CN111447844A - 喷雾干燥的四糖 - Google Patents
喷雾干燥的四糖 Download PDFInfo
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- CN111447844A CN111447844A CN201880079361.6A CN201880079361A CN111447844A CN 111447844 A CN111447844 A CN 111447844A CN 201880079361 A CN201880079361 A CN 201880079361A CN 111447844 A CN111447844 A CN 111447844A
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Abstract
本发明公开了一种用于制造基本上由LNT和/或LNnT组成的喷雾干燥的粉末的方法、所述喷雾干燥的粉末及其用于制造营养组合物的用途以及包含所述喷雾干燥的粉末的营养组合物。
Description
本发明涉及人乳寡糖的制剂。更具体而言，本发明涉及人乳寡糖的固体制剂以及用于制造所述人乳寡糖的固体制剂的方法。
背景技术
人类母乳中含有大量的碳水化合物。这些碳水化合物包括单糖，例如L-岩藻糖和N-乙酰神经氨酸(Neu5Ac)。二糖乳糖也存在于人类母乳中。除乳糖之外，一升人类母乳还含有最高达20g/L的寡糖，即所谓的“母乳寡糖(HMO)”。HMO代表人类母乳中第三大最丰富的成分。据推测，超过150种结构上不同的寡糖存在于人乳中。人乳通常包含10至13种主要的HMO，其以每升几克至几百毫克的浓度存在(Thurl等人，(2017)，Nutrition Reviews 75(11)920-933)。HMO包括中性HMO以及包含一个或多个唾液酸部分的酸性HMO。最主要的HMO示于表1中。这些寡糖的结构复杂性和丰度对于人乳而言是独特的，并且未在其他哺乳动物(例如家养的奶畜)的乳中发现。
由于人类无法消化HMO，因此数十年来一直在研究这些糖类的生理作用。早在100多年前就已经发现HMO的益生元(prebiotic)功效。HMO能够通过喂食有益细菌来调节人类肠道微生物组(gut microbiome)。近年来，对HMO的若干其他功能作用进行了研究，特别是其对新生儿发育的作用。HMO已知可充当诱饵来降低被细菌和病毒性病原体感染的风险，所述细菌和病毒性病原体通过与细胞表面糖蛋白结合而粘附在人类细胞上。另外，各种HMO具有抗炎功效并充当免疫调节剂。因此，有人提出，HMO会降低发生食物过敏的风险。唾液酸化的HMO对新生儿大脑发育的积极作用引起热烈讨论(综述于″Prebiotics and Probioticsin Human Milk，Origins and functions of milk-borne oligosaccharides andbacteria″，Academic Press(2017)编辑：McGuire M.，McGuire M.，和Bode L.)。
主要的HMO为四糖乳-N-四糖(LNT；Gal(β1，3)GlcNAc(β1，3)Gal(β1，4)Glc)和乳-N-新四糖(LNnT，Gal(β1，4)GlcNAc(β1，3)Gal(β1，4)Glc)，其不同之处在于末端半乳糖部分的糖苷键。乳-N-四糖和乳-N-新四糖可通过将GlcNAc和Gal残留物连续添加到乳糖上而酶促地合成。乳-N-四糖和乳-N-新四糖被认为是用于肠道菌群和粘膜免疫系统发育的底物。
利用HMO对奶瓶喂养的婴儿的有益效果的第一步是将单个HMO添加到婴儿配方物中。但是，具有结构上不同的HMO的组合补充婴儿配方物会更好，因为结构上不同的HMO的组合将具有与其原始来源(人乳)的效果更相似的效果，并且所述效果不能由单个HMO产生。
用于补充婴儿配方物的单个HMO的有限供给首先促进了HMO化学合成的发展，然后是使用纯化酶的生物催化方法的发展。如今，基因工程细菌细胞的发酵用于制备商业规模的不同的HMO(WO 2015/150328 A1、WO 2017/043382 A1、WO 2010/070104 A1、WO 2012/097950 A1)。由细菌细胞合成的HMO可从发酵液或细胞裂解物中纯化，以获得基本纯的HMO制剂，使得其可用于人类食品、特别是婴儿食品。
