CN1209729A - 含有天然的还原叶酸盐异构体的食品和维生素制品 - Google Patents
含有天然的还原叶酸盐异构体的食品和维生素制品 Download PDFInfo
- Publication number
- CN1209729A CN1209729A CN97191951A CN97191951A CN1209729A CN 1209729 A CN1209729 A CN 1209729A CN 97191951 A CN97191951 A CN 97191951A CN 97191951 A CN97191951 A CN 97191951A CN 1209729 A CN1209729 A CN 1209729A
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- Prior art keywords
- tetrahydrofolic acid
- food
- acid
- reduced folates
- nutrients
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Abstract
本发明公开一种用于人或动物消费以提供叶酸盐的组合物,该叶酸盐包括天然的还原叶酸盐异构体,如(6S)－四氢叶酸、5－甲基－(6S)－四氢叶酸、5－甲酰基－(6S)－四氢叶酸、10－甲酰基－(6R)－四氢叶酸、5,10－亚甲基－(6R)－四氢叶酸、5,10－次甲基－(6R)－四氢叶酸、5－亚胺甲基－(6S)－四氢叶酸和其多谷氨酰基衍生物。该组合物有:多种维生素制品;早餐食物;婴儿食品;动物饲料及其添加物等。组合物中用于人消费的天然还原叶酸盐异构体的量以每份或剂量计可在每天所需叶酸的5%—200%。
Description
本申请具有1996年1月31日申请的系列号为60/010,898的美国临时专利申请的效果。
本发明涉及营养品领域，更具体地说，本发明涉及含有天然的还原叶酸盐异构体的食品和维生素制品。
叶酸盐几乎遍及所有生命体。人类和许多其它动物缺乏制备它们自己的叶酸盐的能力，叶酸盐是一种必需维生素，一类必需营养物。特别在怀孕期间和老年人中的贫血是其膳食需要叶酸盐的预先暗示。叶酸盐的主要功能是从将要代谢的分子移去一碳单元，然后把它们运送到将要合成的分子上。作为一种例子，叶酸盐参与核酸的形成。而且，部分通过甲基化作用控制DNA活性，并且在涉及叶酸盐的代谢循环中制造主要的甲基化剂(S-腺苷甲硫氨酸)。因此，集中在叶酸盐的状态和癌症，特别是结肠直肠腺瘤的易感性的关系上进行了大量研究。
新生婴儿中发生神经管缺陷时清楚显示了叶酸盐对适宜成长的重要性。几个国家的报告显示这种情况的大多数与母体中的叶酸盐含量低有关。当怀孕初期给妇女服用叶酸(Ⅰ)时可显著降低这些缺陷及裂唇/裂颚的发病率。最近，发现了维生素，特别是叶酸盐的缺乏与主要致死的周围血管疾病之间的重要关系。带有这种痛苦的个体的高百分率具有异常高半胱氨酸的血含量，其是S-腺苷甲硫氨酸循环的依靠叶酸盐步骤中甲硫氨酸的前体。缺乏叶酸盐也与大量不同细胞类型的有缺陷的成熟阶段、神经系统疾病和降低的免疫反应联系在一起。
摄入叶酸盐对于健康的明显的关系使得全世界许多政府机构(例如美国全国科学研究委员会)详细说明了叶酸盐的推荐日摄食量(″RDA")。在美国，食品和药物管理局使用这些值建立推荐的每日营养摄入量标准(＂RDI")列在食品标签上，目前成年人为0.4mg。有一国家推荐的每日叶酸最高摄入量对健康成年人来说为2.0mg。许多含有RDI或接近RDI水准的叶酸(Ⅰ)的产品是可以得到的，这些产品还包括大多数每日所需的多种维生素。既可不用处方也可用处方以固态(例如片、胶囊或粉)或液态购得这些产品。在美国，也可以购得以其自身一般一剂量0.4mg的叶酸(Ⅰ)，但是在保健食品商店也有高达0.8mg的。许多营养完全膳食、婴儿膳食、膳食添加物和减肥制品也含有叶酸(Ⅰ)。在一些国家，添加叶酸到卫生官员指定的特种食品类以向普通人群提供适量的叶酸盐，但没有过分消费。许多早餐食品，例如谷类食物、粮谷制的条状食品、早餐饮料混合物、早餐条状食品和焙烤食品，具有以RDI的适宜量添加的叶酸(Ⅰ)，一般每份饮食成人值的10-50％。在这些用途中，叶酸(Ⅰ)与其它维生素一起，有时以RDI剂量，但有时也或低或高于该水准。经常，虽非总是，也存在必需矿物营养物。而且许多产品也包括假定具有保健价值的化合物，但是这些化合物或者官方不认为其有效，或者其最佳量还没有确定。如上述的那些产品意味着起到了满足对叶酸盐的重要并广泛的需要，特别在那些除非防止摄入大量的这类维生素的膳食习惯的人群中。
叶酸(Ⅰ)为许多动物和宠物食品的一种组分。它也包括在用作动物饲料添加物的粉剂或流食中，经常与其它营养物组合在一起。例如，美国全国科学研究委员会(NRC)推荐狗和猫饮食中每kg干饮食(假定5 kcal可代谢的能量/g)分别含0.2mg和1.0mg叶酸(Ⅰ)。对于鸡，NRC推荐每kg干饮食含0.55mg叶酸，虽然最近文献建议最佳值高于该值约三倍。
目前添加到所有市售维生素制品或添加到食品中的叶酸盐的形式，叶酸(Ⅰ)(也是已知的蝶酰基-L-谷氨酸)，不是天然生鲜食品中发现的主要形式之一。叶酸(Ⅰ)与最丰富的天然叶酸盐存在几个方面的不同。首先，在几乎所有生鲜食品中天然叶酸盐的侧链含有不只一种L-谷氨酸部分。通常，5-7(但是占或多或少的很大数值范围)个这样的氨基酸链在一起成多谷氨酸链。然而，众所周知，叶酸盐能够被吸收的主要形式具有仅仅单一谷氨酸盐残基。通常在消化道内通过酶实现膳食叶酸盐的剩余谷氨酸盐的裂解。在这一点上，与天然存在的叶酸盐相比，叶酸(Ⅰ)不处于不利地位。
叶酸(Ⅰ)和天然叶酸盐之间的第二个不同点在于前者(Ⅰ)的蝶啶环被完全氧化，生鲜未加工的食品中的天然叶酸盐大多数以四氢的形式存在。几乎所有已知的叶酸盐生理功能都通过四氢叶酸、(6S)-FH4(Ⅱ)或其一碳衍生物来实现，该一碳衍生物如下：5-甲基-(6S)-FH4(Ⅲ)、5-甲酰基-(6S)-FH4(Ⅳ)、10-甲酰基-(6R)-FH4(Ⅴ)、5,10-亚甲基-(6R)-FH4(Ⅵ)、5,10-次甲基-(6R)-FH4(Ⅶ)和5-亚胺甲基-(6S)-FH4(Ⅷ)。这些化合物的结构式列如下。人体内没有叶酸(Ⅰ)自身的已知直接辅因子功能。在植物和动物内发现了一些(6S)-四氢叶酸多谷氨酸盐，但是大多数叶酸盐为5-甲基-或5-甲酰基-(6S)-四氢叶酸的多谷氨酸盐形式，有些情况下为10-甲酰基-四氢叶酸。据推测，在生物食物源中发现的大多数叶酸(Ⅰ)会氧化，特别是在贮存期间。当叶酸(Ⅰ)被消化道吸收时，它最终通过二氢叶酸盐还原酶还原成活性(6S)-四氢叶酸(Ⅱ)。
