CN1438884A - 脂肪酸的治疗组合物 - Google Patents
脂肪酸的治疗组合物 Download PDFInfo
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- CN1438884A CN1438884A CN01811931A CN01811931A CN1438884A CN 1438884 A CN1438884 A CN 1438884A CN 01811931 A CN01811931 A CN 01811931A CN 01811931 A CN01811931 A CN 01811931A CN 1438884 A CN1438884 A CN 1438884A
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Abstract
本发明公开了二十碳五烯酸或其任何适宜的衍生物(EPA)与花生四烯酸(AA)或选自DGLA或GLA的AA的前体组合而得到药物制剂。
Description
在人体中存在两个系列的必需脂肪酸(EFA)。所以称之为“基本的”,是因为它们不能在哺乳动物中重新合成。它们的代谢途径如图1所示。这些脂肪酸可以在系列内相互转化,但是在人体中ω-6(n-6)系列不能转化成ω-3系列,ω-3(n-3)系列也不能转化成ω-6系列。饮食中主要的EFA为ω-6系列的亚油酸和ω-3系列的α-亚麻酸。然而,为了实现其大部分生物学作用,这些“亲本”EFA必须代谢成图1所示的其它脂肪酸。每种脂肪酸在体内大概均具有特殊的作用。n-6系列中尤其重要的是双高γ-亚麻酸(DGLA,20:3n-6)和花生四烯酸(AA,20:4n-6),而n-3系列中特别重要的是二十碳五烯酸(EPA,20:5n-3)和二十二碳六烯酸(22:6n-3)。本专利说明书特别涉及AA与EPA的组合。
发现AA是所有细胞膜,尤其是神经细胞的细胞膜的重要组成部分。它是很多信号转导系统的重要组分,可通过多种不同形式的细胞刺激激活。AA通常以磷脂的形式存在于细胞中。细胞活化产生一系列的活化磷脂酶,其可以游离酸的形式释放AA。游离酸本身具有很多直接的作用:调节蛋白质激酶和其它酶,调整钙及其它离子的运动,激活受体如过氧化物酶体增生体活化的受体(peroxisome proliferator activated receptors,PPAR),及调节基因的功能。此外,AA可以转化成范围巨大的甚至更活泼的衍生物,通常称之为类花生酸。这些物质包括前列腺素,白细胞三烯,血栓素,各种类型的羟基酸,脂氧素,hepoxilins及很多其它化合物。在炎性反应和血栓形成反应中经常涉及到这些物质,而且在其整体作用中,这些物质经常被认为是有害的。这种有害的想法通过下列事实来阐述:静脉内的AA因为其血栓形成作用而经常是致命的,以及因其抗炎作用而得到广泛使用的类固醇阻止了磷脂酶释放AA。而且,包含阿司匹林和其它众所周知的化合物,并以其抗血栓形成和抗炎作用而著称的环氧合酶抑制剂类药物,抑制AA转化成前列腺素和血栓素。
这种AA的潜在毒性的概念已经很好地确立了。本领域的专家组织,国际脂肪酸和脂类研究协会(ISSFAL)联合美国国立卫生研究院(NIH)于1999年创办了一个专题研究小组。该研究小组承办的事情是就人类使用EFA的问题向当局提出建议。参与者—本领域的所有一流专家均不怀疑AA的有害作用,并在其最终的陈述中强调了AA的有害作用(AP Simopoulos等,Essentiality of and recommended dietary intakes for ω-6 and ω-3 fatty acid,Nutrition and Metabolism 1999;43:127-130)。报道该研究小组的ISSFAL通讯指出,“经过大量的讨论之后一致认为,对于最佳的大脑和心血管功能而言,减少成人和新生儿饮食中ω-6多不饱和脂肪酸(PUFA)甚至ω-3 PUFA的重要性增加了。必须降低花生四烯酸及其类花生酸产物的副作用”。
