CN102481011A - 含有黄斑色素的叶黄素组合物及其制备方法 - Google Patents
含有黄斑色素的叶黄素组合物及其制备方法 Download PDFInfo
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- CN102481011A CN102481011A CN2010800387550A CN201080038755A CN102481011A CN 102481011 A CN102481011 A CN 102481011A CN 2010800387550 A CN2010800387550 A CN 2010800387550A CN 201080038755 A CN201080038755 A CN 201080038755A CN 102481011 A CN102481011 A CN 102481011A
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Abstract
一种叶黄素组合物,其含有包含反式叶黄素和玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素的黄斑色素,来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。该组合物具有至少80重量%的总叶黄素,该总叶黄素中的反式叶黄素与玉米黄素异构体的比例为约4∶1-6∶1,玉米黄素的异构体的比例为约80-20∶20-80。
Description
技术领域
本发明涉及含有黄斑色素的叶黄素组合物及其制备方法。本发明特别涉及含有黄斑色素的叶黄素组合物及其制备方法,其中黄斑色素由反式叶黄素(trans-lutein)和玉米黄素异构体组成。本发明更特别涉及含有黄斑色素的叶黄素组合物,其中黄斑色素由反式叶黄素和玉米黄素异构体即(R,R)-玉米黄素和(R,S)-玉米黄素组成,其来源于含有叶黄素(xanthophylls)/叶黄素酯(xanthophylls esters)、人食用安全、用于营养保健的植物提取物/油性树脂。更特别的是,本发明涉及含有至少80重量%的总叶黄素(total xanthophylls)的叶黄素组合物,总叶黄素中反式叶黄素的含量为至少80%,其余为玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素,其来源于含有叶黄素/叶黄素酯、人食用安全、用于营养保健的植物提取物/油性树脂。
本发明的叶黄素组合物可用作营养保健成分及食品和饲料的添加剂和/或着色剂。
背景技术
黄斑位于眼睛内晶状体正后方的视网膜中央。它是一块很微小的黄色区域,由像叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-玉米黄素这样的叶黄素(xanthophylls)组成,该叶黄素因此称为黄斑叶黄素。这些色素起抗氧化剂作用,保护视网膜不受氧化降解,并帮助维持视力敏锐,确保清晰地阅读、书写、驾驶及看物。一生当中黄斑会受到缓慢、持续的损害,这可导致老年性黄斑变性(AMD)和白内障。饮食或补充剂中所含的黄斑叶黄素能帮助维持眼睛健康。叶黄素(lutein)和(R,R)-玉米黄素可来源于水果和蔬菜,而(R,S)-玉米黄素来自海鲜食品或膳食添加剂,或者来自体内叶黄素的生物转化。各类色素当中,类胡萝卜素是自然界分布最广的色素之一,具有红色、黄色和橙色,有各种功能,例如在地球上的植物内起到捕光和抵御破坏性光氧化的作用。
虽然在各种水果、蔬菜、鸟羽、蛋黄、家禽皮肤、甲壳动物和眼睛黄斑区中都已经发现含有特定的类胡萝卜素,但是万寿菊花瓣、玉米和叶类蔬菜中尤其富含类胡萝卜素。膳食类胡萝卜素与人血清和血浆中发现的类胡萝卜素之间的关系表明,只有被选中的那些组的类胡萝卜素才会进入人血流中发挥作用。每种类胡萝卜素都有各自的一套吸收、血浆运输和代谢模式。
类胡萝卜素吸收可见光谱中400-500nm区的光线。这一物理特性使这些色素呈现黄/红色特征。类胡萝卜素含有由异戊二烯单元组成的共轭主链,这些单元通常在该分子中央翻转,表现出对称性。双键周围的几何构型的变化,导致许多顺式和反式异构体存在。哺乳类动物不能合成类胡萝卜素,所以只得从饮食来源,如水果、蔬菜和蛋黄中摄取。近年来,已有报道称类胡萝卜素对健康有若干益处,包括对严重健康疾病的保护和/或预防。
类胡萝卜素是非极性化合物,分为两个亚类,即一类是极性化合物,称为叶黄素或含氧类胡萝卜素(oxy-carotenoids),另一类是非极性烃类胡萝卜素,如β-胡萝卜素、番茄红素等。这两个亚类都有至少9个共轭双键,负责类胡萝卜素的特征颜色。叶黄素在其共轭双键链的末端具有环结构,带有极性官能团,如羟基或酮基。叶黄素(xanthophylls)例如包括叶黄素(lutein)、玉米黄素、辣椒黄素、角黄素、β-隐黄素和虾青素等。作为天然的着色剂以及在人类保健中的角色,近年来叶黄素(xanthophylls)如叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-玉米黄素已经引起生物医学、化学和营养领域的科学家和研究学者们的再次关注。
黄色和橙黄色分别归功于叶黄素(lutein)和玉米黄素的作用。叶黄素(lutein)和玉米黄素可在植物材料中既能以游离形式(ftee form)也能以酯类形式存在。叶黄素(lutein)在绿叶蔬菜,如菠菜、甘蓝和西兰花中以游离形式存在,芒果、桔子和木瓜等水果和红辣椒、海藻、黄玉米中含有酯类形式的叶黄素。它还存在于人体血流和各种组织内,尤其存在于眼睛的黄斑、晶状体和视网膜内。
叶黄素(lutein)在化学上命名为β-ε-胡萝卜素3,3’-二醇。玉米黄素是经β-胡萝卜素上加入两个羟基形成。因为羟基位于3和3′-位置上,所以玉米黄素的化学名称是β,β-胡萝卜素-3,3’-二醇。玉米黄素这一通用名来源于玉米(zea mays),因为这种类胡萝卜素最早是在玉米(Zea mays)中发现的。
可以看到(图1),叶黄素(lutein)是不对称的,因为其左环上双键的位置与右环上双键的位置不同。与叶黄素(lutein)相比,玉米黄素多一个共轭双键,所以其左环和右环是完全对称的。
叶黄素(Xanthophylls)能表现为光学异构体(R-和S-立体异构体)和几何异构体(反式,E-和顺式,Z-)。R-和S-立体异构体的构象是根据CD光谱柱和手性柱HPLC研究确定的,而反式和顺式异构体的构象是根据电子、红外、NMR、HPLC-MS和HPLC-NMR在线光谱研究确定的。众所周知,当一个有机分子含有一个与4个不同类型的原子或基团相连的碳原子时,那个碳原子就称为手性碳原子。该手性碳原子产生两种不同的空间排布,导致光学异构体形成;而聚烯烃链上双键数量、甲基的存在以及不存在空间位阻这些条件决定了反式和顺式异构体的数量。在反式玉米黄素的情况下,其两端环上3和3’位置上的碳原子都是手性碳原子。