叶酸(Ⅰ)的口服生物利用率显示出很大的可变性。文献包括了具有肠内对叶酸(Ⅰ)的摄入差的个体而对肌肉内注射叶酸(Ⅰ)反应正常，或在任何叶酸激发之前具有正常的血清叶酸盐状态的报导。几个小范围的调查，并平均其值，结果口服几种还原叶酸盐与口服叶酸(Ⅰ)相似。然而，有理由相信一部分人对还原叶酸盐有适度的口服反应，而对口服叶酸(Ⅰ)则没有反应。
已长期以治疗剂量对几种病人使用5-甲酰基-四氢叶酸(也为公知的甲酰四氢叶酸或亚叶酸)。例子包括对氨甲蝶呤化学治疗术的毒性的拯救，以及与氟尿嘧啶一起协同治疗多种癌症。它也用来治疗非B12缺乏引起的急性贫血。用于治疗抑郁症(和其它神经失调)的高剂量的5-甲基-四氢叶酸(例如，50mg/day)已经获得专利(1990年Le Grazie的EP382019和EP388827，和1992年Le Greca的EP482493)。
部分由于这些化合物的立体化学，忽视了这些还原叶酸盐作为以RDA含量提供的改善源。除了叶酸(Ⅰ)中L-谷氨酸盐链的单一手性中心外，四氢叶酸盐在碳-6上含有第二个立体化学中心。叶酸(Ⅰ)的化学还原在该位置制得两个异构体的纯外消旋混合物。这与天然发现的所有都是由单一非对映异构体组成的还原叶酸盐相反，该天然还原叶酸盐在碳-6上都具有相同L-构型。(化合物Ⅱ-Ⅷ显示的是天然异构体)。多年来，仅5-甲酰基-四氢叶酸(甲酰四氢叶酸)的外消旋6(R,S)混合物用于治病。近来，Lederle针对非天然异构体组分的可能效果得出该纯天然异构体的商业采纳以这些高剂量治疗疾病，虽然费用很高。大多数利用甲酰四氢叶酸的食疗法延续几周或可能几个月。长期使用非天然还原叶酸盐异构体的效果还不清楚。例如，尽管吸收了少量的5-甲酰基-6(R)-四氢叶酸，但是通过肠道和身体的其它细胞吸收了相当大量的非天然5-甲基-四氢叶酸，这种连续的摄入可能导致相反的效果。
直到现在，天然还原叶酸盐异构体的制备方法还是受到规模和/或费用方面的限制。这些包括气相四色谱分离，酶还原，和分级结晶。使用还原叶酸盐作为每天的维生素源需要可大规模生产高纯度的天然异构体的方法，并且费用不能使普通消费者受不了。
本发明涉及一种包括一种或多种天然的还原叶酸盐异构体的组合物和一种营养物。一种或多种天然的还原叶酸盐异构体选自(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸和其多谷氨酰基衍生物。营养物为食品制品、必需营养制品或其组合。当营养物为食品制品时，食品制品包括两种或多种食品组分。每克食品制品含一种或多种天然的还原叶酸盐的异构体的天然的摩尔量为N，N大于或等于零，每克该组合物中一种或多种天然的还原叶酸盐异构体的总摩尔量为T,T大于N。当营养物为必需营养制品时，必需营养制品包括除抗坏血酸之外的一种维生素。
本发明也涉及一种增加营养物的叶酸盐含量的方法。该方法包括提供选自以下的营养物：食品制品、必需营养制品和其组合。该方法还包括向营养物中力入摩尔量的一种或多种天然的还原叶酸盐异构体，该还原叶酸盐异构体选自(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸和其多谷氨酰基衍生物。当营养物为食品制品时，食品制品包括两种或多种食品组分。当营养物为必需营养制品时，必需营养制品包括除抗坏血酸之外的一种维生素。
大量人群缺乏叶酸盐；生活方式没包含足够的叶酸盐生鲜食品源的人群特别易于缺乏叶酸盐。本发明的目的提供一种营养组合物，其中用天然的四氢叶酸异构体代替通用的叶酸(Ⅰ)以满足或部分满足对该维生素的膳食需要。然而，多种维生素制品和早餐谷类食物中的还原叶酸盐内含物可能对有些人的影响不大，但是对于叶酸(Ⅰ)的生物利用率则差的大多数人以及一般健康的人而言，可能通过满足这些需要而得到改善。随着消费者了解到，除了有益的缺少多个谷氨酸盐残基外，该叶酸盐组合物与该维生素最丰富的天然形式相同，消费者对食品或其它营养制品消费的信心将增加。另一种好处是当广泛地使用更均匀的吸收叶酸盐的形式时，卫生机构将帮助推荐最佳含量。
本发明涉及一种包括一种或多种天然的还原叶酸盐异构体的组合物和一种营养物。本发明中适宜使用的天然的还原叶酸盐异构体包括，例如，(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸和5-亚胺甲基-(6S)-四氢叶酸。本发明中适宜使用的另外的天然的还原叶酸盐异构体包括(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸和5-亚胺甲基-(6S)-四氢叶酸的多谷氨酰基的衍生物，例如二谷氨酰基、三谷氨酰基、四谷氨酰基、五谷氨酰基和六谷氨酰基的衍生物。任何或所有天然的还原叶酸盐的异构体都可以以其手性纯的形式存在，或者该组合物可以选择性地包含1摩尔量的一种或多种非天然的还原叶酸盐异构体，例如(6R)-四氢叶酸、5-甲基-(6R)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6S)-四氢叶酸、5,10-亚甲基-(6S)-四氢叶酸、5,10-次甲基-(6S)-四氢叶酸和5-亚胺甲基-(6R)-四氢叶酸，和其多谷氨酰基衍生物。该天然的还原叶酸盐异构体的摩尔量可以等于其相应的非天然异构体的摩尔量(此时非天然和天然异构体以外消旋混合物存在)，或者，优选地，天然的还原叶酸盐异构体可以以摩尔量大于相应的非天然异构体的摩尔量而存在。该组合物中存在的一种或多种天然的还原叶酸盐异构体的总摩尔量可以以每次习惯消费该组合物的量计为人体每天对叶酸盐的所需量的5％-200％之间。这里所使用的一种或多种天然的还原叶酸盐异构体的总摩尔量包括天然存在于营养物中的天然的还原叶酸盐异构体，也包括可能添加到营养物中天然的还原叶酸盐异构体。自然，各种组合物的习惯消费量依赖该组合物的性质。当该组合物包括食品制品时，习惯消费量为每次吃的习惯消费的食品制品量，例如，美国食品和药物管理局宣布的，目的在于用在食品标签上以建立实际可行的和一致的服用量。可以在21 C.F.R.§101.12中找到不同食品的习惯消费量的例子，该文献引入本文作为参考。