与这种AA有毒的一般观点相反,ISSFAL和NIH的专家热心宣传n-3EFA的价值,特别是EPA和DHA对人类健康的价值。该观点认为,EPA和DHA将在细胞膜磷脂中代替AA并且可以降低从亚油酸到AA的合成。预期通过EPA和/或DHA降低AA的水平,将对人类的健康具有广泛的益处。
本发明来源发明人最近意想不到的观察结果,该结果暗示这种观点可能是错误的。与一般的专家意见相反,如今已经发现AA更理想而不是不合乎需要的,同EPA结合起来给药AA可能是有益的。本发明提供这种组合治疗。
本发明提供药物制剂,其包含二十碳五烯酸或其任何适宜的衍生物(下文中将其共同称为EPA)和花生四烯酸(AA),如所附权利要求书中所陈述的。AA可以用其前体一DGLA或GLA中的一种或多种替换。EPA与AA的比例优选为1∶1~20∶1。
优选EPA的剂量为100~0000mg/天。该制剂可以是包含100~0000mgEPA的单独制剂。可供选择的上限为5000mg EPA。优选本发明的制剂包含1~4g EPA和0.1~2.0g花生四烯酸(AA)。更优选量是1.5~3g EPA和0.2~1gAA。
该制剂可以是单独的日剂量制剂,以一个剂量的形式给药上述摄入量,也可以方便地分成若干剂量,例如由四个分别包含500mg适宜形式EPA和150mg适宜形式AA的软凝胶或其它胶囊构成的日剂量。
第一方面,本发明的组合物是通过混合生物学上可同化的EPA(其中EPA的纯度至少为50%,优选纯度至少为90%)与生物学上可同化的花生四烯酸(AA)而制备的。原料必须包括含有大量EPA的原料。该原料能够接纳AA,其纯度可以为至少30%,优选至少90%。
还优选本发明制剂的活性成分基本上全部由EPA和AA或AA前体组成。这种情况下,不存在显著量的其它EFA。
可以包含调味剂或乳化剂,以使制剂可口。可以加入其它常规添加剂,稀释剂和赋形剂。摄取的制剂可以是胶囊,干粉,片剂,油状物,乳剂或任何其它适宜的形式。胶囊可以是硬的或软的明胶胶囊,琼脂胶囊,或者其它任何适宜的胶囊。
优选EPA由甘油三酸酯或乙酯组成,其纯度为50%或更纯,更优选其纯度大于90%。可以使用的其它形式的脂肪酸包括游离酸,盐,任何类型的酯,酰胺,一、二或三酸甘油酯,磷脂,或者能够将EPA引入身体组织的任何其它形式。如果考虑磷脂,则本发明明确排除使用包含两种不同脂肪酸即包含EPA和AA(或AA前体)的磷脂。但是,当与含有AA或AA前体的磷脂混合时,在本发明的制剂中可以使用包含EPA的磷脂。
本发明的制剂可以用于治疗范围宽广的疾病和病症,包括:
任何精神病学,神经病学或其它中枢或周围神经系统的疾病,特别是精神分裂症,抑郁症,双相精神障碍以及大脑的退化性疾病,包括早老性痴呆和其它痴呆以及帕金森病;
哮喘及其它呼吸系疾病;
胃肠道疾病包括炎性肠道疾病和过敏性肠道综合症;
涉及任何系统的炎性疾病;
心血管疾病;
任何形式的脂肪代谢障碍,任何形式的糖尿病或任何形式的代谢疾病;
任何形式的皮肤病;
任何形式的肾或泌尿道疾病;
任何形式的肝疾病;
任何形式的男女生殖系统或有关第二性器官如乳房或前列腺的疾病;
任何形式的癌症或癌症恶病质;
任何头部或颈部的疾病,包括口腔和牙齿的疾病、眼睛的疾病或耳朵的疾病;及
任何形式的病毒、细菌、真菌、原生动物或其它有机体的传染病。
本发明的制剂也可以一般的营养补剂使用。