因此,基于与反式玉米黄素的C3和C3’碳原子相连的二级羟基的位置,反式玉米黄素在C3和C3’碳原子的位置有两个手性中心。所以,反式玉米黄素有四种可能的立体异构体,即(3R-3′R)-异构体、(3S-3′S)-异构体和(3R-3′S)-或(3S-3′R)-异构体。这些异构体中,(3S-3′S)-和(3S-3′R)-异构体相同。所以,反式玉米黄素有三种手性异构体。引起极性光右旋的异构体称为R-立体异构体,引起左旋的异构体为S-立体异构体,具有两倍互为相反效果(R,S;无旋光的)的第三种异构体称为内消旋型玉米黄素。叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-内消旋型玉米黄素的结构式如下图1所示。
图1黄斑叶黄素的化学结构
叶黄素(lutein)和玉米黄素的共轭双键帮助产生各色素的不同颜色,而且还影响这些色素清除单线态氧的能力。由于多一个共轭双键,玉米黄素被认为是比叶黄素(lutein)更强的抗氧化物。
眼睛内的黄斑色素主要由三种叶黄素色素(或黄斑叶黄素)组成,即(3R,3’R,6’R)-叶黄素、(3R,3’R)-玉米黄素和(3R,3’S)-玉米黄素,它们依次占视网膜中全部类胡萝卜素含量的36%、18%和18%,其余20%由少量的含氧叶黄素(oxo-lutein)、epi-叶黄素和ε-,-ε-胡萝卜素3,3′-二酮组成(J.T.Landrum and R.A.Bone,Lutein,Zeaxanthin and the Macular Pigment,Arch.Biochem.Biophys.,385,28-40,2001)。虽然眼睛的所有组织内都发现存在这些叶黄素色素,但是它们在视网膜黄斑区,包括视网膜上中心凹陷区(称为中央凹)的浓度最高。叶黄素色素的浓度向黄斑区中心递进增加,中央凹中这些叶黄素色素的浓度比人其它组织内的高出千倍左右(Landrum等,Analysis of Zeaxanthin Distribution withinIndividual Human Retinas,Methods in Enzymology,L.Packer(editor)213A,457-467,Academic Press 1992)。中央凹是黄斑区内的一个较小区域,其中视锥细胞光感受器达到其最大浓度。叶黄素(xanthophylls)总量的约50%都集中在黄斑内,其中玉米黄素浓度高于叶黄素(lutein),其比例为2∶1(Handelman等,Measurements of Carotenoids in Human and Monkey Retinas,in Methods inEnzymology,L.Packer(editor)213A,220-230,Academic Press,NY,1992;Billsten等,Photophysical Properties of Xanthophylls in Carotene Proteins from Human Retina,Photochemistry and Photobiology,78,138-145,2003)。在视网膜中央凹的中央,玉米黄素是(反式-3R,3′R)-玉米黄素和(反式-3R,3′S)-玉米黄素的50∶50混合体外加少量的(3S,3′S)-玉米黄素(J.T.Landrum and R.A.Bone,Lutein,Zeaxanthin and TheMacular Pigment,Arch.Biochem,Biophy,385,28-40,2001)。
中央凹对正常视觉功能(如视觉敏锐)疾病来说尤其重要,已知这个区域受损会导致法定盲。例如,老年性黄斑变性(AMD)表现为视网膜、视网膜色素上皮细胞(RPE)和/或脉络膜发生病理变化,最先影响视网膜的黄斑区。在美国,这是65岁以上老人出现不可逆失明的首要原因,对于大多数患者尚无成熟的治疗手段。中心视力丧失导致可能无法分辨面孔、阅读、或书写或者开车,所以严重影响个人独立生活的能力。有大量流行病学证据支持饮食上摄入不同异构体形式的叶黄素和玉米黄素在预防老年性白内障和黄斑变性方面所起的作用。在人视网膜上检测到叶黄素和玉米黄素的氧化产物的事实支持了膳食摄入的叶黄素和玉米黄素在黄斑区可充当抗氧化剂的推测(Khachik等,Identification of Luteinand Zeaxanthin Oxidation Products in Human and Monkey Retinas,Invest.Opthalmoland Vis.Sci.,38,1802-1811,1997)。
在人饮食中通常摄入的40-50种类胡萝卜素中,叶黄素(lutein)和玉米黄素沉积在视网膜黄斑区的量要比沉积在外围视网膜上的量高达5倍之多。玉米黄素最先聚集在中央凹区,而叶黄素则富集在凹部周边的区域。
关于叶黄素(xanthophylls)在细胞水平的位置,据报道称,它与被称作叶黄素结合蛋白(XBP)的特异性蛋白结合在一起。研究暗示,XBP参与了从血流中吸收叶黄素(lutein)和玉米黄素以及保持视网膜内叶黄素和玉米黄素稳定的过程。利用飞秒瞬态吸收光谱对叶黄素(xanthophylls)和XBP进行的研究显示,与(3R,3′R)-玉米黄素相比,富集XBP的(3R,3′S)-玉米黄素更稳定,而叶黄素(xanthophylls):(3R,3′R)-玉米黄素和(3R,3′S)-玉米黄素的光学物理特性通常都是一样的。有可能内消旋型玉米黄素更适于与XBP配合,其中该蛋白质保护该叶黄素免受自由基的降解。所以,该复合物可能是比游离叶黄素更优的抗氧化物,有助于增强对眼组织的保护,使其不受氧化损害(Billsten等,PhotophysicalProperties of Xanthophylls in Caroteno proteins from Human Retina,Photochemistryand Photobiology,78,138-145,2003)。
由于类胡萝卜素的抗氧化特性,已经将若干功能归因于黄斑色素作用的结果,包括降低眼睛吸收的蓝光造成的光氧化损害,降低光散射和色差对视觉功能的影响,以及抵御光化学反应的不利影响。
已经证实,通过叶黄素(lutein)的膳食补充能增加黄斑色素的含量(Landrum等,Dietary Lutein Supplementation Increases Macular Pigment,FASEB.J,10,A242,1996)。食用水果、蔬菜和含有可从拒绝素食人群的海鲜食品中获得的叶黄素、(R,R)-玉米黄素和(R,S)-玉米黄素的膳食补充剂能极大控制由于白内障引起的视觉功能减退和AMD引起的成年人失明。虽然眼睛内的(R,S)-玉米黄素被认为是叶黄素(lutein)的代谢产物,但目前认识到有必要通过(R,S)-玉米黄素的膳食补充来提高黄斑色素的密度(Landrum and Bone,Functional Foods and Nutraceuticals,1Sep.2001)。同样,研究已经显示(R,R)-玉米黄素先进入血液中,最后进入黄斑区(Breithaupt等,Comparison of Plasma Responses in Human subjects after theIngestion of(3R,3’R)-zeaxanthin Dipalmitate from Wolfberry(Lycium barbarum)andNon-esterified(3R,3’R)-zeaxanthin using Chiral HPLC,Brit.J.Nutr.91,707-713,2004)。人体试验显示,叶黄素(lutein)和玉米黄素的膳食补充剂能增加黄斑色素的密度以及这些类胡萝卜素的血清浓度(Bone等,Lutein and Zeaxanthin DietarySupplements Raise Macular Pigment Density and Serum Concentrations of TheseCarotenoids in Humans,J.Nutr.,133,992-.998,2003)。