每天对叶酸盐的需要因人而异，依赖于例如体重、年龄、健康状况、性别等的因素。人每天对叶酸盐的需要的适宜值包括分别由FDA和美国全国科学研究委员会(＂NRC＂)公布的RDI和RDA值。现在，RDI值，以叶酸的微克数(叶酸的纳摩尔)表示，成年人为400μg(907nmol)和孕妇为800μg(1814nmol)。在这种情况下，本发明的组合物以每次习惯消费的营养物的量计可以具有在45-1814nmol之间或91-3625nmol之间的叶酸盐。目前的RDA值公布在National Research Council:RecommendedDaily Allowances，第10版，Washington,D.C.(1989)，该文献引入本文作参考。它们也以叶酸的微克数(叶酸的纳摩尔)表示，它们是，0-6个月的婴儿为25μg(57nmol),6个月-1岁的婴儿为35μg(79nmol),1-3岁的婴儿为50(g(113nmol),7-10岁的儿童为100(g(227nmol)，男性成年人为200(g(454nmol)，女性非孕妇成年人为180(g(408nmol)，以及孕妇为400(g(907nmol)。在这种情况下，本发明的一般组合物以每次习惯消费的营养物的量计可以具有在2.8-113nmol之间、4-159nmol之间、28-227nmol之间、11-454nmol之间、22-907nmol之间、20-816nmol之间或45-1812nmol之间的叶酸盐。世界卫生组织也建立了人每天对叶酸盐的需要的适宜值，为7.03nmol/kg体重。对孕妇来说，以体重为基础计算的值将增加到约454-680nmol。
或者，该组合物中存在的一种或多种天然的还原叶酸盐异构体的总摩尔量可以以每次习惯消费营养物的量计为动物每天对叶酸盐的所需量的5％-3000％之间。每天对叶酸的需要量参照上面的动物可以是，例如，狗、猫、鸡、牛、家畜、山羊、马、貂、狐狸、绵羊或猪。由例如NRC在Nutrient Requirements of Domestic Animals(Washington:NationalAcademy Press)中颁布了动物每天所需叶酸盐的适宜值，特别在那些具有以下副标题的出版物中：＂Nutrient Requirements of Beef Cattle，＂第七次修订版(1986,ISBN 0-309-05426-5)；＂Nutrient Requirements of Cats,＂修订版(1986,ISBN 0-309-03682-8)；＂Nutrient Requirements of DairyCattle，＂第六次修订版，修订(1989,ISBN 0-309-03826-X)；＂NutrientRequirements of Dogs，＂修订过的(1985,ISBN 0-309-03496-5)；＂NutrientRequirements of Fish,＂(ISBN 0-309-04891-5)；＂Nutrient Requirements ofGoats:Angora,Dairy,and Meat Goats in Temperate and TropicalCountries,＂(ISBN 0-309-03185-0)；＂Nutrient Requirements of Horses,＂第五次修订版(1989,ISBN 0-309-03989-4)；＂Nutrient Requirements ofLaboratory Animals，＂第四次修订版(1995,ISBN 0-309-05126-6)；＂NutrientRequirements of Mink and Foxes，＂第二次修订版(1982,ISBN 0-309-03325-X)；＂Nutrient Requirements of Poultry，＂第九次修订版(1994,ISBN0-309-04892-3)；＂Nutrient Requirements of Sheep，＂第六次修订版(1985,ISBN 0-309-03596-1)；和＂Nutrient Requirements of Swine，＂第九次修订版(1988,ISBN 0-309-03779-4)(总的指＂NRC Animal NutrientRequirements″)，特此引用作参考。
上述的营养物可以是食品制品或必需营养制品。必需营养制品为含有一种或多种必需营养素的物料。其中在必需营养制品中仅存在一种必需营养素，该必需营养素可以是除抗坏血酸之外的一种维生素。或者，必需营养制品可以包括除抗坏血酸之外的一种维生素以及另外的抗坏血酸。这里使用的＂必需营养素＂为那些维持身体健康所必需的但一种或多种动物或人类不能有效制得的。在许多出版物中收集了必需营养素的例子，这些出版物包括Modem Nutrition in Health and Disease，第八版，Shils等编辑，Philadelphia:Lea and Febiger(1994)，特此引用来作参考。所说的必需营养素包括必需维生素和其维生素前体、必需脂肪、必需矿物质，例如推荐每天摄入量标准的那些矿物质，和必需氨基酸。必需营养制品的一种例子为含有一种维生素和每克干物质少于2.5cal的热量的制剂，优选每克干物质少于2kal，最优选每克干物质少于1.8kal。必需营养制品也包括那些含有至少一种维生素，且其量大于每克必需营养制品中美国成人的必需营养素的RDA的15％的物质，优选大于20％，更优选大于40％。但是其它营养适宜的必需营养制品包含至少两种维生素，每个的量大于每克必需营养制品中美国成人的必需营养素的RDA的10％，优选大于15％，更优选大于20％。适宜必需营养制品通常指的是膳食添加物、维生素添加物和矿物添加物、多种维生素添加物等，一般可以以丸、片、胶囊、粉、浆和悬浮液商购得到。优选地，以每次习惯消费的必需营养制品的量计，该必需营养组合物含有至少一种含量大于每天必需营养素的需要量的25％的必需营养素，更优选大于50％，而且最优选大于或等于100％。
如上所述，营养物也可为食品制品。食品制品为含有一种或多种适宜人或动物消费且不是必需营养制品的氨基酸、碳氢化合物或脂肪的物质。优选食品制品为两种或多种组分食品制品。例如，两种或多种组分食品制品可以为两种或多种单组分食品的混合物。单组分食品为由基本上单一天然源得到的食品。百分比小的单组分食品可从第二个天然源得到，但该百分比(重量比)优选小于5％，更优选小于1％，更优选小于0.1％。单组分食品包括例如，糖、未加糖的果汁、花蜜或来自单一植物品种的果泥，例如未加糖的苹果汁(包括不同品种的苹果汁混合物)，葡萄汁、橙汁、苹果酱、杏花蜜、土豆汁、土豆泥，等。单一品种的谷类植物和由单一品种的谷类植物制得的物质，例如玉米浆、黑麦粉、小麦粉、燕麦麸，等也认为时单一组分食品。或者，两种或多种组分的食品制品可以为一种或多种单一组分食品与一种或多种必需营养素的混合物。优选地，双组分食品中一种或多种必需营养素的至少一种的量大于至少一种天然地总存在于一种或多种单一组分食品中的必需营养素的量。例如，其中必需营养素为维生素X和维生素Y，而且其中单一组分食品为橙汁，并且橙汁天然含有维生素X和维生素Y，其含量分别为＂Nx＂和＂Ny＂，优选组合物含有含量分别为＂Tx＂和＂Ty＂的维生素X和维生素Y，以便Tx大于Nx,Ty大于Ny，或者两者同时成立。