在其纯化过程中，LNT和/或LNnT通常以液体工艺物料流(process stream)的形式存在。随着纯化进行，工艺物料流中LNT和/或LNnT的浓度增加。然而，LNT和/或LNnT的水溶液很容易受到细菌或真菌的污染。因此，优选提供LNT和/或LNnT作为具有低水含量的干产物，使得微生物生长是不可能的。
通常，糖通过结晶以固体形式获得。已经记载了以下的单个HMO的结晶：3-岩藻糖基乳糖(fucosyllactose)(WO 2014/075680 A)、2′-岩藻糖基乳糖(WO 2011/150939 A)、双岩藻糖基乳糖(WO 2016/086947 A)、乳-N-四糖(WO 2017/101953 A)、乳-N-新四糖(WO2014/094783 A)。HMO的结晶涉及使用有机溶剂，例如醇类，主要是乙醇或甲醇；或有机酸，例如冰醋酸。然而，如果将HMO用作食品成分，则使用有机溶剂使HMO结晶作为获得固体形式终产物的方法中的最后步骤是不适合的。另外，有机溶剂对环境和任何对其进行处理的个人都是有害的。因此，使用有机溶剂需要职业安全措施和适当的处置，这使得使用有机溶剂的成本很高。因此，使HMO结晶以提供固体形式的HMOs必须被认为是以工业规模制备HMO的缺点。
因此，需要提供固体形式的HMO、特别是LNT和/或LNnT的方法，所述方法可用于工业规模制备HMO，并且在纯化方案结束时不涉及有机溶剂的使用以提供所述HMO的固体制剂。
通过一种提供基本上由纯化的HMO组成的粉末的方法解决了该问题，其中所述方法包括将包含所述HMO的水溶液喷雾干燥。
发明内容
在第一个方面，提供一种方法，所述方法提供喷雾干燥的粉末，所述喷雾干燥的粉末基本上由一种或多种四糖、优选LNT和/或LNnT组成。
在第二个方面，一种用于制造喷雾干燥的粉末的方法，所述喷雾干燥的粉末基本上由一种或多种四糖、优选LNT和/或LNnT组成。
在第三个方面，提供基本上由一种或多种四糖、优选LNT和/或LNnT组成的喷雾干燥的粉末用于制造营养组合物的用途。
在第四个方面，提供一种包含基本上由一种或多种四糖、优选LNT和/或LNnT组成的喷雾干燥的粉末的营养组合物。
附图说明
图1示出了说明喷雾干燥的3-岩藻糖基乳糖的X射线粉末衍射结果的图。
图2示出了说明喷雾干燥的乳-N-四糖的X射线粉末衍射结果的图。
图3示出了说明喷雾干燥的6′-唾液酸乳糖的X射线粉末衍射结果的图。
图4示出了说明喷雾干燥的3′-唾液酸乳糖的X射线粉末衍射结果的图。
图5示出了说明喷雾干燥的2′-岩藻糖基乳糖和乳-N-四糖的混合物的X射线粉末衍射结果的图。
图6示出了说明喷雾干燥的2′-岩藻糖基乳糖、3-岩藻糖基乳糖、乳-N-四糖、3′-唾液酸乳糖和6′-唾液酸乳糖的混合物的X射线粉末衍射结果的图。
具体实施方式
根据第一个方面，提供一种基本上由通过微生物发酵制备的LNT和/或LNnT组成的喷雾干燥的粉末。
LNT和/或LNnT通过如下文所述的微生物发酵进行制备。如本文中所用，术语“基本上由……组成”意指喷雾干燥的粉末由LNT和/或LNnT以及——任选地——在用于制备LNT和/或LNnT的微生物发酵期间产生的但不能将其从由微生物发酵获得的工艺物料流中除去的副产物组成。术语“基本上由……组成”包括由至少80重量％、至少85重量％、至少90重量％、至少93重量％、至少95重量％或至少98重量％的LNT和/或LNnT组成的喷雾干燥的粉末。
在另外的和/或替代实施方案中，LNT和/或LNnT以无定形形式存在于喷雾干燥的粉末中。
在另外的和/或替代实施方案中，喷雾干燥的粉末包含≤15重量％的水、优选≤10重量％的水、更优选≤7重量％的水、最优选≤5重量％的水。
在另外的和/或替代实施方案中，喷雾干燥的粉末不含基因工程微生物和来源于基因工程微生物的核酸分子。
根据第二个方面，提供一种用于制造基本上由已通过微生物发酵制备的LNT和/或LNnT组成的喷雾干燥粉末的方法。所述方法包括以下步骤：