叶黄素(lutein)和玉米黄素的膳食来源
叶黄素(lutein)是大多数水果和蔬菜中存在的一种常见类胡萝卜素,而大多数水果和蔬菜中只存在微量的(R,R)-异构体形式的玉米黄素。玉米黄素的膳食来源局限于绿色的、某些黄色/橙色的水果和蔬菜,如玉米、油桃、桔子、木瓜、柿子和南瓜。五彩椒(Capsicum annum)是另一种广泛使用的最常见的辣椒,它是玉米黄素的良好来源。西方雪果(枸杞),枸杞子或枸杞子植物结有小红果,中国家庭烹饪中经常用到,研究显示其中的玉米黄素(主要以玉米黄素双棕榈酸酯形式存在)含量很高,但叶黄素(lutein)含量可忽略不计。中国的中医在药方中将枸杞子的干果作为许多眼疾的治疗剂。据报道,在法国从堆心菊(Heleniumautumnale)的花叶中提取出玉米黄素双棕榈酸酯(Helenien)用于治疗视觉障碍(Wolfgang Gau,Hans-Jurgen Ploschke and Christian Wunsche,Mass SpectrometricIdentification of Xanthophylls Fatty Acid Esters From marigold Flowers(Tageteserecta)Obtained by HPLC and Craig Counter Current Distribution,J.Chrom.262,277-284,1983)。
如前所述,内消旋型玉米黄素的膳食来源主要来自海鲜食品,如虾、鱼、龟等,所以素食人群缺乏内消旋型玉米黄素。但是,已有一项专利涉及含有内消旋型玉米黄素的药物组合物,用于治疗视网膜障碍,如增加人眼内黄斑色素沉积,以及治疗或预防AMD(Howard等,Meso-zeaxanthin Formulations forTreatment of Retinal Disorders,U.S.Pat.No.6,329,432,2001)。
水果、蔬菜和花卉(万寿菊)中天然的叶黄素(lutein)和玉米黄素以反式异构体形式存在。在光热引起的转化条件的作用下,一小部分反式异构体转化成顺式异构体。所以,根据对人血浆进行的几何异构体组分分析数据证实,优选的生物利用形式为反式异构体形式(Khachik等,Isolation and Structure Elucidation ofGeometric Isomers of Lutein,Zeaxanthin in Extracts of Human Plasma,J.Chrom.582,153-156,1992)。由此,需要在膳食补充剂中使用反式异构体形式的叶黄素和(R,R)-,(R,S)-形式的玉米黄素。
目前,有关眼睛视网膜内,内消旋型玉米黄素的形成、吸收和沉积的机理知之甚少。Khachik等人已经报道,在20份正常人血浆样品中发现存在2-3%的(3R,3′S,内消旋)-玉米黄素,并提出了(3R,3′S,内消旋)-玉米黄素由膳食摄入的叶黄素和玉米黄素形成的代谢途径一说。内消旋型玉米黄素沉积在视网膜上的途径是通过血清进入还是在视网膜内由叶黄素/玉米黄素生成尚不清楚(Khachik等,章:Dietary carotenoids and their metabolites as potentially useful chemo protectiveagents against cancer,″Antioxidant food supplement in human health,Eds.Packer等,Academic Press London,203-29页,1999)。但是,Breithaupt等人对各有6名志愿者的两组人员进行了单盲交叉研究,在两组人员摄入(3R,3′R)-玉米黄素(酯或游离形式)24小时后采集的人血浆中并未发现内消旋型玉米黄素的存在。手性LC-ApcI-MS被用于进行混合血浆样品的检测(Breithaupt等,Comparison of plasmaresponses in human subjects after the Ingestion of(3R,3’R)-zeaxanthin Dipalmitatefrom Wolfberry(Lycium barbarum)and Non-esterified(3R,3’R)-zeaxanthin usingChiral HPLC,Brit.J.Nutr.91,707-713,2004)。
有证据和理由支持以下假说:类胡萝卜素中的叶黄素、玉米黄素和内消旋型玉米黄素易于生物利用,所以增加了黄斑的色素水平(Landrum and Bone,Meso-zeaxanthin-A Cutting Edge Carotenoid,Functional Foods and Nutraceuticals,10 Sep.2001;Bone等.Thurnham等,Macular Zeaxanthin and Lutein-a Review ofDietary Sources and Bio-availability and Some Relationship with Macular PigmentOptical Density and Age-related Macular Disease,Nutr.Res.Reviews,20,163-179(2007);Thurnham等,A Supplementation Study in Human Subjects with aCombination of meso-zeaxanthin,(3R,3’R)-Zeaxanthin and(3R,3’R,6’R)-Lutein,Brit.J.Nutr.99,1-8,2008)。
目前,对将含有高含量的反式叶黄素和/或玉米黄素的叶黄素晶体用作抗氧化剂预防白内障和黄斑变性、用作防肺癌制剂、用作吸收太阳射线中有害紫外光的制剂,以及用作光诱导自由基和活性氧等的清除剂有很高的需求。现在已有大量来自天然来源的商业产品被用于促进含叶黄素或(R,R)-玉米黄素的工商业产品的制备。但是,就我们所知,还不存在含所有基本的黄斑叶黄素和高浓度的、尤其是至少85%的反式叶黄素(lutein)以及其余物质由来自于与商业用叶黄素或玉米黄素同样的天然来源(万寿菊花瓣)的(R,R)-玉米黄素和(R,S)-玉米黄素(等量或更多比例)组成的叶黄素组合物。基于膳食补充剂相对血清水平和黄斑色素密度之间的关系,已经发现了证明反式叶黄素、(R,R)-玉米黄素和(R,S)-玉米黄素在维持眼健康方面充当保护角色的证据(Bone等,Macular Pigment Responseto a Supplement Containing Meso-zeaxanthin,Lutein and Zeaxanthin,Nutr.Metabol.11.1-8(2007);Bone等,Macular Pigment Response to a Xanthophyll Supplement ofLutein,Zeaxanthin and Meso-zeaxanthin.Proc.Nutr.Soc.,105A,(2006);Thurnham等,A Supplementation Study in Human Subjects with a Combination of Meso-zeaxanthin,(3R,3’R)-zeaxanthin and(3R,3’R,6’R)lutein,Brit.J.Nutr.99,1-8(2008))。