本发明还提供一种治疗或预防任何前述疾病或症状的方法,特别是治疗或预防神经病学和精神病学紊乱,尤其是精神分裂症,抑郁症,双相精神障碍以及大脑的退化性疾病,包括早老性痴呆和其它痴呆以及帕金森病的方法。举例来说,该治疗或预防方法是以100~10000mg EPA/天的处方剂量混合使用EPA和AA,且EPA与AA的比例为1∶1~20∶1。可以使用选自DGLA和GLA的AA的前体代替AA。优选EPA与AA(或其前体)的比例范围为1∶1~5∶1。
本发明还提供一种治疗或预防选自下列疾病的方法:
哮喘及其它呼吸系疾病;
胃肠道疾病包括炎性肠道疾病和过敏性肠道综合症;
涉及任何系统的炎性疾病;
心血管疾病;
任何形式的脂肪代谢障碍,任何形式的糖尿病或任何形式的代谢疾病;
任何形式的皮肤病;
任何形式的肾或泌尿道疾病;
任何形式的肝疾病;
任何形式的男女生殖系统或有关第二性器官如乳房或前列腺的疾病;
任何形式的癌症或癌症恶病质;
任何头部或颈部的疾病,包括口腔和牙齿的疾病、眼睛的疾病或耳朵的疾病;及
任何形式的病毒、细菌、真菌、原生动物或其它有机体的传染病,例如,该方法是以100~10000mg EPA/天的处方剂量混合使用EPA和AA,且EPA与AA的比例为1∶1~20∶1。可以使用AA的前体即DGLA和GLA代替AA。优选EPA与AA(或其前体)的比例范围为1∶1~5∶1。
本发明还包括本发明的制剂在制备治疗或预防上述疾病或病症的药物中的应用。
所推荐的具体的治疗组合物是:剂量为100~10000mg EPA/天,且提供不小于100mg并不大于10000mg EPA/天的EPA与AA、DGLA或GLA混合物。可供选择的上限为5000mg/天的脂肪酸。特别优选的量为每天1~4gEPA,同时混有每天0.1~2.0g花生四烯酸或者其前体GLA或DGLA中的一种。更优选的组合物包含1.5~3g EPA和0.2~1g AA。本发明还提供一种制剂,例如一日剂量形式的制剂,其包含1.5~3g EPA和0.1~2.0g花生四烯酸或其前体之一。
EPA与ω-6脂肪酸的比例是重要的,因为太多的EPA可能导致AA从细胞膜中丧失,而太多的AA则可能导致副作用,因为AA过度地转化为类花生酸。因此,EPA与AA或DGLA或GLA的比例应当决不小于1∶1,优选为20∶1~1∶1,更优选为5∶1~1∶1。这种混合比将确保即使在较高EPA剂量时也能增强并保持EPA的有益作用,因为提供AA及其前体将防止单独给药太多EPA时可能发生的AA耗尽。
当在消化道和体内吸收时,EPA部分容易从一种化学形式完整地转化成另一种化学形式。简单的酯如乙酯或甲酯容易被酯酶分解,然后,所游离出的脂肪酸可与白蛋白或者其它结合或转运蛋白结合,或者混入复合脂质如磷脂,胆固醇酯或甘油酯中。因此,本发明制剂中的脂肪酸可以任何形式给药,如甘油酯,酯,游离酸,盐,磷脂,酰胺或能够将其引入血液和细胞膜的任何其它形式。
EPA,AA,DGLA或GLA可以来自任何适宜的来源,包括植物籽油,源于海藻或真菌的微生物油,或者来自鱼或其它海洋动物的海生动物油。它们可以天然油的形式使用,只要符合所需的原料纯度要求,或者将它们纯化成包含30%,40%,50%,60%,70%,80%,90%或更高脂肪酸的产品。特别有用的EPA是高度纯化的乙酯形式,见最早的英国9901809.5的专利文档中所描述的。合成途径的脂肪酸也可以,只是目前在经济上是不可行的。
一旦得到含有单一脂肪酸的油,并且按照需要进行纯化之后,就可以将原料进行混合,得到符合上述需要的EPA与AA,DGLA或GLA的比例。
然后,可以将混合的脂肪酸组合物混入任何适宜的剂型中,以用于经口,经肠,不经肠,经直肠,经阴道,经皮或其它给药途径。软硬明胶胶囊,添加调味剂的混合油,乳剂或其它液体形式,以及微胶囊化粉末或其它干燥形式的载体,均为给药该产品的适宜途径。
制剂实施例
(a)软硬明胶胶囊,每个胶囊包含500mg或1000mg 10份纯度95%的乙基-EPA与2份纯度95%的AA的混合物;