a)从发酵液中纯化LNT和/或LNnT；
b)提供步骤a)的LNT和/或LNnT的水溶液；和
c)将步骤b)的溶液进行喷雾干燥。
在另外的和/或替代实施方案中，从发酵液中纯化LNT和/或LNnT包括以下的一个或多个步骤：
i)将微生物细胞从发酵液中除去，以获得澄清的工艺物料流；
ii)使澄清的工艺物料流进行至少一次超滤；
iii)使用阳离子交换树脂处理澄清的工艺物料流至少一次和/或使用阴离子交换树脂处理澄清的工艺物料流至少一次；
iv)使澄清的工艺物料流进行至少一次纳滤；
v)使澄清的工艺物料流进行至少一次电渗析；
vi)使用活性炭处理澄清的工艺物料流至少一次；和/或
vii)使澄清的工艺物料流进行至少一次结晶和/或沉淀步骤。
LNT和/或LNnT可通过微生物发酵进行制备，其中能够合成LNT和/或LNnT的基因工程微生物在培养基(发酵液)中并在允许通过所述基因工程微生物合成LNT和/或LNnT的条件下培养。通过微生物发酵制备的LNT和/或LNnT的纯化包括将微生物细胞从发酵液中分离以获得基本上不含细胞且包含LNT和/或LNnT的澄清工艺物料流的步骤。该步骤是纯化所需寡糖的方法中的第一步。
将微生物细胞从发酵液中分离的合适的方法包括离心，其中所述微生物细胞以微丸(pellet)形式获得并且发酵液为上清液。在另外的和/或替代实施方案中，通过过滤将所述微生物细胞从发酵液中分离。将细胞从发酵液中分离的合适的过滤方法包括微滤和超滤。
微滤本身是一种物理过滤方法，其中使含颗粒的流体通过特殊的孔径膜，以将颗粒从流体中分离。如本文中所用，术语“微滤”是指其中将细胞从发酵液中分离的物理过滤方法。
超滤是膜过滤的一种变化形式，并没有根本上的不同。在超滤中，诸如压力或浓度梯度的力产生通过半透膜的分离。细胞(高分子量的悬浮固体物和溶质)保留在所谓的渗余物(retentate)中，而水和低分子量溶质(例如所需的唾液酸化的寡糖)穿过膜进入渗透液(滤液)中。
超滤膜由所用膜的截留分子量(MWCO)定义。超滤以错流(cross-flow)或盲端(dead-end)模式施用。
通常，微生物细胞在细胞内合成LNT和/或LNnT，并将其分泌到发酵液中。由此制备的LNT和/或LNnT终止于发酵液中，然后如下文所述将其进行进一步的工艺步骤以纯化LNT和/或LNnT。如果在发酵结束时发酵液中存在LNT和/或LNnT，则在除去细胞后，所述发酵液变成澄清的工艺物料流。如果全部或部分的LNT和/或LNnT保留在细胞内，则可将细胞从发酵液中移出并使细胞裂解。可将不溶性成分从细胞裂解物中除去，然后所述细胞裂解物变成包含LNT和/或LNnT的澄清的工艺物料流。
尽管该方法用于纯化已通过微生物发酵制备的LNT和/或LNnT，但是所述方法也可用于纯化通过体外酶催化制备的LNT和/或LNnT。可在生物催化反应结束时将所述LNT和/或LNnT从反应混合物中纯化。所述反应混合物作为澄清的工艺物料流进行纯化的工艺。
澄清的工艺物料流包含LNT和/或LNnT以及副产物和不想要的杂质，例如单糖、二糖、不想要的寡糖副产物、离子、氨基酸、多肽、蛋白质和/或核酸。
在另外的和/或替代实施方案中，用于纯化LNT和/或LNnT的方法包括以下步骤：至少一种阳离子交换处理，以从澄清的工艺物料流中除去带正电荷的化合物。
用于除去带正电荷的化合物的合适的阳离子交换树脂包括Lewatit S2568(H+)(Lanxess AG，Cologne，DE)。
在另外的和/或替代实施方案中，用于纯化LNT和/或LNnT的方法包括以下步骤：阴离子交换处理，以从澄清的工艺物料流中除去不想要的带负电荷的化合物。
合适的阴离子交换树脂包括Lewatit S6368 A、Lewatit S4268、Lewatit S5528、Lewatit S6368A(Lanxess AG.Cologne，DE)、Dowex AG 1x2(200-400目)、Dowex 1x8(100-200目)、Purolite Chromalite CGA100x4(Purolite GmbH，Ratingen，DE)、Dow AmberliteFPA51(Dow Chemicals，MI，USA)。