现有技术
眼睛视网膜上的黄斑色素主要由叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-玉米黄素组成,比例约为2∶1∶1。这些色素占眼睛内类胡萝卜素总量的72%,其余为其它类胡萝卜素(Landrum and Bone,Lutein Zeaxanthin and the Macular Pigments,Arch.Biochem.Biophys.385,28-40,2001)。饮食中主要的叶黄素色素是叶黄素(lutein),来自水果和蔬菜。在美国,叶黄素的平均摄入量是每天1-3mg,其中包括约10-20%的(R,R)-玉米黄素(E.Y.Chew and San Gio Vanni,“Lutein”inEncyclopedia of Dietary Supplements,409-420页,2005Marcel Dekker出版)。正常饮食中没有发现(R,S)-玉米黄素,但某些海鲜食品如虾、鱼和龟中存在(R,S)-玉米黄素(Maoka等,The First Isolation of Enantiomeric and Meso-zeaxanthin in Nature.Comp.Biochem.Physiol.,83B,121-124,1986)。近年来,有报道称,在墨西哥发现鸡蛋黄中存在很高含量的玉米黄素,即(R,R)-玉米黄素和(R,S)-玉米黄素,其来源于同时含有(R,R)-玉米黄素和(R,S)-玉米黄素的鸡饲料(Thurnham等,ASupplementation Study in Human Subjects with a Combination of Meso-zeaxanthin,(3R,3’R)-zeaxanthin and(3R,3’R,6’R)-lutein,Brit.J.Nutr.991-8(2008))。最近5年中,美国市场上已在销售含(R,S)-玉米黄素的膳食补充剂,商标名为“LuteinPlus”和“LMZ3”,欧洲也有销售,商标名为“Lutein Plus”和“Macushield”。
另外,还有含(R,S)-玉米黄素的药物制剂,用于增加人眼内的黄斑色素密度及用于治疗和预防黄斑疾病和障碍(Howard等,Meso-zeaxanthin Formulations forTreatment of Retinal Disorders,US Patent No.6,379,432,2001)。膳食性叶黄素补充剂主要含有80-90%的叶黄素(lutein)和少量的玉米黄素,完全不含(R,S)-玉米黄素。混合样品的叶黄素组合物:即Lutein Plus;叶黄素50%、(R,R)-玉米黄素13%和(R,S)-玉米黄素37%;叶黄素54%、(R,R)-玉米黄素6%和(R,S)-玉米黄素40%(Thurnham等,A Supplementation Study in Human Subjects with a Combinationof Meso-Zeaxanthin,(R,R)-zeaxanthin and Lutein,Brit.J.Nutr.99,1-8(2008);Quantum Nutritionals,MI 48390,USA;Lutein 25%,(R,R)-zeaxanthin 6%and(R,S)-zeaxanthin 68%;Bone等,Macular Pigment Response to a Supplement ContainingMeso-zeaxanthin,Lutein and Zeaxanthin,Nutri.Metabol 4,12,2007);内消旋型玉米黄素浓缩剂,叶黄素5%、(R,R)-玉米黄素5%和(R,S)-玉米黄素85%;鸡蛋冻干后的蛋黄:叶黄素34%、(R,R)-玉米黄素12.80%和(R,S)-玉米黄素7.20%,以及其它类胡萝卜素(hurnham,Macular Zeaxanthin and Lutein-A Review of DietarySources and Bio-availability and Some Relations with MPOD and ARMD,Nutri.Res.reviews 20,163-179,2007)。纯度大于99%的纯(R,S)-玉米黄素(Schlatterer等,Quantification of(3R,3’R)-zeaxanthin in Plant Derived Food by diastereoisomericdilution assay applying Chiral HPLC,J.Chromatography A,1137,216-222,2006);(R,S)-玉米黄素(合成物)99%(Ernst等,US.Patent NO.6,743,954,2004);叶黄素组合物:叶黄素3.53%、(R,R)-玉米黄素5.77%和(R,S)-玉米黄素90.57%(Kumar等,US专利公开号No.2007/0265351)。最近,据报道,含有叶黄素2mg、玉米黄素0.5mg和(R,S)-玉米黄素0.5mg的膳食补充剂-共微囊制剂组合被用于抑制黄斑变性进程和促进健康视觉(Lang,Composition and methods for inhibiting theprogression of macular degeneration and promoting healthy vision,US专利No.7,267,830,2007)。
早在1946年,Karrer和Jucker就报道了用乙醇钠催化使叶黄素变为玉米黄素的异构化反应(P.Karrer and E.Jucker,Helv.Chim.Acta,30,266,1947)。后来在1971-72年,基于PMR分析结果以及试图将叶黄素异构化为(R,R)-玉米黄素但未获成功的事实,Buchecker等人认为叶黄素具有R-手性。Andrewes等人报道了(3R,3′R,6R)-叶黄素(有旋光性的)的异构化反应的立体化学情况,根据CD光谱研究,上述反应得到无旋光性、反式异构体形式的(3R,3′S)-玉米黄素(Isomerization of Epsilon-carotene to Beta-carotene and Lutein to Zeaxanthin,ActaChem.Scand.,B28,139,1974)。以上反应过程得到低产量的、10-15%、无旋光性的(3R,3′S,内消旋)-玉米黄素,反应中使用了禁止在食品和保健补充剂中使用的苯和DMSO。
