CN112867486A - 表现出增强的氧化稳定性的组合物 - Google Patents
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Abstract
包含α‑生育酚乙酸酯(也称为维生素E乙酸酯、“Vit E乙酸酯”)和二十二碳六烯酸乙酯(“DHA EE”)的组合物表现出了令人惊讶的氧化稳定性。
Description
技术领域
本发明是一种组合物,所述组合物包含α-生育酚乙酸酯(也称为维生素E乙酸酯、“Vit E乙酸酯”)和二十二碳六烯酸乙酯(“DHA EE”),所述组合物表现出了令人惊讶的氧化稳定性。
背景技术
DHA是一种长链脂肪酸,并且是大脑、皮肤和视网膜的结构组分。它通常作为营养补充剂出售,并且可以从鱼油、藻油和人类母乳中获得。
有两种常见的DHA市售形式:甘油三酯形式和乙酯形式。乙酯形式是合成形式,并且通常是存在于含有DHA浓缩物的市售胶囊中的形式。关于哪种形式是更生物可利用的形式存在争议。两者的生物活性似乎总体上相似,但是一些研究表明甘油三酯形式可能略微更有益。
维生素E是应用于八种天然存在的脂溶性植物源异构体和合成的全外消旋(全rac)-α-生育酚异构体混合物的统称。维生素E同种型不是生物等效的。人体循环中只存在来自天然存在的RRR-α-生育酚的α-生育酚和常用于补充剂中的维生素E的其他合成2R-立体异构形式。
在本领域中已经描述了将一种形式的DHA和一种类型的维生素E同时施用的组合使用。例如WO16/096685(DSM IP ASSETS,B.V.)描述了DHA和维生素E的组合用于治疗非酒精性脂肪肝病的用途。Sadeghi等人在2018年描述了用于治疗痛经的组合(GynecologicalEndocrinology,在PrintDOI:10.1080/09513590.2018.1450377之前的页);并且WO2016/095778(DSM IP ASSETS,B.V.)描述了一种用于改善与微粒空气污染相关联的疾病的组合。这些文献都没有公开维生素E乙酸酯和DHA乙酯的组合。
像所有的油一样,DHA EE易氧化,并且易酸败。期望有更稳定的包含DHA EE的组合物。
发明内容
已经发现,根据本发明,包含DHA EE和维生素E乙酸酯(“Vit E Ac”)的组合的组合物表现出了显著的氧化稳定性。所述组合物可用作营养品或药物,并具有延长的保质期。
在本发明的优选实施方式中,用于制备本发明的组合物的DHA EE是高度浓缩的DHA EE,意味着DHA EE含有至少92重量%的DHA EE,优选至少93重量%的DHA EE,更优选至少94重量%的DHA EE。在一些实施方式中,它是至少95%的DHA EE。高度浓缩的DHA EE可从瑞士帝斯曼营养产品公司(DSM Nutritional Products,Switzerland)购得。
Vit E Ac可从瑞士帝斯曼营养产品公司获得。
定义
如贯穿说明书和权利要求书中所使用的,以下定义适用:
“α生育酚”是指维生素E的任何异构体
“生育酚乙酸酯”是指维生素E乙酸酯。
“维生素E乙酸酯或Vit E Ac”指全外消旋α-生育酚乙酸酯。
“唯一的活性成分”是指所述组合物可含有除Vit E Ac和DHA之外的成分,例如至多0.25%(按重量计)的混合天然生育酚,和/或乙酰棕榈酸酯或其他长链脂肪酸酯等,所述成分被认为对DHA EE和Vit E Ac组合物的生物活性没有实质性贡献。组合物中可能存在的其他成分是加工助剂,例如填充剂、粘合剂和其他赋形剂。