在作为另外的/或替代的实施方案中，用于纯化LNT和/或LNnT的方法包括纳滤和/或渗滤(diafiltration)步骤，以除去具有较低分子量的杂质，并浓缩所需的寡糖。
渗滤包括向溶液中添加淡水，以除去(洗出)膜可渗透的组分。渗滤可根据组分的分子大小和电荷通过使用适当的膜来分离组分，其中一种或多种物质(species)被有效地保留，而其他物质是膜可渗透的。具体地，使用纳滤膜的渗滤对于诸如小分子和盐的低分子量化合物的分离是有效的。纳滤膜通常具有的截留分子量为150-1000道尔顿(Dalton)。纳滤被广泛地用在乳制品行业中用于乳清的浓缩和去矿化。
用于纳滤和/或渗滤的合适的膜包括Dow Filmtec NF270-4040、Trisep 4040-XN45-TSF(Microdyn-Nadir GmbH，Wiesbaden，DE)、GE4040F30和GH4040F50(GE Water&Process Technologies，Ratingen，DE)。
使用纳滤膜的渗滤被发现作为预处理是有效的，以在电渗析处理含有寡糖的溶液之前除去大量的污染物。在纯化HMO的过程中使用纳滤膜进行浓缩和渗滤会降低能耗和加工成本，并且由于减少热暴露而使产品质量更好，从而减少美拉德反应(Maillardreaction)和醛醇缩合反应(aldolreaction)。
在另外的和/或替代实施方案中，用于纯化LNT和/或LNnT的方法包括至少一个电渗析步骤。
电渗析(ED)将渗析和电解组合，并且基于溶液中离子通过半透膜的选择性电迁移可用于分离或浓缩溶液中的离子。
电渗析的基本原理由一个电解池组成，该电解池包括一对浸没在用于传导离子的电解质中的电极，所述电极与直流发生器相连。连接到直流发生器的正极的电极为阳极，而连接到负极的电极为阴极。然后电解质溶液支持电流，这是由于负离子和正离子分别向阳极和阴极移动而产生。用于电渗析的膜基本上是带有负电荷或正电荷基团的多孔离子交换树脂片，并且因此分别被称为阳离子膜或阴离子膜。离子交换膜通常由带有合适的官能团(例如用于阳离子膜的磺酸或用于阴离子膜的季铵基)的聚苯乙烯与二乙烯基苯交联制成。所述电解质可为例如氯化钠、乙酸钠、丙酸钠或氨基磺酸。然后以这样的方式组装电渗析堆(electrodialysis stack)，使阴离子膜和阳离子膜在两个电极块之间的压滤机中是平行的，以使经历离子消耗的料流与经历离子富集的料流充分分离(这两种溶液也称为稀释液(经历离子消耗)和浓缩液(经历离子富集))。电渗析过程的核心是膜堆(membrane stack)，其由安装在两个电极之间被隔板(spacer)隔开的数个阴离子交换膜和阳离子交换膜组成。通过施加直流电流，阴离子和阳离子将穿过膜向电极迁移。
在另外的和/或替代实施方案中，用于纯化LNT和/或LNnT的方法还包括诸如模拟移动床(SMB)色谱的连续色谱的步骤。
模拟移动床(SMB)色谱法起源于石化和矿物工业。如今，制药业使用SMB色谱法从外消旋混合物中分离对映异构体。大规模SMB色谱已用于从果糖-葡萄糖溶液中分离单糖果糖，以及用于从甜菜或甘蔗糖浆中分离二糖蔗糖。
用于分离糖类的SMB方法使用例如钙离子(calcium charged)、交联的聚苯乙烯树脂，亚硫酸氢盐形式的阴离子树脂(Bechthold M.等人，Chemie Ingenieur Technik，2010，82，65-75)或氢形式的聚苯乙烯凝胶强酸阳离子树脂(Purolite PCR833H)(Purolite，BalaCynwyd，USA)。
考虑到连续的操作模式、流动相的回收以及使用大的色谱柱规格的潜力，SMB系统原则上可规模化以实现数百吨的产量。
模拟移动床色谱法的工艺步骤的优点在于，该工艺步骤允许进一步除去结构上与所需寡糖密切相关的寡糖。
在另外的和/或替代实施方案中，用于纯化LNT和/或LNnT的方法包括使用活性炭处理工艺物料流以从工艺物料流中除去污染性物质，例如着色剂。
在另外的和/或替代实施方案中，用于纯化LNT和/或LNnT的方法包括从澄清的工艺物料流中结晶或沉淀LNT和/或LNnT的至少一个步骤。从工艺物料流中结晶或沉淀LNT和/或LNnT可通过向包含LNT和/或LNnT的工艺物料流中加入适量的可与水混溶的有机溶剂来进行。所述有机溶剂可选自C1-C6-醇和C1-C4-碳酸。