Rodriguez已经介绍了一种利用非水性介质并加热碱和丙二醇混合物从而将叶黄素异构化得到玉米黄素差向异构体混合物的方法。虽然圆二色谱表明玉米黄素的内消旋型异构体形成,但是并未尝试将内消旋型玉米黄素含量进行定量而且也未提供异构化产物的成分(U.S.专利No.5,973,211,1999)。就我们所知,至今未见报道涉及包含至少80重量%的总叶黄素(更高水平的反式叶黄素(lutein)含量(70-80%)),其余物质为(R,R)-玉米黄素和(R,S)-玉米黄素)的食品级叶黄素组合物。这样一种组合物将形成理想的基本膳食补充剂,有助于维持健康的视觉。而且,根据支持反应过程中所用试剂的因素和现有的关于类似的各叶黄素的毒理安全性文献数据,该组合物可视为是安全的(Kruger等,Food&Chem.Toxicol.,40,1535-1549(2002);Chang,Thirteen week Toxicity of Meso-zeaxanthinin Han Wister Rats with a Four Week Recovery Gene Logic No.156704370(2006))。
人每天消耗1-3mg叶黄素(lutein),饮食中叶黄素(lutein)与玉米黄素的比例约为5∶1(Petra A Thürmann,Wolfgang Schalch,Jean-Claude Aebischer,Ute Tenterand William Cohn,Plasma kinetics of lutein,zeaxanthin,and 3-dehydro-lutein aftermultiple oral doses of a lutein supplement,American Journal of Clinical Nutrition,Vol.82,No.1,88-97,July 2005;Nebeling LC,Forman MR,Graubard BI,Snyder RA.Changes in carotenoid intake in the United States:the 1987 and 1992 National HealthInterview Surveys.J Am Diet Assoc,991-6.1997;Le Marchand L,Hankin JH,Bach F等.An ecological study of diet and lung cancer in the South Pacific.Int J Cancer;63:18-23,1995.Mohamedshah F,Douglas JS,Amann MM,Heimbach JM.Dietaryintakes of lutein+zeaxanthin and total carotenoids among Americans age 50 andabove.FASEB J,13:A554(abstr).,1999)。
血浆中叶黄素(lutein)与玉米黄素的比例是4∶1或5∶1(Emily Chew and JohnPaul SanGiovanni,in Encyclopedia of Dietary Supplements,Ed.Paul Coates,MarcelDekker,pages 409-421,2005)。
在上面所解释的情况下,对工业和营养产品配方设计师来说,需要有这样一种有实用价值的叶黄素(xanthophyll)浓缩剂,它含有从商业化规模的生产工艺中获取的和用那些与市场上已经认可的叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-玉米黄素制备原料一样的天然原材料生产的所有黄斑叶黄素。所制备的产品中,叶黄素(lutein)与玉米黄素的比例为5∶1,与常规饮食和血浆中的一样。如此制备的产品还应该采用用于生产适于人食用的膳食补充剂的安全溶剂(GRAS)制造,溶剂残留量最低,叶黄素(lutein)和玉米异构体的规格应考虑视觉功能和市场需求。
本发明的目的
所以,本发明的主要目的是提供一种含有黄斑色素的叶黄素组合物,其中该黄斑色素由反式叶黄素和玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素组成,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
本发明的另一目的是提供一种含有至少80重量%的总叶黄素的叶黄素组合物,该总叶黄素中反式叶黄素(lutein)的含量至少占80重量%,其余为玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
本发明的再一目的是提供一种含有至少85重量%的总叶黄素的叶黄素组合物,总叶黄素中反式叶黄素(lutein)的含量至少占85重量%,其余为玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
本发明的再一目的是提供一种含有至少85重量%的总叶黄素的叶黄素组合物,总叶黄素中至少80重量%是反式叶黄素(lutein),至少6重量%是(R,R)-玉米黄素,至少6重量%是(R,S)-玉米黄素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
本发明的还一目的是提供一种叶黄素组合物,其中该组合物含有至少85重量%的反式叶黄素(lutein)和至少4重量%的(R,R)-玉米黄素和至少5重量%的(R,S)-玉米黄素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
本发明的再一目的是提供一种叶黄素组合物,其中该组合物含有至少85重量%的总叶黄素,总叶黄素中至少80重量%是反式叶黄素(lutein),其余的15重量%是玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
本发明的还一目的是提供一种含有黄斑色素的叶黄素组合物的制备方法,该黄斑色素由反式叶黄素和玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素组成,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
本发明根据我们以下的研究结果实现上述目的:
a)将植物提取物/油性树脂中存在的叶黄素酯转化成脱脂形式的皂化步骤能与叶黄素(lutein)的不完全异构化反应结合,制备出叶黄素组合物,该组合物含有更高含量的反式叶黄素、其余为玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素,以及痕量的其它类胡萝卜素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。
b)皂化步骤中,可将氢氧化钾或氢氧化钠溶解到1-丙醇中,不加水。
c)所述皂化/异构化反应的温度可在70-100℃,优选约为95℃,皂化时间可为1-2小时。
d)必要的话,上述反应过程中使用的醋酸乙酯可回收再用,使整个工艺更经济。
发明内容