特别适于实现本发明的食品制品包括早餐食品、例如预制食品、烤焙制品和早餐饮料混合物；婴儿食品；膳食添加物；完全食品；和减肥制品，例如减肥饮料和减肥条状食品。
食品制品可以是天然地含有非天然的还原叶酸盐异构体的制品。或者，它可以含有天然摩尔量的天然的还原叶酸盐异构体。为了该应用的目的，每克食品含有的天然的还原叶酸盐异构体的摩尔量(即，(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸和其多谷氨酰基衍生物的总摩尔量)定为＂N＂。对于有些食品，天然存在的天然的还原叶酸盐异构体的摩尔量为已知。对于其它的食品，天然的还原叶酸盐异构体的摩尔量可以由许多灵敏性和特异性方法确定，例如依赖微生物成长、以叶酸盐结合蛋白为基础测定、高性能液相色谱(＂HPLC")和气相色谱(＂GC")。例如，在Cossins,E.A.,＂Folates in Biological Materials,″in Folates and Pterins,Vol.1,Blakley等，eds.,New York:John Wiley & Sons,pp.1-60(1984)描述了适宜的方法，特此引用作参考。
本发明的组合物中存在的天然的还原叶酸盐异构体的摩尔量大于食品制品中存在的天然的还原叶酸盐异构体的摩尔量。为了该应用的目的，每克组合物中含有的天然的还原叶酸盐异构体的摩尔量(即，(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸和其多谷氨酰基衍生物的总摩尔量)定为＂T″。因此，T必需大于N。优选地，T/N大于105％；更优选地，T/N大于110％；最优选地，T/N大于120％。
如上所述，组合物可以选择性地包括一种或多种非天然的还原叶酸盐异构体。当存在于该组合物中时，该一种或多种非天然的还原叶酸盐异构体优选以其摩尔量小于T减去N的量存在。
本发明也涉及一种增加营养物的叶酸盐含量的方法。营养物可以是食品制品、必需营养制品或食品制品和必需营养制品的组合。通过向营养物中或与营养物一起掺合一种或多种天然的还原叶酸盐异构体增加营养物的叶酸盐含量。这可以通过食品技术领域中熟知的方法来完成，例如通过均质、涂敷、喷涂粗混、拌匀、捏合、成丸和挤出单个或组合形式的一种或多种天然的还原叶酸盐异构体施加在营养物上或与营养物一起进行处理。
根据本发明，加到营养物中的一种或多种天然的还原叶酸盐异构体中的一种或多种可以是基本手性纯或一种或多种天然的还原叶酸盐异构体的每一种可以是手性纯。或者，一种或多种天然的还原叶酸盐异构体的一种或多种可以与一种或多种非天然的还原叶酸盐异构体一起以混合物存在。当添加外消旋混合物的情况下，添加到营养物的混合物中的一种或多种天然的还原叶酸盐异构体和一种或多种非天然的还原叶酸盐异构体的摩尔量可以相同，否则它们可以不同。优选天然异构体的摩尔量大于非天然异构体的摩尔量。另外，非天然的还原叶酸盐异构体可以在一种或多种天然的还原叶酸盐异构体加入之后或之前分步加入营养物中。优选在天然的还原叶酸盐异构体加入之前、之间和/或之后加入的非天然的还原叶酸盐异构体的总摩尔量小于添加的天然异构体总摩尔量。
基本手性纯的天然的还原叶酸盐异构体可以通过任何适宜方法制得，包括例如，Bailey等在美国专利No.5,350,851中描述的方法，特此引用作参考。
当营养物为食品制品时，除了向食品制品中加入天然的还原叶酸盐异构体之外，选择性地可以加入一种或多种必需营养素。必需营养素例如可以在天然的还原叶酸盐异构体加入之前、之间或之后加入到食品制品中。
本发明的组合物可以通过给施用对象服用该组合物增加施用对象对叶酸盐的膳食吸收。该施用对象可以为例如狗或猫的动物；或者，该施用对象可以为人。通过增加叶酸盐的膳食吸收，可以看到一定类别的个体的效果显著。这些个体包括孕妇；有过流产的妇女；怀有神经管缺陷、裂唇缺陷或裂鄂缺陷的胎儿的妇女；和有血管疾病的人。
也可以用该组合物治疗有肠内吸收障碍，特别是叶酸盐吸收障碍的施用对象。当治疗有肠内吸收障碍的施用对象时，该组合物的服用量优选达到使施用对象的血液叶酸盐含量增加的效果。更优选，服用量使得血液叶酸盐含量在正常范围内，该含量通过传统的血液叶酸盐分析法测定，例如用the Quanta Phase Ⅱ assay from BioRad Laboratories,Hercules,California。
该组合物可以通过肠溶服用，例如口服、胃或经幽门。本领域技术人员可以考虑到可以改变该组合物的作用的许多因素；例如，体重、性别、饮食、服用时间、服用途径、排泄频率、身体条件和反应灵敏性和剧烈性。可以连续或周期性地服用，例如一天一次或一顿饭一次。
含有天然的还原叶酸盐异构体的组合物优选肠溶食用(肠溶包括口腔、胃或经幽门)，并且是任何食品制品、食品添加物必需营养制品或维生素制品。这样的食品或维生素制品的一般例子为目前加有叶酸(Ⅰ)并用于人或其它动物的那些。天然异构体意思是在谷氨酸盐的(-和蝶啶的6-碳上具有天然构型的四氢叶酸盐。更具体地说，这些维生素是但不限于：多种维生素(有或没有矿物质和其它营养素)制品(这样的制品可以是固态、液态或悬浮液)；例如预制食品的早餐谷类食品、早餐饮料混合物、烤焙制品和早餐条状食品；婴儿食品；膳食添加物和完全食品和减肥制品和条状食品；动物饲料或动物饲料添加物(例如，家禽的)，和宠物食品。该天然的还原叶酸盐异构体也可以用在未来卫生官员可能认为用来满足每天叶酸盐需要的适当载体的产品中。本发明的组合物可以包括天然的四氢叶酸盐的异构体，例如Ⅱ-Ⅷ，优选单谷氨酸盐形式，在维生素制剂中优选含有至少一种除抗坏血酸(维生素C)以外的其它维生素(例如，如维生素B的其它维生素)，尽管抗坏血酸可以是添加组分。这些营养素或维生素可以是打算用于人或动物的那些。也可以有其它辅料，例如本领域技术人员已知的维生素制剂中采用的填料、粘合剂、稳定剂、甜味剂包括营养甜味剂(例如蔗糖、山梨糖醇和其它多元醇)和非营养甜味剂(例如糖精、天冬甜素和双氧恶噻嗪K)，着色剂、香料、缓冲剂、盐、糖衣等。
所述的还原叶酸盐(Ⅱ-Ⅷ)的应用中，优选5-甲基-(6S)-四氢叶酸(Ⅲ)、5-甲酰基-(6S)-四氢叶酸(Ⅳ)和5,10-次甲基-(6R)-四氢叶酸(Ⅶ)。所有这些还原叶酸盐都不同程度地受到空气的氧化。几个因素影响该易感性，首先是相当慢氧化的5-氮的衍生物。5-甲基-和5-甲酰衍生物是身体大多数组织中最富有的叶酸盐形式。人体血液中的绝大多数叶酸盐是5-甲基-(6S)-四氢叶酸(Ⅲ)。