“高度浓缩的DHA EE”指含有至少92%DHA EE的DHA EE。
附图说明
图1是示出如实施例1所述的含有α-生育酚和生育酚乙酸酯的高度浓缩的DHA-EE的氧化稳定性的图。
图2是示出如实施例1所述的PV随α生育酚和生育酚乙酸酯变化的图。
图3示出了如实施例1所述的p-AV随α-生育酚和生育酚乙酸酯的变化。
图4示出了如实施例1所述的CD随α-生育酚和生育酚乙酸酯的变化。
图5示出了如实施例1所述的DHA-EE水平随时间推移的变化。
比率
DHA EE与Vit E Ac的比率可基于这两种成分的重量%在10:1至1:10的范围内。在一些优选实施方式中,所述比率为5:1至1:5;在另一个实施方式中为小于2:1。
剂量
在一个优选实施方式中,用于成人的Vit E Ac日剂量在500IU至2000IU的范围内。在一个优选实施方式中,所存在的Vit E Ac的量将在8000IU/日剂量至1200IU/日剂量的范围内。在一些特别优选的实施方式中,Vit E乙酸酯为1000IU/日剂量。
DHA EE的量可在500mg/日剂量至3克/日剂量的范围内。在一个优选实施方式中,DHA EE将在1.5克/日剂量至2.5克/日剂量的范围内。在一些特别优选的实施方式中,DHAEE的量为2克。
因此,本发明包括的一些特别优选的日剂量包含:
日剂量为1000IU的Vit E Ac和2克DHA EE
日剂量为800-1200IU的Vit E Ac和1.5-2.5g的DHA EE;
日剂量为800IU的VIt E Ac和1.5g的DHA EE;以及
日剂量为1200IU的Vit E和2.5g的DHA EE。
由于这些量相对较大,所以优选的是单独胶囊或其他口服剂型含有所述日剂量的一部分。因此,上述日剂量可以优选地以例如两种形式施用,每种形式含有日剂量的一半,或者交替地以三种形式施用,每种形式含有日剂量的三分之一,依次类推。这是为了方便患者和增强依从性。
在一些实施方式中,将Vit E乙酸酯和DHA EE与常规施用以治疗病症的其他已知活性成分组合。
在一些实施方式中,还加入抗坏血酸棕榈酸酯(AP)以进一步改善Vit E乙酸酯和DHA EE组合的氧化稳定性。在一些实施方式中,唯一的活性成分是Vit E乙酸酯、DHA EE和AP。
在本发明的另一实施方式中,所述组合物包含Vit E乙酸酯和DHA EE作为其唯一的活性成分。唯一的活性成分构成最终成品形式(片剂、胶囊等)的至少95重量%,优选地至少96重量%,更优选地至少96.4重量%。附加成分作为加工助剂存在。
根据本发明的包含Vit E Ac和DHA EE的组合物可用作营养保健组合物,即作为饮食组合物的补充物,即(强化的)食物/饲料或饮料,或作为剂量单位形式的组合物,例如药物组合物,例如胶囊、片剂、颗粒剂、糊剂或泡腾制剂,所述药物组合物还可包含药学上可接受的载体、赋形剂或稀释剂,包括但不限于润滑剂、着色剂、润湿剂、填充剂、崩解剂和调味剂。可将糊剂填充到硬或软明胶胶囊中。
在优选的实施方式中,所述组合物为液体形式,并且用于填充胶囊,包括软明胶胶囊。
以下非限制性实施例进一步说明了本发明。
实施例
实施例1
DHA-α-生育酚和DHA-α-生育酚乙酸酯的氧化稳定性
目的:
为了研究维生素E和维生素E乙酸酯对95%DHA浓缩物EE的氧化稳定性的影响。
材料和方法
浓度为1000IU/g的真正标准维生素E(α-生育酚)和浓度为1360IU/g的维生素E乙酸酯(α-生育酚乙酸酯)购自加拿大西格玛奥德里奇公司(Sigma-Aldrich,Canada)。本研究中使用了具有95%的乙酯形式的二十二碳六烯酸(DHA)(95DHA-EE)的鱼油浓缩物,所述鱼油浓缩物已经用2mg/g的混合天然生育酚(MNT)稳定化。用两种基本方法来评估氧化稳定性。