因此,本发明提供了一种含有黄斑色素的叶黄素组合物,该黄斑色素由反式叶黄素和玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素组成,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂,该组合物中至少80重量%是总叶黄素,该总叶黄素中反式叶黄素(lutein)与玉米黄素异构体的比例为4∶1-6∶1,玉米黄素的异构体比例为80-20∶20-80。
根据本发明的另一实施例,其提供了一种叶黄素组合物,其中,该组合物含有至少85重量%的总叶黄素,总叶黄素中反式叶黄素的含量占至少85%,反式叶黄素(lutein)与玉米黄素异构体的比例为4∶1-6∶1,玉米黄素的异构体比例为80-20∶20-80。
根据本发明的再一实施例,其提供了一种叶黄素组合物,其中,该组合物含有至少85重量%的总叶黄素,总叶黄素中至少80重量%是反式叶黄素,至少6重量%是(R,R)-玉米黄素,至少6重量%是(R,S)-玉米黄素。
根据本发明的另一实施例,其提供了一种叶黄素组合物,其中,该组合物含有至少85重量%的反式叶黄素,至少4重量%的(R,R)-玉米黄素,至少5重量%的(R,S)-玉米黄素。
根据本发明的再一实施例,其提供了一种叶黄素组合物,其中,该组合物含有至少85重量%的总叶黄素,总叶黄素中至少80重量%是反式叶黄素,其余15重量%是玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素。
根据本发明进一步的实施例,其提供了一种含有黄斑色素的叶黄素组合物的制备方法,该黄斑色素由反式叶黄素和玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素组成,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂。该方法包括:
(a)将含有叶黄素酯的植物提取物/油性树脂与1-丙醇碱性溶液混合,使其中的叶黄素酯同时发生皂化和部分异构化反应,其中,碱与1-丙醇的重量/体积比为1∶0.5-1∶1,在70-100℃,优选95℃,加热所得物质,1-5小时,得到皂化/异构化浓缩粗品。
(b)将步骤(a)中获得的皂化/异构化浓缩粗品与水按1∶2-1∶3的体积/体积比混合,得到稀释的油性混合物。
(c)用醋酸乙酯对步骤(b)中得到的稀释的油性混合物进行萃取,所用的稀释的油性混合物与醋酸乙酯的体积/体积比为1∶1.5-1∶2,萃取后得到含有叶黄素组合物的萃取液。
(d)将步骤(c)中得到的组合物蒸发,除去醋酸乙酯。
(e)将步骤(d)中所得组合物进行纯化,即先用非极性溶剂再用极性溶剂先后洗涤,然后过滤;
(f)在40-45℃将所得组合物真空干燥48-72小时;
(g)如果需要的话,用传统方法回收步骤(c)中使用的醋酸乙酯,必要的话重复利用;以及
(h)将所得组合物在-20℃储存在惰性气氛中。
通过调节步骤(a)中的温度、时间和碱量,步骤(b)和(c)中的比例,可以获得本发明所需的组合物。
应注意,本发明想到使用叶类和绿色蔬菜、玉米、水果和万寿菊作为叶黄素油性树脂来源。但是,考虑到叶黄素(lutein)与游离型玉米黄素以及大量叶绿素和其它非所需的类胡萝卜素一并存在于大多数水果中,虽然根据本发明,使用叶类和绿色蔬菜、玉米和水果并非不可能,但考虑到上述材料中低浓度的叶黄素(lutein)和玉米黄素而且需要精细的纯化步骤,不经济,所以优选万寿菊作为原材料用于制备本发明的组合物。
具体来说,用己烷萃取法制得的商用食品级万寿菊油性树脂可用作原材料(Kumar等,Process for the Preparation of Xanthophylls Crystals,US专利No.6,743,953,2004;Kumar US专利No.6,737,535,2004)来制备含有反式叶黄素(lutein)和玉米黄素异构体的叶黄素组合物。
万寿菊花(万寿菊种)被认为是最有可能提取反式叶黄素(lutein)的商业来源,因为它含有作为主要的类胡萝卜素成分的叶黄素单酯和叶黄素二酯。从万寿菊干花碎末中制取的万寿菊提取物/油性树脂含有约20-40%的叶黄素酯,具体含量依培育的品种和提取工艺而定。除叶黄素(lutein)外,万寿菊还含有5%的(R,R)-玉米黄素和痕量α-和β-隐黄素和β-胡萝卜素(Khachik US专利5,382,714,1995)。
步骤(a)中使用的碱可选自氢氧化钠或氢氧化钾。
步骤(d)中使用的非极性溶剂可以是烃类溶剂,可选自戊烷、己烷和庚烷等,优选为己烷。步骤(e)中使用的极性溶剂可选自低级脂肪醇。
储存制得的组合物所用的惰性气氛可以是持续的惰性的气体,如氮气。
生产工艺的详细说明
本发明中,将含有叶黄素酯的提取物与1-丙醇混合,其中碱已经溶解在1-丙醇中。碱与1-丙醇和植物提取物的比例分别为0.5-1∶0.5-1.0和0.5-1∶1.0。将混合物加热到90℃,维持1-5小时,持续搅拌。利用分光光度分析法(AOAC-第16版方法970.64)确定反应混合物中的总叶黄素(xanthophylls),同时对该样品进行HPLC分析,确定反式叶黄素(lutein)和玉米黄素的百分比含量(Hadden等,J.Agric.Food.Chem,47,4189-494,1999)。
提取物/油性树脂的皂化反应,导致释放出游离的叶黄素以及脂肪酸的碱式盐。异构化反应将万寿菊中部分叶黄素(lutein)转化成(R,S)-玉米黄素。采用以下步骤对反应混合物中的叶黄素组合物进行分析:用己烷∶丙酮∶乙醇∶甲苯(10∶7∶6∶7,v/v)萃取,然后加入己烷和10%硫酸钠溶液,对上层进行HPLC分析。
得到想要的异构化程度以及反式叶黄素含量一般约85%的叶黄素组合物后,将反应混合物用水稀释,室温搅拌均匀,得到黄色油层,其中含有游离的叶黄素以及脂肪酸、肥皂和杂质。
将该油层转到分液漏斗内,然后加入醋酸乙酯和萃取叶黄素。用等体积的去离子水洗涤醋酸乙酯层两次。这样就将脂肪酸和肥皂物质转移到水中然后废弃。用减压蒸馏去除溶剂的方法对醋酸乙酯萃取液进行浓缩,回收醋酸乙酯,得到叶黄素的浓缩粗品。
接下来对该叶黄素的浓缩组合物进行纯化,即室温下用己烷搅动,1小时后过滤。进一步用乙醇洗涤叶黄素块,所得橙色结晶在室温真空干燥72小时。
经分光光度分析,纯化后的叶黄素产物组合物显示由约80-90重量%的总叶黄素组成,经HPLC分析,该叶黄素类胡萝卜素的组合物由80-85%的反式叶黄素(lutein)和一般约15-20%的玉米黄素异构体组成,该HPLC分析使用日本东京Nacali Tesque公司生产的Cosmosil 5SL-11-色谱柱250 4.61内径(i.d.)5m、丙酮∶正己烷(1∶9)、流速1mL/min,使用Hitachi L 6200泵和L-4250UV-Vis检测器,设定450nm。使用Sumichiral OA-2000,进行手性HPLC,用于(R,R)-玉米黄素和(R,S)-玉米黄素(本文统称为玉米黄素异构体)的分离和定量。
