然后10天后终止泛醌。4天后,心率以及节律波动又恢复了。再服用泛醌,又恢复到正常的心率以及节律。病人因此继续服用泛醌以及高剂量的EPA,在四个月的时间内没有出现心律以及节律异常的反弹。
制剂实施例
1.含500mg乙基酯形式的EPA的软或硬明胶胶囊,其中乙基-EPA的纯度高于90%以及其中二十二碳六烯酸以及亚油酸各自低于5%以及在其中加入30mg泛醌。每天服用1~30粒这种胶囊。
2.95%纯度的乙基-EPA液体,其中DHA以及亚油酸各自少于1%,调味使之可口,每克含50mg泛醌。每天口服0.5g~20g。
3.微胶囊的(Micro-encapsulated)80%纯度的乙基-EPA,其中DHA少于10%,含100mg泛醌/g。每天服用提供100mg~20g EPA的所述制剂。
4.如实施例1-3中的制剂,但EPA以游离酸、钠盐、锂盐、酰胺、磷脂,单-、二-或三甘油酯的形式,或任何其他的可吸收形式进行提供。
5.如实施例1-4中的制剂,其中EPA以其中包含多于70%的二十碳五烯酸以及其中DHA以及亚油酸含量各少于10%的形式进行提供。
6.如实施例1-5中的制剂,但其中EPA以及泛醌以适合经静脉内、肌内或皮下途径进行的肠胃外给药的制剂形式进行提供。
7.如实施例1-5中的制剂,但其中EPA以及泛醌以适合局部给药的制剂形式提供。
8.如实施例1-7中的制剂,但其中EPA用一或多种选自γ-亚麻酸、二高-γ-亚麻酸、花生四烯酸以及十八碳四烯酸的脂肪酸进行补充或替换。
Claims (20)
1.药用或营养用制剂,自下列组份制备:
二十碳五烯酸(EPA)制剂,含多于90%的EPA和少于5%的二十二碳六烯酸(DHA)以及少于5%的亚油酸;以及
任何合适的可吸收形式的泛醌。
2.根据权利要求1的制剂,其中EPA与泛醌之比介于2000∶1和1∶1之间。
3.权利要求2的制剂,其中EPA与泛醌之比介于200∶1和3∶1之间。
4.根据权利要求1~3中任何一项的制剂,其中EPA为乙基酯形式。
5.根据前述权利要求中任何一项的制剂,其中EPA制剂的纯度为95%,并且其中DHA含量少于1%,并且其中亚油酸含量也少于1%。
6.根据权利要求1或2的制剂,其中EPA为游离酸、钠盐、锂盐或其他盐、任何酯、酰胺、磷脂或三-、二-或单甘油酯的形式。
7.权利要求1~6中任何一项的制剂,其中EPA的每日剂量介于100mg和100g之间,并且泛醌的每日剂量介于10mg和2000mg之间。
8.根据权利要求7的制剂,其中EPA的每日剂量介于0.5g和20g之间,并且泛醌的每日剂量介于50mg和500mg之间。
9.权利要求1~8中任何一项的制剂,其中将含EPA或其他脂肪酸的物质与泛醌一起制备成适合口服给药或经肠给药。
10.权利要求1~8中任何一项的制剂,其中将含EPA或其他脂肪酸的物质与泛醌一起配制成适合经局部、阴道或直肠给药。
11.权利要求1~8中任何一项的制剂,其中将含EPA或其他脂肪酸的物质与泛醌一起配制成适合经静脉内、肌内或皮下途径进行经肠胃外给药。
12.权利要求1-11中任何一项的药用制剂用来治疗任何形式的癌症或癌症恶病质。
13.二十碳五烯酸(EPA)制剂在制备用于治疗任何一种下述疾病或失调的药物中的用途:
非Hodgkin氏淋巴瘤;
精神分裂症、分裂情感性失调、分裂型精神性疾病、抑郁症、焦虑症、两极失调、躁狂症、边缘型个性失调、酒精中毒以及注意力不足极度活跃失调或任何其他的精神性疾病;
帕金森氏疾病、阿尔茨海默氏疾病、亨廷顿氏疾病或任何其他的″三联重复″疾病、肌萎缩外侧硬化症、多发性梗塞或其他形式的痴呆、多发性硬化症、慢性疲劳以及癫痫症;
所述的二十碳五烯酸(EPA)制剂包含多于90%的EPA和少于5%的二十二碳六烯酸(DHA)以及少于5%的亚油酸;以及任何合适的可吸收形式的泛醌。
14.权利要求13的用途,其中EPA制剂包含多于95%的EPA以及少于1%的二十二碳六烯酸(DHA)以及少于1%的亚油酸。
15.权利要求13的用途,其中EPA与泛醌之比介于2000∶1和1∶1之间。
16.权利要求15的用途,其中EPA与泛醌之比介于200∶1和3∶1之间。
17.权利要求13的用途,其中EPA为游离酸、钠盐、锂盐或其他盐、任何酯、酰胺、磷脂或三-、二-或单甘油酯的形式。
18.权利要求17的用途,其中EPA为乙基酯形式。
19.权利要求13的用途,其中所述的药物包括介于100mg和100g之间的EPA每日剂量,以及介于10mg和2000mg之间的泛醌每日剂量。
20.根据权利要求19的制剂,其中EPA的每日剂量介于0.5g和20g之间,并且泛醌的每日剂量介于50mg和500mg之间。
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EP1390025A1 (en) | 2004-02-25 |
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HRP20030988A2 (en) | 2004-06-30 |
WO2002096408A1 (en) | 2002-12-05 |
RU2003133142A (ru) | 2005-04-20 |
IS7005A (is) | 2003-10-30 |
ES2238568T3 (es) | 2005-09-01 |
PL364093A1 (en) | 2004-12-13 |
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DE60203494T2 (de) | 2006-02-09 |
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