1.氧化稳定性指数或油稳定性指数(OSI)
2.常规存储稳定性研究
氧化稳定性指数或油稳定性指数
用氧化稳定性仪测定具有不同类型和量的抗氧化剂的油样品的OSI。一式两份地,将维生素E(α-生育酚)和维生素E乙酸酯(α-生育酚乙酸酯)以400IU的量称量到OSI试管中并单独加入至多5g含有或不含0.5mg/g抗坏血酸棕榈酸酯(AP)的油样品。将含有约2mg/gMNT的空白油样品用作阴性对照,以比较含有和不含抗坏血酸棕榈酸酯的α-生育酚和α-生育酚乙酸酯的功效。将这些样品在氧化稳定性仪中在70℃温育,与此同时使用约5.5psi的空气压力使空气鼓泡通过油。每个油样品的诱导时间被视为氧化稳定性指数。
常规存储稳定性研究
为了进行存储稳定性研究,在琥珀色玻璃瓶中制备25g的95DHA-EE样品。以每2gDHA 800IU的浓度加入α-生育酚和α-生育酚乙酸酯。根据表(1)制备油样品,以获得正确的组合。
表1.制备25g样品共混物
将这些油样品在环境温度(23-25℃)下对空气开放地存储,并在不同时间取样以测定过氧化值(PV)、对茴香胺值、共轭二烯(CD)和乙酯形式的DHA的含量。
结果在图1至图5中给出。虽然抗坏血酸棕榈酸酯、α-生育酚和α-生育酚乙酸酯是已知的抗氧化剂,但是这些化合物当各自单独加入时并没有提高已经用2mg/g的混合天然生育酚(MNT)稳定化的DHA-EE的油稳定性指数(图1)。如通过OSI测定的,即使加入抗坏血酸棕榈酸酯(其通常用作鱼油中的抗氧化剂)也没有提高α-生育酚的抗氧化活性,而抗坏血酸棕榈酸酯与α-生育酚乙酸酯组合时显著地提高了油稳定性指数。
氢过氧化物是一次氧化产物,所述一次氧化产物指示了不饱和脂肪酸的初始氧化水平,并且这些产物被测定作为过氧化值(PV)。除了含有抗坏血酸棕榈酸酯+α-生育酚乙酸酯的油样品外,所有样品的PV都显著增加,表明了这2种化合物一起时的强协同抗氧化活性(图2)。
被确定为茴香胺反应性物质的二次氧化产物被测定作为为p-AV(图3)。含有抗坏血酸棕榈酸酯加α-生育酚乙酸酯的样品中的p-AV在存储期间完全没有增加,而所有其他样品的该值在21天的存储期期间逐渐增加。共轭二烯也指示一次氧化水平在含有抗坏血酸棕榈酸酯和α-生育酚乙酸酯的样品中没有增加(图4)。因此,所有这些稳定性指数清楚地表明抗坏血酸棕榈酸酯的加入显著地提高了α-生育酚乙酸酯和DHA-EE组合的氧化稳定性。
此外,在环境温度下存储21天后,油样品中的DHA的量没有显著变化(图5)。
一种软胶囊含有(按重量百分比计):
Claims (7)
1.一种组合物,所述组合物包含二十二碳六烯酸乙酯(DHA EE)和维生素E乙酸酯(VitE Ac)。
2.根据权利要求1所述的组合物,其中所述DHA EE和Vit E乙酸酯是唯一的活性成分。
3.根据权利要求1所述的组合物,其中所述DHA EE是高度浓缩的DHA EE。
4.根据权利要求3所述的组合物,其中所述DHA EE是至少90%的DHA EE。
5.根据权利要求1所述的组合物,其中DHA EE、Vit E Ac和抗坏血酸棕榈酸酯是唯一的活性成分。
6.根据权利要求5所述的组合物,其中所述DHA EE是高度浓缩的DHA EE。
7.一种软胶囊,所述软胶囊包含根据权利要求1-5中任一项所述的组合物。
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