本发明的组合物含有至少80重量%的叶黄素(lutein),其来源于含有叶黄素/叶黄素酯的植物提取物/油性树脂,其安全性已得到确认(KuzhuvelilBhaskarannair Harikumar等,Toxicity Profile of Lutein and Lutein Ester IsolatedFrom marigold Flowers(Tagetes erecta),International Journal of Toxicology,Vol.27,No.1,1-9(2008))。剩余的组合物由(R,R)-玉米黄素组成,它同叶黄素(lutein)一起经萃取获得,在上述研究中其安全性与叶黄素(lutein)一并得到确认。该组合物的其余组分由玉米黄素的(R,S)异构体组成,它也由叶黄素(lutein)形成。进一步,制备本发明的组合物的生产工艺在cGMP(现行良好生产操作规程)条件下完成。按照ISO22000指南实施该工艺,其食品安全性通过如下所述的HACCP(危害分析和临界控制点)加以监控。
所以,本发明的组合物符合所有安全性要求,可以认为人食用该组合物是安全的。如前面段落所解释的,玉米黄素的(R,S)-异构体存在于黄斑内,由体内酶对叶黄素(lutein)作用后形成。
因此,人食用由叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-玉米黄素组成的本发明组合物是安全的。
以下实施例中给出了本发明的细节,其目的在于将本发明阐述清楚,所以不应视为对本发明的范围作出限制。
实施例1
将含有135.40g/kg叶黄素(经分光光度法确定)的万寿菊油性树脂(100.3g)与溶解在50ml 1-丙醇中的50g氢氧化钾混合。加热反应混合物并维持在95℃,2小时。反应期间,取样进行HPLC,分析反式叶黄素和玉米黄素的含量。室温下往反应块中加入500ml蒸馏水搅拌,将反应混合物置于分液漏斗内,用等体积的醋酸乙酯萃取。这个步骤进行5次。收集醋酸乙酯层,用蒸馏水洗涤,除去多余的碱、肥皂物质和其他水溶性杂质。对醋酸乙酯层进行减压蒸馏,得到72.10g皂化后的萃取粗品。
室温下往上述得到的萃取粗品(72g)中加入360ml己烷,搅拌1小时提纯后过滤。得到湿重26.20g的沉淀,再在室温用262ml乙醇洗涤1小时后,过滤。所得橙色结晶在室温真空干燥72小时后,氮气中储存。
该叶黄素组合物的产量为10.40g,其含有93.29重量%的叶黄素(经UV/Vis分光光度法确定)。经HPLC分析,该产物的组合物中含反式叶黄素80.80%和玉米黄素异构体19.2%。手性HPLC分析(Sumichiral OA-2000色谱柱;溶剂为正己烷∶氯仿(48∶8))显示含(R,R)-玉米黄素46.3%和(R,S)-玉米黄素53.7%。
实施例2
将含有124.10g/kg叶黄素(经分光光度法确定)的万寿菊油性树脂(50g)与溶解在25ml 1-丙醇中的25g氢氧化钾混合。加热反应混合物并维持在95℃,1小时。反应期间,取样进行HPLC,分析反式叶黄素和玉米黄素的含量。室温下加入250ml蒸馏水搅拌反应块,将混合物置于分液漏斗内,用等体积的醋酸乙酯萃取。这个操作进行5次。收集醋酸乙酯层,用蒸馏水洗涤,除去多余的碱、肥皂物质和其他水溶性杂质。对醋酸乙酯层进行减压蒸馏,得到30g皂化的萃取粗品。
室温下往上述得到的萃取粗品(30g)加入150ml己烷,搅拌1小时提纯后过滤。得到9g沉淀,再在室温用90ml乙醇洗涤1小时后,过滤。所得橙色结晶室温真空干燥72小时后,氮气中储存。
该叶黄素组合物的产量为4.30g,其含有82.59重量%的叶黄素(经UV/Vis分光光度法确定)。经HPLC分析,该产物的组合物中含反式叶黄素83.32%和玉米黄素异构体15.32%。
实施例3
将含有160.07g/kg叶黄素(经分光光度法确定)的万寿菊油性树脂(50g)与溶解在25ml 1-丙醇中的25g氢氧化钾混合。加热反应混合物并维持在95℃,2小时。反应期间,取样进行HPLC,分析反式叶黄素和玉米黄素的含量。室温下加入250ml蒸馏水搅拌反应块。将混合物置于分液漏斗内,用等体积的醋酸乙酯萃取。这个操作进行5次。收集醋酸乙酯层,用蒸馏水洗涤,除去多余的碱、肥皂物质和其他水溶性杂质。对醋酸乙酯层进行减压蒸馏,得到36g皂化的萃取粗品。
对所得萃取粗品(36.90g)进行纯化,即室温下加入185ml己烷,搅拌1小时后过滤。得到10.33g沉淀,再在室温用103ml乙醇洗涤1小时后,过滤。所得橙色结晶室温真空干燥72小时后,氮气中储存。
该叶黄素组合物的产量为7.02g,其含有85.59重量%的叶黄素(经UV/Vis分光光度法确定)。经HPLC分析,该产物的组合物中含86.50%的反式叶黄素和13.2%的玉米黄素异构体。
实施例4
将含有132.2g/kg叶黄素(经分光光度法确定)的万寿菊油性树脂(52g)与溶解在26ml 1-丙醇中的26g氢氧化钾混合。加热反应混合物并维持在95℃,1小时。反应期间,取样进行HPLC,分析反式叶黄素和玉米黄素的含量。室温下加入250ml蒸馏水搅拌反应块。将混合物置于分液漏斗内,用等体积的醋酸乙酯萃取。这个操作进行5次。收集醋酸乙酯层,用蒸馏水洗涤,除去多余的碱、肥皂物质和其他水溶性杂质。对醋酸乙酯层进行减压蒸馏,得到30.30g皂化的萃取粗品。
对所得萃取粗品(30.30g)进行纯化,即室温下加入150ml己烷,搅拌1小时后过滤。所得沉淀(8.00g)在室温用80ml乙醇洗涤1小时后,过滤。所得橙色结晶在室温真空干燥72小时后,氮气中储存。
该叶黄素组合物的产量为4.40g,其含有81.50重量%的叶黄素(经UV/Vis分光光度法确定)。经HPLC分析,该产物的组合物中含反式叶黄素86.64%和玉米黄素异构体11.49%和痕量的其他类胡萝卜素。
本发明的优点
1.所述叶黄素组合物包含
(a)黄斑色素,例如按特定比例组合的反式叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-玉米黄素。
(b)至少80%的总叶黄素,其中反式叶黄素(lutein)占至少80%、其余的15-20%一般为玉米黄素异构体,分别为(R,R)-玉米黄素和(R,S)-玉米黄素。
2..由于使用GRAS试剂,该叶黄素组合物满足安全性管理要求,所以人食用安全,可用于营养保健。
3.该叶黄素组合物是单一来源膳食补充剂,含所有基本的黄斑色素,能帮助维持眼健康。
4.目前许多配方设计师都要求有活性的成分形式,其中大多数万寿菊提取产品中叶黄素(lutein)与玉米黄素异构体的比例都大于20∶1。为了增加终产品中玉米黄素所占比例,除叶黄素(lutein)来源外还得加入玉米黄素的补充来源。
本发明中,所有三种叶黄素都存在,所以无需加入任何补充来源。
5.同样,某些配方设计师寻求所有三种形式的黄斑类胡萝卜素,即发现在视网膜黄斑内扮演保护角色的三种色素。(即,叶黄素(lutein)、(R,R)-玉米黄素和(R,S)-玉米黄素)。目前,从一种来源很难得到所有三种类胡萝卜素,所以,配方设计师经常需要使用3种不同的成分来生产含所有三种黄斑色素的平衡制剂。
6.某些配方设计师正寻求其中叶黄素(lutein)与玉米黄素异构体比例为5∶1的成分组成(另外,其中的(R,R)-玉米黄素与(R,S)-玉米黄素的比例(1∶1)与黄斑色素中叶黄素与玉米黄素异构体的比例相符)。
7.对4000名研究对象进行AREDS II(老年性眼病研究)研究,评估高剂量黄斑叶黄素(即叶黄素(lutein)和玉米黄素)口服补充剂的效果,该剂量包括补充剂中叶黄素(lutein)与玉米黄素的比例为5∶1的剂量(10mg叶黄素(lutein):2mg玉米黄素)。参见https://web.emmes.com/study/areds2/resources/areds2 mop.pdf。研究预期,能提供叶黄素(lutein)与玉米黄素比例为5∶1的单一成分可能让那些正在急切等待AREDS II试验结果的制剂商们大大受益。现如今,使用多成分而导致成本、人力和多种原料储备处理程序增加,这使这一目标得以满足。