在使用四氢叶酸盐增加营养组合物中叶酸盐时，要考虑几个因素。许多营养素加工时不稳定，包括几种维生素。例如，维生素A、B1(硫胺素)和抗坏血酸在一些条件下特别不稳定。已知许多方法用来强化不同营养素的稳定性，例如控制组合物的pH和水分。彼此间达到不相容的程度的组分，例如抗坏血酸与最易被氧化的铁或铜，可以使其在组合物中以多相形式存在。经常在烤焙步骤之后加入热不稳定的营养素；例如，经常在早餐谷类食物烤过之后喷上维生素。对空气不稳定的营养素可以在低氧条件下包装，和/或在低氧或氧不可渗透的容器中包装。对本领域技术人员已知的这些和其它方法对保持叶酸盐在其天然的还原形式时有用的。
在水溶液中空气存在下的还原叶酸盐的氧化速度将增加。如果液体制品优选保持在密封容器中，它们的贮藏限期将大大延长。用例如氮气或氩气代替空气也阻滞损失。用大量的还原剂和抗氧化剂也可防止叶酸盐氧化，最适宜的那些是经常包括在多种维生素混合物或营养组合物中的其它维生素。在生物化学实验和生物样品的实验室分析步骤中使用抗坏血酸来保护还原叶酸盐。这种保护不必限于使用抗坏血酸或其它维生素；可使用适宜人或动物消费的其它试剂，例如异抗坏血酸和某种硫醇，例如谷胱甘肽。已知的增加例如抗坏血酸或其它空气不稳定的物质的化合物的包装和配制技术(例如，涂敷形式、鼓泡塑料衬垫包装和还原金属或金属复合物)用于保护还原叶酸盐。还原叶酸盐的盐形式也或多或少影响稳定性和溶解性，而且这可以根据每个产品的需要使其最佳化。也可以根据使用的具体还原叶酸盐和存在的其它组分的稳定性能使最终组合物的pH值最佳化，这在加工营养素和叶酸盐化合物的技术中是很好理解的。例如，存在水分的条件下，依赖pH的方式，5,10-次甲基-(6R)-FH4(Ⅶ)可以变成10-甲酰基-(6R)-FH4和5-甲酰基-(6S)-FH4(Ⅳ)(后者也为优选化合物)。当或者基本干和/或具有pH小于约4的酸性时，含有5,10-次甲基-(6R)-FH4(Ⅶ)的组合物对氧是最稳定的。适当留心上面的因素，还原叶酸盐的易变性不必限制制品的寿命，特别是Ⅲ和Ⅳ比抗坏血酸对许多氧化反应更稳定。
还原叶酸盐代替叶酸(Ⅰ)应当考虑不同形式的分子量不同。例如，目前美国推荐的每日叶酸(Ⅰ)摄入量标0.4mg相应于使用无水分子量441.4的0.91nmol。还原叶酸盐的有效分子量依赖于使用的衍生物(即Ⅱ-Ⅷ)、盐形式和水分含量。例如，0.91nmol的5-甲酰基-(6S)-四氢叶酸(Ⅳ)钙盐-五水合物重0.545mg,0.91nmol的5-甲基-(6S)-四氢叶酸(Ⅲ)二钠盐重0.456mg。在文献中描述了还原叶酸盐的几种盐形式，例如盐酸盐、钠、钾、镁、钙和其它物并具有不同水分含量。对这些形式的每一种，可进行相似的计算。实现RDI所需部分的摩尔当量所需的量将是该新的重量部分。举一种例子，25％RDI的5-甲基-(6S)-四氢叶酸(Ⅲ)二钠盐为0.25×0.456=0.114mg,0.10mg的叶酸(Ⅰ)的摩尔当量。以前对几组具有正常的叶酸(Ⅰ)摄入的个体的研究显示还原叶酸盐的生物利用率以摩尔计是相似的。
如上所述，在加工过程中营养素的损失，特别是食品的营养素的损失是本领域技术人员公知的。通常采取的步骤是添加特别是营养素的开始的过量物，一＂超过部分″，以便最终加工后的量为所需的含量。已知许多高灵敏性和特异性的方法(例如依靠微生物成长，以叶酸盐粘合蛋白为基础测定、HPLC和GC)用于叶酸盐、还原和氧化的形式及其不同衍生物的分析。这些测定允许添加一定量的天然的还原叶酸盐异构体来调整以便在加工和包装后得到所需的最终量。天然的还原叶酸盐异构体在本发明组合物中的范围优选实现RDI的人对叶酸盐的约5％-约200％之间，而且应该使其既包括弥补加工损失的允许量的情况，也包括没有这样的允许量的情况。对不同的人群具体说明了不同的RDA剂量，例如，孕妇和未怀孕的妇女。而且，虽然RDI含量依赖RDA值，但RDI可以与RDA值区别开。上面的范围＂RDI对叶酸盐的约5％-约200％之间＂应该单独地针对每个这些不同的RDA和RDI说明进行，或者它们的外来当量，如目前确定的或者未来改变了的。为了本发明目的，这几个说明指的是叶酸每天所需量。除非推荐的人对叶酸盐膳食限量增加，人使用每天所需叶酸量的组合物中天然的还原叶酸盐异构体的最终最大量优选每剂量或每份普通消费不超过约4.5(mol。然而，对于患肠内吸收障碍，例如腹腔疾病或热带性斯泼卢(tropical sprue)，的个体，含天然的还原叶酸盐异构体量高的组合物是有效的。
为了本发明目的，必需营养组合物可以是膳食添加物或类似物，由基本上纯的四氢叶酸或其衍生物得到的大量的叶酸盐组分，例如化合物Ⅱ-Ⅷ。本发明包括的必需营养组合物包括优选上述范围内的天然的还原叶酸盐异构体和其它维生素和/或优选每个用量认为安全的其它营养素。动物消费生产厂配制的组合物中经常大大超过NRC推荐的叶酸盐的剂量(10倍，20倍，或有时更多)，不仅克服了加工中的损失，而且包括了可能增加的对叶酸盐需要的情况，例如在抗菌治疗中。其它维生素和营养组分存在的量可以与NRC推荐的有很大的不同。以下的实施例进一步说明本发明，而且无论如何不用来限定其范围。
实施例1)普通即食性早餐谷类食物：玉米(和/或其它谷物)、糖、盐、麦芽粉，以便30g一份的食物提供约2g蛋白质、26g总碳水化合物和330mg的钠，也含有每份饮食量的维生素A棕榈酸盐(RDI的15％)、抗坏血酸(RDI的25％)、还原性铁(RDI的45％)、维生素D(RDI的10％)、硫胺素盐酸盐(RDI的25％)、核黄素(RDI的25％)、烟酰胺(RDI的25％)、吡哆素盐酸盐(RDI的25％)和0.114mg的5-甲基-(6S)-四氢叶酸(Ⅲ)二钠盐(0.1mg叶酸的摩尔当量，RDI的25％)。2)普通每天的多种维生素片剂：碳酸钙、抗坏血酸(60mg,100％RDI)、明胶、维生素E醋酸酯(30 I.U.,100％RDI)、淀粉、烟酰胺(20mg,100％RDI)、羟丙基-甲基纤维素、泛酸钙(10mg,100％RDI)、硅酸钙、羟丙基纤维素、吡哆素盐酸盐(2mg,100％RDI)、核黄素(1.7mg,100％RDI)、硫胺素单硝酯(1.5mg,100％RDI)、(-胡萝卜素&维生素A醋酸酯(5000 I.U.,100％RDI)、六偏磷酸钠、硬脂酸镁、维生素D(400 I.U.,100％RDI)、维生素B12(6(g,100％RDI)、卵磷脂和0.437mg的5-甲基-(6S)-四氢叶酸(Ⅲ)镁盐(0.4mg叶酸的摩尔当量，RDI的100％)。