在用于纯化LNT和/或LNnT的方法的另外的和/或替代实施方案中，包括步骤无菌过滤和/或内毒素去除，优选通过经由3kDa过滤器或6kDa过滤器过滤工艺物料流来进行。
在另外的和/或替代实施方案中，用于纯化LNT和/或LNnT的方法包括增加工艺物料流中LNT和/或LNnT的浓度的步骤。工艺物料流中LNT和/或LNnT的浓度可通过使所述工艺物料流进行真空蒸发、反渗透或纳滤(例如，使用
的纳滤膜进行纳滤)来增加。或者，将结晶或沉淀的LNT和/或LNnT溶解于水中，以获得具有所需浓度的LNT和/或LNnT的LNT和/或LNnT溶液。
在另外的和/或替代实施方案中，所得的工艺物料流为包含的LNT和/或LNnT的浓度为≥20g/L、≥25g/L、≥30g/L、≥40g/L、≥60g/L、≥100g/L、≥200g/L或甚至≥300g/L的水溶液。
在另外的和/或替代实施方案中，相对于溶液中干物质/溶质的重量，所述水溶液包含纯度为至少80％、至少85％、至少90％、至少93％、至少95％或至少98％的LNT和/或LNnT。
所得的包含纯化的LNT和/或LNnT的浓缩物可在适当的条件下储存。
用于纯化LNT和/或LNnT的方法具有成本效益且易于规模化，使其适合作为多吨级规模制造工艺的基础。
用于纯化LNT和/或LNnT的方法还是有利的，因为水溶液不含基因工程微生物和来源于基因工程微生物的核酸分子。另外，所述水溶液不含蛋白质。蛋白质的全部去除消除了对潜在消费者造成过敏的风险。
用于制造喷雾干燥的粉末的方法包括提供包含LNT和/或LNnT的水溶液的步骤。
在另外的和/或替代实施方案中，所述水溶液包含的LNT和/或LNnT的量为至少20％(w/v)、30％(w/v)、35％(w/v)且最高达45％(w/v)、50％(w/v)、60％(w/v)。
在另外的和/或替代实施方案中，相对于溶液中干物质/溶质的重量，所述水溶液包含纯度为至少80％、至少85％、至少90％、至少93％、至少95％或至少98％的LNT和/或LNnT。
在另外的和/或替代实施方案中，所述水溶液不包含基因工程微生物、来源于基因工程微生物的核酸分子和蛋白质。
在喷雾干燥粉末的制造过程中，将包含LNT和/或LNnT的水溶液进行喷雾干燥。
喷雾干燥是一种获得干粉的方法，其中首先将包含目标物质(即LNT和/或LNnT)的溶液喷雾成液滴，然后通过热空气使其迅速干燥。喷雾干燥非常快，并且待干燥的物质暴露于高温的时间很短。
在另外的和/或替代实施方案中，将包含已从发酵液或工艺物料流中纯化的LNT和/或LNnT的水溶液在至少110℃、优选至少120℃、更优选至少125℃并且小于150℃、优选小于140℃且更优选小于135℃的喷嘴温度下进行喷雾干燥。
在另外的和/或替代实施方案中，将包含已从发酵液或工艺物料流中纯化的LNT和/或LNnT的水溶液在至少60℃、优选至少65℃并且小于80℃、优选小于70℃的出口温度下进行喷雾干燥。在一个特别优选的实施方案中，将包含LNT和/或LNnT的水溶液在约68℃至约70℃的喷嘴温度下喷雾干燥。
应当理解，LNT和LNnT可以分别纯化和喷雾干燥，并且所得的喷雾干燥的粉末可以任何所需比例混合。在另外的和/或替代实施方案中，分别包含LNT或LNnT的单独的水溶液可以任何所需比例混合，并且可将所得的包含所需比例的LNT和LNnT的水溶液进行喷雾干燥。所得的喷雾干燥的粉末中LNT和LNnT的比例对应于水溶液中LNT和LNnT的比例。
包含3-岩藻糖基乳糖的水溶液的喷雾干燥提供低吸湿性(hygroscopy)的粉末，其中所述LNT和/或LNnT以无定形形式存在，并且其中粒度是均匀的。
根据第三个方面，提供包含已从工艺物料流中纯化的LNT和/或LNnT的喷雾干燥的粉末用于制造营养组合物的用途。基本上由LNT和/或LNnT组成的喷雾干燥的粉末适合供人食用，并且因此可包括在供人食用的制剂中，例如药物制剂、婴儿配方物、乳品饮料或膳食补充剂。
根据第四个方面，提供包含根据第二个方面制造的如第一个方面所述的喷雾干燥的粉末的营养组合物。