8.该叶黄素组合物使标准化组合物的研发成为可能,该组合物中所含来自单一来源的叶黄素(lutein)与玉米黄素,或叶黄素(lutein)、(R,R)-玉米黄素与(R,S)-玉米黄素按所需比例组合。
Claims (8)
1.一种叶黄素组合物,其含有包含反式叶黄素和玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素的黄斑色素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂,该组合物包含至少80重量%的总叶黄素,该总叶黄素中的反式叶黄素与玉米黄素异构体的比例为约4∶1-6∶1,玉米黄素的异构体的比例为80-20∶20-80。
2.如权利要求1所述的叶黄素组合物,其中所述组合物含有至少85重量%的总叶黄素,该总叶黄素中的反式叶黄素的含量为至少85%。
3.如权利要求1或2所述的叶黄素组合物,其中所述组合物含有至少85重量%的总叶黄素,该总叶黄素中至少80重量%是反式叶黄素、至少6重量%是(R,R)-玉米黄素,至少6重量%是(R,S)-玉米黄素。
4.如权利要求1-3之任一项所述的叶黄素组合物,其中所述组合物含有至少85重量%的反式叶黄素、至少4重量%的(R,R)-玉米黄素和至少5重量%的(R,S)-玉米黄素。
5.如权利要求1-4之任一项所述的叶黄素组合物,其中所述组合物含有至少85重量%的总叶黄素,该总叶黄素中至少80重量%是反式叶黄素,其余15重量%是玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素。
6.一种叶黄素组合物的制备方法,该组合物含有包含反式叶黄素和玉米黄素异构体,即(R,R)-玉米黄素和(R,S)-玉米黄素的黄斑色素,其来源于含有叶黄素/叶黄素酯、人食用安全、可用于营养保健的植物提取物/油性树脂,该方法包括:
(a)将含有叶黄素酯的植物提取物/油性树脂与1-丙醇碱溶液混合,使其中的叶黄素酯同时发生皂化和部分异构化反应,其中,碱与1-丙醇的重量/体积比为1∶0.5-1∶1,在70-100℃,优选为95℃加热所得物质,1-5小时,得到皂化/异构化的浓缩粗品;
(b)将步骤(a)中获得的皂化/异构化的浓缩粗品与水按1∶2-1∶3的体积/体积比混合,得到稀释的油性混合物;
(c)用醋酸乙酯对步骤(b)中得到的稀释的油性混合物进行萃取,稀释的油性混合物与所用的醋酸乙酯的体积/体积比为1∶1.5-1∶2,得到含有叶黄素组合物的萃取液;
(d)将步骤(c)中得到的组合物蒸发,以除去醋酸乙酯;
(e)对步骤(d)中所得组合物进行纯化,即先用非极性溶剂洗涤,再用极性溶剂洗涤,然后过滤;
(f)在40-45℃将所得组合物真空干燥48-72小时;
(g)如果需要的话,用传统方法回收步骤(c)中使用的醋酸乙酯,必要的话重复利用;以及
(h)将所得组合物在-20℃储存于惰性气氛中。
7.如权利要求6所述的方法,其中所述含有叶黄素酯的植物提取物/油性树脂来源于万寿菊花。
8.如权利要求6或7所述的方法,其中步骤(e)中使用的非极性溶剂选自烃类溶剂,该烃类溶剂选自戊烷、己烷和庚烷等,优选为己烷,所使用的极性溶剂选自低级脂肪醇。
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Cited By (8)
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CN103566049A (zh) * | 2012-08-08 | 2014-02-12 | 浙江医药股份有限公司新昌制药厂 | 用于提高眼睛中视黄斑色素密度并预防或治疗年龄相关性视黄斑衰退症的组合物 |
US20160074456A1 (en) * | 2012-12-19 | 2016-03-17 | Novus International Inc. | Xanthophyll compositions and methods of use |
US9827283B2 (en) * | 2012-12-19 | 2017-11-28 | Novus International, Inc. | Xanthophyll compositions and methods of use |
CN105188408B (zh) * | 2012-12-19 | 2019-03-01 | 诺华丝国际股份有限公司 | 叶黄素类组合物和使用方法 |
CN105969725A (zh) * | 2016-06-12 | 2016-09-28 | 暨南大学 | 枸杞红素的用途 |
CN105969725B (zh) * | 2016-06-12 | 2019-04-26 | 暨南大学 | 枸杞红素的用途 |
CN107802619A (zh) * | 2017-12-06 | 2018-03-16 | 北京市眼科研究所 | 一种用于眼部健康的浓缩物 |
CN114502147A (zh) * | 2019-10-15 | 2022-05-13 | 奥米尼埃克蒂夫健康科技有限公司 | 包含黄体素和玉米黄质的具有增强的生物利用度的叶黄素组合物 |
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AU2010290970A1 (en) | 2012-03-15 |
CN102481011B (zh) | 2015-04-15 |
DK2473065T3 (en) | 2016-06-27 |
IL218240A0 (en) | 2012-04-30 |
AU2010290970B2 (en) | 2014-12-04 |
KR101479821B1 (ko) | 2015-01-06 |
JP5778676B2 (ja) | 2015-09-16 |
US10485833B2 (en) | 2019-11-26 |
PT2473065E (pt) | 2016-06-03 |
WO2011027209A1 (en) | 2011-03-10 |
CA2771967A1 (en) | 2011-03-10 |
HUE028031T2 (en) | 2016-11-28 |
EP2473065A1 (en) | 2012-07-11 |
ES2568937T3 (es) | 2016-05-05 |
CA2771967C (en) | 2015-04-07 |
EP2473065B1 (en) | 2016-04-13 |
PL2473065T3 (pl) | 2017-02-28 |
KR20120083372A (ko) | 2012-07-25 |
US20110065805A1 (en) | 2011-03-17 |
JP2013503844A (ja) | 2013-02-04 |
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