3)普通每天的多种维生素和矿物质片剂：磷酸钙(130mg的元素钙)、氢氧化镁&硬脂酸镁(100mg,25％RDI)、纤维素、氯化钾、抗坏血酸(60mg,100％RDI)、明胶、富马酸铁(18mg元素铁，100％RDI)、硫酸锌(15mg,100％RDI)改性纤维素植物胶、维生素E醋酸酯(30 I.U.,100％RDI)、柠檬酸、烟酰胺(20mg,100％RDI)、硬脂酸镁、羟丙基-甲基纤维素、泛酸钙(10mg,100％RDI)、酵母硒、聚乙烯吡咯烷酮、羟丙基纤维素、硫酸锰、二氧化硅、氧化铜(2mg,100％RDI)、酵母铬、酵母钼、吡哆素盐酸盐(2mg,100％RDI)、核黄素(1.7mg,100％RDI)、硫胺素单硝酯(1.5mg,100％RDI)、(-胡萝卜素&维生素A醋酸酯(5000I.U.,100％RDI)、碘化钾(150(g,100％RDI)、六偏磷酸钠、生物素(30(g,100％RDI)、维生素D(400 I.U.,100％RDI)、维生素B12(6(g,100％RDI)、卵磷脂和0.545mg的5-甲酰基-(6S)-四氢叶酸(Ⅳ)钙盐-五水合物(0.4mg叶酸的摩尔当量，RDI的100％)。4)用于老年人的普通每天多种维生素和矿物质片剂：碳酸钙、磷酸钙(200mg钙，20％RDI；48mg三价磷，5％RDI)、氢氧化镁、硬脂酸盐(100mg,25％RDI)、氯化钾(80mg,2％RDI)、微晶纤维素、抗坏血酸(60mg,100％RDI)、明胶、d1-(-生育酚硬脂酸酯(45 I.U.,150％RDI)、改性的食用淀粉、麦芽糊精、交联吡咯烷酮、还原铁(4mg,22 RDI)、羟丙基-甲基纤维素、烟酰胺(20mg,100％RDI)、氧化锌(15mg,100％RDI)、泛酸钙、硫酸镁(3.5mg)、维生素D(400 I.U.,100％RDI)、二氧化钛、维生素A和(-胡萝卜素(5000 I.U.,100％RDI)、硬脂酸、吡哆素盐酸盐(3mg,150％RDI)、核黄素(1.7mg,100％RDI)、二氧化硅、氧化铜(2mg,100％RDI)、葡萄糖、硫胺素单硝酯(1.5mg,100％RDI)、柠檬酸三乙酯、聚山梨酸酯80、氯化铬(130(g)、人工色素、碘化钾(150(g,100％RDI)、偏硅酸钠(2mg)、钼酸钠(160(g)、硼酸盐、硒酸钠(20(g)、生物素(30(g,10％RDI)、偏钒酸钠(10(g)、氰钴胺素(25(g,417％RDI)、硫酸镍(5(g)和维生素K1和5,10-次甲基-(6R)-四氢叶酸盐酸盐(Ⅶ)(0.44mg,0.4mg叶酸的摩尔当量，100％RDI)。5)普通完全膳食饮料：水、糖、酪朊酸钙和钠、麦芽糊精、高油酸的红花油、大豆蛋白、大豆油、canola油、可可、柠檬酸钠和钾、碳酸钙和磷酸钙(250mg钙，25％RDI)、氯化镁和磷酸镁(100mg钙，25％RDI)、氯化钠、大豆卵磷脂、氯化胆碱、食用香精、抗坏血酸(30mg,50％RDI)、卡拉胶、硫酸锌(5.6mg,37％RDI)、硫酸铁(4.5mg铁，25％RDI)、(-生育酚硬脂酸酯(11.3 I.U.,37.7％RDI)、烟酰胺(5mg,25％RDI)、泛酸钙(2.5mg,25％RDI)、硫酸锰(1.3mg)、铜盐(25％RDI)、维生素A棕榈酸酯(1250 I.U.,25％RDI)、吡哆素盐酸盐(0.5mg,25％RDI)、核黄素(0.425mg,25％RDI)、生物素(75(g,25％RDI)、钼酸钠(38(g)、氯化铬(25(g)、碘化钾(37.5(g,25％RDI)、硒酸钠(18(g)、叶绿醌(维生素K1)、氰钴胺素(1.5(g,25％RDI)、维生素D3(100 I.U.,25％RDI)和0.136mg的5-甲酰基-(6S)-四氢叶酸(Ⅳ)钙盐-五水合物(0.1mg叶酸的摩尔当量，25％RDI)，包装在密封容器中，并提供约225cals的热量。6)普通强化B族维生素/四氢叶酸盐片剂：磷酸氢二钙、吡哆素盐酸盐(50mg,2,500％RDI)、纤维素、硬脂酸、硬脂酸镁和0.912mg的5-甲基-(6S)-四氢叶酸(Ⅲ)二钠盐(0.8mg叶酸的摩尔当量，成人RDI的200％，孕妇RDA的100％)。7)普通家禽饲料维生素添加物：(每kg饮食的量)维生素A(反式视黄基醋酸酯，5500 I.U.)、维生素E(11 I.U.)、甲基荼醌亚硫酸氢钠(1.1mg)、维生素D3(1100 I.U.)、核黄素(4.4mg)、维生素B12(10(g)、维生素B6(3.0mg)、硫胺素单硝酯(2.2mg)、生物素(0.3mg)、乙氧基奎(125mg)和2.0mg的5-甲酰基-(6S)-四氢叶酸(Ⅳ)钙盐-五水合物(1.45mg叶酸的摩尔当量)。8)普通干猫食：磨碎的黄玉米、玉米面筋粉、大豆粉、家禽副产品粉、动物脂肪、鱼粉、肉和骨头粉、磨碎的小麦、磷酸、碳酸钙、干动物水解液、盐、酿酒干酵母、氯化钾、干乳清可溶物、氯化胆碱、干脱脂乳、牛磺酸、L-赖氨酸、氧化锌、硫酸铁、维生素PP、维生素A、维生素D3、维生素B12、泛酸钙、柠檬酸、硫酸锰、核黄素添加物、生物素、铜盐、硫胺素单硝酯、吡哆素盐酸盐、甲基荼醌亚硫酸氢钠复合物，使得粗蛋白不少于31％、粗脂肪不少于8％、粗纤维不大于4.5％、水分不大于12％、钙不少于1.2％、磷不少于1.0％、氯化钠不大于1.5％、可代谢能量为约3,600kcal/kg，牛磺酸、铁、维生素A、D3、B12和E为美国饲料控制局协会(the Association of American Feed Control Officials)推荐的至少100％的水平，并且含有不少于0.97mg/kg饮食的5-甲基-6(S)-四氢叶酸(Ⅲ)钙盐二水合物(0.8mg/kg饮食的叶酸的摩尔当量)。9)普通大豆为原料的婴儿配方：75.5％的水；13％的蔗糖；6.6％的含油酸的固定油：椰子、高油酸(红花或向曰葵)和大豆油；3.8％的大豆蛋白离析物；(蛋白2.7g，脂肪5.3g，碳水化合物10.2，亚油酸500mg)；柠檬酸钾和碳酸氢钾(105mg的钾)；磷酸二氢钾和磷酸氢二钙(63mg的磷酸)；大豆卵磷脂；牛磺酸、卡拉胶钙；氢氧化钙、氯化钙和柠檬酸钙(90mg的钙)；氯化钠(30mg的钠)；L-甲硫氨酸；锌(Zn0.8mg)、铁(Fe1.8mg)和锰(Mn30(g)的硫酸盐；铜盐(Cu70(g)；牛磺酸；L-肉碱；碘化钾(I9(g)；抗坏血酸(8.3mg)；氯化胆碱；(-生育酚醋酸酯(1.4 I.U.)；烟酰胺(750(g)；维生素A棕榈酸酯和(-胡萝卜素(300 I.U.)；泛酸钙(450(g)；硫胺素盐酸盐(100(g)；核黄素(150(g)；吡哆素盐酸盐(62.5(g)；维生素K1(15(g)；生物素(5.5(g)；维生素D3(60 I.U.)；氰钴胺素(0.3(g)；和9.1(g的5-甲基-6(S)-四氢叶酸(Ⅲ)钙盐二水合物(7.5(g叶酸的摩尔当量)，包装在密封容器(量为每150ml的1∶1稀释配方)内。