在另外的和/或替代实施方案中，所述营养组合物包含至少一种非LNT和/或LNnT的其他HMO。至少一种其他HMO可为中性的HMO，其优选选自2′-岩藻糖基乳糖(2′-FL)、3-岩藻糖基乳糖(3-FL)、乳-N-四糖(LNT)、乳-N-新四糖(LNnT)和乳-N-岩藻戊糖I(LNFPI)。在另外的和/或替代实施方案中，所述至少一种其他HMO可为唾液酸化的HMO，其优选选自3′-唾液酸乳糖(3′-SL)、6′-唾液酸乳糖(6-SL)、唾液酸乳糖-N-四糖(LST)-a、LST-b、LST-c和二唾液酸乳糖-N-四糖(DSLNT)。
| 化合物 | 混合物中的比例(重量百分比) | 婴儿配方物中的最终浓度(g/L) |
| 2′-FL | 34 | 2.5 |
| 3-FL | 11 | 0.8 |
| LNT | 20 | 1.5 |
| LNnT | 2 | 0.15 |
| LNFPI | 13 | 1.0 |
| 3′-SL | 3 | 0.2 |
| 6-SL | 4 | 0.3 |
| Neu5Ac | 8 | 0.6 |
| L-岩藻糖 | 5 | 0.4 |
| 总计 | 100 | 7.45 |
表1：包含适合作为婴儿配方物的补充剂的示例性混合物的组成。
在另外的和/或替代实施方案中，所述营养组合物包括基本上由Neu5Ac、2′-FL、3-FL、LNT、LNnT、LNFPI、3′-SL、6′-SL、唾液酸和L-岩藻糖组成的混合物。表1提供了包括优选量的每种所述化合物的营养组合物。
表1中第二列的组合物特别有利于补充婴儿配方物，使得用于直接食用的最终婴儿配方物可包含如表1第三列中所指定浓度的混合物的化合物。
在另外的和/或替代实施方案中，所述营养组合物包含一种或多种其他成分。所述一种或多种其他成分选自油、脂肪和脂肪酸(例如橄榄油、葵花籽油、椰子油、坚果油、菜籽油、棕榈油、亚麻籽油、鱼油、亚麻酸、大豆油等)、碳水化合物(例如葡萄糖、果糖、乳糖、麦芽糖糊精、淀粉、蔗糖、肌醇等)、蛋白质(来自脱脂牛奶、乳清、酪蛋白(源自任何家养的奶畜)或大豆)、维生素(A、B1、B2、B5、B6、B12、C、D、E、K、生物素、叶酸、烟酸、胆碱)、无机物和微量元素(钠、钾、氯、钙、磷、镁、铁、锌、锰、氟、硒、碘、铜)。
在一个优选的实施方案中，包含喷雾干燥的人乳寡糖或人乳寡糖的混合物或人乳寡糖与功能性单糖的混合物或人乳寡糖与其他纤维的混合物的营养组合物是符合法规(EU)16/127和/或美国联邦法规(Code of Federal Regulations)(USA)标题21 107.100(营养规范)中所述的组成要求的婴儿配方物。婴儿配方物的代表性组成在表2和表3中具体指明。
表2：示例性婴儿配方物的组分。
表3：示例性婴儿配方物的组成。最终浓度是基于13.5g粉末于90mL水中的制剂计。
在另外的和/或替代实施方案中，所述营养组合物还包含微生物，优选益生菌微生物。对于婴儿食品应用而言，优选的微生物源自或可见于健康人的微生物组。所述微生物优选但不限于选自双歧杆菌属(Bifidobacterium)、乳杆菌属(Lactobacillus)、肠球菌属(Enterococcus)、链球菌属(Streptococcus)、葡萄球菌属(Staphylococcus)、消化链球菌属(Peptostreptococcus)、明串珠菌属(Leuconostoc)、梭状芽孢杆菌属(Clostridium)、真杆菌属(Eubacterium)、韦荣氏球菌属(Veilonella)、梭杆菌属(Fusobacterium)、厌氧杆菌属(Bacterioides)、普式菌属(Prevotella)、埃希式杆菌属(Escherichia)、丙酸杆菌属(Propionibacterium)和酵母菌属(Saccharomyces)。