(b)如(a)中的那样,只是AA和EPA乙酯被其它任何适宜可生物同化形式的脂肪酸代替,所述脂肪酸有如游离酸,三、二或一酸甘油酯,其它的酯,诸如钠、钾或锂的盐,酰胺,磷脂或任何其它适宜的衍生物;
(c)如(a)或(b)中的那样,只是EPA或EPA衍生物的纯度为50%,60%,70%,80%或90%,且AA或AA衍生物的纯度为30%,40%,50%,60%,70%,80%或90%;
(d)如(a)~(c)中的那样,只是EPA与AA的比例为1∶1~20∶1;
(e)如(a)~(d)中的那样,只是原料为微胶囊化的粉末,其可以粉末或压制成的片剂形式使用。这种粉末可以根据本领域的技术人员已知的各种方法制备;
(f)如(a)~(d)中的那样,只是该制剂为液体或乳剂,并为了适于经口给药而添加了调味剂;
(g)如(a)~(d)中的同样,只是将原料配制成适于局部使用的剂型如乳膏或软膏;
(h)如(a)~(g)中的同样,只是AA被其前体GLA或DGLA之一替换。
附图说明
图1为两个系列的必需脂肪酸的代谢途径。
实验数据
在精神分裂症患者的治疗中,进行给药安慰剂和三种不同剂量EPA(1g,2g和4g/天)的试验,该患者还给药了抗精神分裂药物氯氮平。早先的试验性研究表明,EPA会具有所需的效果,并且预期EPA的剂量越高,效果会越好。对31位患者进行研究,并跟踪12周。利用阳性和阴性精神分裂症症状分级(PANSS),对这些患者在开始时和12周时进行评价。自开始时的改善百分数示于表1中。安慰剂产生的效果小,1g/天产生较大的效果,2g/天产生26.0%的大效果,与现有精神分裂症药物所产生的按照该等级来说通常为15-20%的改善相比较。预期4g/天将产生最好的效果,但是这并没有产生。4g/天的效果实际上小于2g/天的效果,而与1g/天的效果相当。
表1.根据精神分裂症阳性和阴性症状分级(PANSS),给药安慰剂,1g/天,2g/天或4g/天二十碳五烯酸乙酯的患者从开始到12周时的改善百分数
安慰剂
1g
2g
4g
N(人数) 7 9 9 6
改善 6.0% 18.3% 26.0% 16.3%
在这些患者中,以及另一组的患者中,测量开始治疗之前以及12周之后人红细胞中DGLA,AA,EPA和DHA的水平。部分结果是预期到的,部分结果是意想不到的,并且均示于表2中。如所预期的,存在EPA剂量相关性的升高,该升高越大,剂量就越大。还预期到,存在AA的逐步降低,EPA剂量越大,AA的降低就越大。但是,这并未发生。1g/天的EPA产生小的AA升高,2g/天的EPA产生较大的升高。4g/天的EPA产生预期的AA降低。
表2.四组给药安慰剂或者1g/天,2g/天或4g/天乙基-EPA的患者的血红细胞中,二十碳五烯酸(EPA)和花生四烯酸(AA)自开始至12周时在红细胞中的浓度的变化(单位为g/g)。+表示升高,-表示降低。
安慰剂
1g
2g
3g
EPA -0.6 +2.4 +33.7 +49.0
AA -12.6 +2.7 +29.4 -26.5
可以看出,与EPA的变化相比,精神分裂症候的改善与AA的变化更相关。这在更大系列的患者试验中得到验证,其中PANSS的改善与绝大部分EFA的改变相关。相关系数r的值示于表3中,其为相关性的统计学上的显著性。1.0的r值表示两个参数完全相关,0.0的r值表示没有任何相关性。
表3.自开始至12周时PANSS总分数的变化与自开始至12周时各种必需脂肪酸在红细胞浓度变化的相关性。线性回归分析的相关系数用r来表示。p为相关性的统计学显著性。
脂肪酸
相关系数r
显著性p
双高γ-亚麻酸(DGLA) -0.51 0.09
花生四烯酸(AA) -0.81 0.001
二十碳五烯酸(EPA) -0.07 0.84