本领域技术人员容易地理解，本发明可较好地实施，以实现其目的并得到所述的结果和好处。虽然上面的说明包括了许多特例，但这些不用来解释作为本发明范围的限制，只是作为其优选实施方式的例证。对本领域技术人员来说，出现的其中的改变和其它用途都包括在权利要求书限定范围内的本发明宗旨内而且其法律意义相同。
Claims (26)
1、一种组合物，其特征在于：它包括：
一种或多种选自(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸和其多谷氨酰基衍生物的天然的还原叶酸盐异构体；
一种营养物，选自食品制品、必需营养制品，和其组合；
其中，当营养物为食品制品时，食品制品包括两种或多种食品组分，并且每克的所述的食品制品具有所述一种或多种天然的还原叶酸盐异构体的天然摩尔量为N，其中N大于或等于零，其中每克所述组合物具有大于N的所述一种或多种天然的还原叶酸盐异构体总摩尔量T；和
其中，当营养物为必需营养制品时，必需营养制品包括除抗坏血酸之外的一种维生素。
2、根据权利要求1所述的组合物，其特征在于：一种或多种天然的还原叶酸盐异构体选自5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸和其多谷氨酰基衍生物。
3、根据权利要求1所述的组合物，其特征在于：以每次习惯消费所述组合物的量计所述一种或多种天然的还原叶酸盐异构体的总摩尔量为人每天所需叶酸盐的5％-200％之间。
4、根据权利要求1所述的组合物，其特征在于：以每次习惯消费所述组合物的量计所述一种或多种天然的还原叶酸盐异构体的总摩尔量为动物每天所需叶酸盐的5％-3000％之间。
5、根据权利要求1所述的组合物，其特征在于：所述营养物为食品制品。
6、根据权利要求5所述的组合物，其特征在于：营养物为食品制品，并且其中每克的所述食品制品还不包括选自(6R)-四氢叶酸、5-甲基-(6R)-四氢叶酸、5-甲酰基-(6R)-四氢叶酸、10-甲酰基-(6S)-四氢叶酸、5,10-亚甲基-(6S)-四氢叶酸、5,10-次甲基-(6S)-四氢叶酸和5-亚胺甲基-(6R)-四氢叶酸和其多谷氨酰基衍生物的非天然的还原叶酸盐异构体，或者一种或多种所述非天然的还原叶酸盐异构体的摩尔量小于T减去N。
7、根据权利要求5所述的组合物，其特征在于：食品制品选自早餐食物、婴儿食品、膳食添加物、完全饮食食品和减肥制品。
8、根据权利要求7所述的组合物，其特征在于：早餐食物为预制食品、早餐饮料混合物或焙烤食品，并且其中减肥制品为减肥饮料或减肥条状食品。
9、根据权利要求1所述的组合物，其特征在于：营养物为包含除抗坏血酸之外的一种维生素的必需营养制品。
10、根据权利要求9所述的组合物，其特征在于：必需营养制品还包括抗坏血酸。
11、根据权利要求9所述的组合物，其特征在于：以每次习惯消费所述必需营养制品的量计维生素以等于或大于每天所需该维生素的25％的量存在其中。
12、一种增加营养物的叶酸盐含量的方法，其特征在于：它包括：
提供选自食品制品、必需营养制品和其组合的营养物；和
向营养物中加入摩尔量的一种或多种选自(6S)-四氢叶酸、5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、10-甲酰基-(6R)-四氢叶酸、5,10-亚甲基-(6R)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸、5-亚胺甲基-(6S)-四氢叶酸和其多谷氨酰基衍生物的天然的还原叶酸盐异构体；
其中，当营养物为食品制品时，食品制品包括两种或多种食品组分；和
其中，当营养物为必需营养制品时，必需营养制品包括除抗坏血酸之外的一种维生素。
13、根据权利要求12所述的方法，其特征在于：它还包括：向营养物中加入摩尔量的一种或多种选自(6R)-四氢叶酸、5-甲基-(6R)-四氢叶酸、5-甲酰基-(6R)-四氢叶酸、10-甲酰基-(6S)-四氢叶酸、5,10-亚甲基-(6S)-四氢叶酸、5,10-次甲基-(6S)-四氢叶酸和5-亚胺甲基-(6R)-四氢叶酸和其多谷氨酰基衍生物的非天然的还原叶酸盐异构体，其中一种或多种非天然的还原叶酸盐异构体的摩尔量小于一种或多种天然的还原叶酸盐异构体的摩尔量。
14、根据权利要求12所述的方法，其特征在于：一种或多种天然的还原叶酸盐异构体的每一种基本上为手性纯。
15、根据权利要求12所述的方法，其特征在于：一种或多种天然的还原叶酸盐异构体选自5-甲基-(6S)-四氢叶酸、5-甲酰基-(6S)-四氢叶酸、5,10-次甲基-(6R)-四氢叶酸和其多谷氨酰基衍生物。
16、根据权利要求12所述的方法，其特征在于：营养物为包含除抗坏血酸之外的一种维生素的必需营养制品。
17、根据权利要求16所述的方法，其特征在于：必需营养制品还包括抗坏血酸。
18、根据权利要求12所述的方法，其特征在于：其中营养物为食品制品，并且其中所述方法还包括：
把一种维生素加入食品制品中。
19、一种增加施用对象对叶酸盐膳食吸收的方法：其特征在于：给施用对象服用权利要求1的组合物。
20、根据权利要求19所述的方法，其特征在于：所述的服用是通过肠溶服用的。
21、根据权利要求19所述的方法，其特征在于：施用对象为动物。
22、根据权利要求21所述的方法，其特征在于：以每次习惯消费所述组合物的量计所述一种或多种天然的还原叶酸盐异构体的总摩尔量为动物每天所需叶酸盐的5％-3000％之间。
23、根据权利要求19所述的方法，其特征在于：施用对象为人。
24、根据权利要求23所述的方法，其特征在于：以每次习惯消费所述组合物的量计所述一种或多种天然的还原叶酸盐异构体的总摩尔量为人每天所需叶酸盐的5％-200％之间。
25、根据权利要求23所述的方法，其特征在于：人选自孕妇；流产的妇女；怀有有神经管缺陷、裂唇缺陷或裂鄂缺陷的胎儿的妇女；和患有血管疾病的人。
26、对患有肠内吸收障碍的施用对象治疗的方法，其特征在于：给该施用对象服用有效量的权利要求1的组合物以增加施用对象的血液叶酸盐含量。
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-
1997
- 1997-01-31 DK DK97905791T patent/DK0877563T3/da active