在另外的和/或替代实施方案中，所述微生物选自青春双歧杆菌(Bifidobacterium adolescentis)、动物双歧杆菌(B.animalis)，两歧双歧杆菌(B.bifidum)、短双歧杆菌(B.breve)、婴儿双歧杆菌(B.infantis)、乳双歧杆菌(B.lactis)、长双歧杆菌(B.longum)；屎肠球菌(Enterococcusfaecium)；大肠杆菌(Escherichia coli)；马克斯克鲁维酵母菌(Klyveromycesmarxianus)；嗜酸乳杆菌(Lactobacillus acidophilus)、保加利亚乳杆菌(L.bulgaricus)、干酪乳杆菌(L.casei)、卷曲乳杆菌(L.crispatus)、发酵乳杆菌(L.fermentum)、格氏乳杆菌(L.gasseri)、瑞士乳杆菌(L.helveticus)、约式乳杆菌(L.johnsonii)、副干酪乳杆菌(L.paracasei)、植物乳杆菌(L.plantarum)、罗伊氏乳杆菌(L.reuteri)、鼠李糖乳杆菌(L.rhamnosus)、唾液酸乳杆菌(L.salivarius)、清酒乳杆菌(L.sakei)；乳酸乳球菌(Lactococcus lactis)(包括但不限于乳酸(lactis)、乳脂(cremoris)和双乙酰(diacetylactis)亚种)；肠膜明串珠菌(Leuconostocmesenteroides)(包括但不限于肠膜亚种)；乳酸片球菌(Pedicoccus acidilactici)、戊糖片球菌(P.pentosaceus)；丙酸丙酸杆菌(Propionibacterium acidipropionici)、费式丙酸杆菌谢式亚种(P.freudenreichii ssp.shermanii)；肉葡萄球菌(Staphylococcuscarnosus)；和嗜热链球菌(Streptococcus thermophilus)。
除了组合活的生物体之外，所述营养组合物还可包括死的细胞培养物。在益生菌领域，有时使用杀死的细胞培养物(例如间歇杀灭的(tyndalized)细菌)。这些杀死的培养物可提供蛋白质、多肽、寡糖、细胞外壁碎片和天然产物，从而产生免疫系统的短期刺激。
营养组合物中包括益生菌微生物，特别是在HMO的存在下，是特别有利的，因为其还促进建立健康的肠道微生物组。
在另外的和/或替代实施方案中，所述营养组合物还包括益生元，例如低聚半乳糖(GOS)、低聚果糖(FOS)、菊粉或其组合。
所述营养组合物以固体形式存在，所述固体形式包括但不限于粉末、颗粒、薄片、微丸或其组合。
在另外的实施方案中，所述营养组合物选自药物制剂、婴儿配方物、乳品饮料和膳食补充剂。
作为药物制剂，所述营养组合物可用于改善认知能力，特别是用于改善注意力、学习和/或记忆力。
将通过具体实施方案并参考附图来描述本发明，但是本发明不限于此，而是仅由权利要求书来限定。此外，说明书和权利要求书中的术语“第一”、“第二”等用于区分相似的元素，而不一定用于描述时间、空间、等级或任何其他方面的顺序。应理解，如此使用的术语在适当的情况下是可互换的，并且本文描述的本发明的实施方案能够以不同于本文描述或说明的其他顺序来操作。
应注意，权利要求书中使用的术语“包括”不应解释为限于其后列出的方式；其不排除其他元素或步骤。因此，应将其解释为具体指明所提及的所述特征、整数、步骤或组件的存在，但并不排除存在或增加一个或多个其他特征、整数、步骤或组件或其组合。因此，表述“包括装置A和B的装置”的范围不应限于仅由组件A和B组成的装置。这意指就本发明而言，所述装置的相关组件仅为A和B。
在整个说明书中，提及“一个(one或a)实施方案”意指关于该实施方案描述的具体特征、结构或特性包括在本发明的至少一个实施方案中。因此，贯穿本说明书在各处出现的短语“在一个实施方案中”并不一定总是指相同的实施方案。此外，在一个或多个实施方案中，具体特征、结构或特性可以以任何合适的方式组合，这对于本领域普通技术人员从本公开内容是显而易见的。
类似地，应理解，在本发明的代表性实施方案的描述中，有时将本发明的各特征在单个实施方案、其附图或描述中组合在一起，以简化公开内容并促进对各个发明方面中的一个或多个的理解。本公开内容的方法不应解释为反映了以下意图：与各权利要求中明确列出的特征相比，所要求保护的发明需要更多的特征。而是，如以下权利要求所反映的，发明方面可需要比任何前文公开的实施方案的所有特征更少的特征。因此，详细说明之后的权利要求在此被明确地纳入该详细说明中，其中各权利要求独立地作为本发明的独立实施方案。