二十二碳五烯酸(DPA) -0.12 0.76
二十二碳六烯酸(DHA) -0.35 0.13
从表中可以清楚地看出,最强的相互关系是与AA的关系,第二强的相互关系是与DGLA的关系。这两种脂肪酸的升高与精神分裂症状的改善强烈地相关,正如PANSS分数降低所表明的,因此是负的相关性。与此相反,几乎不存在与EPA的相关性,因为高剂量的EPA与红细胞AA水平的下降和临床效果的降低相关。
这些结果完全是意想不到的。EPA本身不是细胞膜中最需要的脂肪酸,看来AA和DGLA比EPA更有用。对此的最可能的解释是:当AA保持在细胞膜磷脂中并没有转化成具有潜在危险的类花生酸时,其是合乎需要的。EPA的作用可能抑制磷脂酶,因此将AA保持为磷脂的形式。但是,如果很高剂量的EPA代替AA,则治疗作用丧失。
这种解释得到了试验性研究的支持,其中将AA本身给药于5位精神分裂症患者。预期这些患者将得到改善,但实际上他们的病情恶化了。在没有抑制磷脂酶的EPA的情况下给药AA,可能导致类花生酸形成的增加,而不是将AA引入磷脂中。
从这些研究中得出的结论是,EPA是合乎需要的,不在乎其本身,而是因为它提高了AA在细胞膜磷脂中的水平。高剂量的EPA本身不仅没有价值,而且可能是不合乎需要的,因为它们导致AA从细胞膜中过度地丧失。回避这种问题,以及促进EPA的这种明显合乎需要的作用的途径是保持较低剂量的EPA,同时通过给药EPA与AA或其前体(DGLA或γ-亚麻酸GLA)之一提高AA的水平。当对两个已经以2g/天的剂量使用EPA三个月的患者给药剂量为1g/天的AA时,他们感受到了进一步的显著的改善,而且在单独给药AA时没有发现任何恶化。
美国专利4977187提供了用于治疗精神分裂症的n-3脂肪酸和n-6脂肪酸与维生素E的组合物。然而,该专利既没有明确地关注本说明书中所描述的AA或者明确地关注EPA,也没有关注EPA与AA或其前体的特定组合,更没有关注具体的剂量以及EPA与AA的比例。在US 4977198及对应的专利中,任何n-6脂肪酸可以与任何n-3脂肪酸以任意比例混合。
文献综述提出,本文所描述的现象不仅给出精神分裂症而且给出了几种可以使用EPA作为治疗剂的病症的实际情况。很多研究说明了含低剂量EPA的产品在心血管疾病,炎性疾病及其它病症中的价值。但是,当研究者使用较高剂量时,却失去这些想要的治疗效果。考虑两个实例,对于因冠状血管疾病而经受血管成形术的患者或者患有炎性肠道疾病的患者,高剂量的EPA完全不能起到有益的作用,即使EPA剂量较小的早期研究给出强有力的有益的证据。作者没有给出试验失败的客观解释,并且没有考虑到可能导致AA过度消耗的可能性。
本发明的制剂可以在非常广的范围中使用。
Claims (18)
1.药物制剂,其是通过混合下列物质制备的:
任何生物学上可同化形式的二十碳五烯酸或其任何适宜的衍生物(EPA),其中EPA的纯度至少为50%;及
任何生物学上可同化形式的花生四烯酸(AA)。
2.权利要求1的药物制剂,其中EPA的纯度至少为90%。
3.权利要求1或2的药物制剂,其中AA的纯度至少为30%。
4.权利要求3的药物制剂,其中AA的纯度至少为90%。
5.前述权利要求任一项的药物制剂,其中EPA与AA的比例为1∶1~20∶1。
6.前述权利要求任一项的药物制剂,其中EPA的剂量为100~10000mg/天。
7.前述权利要求任一项的药物制剂,其包含1~4g的EPA和0.1~2.0g的花生四烯酸(AA)。
8.药物制剂,其包含:
1.5~3g任何生物学上可同化形式的二十碳五烯酸或其任何适宜的衍生物(EPA);及
0.1~2.0g任何生物学上可同化形式的花生四烯酸(AA)。
9.前述权利要求任一项的药物制剂,其中的活性成分基本上全部由EPA和AA组成。