- 1997-01-31 ES ES97905791T patent/ES2218662T3/es not_active Expired - Lifetime
- 1997-01-31 PT PT97905791T patent/PT877563E/pt unknown
- 1997-01-31 CA CA002243981A patent/CA2243981C/en not_active Expired - Lifetime
- 1997-01-31 AT AT97905791T patent/ATE262799T1/de active
- 1997-01-31 JP JP52793997A patent/JP3602141B2/ja not_active Expired - Fee Related
- 1997-01-31 CN CN97191951A patent/CN1122456C/zh not_active Expired - Lifetime
- 1997-01-31 EP EP97905791A patent/EP0877563B1/en not_active Expired - Lifetime
- 1997-01-31 US US09/117,586 patent/US5997915A/en not_active Expired - Lifetime
- 1997-01-31 AU AU22602/97A patent/AU722050B2/en not_active Expired
- 1997-01-31 WO PCT/US1997/001870 patent/WO1997027764A1/en active IP Right Grant
- 1997-01-31 DE DE69728379T patent/DE69728379T2/de not_active Expired - Lifetime
-
1999
- 1999-10-15 US US09/418,649 patent/US6254904B1/en not_active Expired - Lifetime
-
2001
- 2001-06-25 US US09/888,798 patent/US6451360B2/en not_active Expired - Lifetime
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2002
- 2002-06-18 US US10/174,272 patent/US6808725B2/en not_active Expired - Lifetime
- 2002-07-16 US US10/196,118 patent/US6673381B2/en not_active Expired - Lifetime
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2003
- 2003-12-30 US US10/748,116 patent/US7172778B2/en not_active Expired - Fee Related
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2007
- 2007-02-03 US US11/702,006 patent/US7674490B2/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102861020A (zh) * | 2012-09-25 | 2013-01-09 | 上海交通大学医学院附属仁济医院 | 叶酸在制备预防大肠腺瘤初发药物中的应用 |
| CN108902575A (zh) * | 2018-07-24 | 2018-11-30 | 河北冀衡（集团）药业有限公司 | 饮料及其制备方法 |
| CN108902575B (zh) * | 2018-07-24 | 2021-12-28 | 河北冀衡药业股份有限公司 | 饮料及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| DE69728379D1 (de) | 2004-05-06 |
| AU722050B2 (en) | 2000-07-20 |
| PT877563E (pt) | 2004-08-31 |
| CN1122456C (zh) | 2003-10-01 |
| US6673381B2 (en) | 2004-01-06 |
| US6808725B2 (en) | 2004-10-26 |
| CA2243981C (en) | 2005-09-06 |
| US20020176912A1 (en) | 2002-11-28 |
| US6451360B2 (en) | 2002-09-17 |
| JP2000505286A (ja) | 2000-05-09 |
| US5997915A (en) | 1999-12-07 |
| CA2243981A1 (en) | 1997-08-07 |
| US20070207136A1 (en) | 2007-09-06 |
| AU2260297A (en) | 1997-08-22 |
| JP3602141B2 (ja) | 2004-12-15 |
| DE69728379T2 (de) | 2005-02-24 |
| ES2218662T3 (es) | 2004-11-16 |
| WO1997027764A1 (en) | 1997-08-07 |
| US7172778B2 (en) | 2007-02-06 |
| US7674490B2 (en) | 2010-03-09 |
| DK0877563T3 (da) | 2004-07-26 |
| ATE262799T1 (de) | 2004-04-15 |
| US20010046533A1 (en) | 2001-11-29 |
| US20020150653A1 (en) | 2002-10-17 |
| US6254904B1 (en) | 2001-07-03 |
| US20040219262A1 (en) | 2004-11-04 |
| EP0877563B1 (en) | 2004-03-31 |
| EP0877563A4 (en) | 1999-06-09 |
| EP0877563A1 (en) | 1998-11-18 |
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