10.前述权利要求任一项的药物制剂,其中AA被其前体DGLA代替。
11.前述权利要求任一项的药物制剂,其中AA被其前体GLA代替。
12.药物制剂,其包含EPA及选自DGLA和GLA的AA前体,其中EPA的剂量为100~10000mg/天,且其中EPA与AA前体的比例为1∶1~20∶1。
13.前述权利要求任一项的药物制剂,还包含调味剂和乳化剂。
14.前述权利要求任一项的药物制剂,其中EPA由甘油三酸酯或乙酯组成,其纯度为50%或更纯,优选纯度大于90%。
15.前述权利要求任一项的药物制剂,其用于治疗任何精神病学,神经病学或者其它中枢或周围神经系统的疾病,特别是精神分裂症,抑郁症,双相性精神障碍以及大脑的退化性疾病,包括早老性痴呆和其它痴呆以及帕金森病。
16.权利要求1~14的药物制剂,用于治疗选自下列任意疾病:
哮喘及其它呼吸系疾病;
胃肠道疾病,包括炎性肠道疾病和过敏性肠道综合症;
涉及任何系统的炎性疾病;
心血管疾病;
任何形式的脂肪代谢障碍,任何形式的糖尿病或任何形式的代谢疾病;
任何形式的皮肤病;
任何形式的肾或泌尿道疾病;
任何形式的肝疾病;
任何形式的男女生殖系统或有关第二性器官如乳房或前列腺的疾病;
任何形式的癌症或癌症恶病质;
任何头部或颈部的疾病,包括口腔和牙齿的疾病、眼睛的疾病或耳朵的疾病;及
任何形式的病毒、细菌、真菌、原生动物或其它有机体的传染病。
17.一种通过给药权利要求1~14任一项的药物制剂治疗或预防下列疾病的方法:任何精神病学,神经病学或者其它中枢或周围神经系统的疾病,特别是精神分裂症,抑郁症,双相性精神障碍以及大脑的退化性疾病,包括早老性痴呆和其它痴呆以及帕金森病。
18.一种通过给药权利要求1~14任一项的药物制剂治疗或预防选自下列的任何疾病的方法:
哮喘及其它呼吸系疾病;
胃肠道疾病包括炎性肠道疾病和过敏性肠道综合症;
涉及任何系统的炎性疾病;
心血管疾病;
任何形式的脂肪代谢障碍,任何形式的糖尿病或任何形式的代谢疾病;
任何形式的皮肤病;
任何形式的肾或泌尿道疾病;
任何形式的肝疾病;
任何形式的男女生殖系统或有关第二性器官如乳房或前列腺的疾病;
任何形式的癌症或癌症恶病质;
任何头部或颈部的疾病,包括口腔和牙齿的疾病、眼睛的疾病或耳朵的疾病;及
任何形式的病毒、细菌、真菌、原生动物或其它有机体的传染病。
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Cited By (3)
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US9006287B2 (en) | 2005-02-14 | 2015-04-14 | Suntory Holdings Limited | Composition comprising dihomo-γ-linolenic acid (DGLA) as active ingredient |
US9943495B2 (en) | 2005-02-14 | 2018-04-17 | Suntory Holdings Limited | Composition containing dihomo-γ-linolenic acid (DGLA) as the active ingredient |
US10342773B2 (en) | 2005-02-14 | 2019-07-09 | Suntory Holdings Limited | Composition containing dihomo-γ-linolenic acid (DGLA) as the active ingredient |
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