此外，尽管本文所描述的一些实施方案包括一些特征，而不包括其他实施方案中所包括的其他特征，但是不同实施方案的特征的组合意欲落入本发明的范围内，并且形成不同的实施方案，如熟悉本领域的技术人员所理解的那样。例如，在下面的权利要求中，任何要求保护的实施例都可以以任意组合使用。
此外，本文中，一些实施方案被描述为可由计算机系统的处理器或通过执行功能的其他工具来执行的方法或方法的元素的组合。因此，具有用于执行所述方法或方法的元素的必要指令的处理器形成用于执行所述方法或方法的元素的工具。此外，本文描述的设备实施方案的元件为用于执行这样的功能的工具的示例，所述功能由用于实现本发明的目的的元件执行。
在本文提供的描述和附图中，阐述了许多具体细节。然而，应理解，可在没有这些具体细节的情况下实践本发明的实施方案。在其他情况下，未详细示出众所周知的方法、结构和技术，以促进对说明书和附图的理解。
现将通过对本发明的几个实施方案的详细描述来描述本发明。显然，在不脱离本发明的真实精神或技术优点的情况下，可根据本领域技术人员的知识来设置本发明的其他实施方案，本发明仅由所附各项权利要求来限制。
实施例1：从发酵液中纯化2′-岩藻糖基乳糖
通过使用遗传修饰的大肠杆菌菌株(E.coli strain)发酵来进行2′-岩藻糖基乳糖的制备，如欧洲专利申请16196486.1中所记载。通过过滤、离子交换色谱、纳滤、渗滤或电渗析，并用炭处理来从发酵液中纯化2′-岩藻糖基乳糖，如WO 2015/106943 A1中所记载。将所得的包含2′-岩藻糖基乳糖的溶液进行喷雾干燥以得到稳定的固体产物。
实施例2：从发酵液中纯化3-岩藻糖基乳糖
通过使用遗传修饰的大肠杆菌菌株发酵来制备3-岩藻糖基乳糖，如欧洲专利申请16 196 486.1中所记载。
通过超滤(截留值为0.05μm)(CUT膜技术，Erkrath，Germany)然后通过MWCO为150kDa的错流过滤器(Microdyn-Nadir，Wiesbaden，Germany)将细胞从培养基中分离。使包含约30g/L 3-岩藻糖基乳糖的无细胞发酵培养基穿过H+形式的强阳离子交换剂(LewatitS 2568(Lanxess，Cologne，Germany))以除去带正电的污染物。然后用氢氧化钠将溶液调节至pH 7.0，并以氯化物形式施用到阴离子交换剂(Lewatit S6368 A，Lanxess)上。两种离子交换剂均以200L体积使用。在第二次过滤(150kDa；Microdyn-Nadir，Wiesbaden，Germany)之后，使用Filmtech NF270膜(Dow，Midland，USA)通过纳滤将无颗粒溶液浓缩5倍，并通过真空蒸发将其浓缩2.5倍。将浓缩溶液过滤且电导率为约15mS cm-1(10kDa；Microdyn-Nadir，Wiesbaden，Germany)，通过活性炭(CAS：7440-44-0，Carl Roth，Karlsruhe，Germany)澄清，并通过电渗析去离子。因此，使用带有PC-Cell E200膜堆的PC-Cell BED 1-3电渗析装置(PC-Cell，Heusweiler，Germany)，其包含以下膜：阳离子交换膜CEM：PC SK和阴离子膜AEM：PCAcid60。在该过程中使用0.25M氨基磺酸作为电解质。为了减少由美拉德反应引起的棕褐色和源自发酵过程的醛醇缩合产物，使用与上述Na+和Cl-形式相同的离子交换材料进行第二轮离子交换色谱，但是体积为50L。通过蒸发浓缩糖溶液后，再次使用前述的PC-Cell BED 1-3通过电渗析将电导率从4mS cm-1降低至0.4mS cm-1或更小。为了进一步脱色，将溶液与活性炭(CAS：7440-44-0，Carl Roth，Karlsruhe，Germany)混合，并通过过滤得到几乎无色的溶液。
实施例3：从发酵液中纯化乳-N-四糖
乳-N-四糖的发酵制备使用遗传修饰的大肠杆菌BL21(DE3)ΔlacZ菌株进行，其中基因组整合的基因对于体内合成乳-N-四糖至关重要，即，N-乙酰氨基葡萄糖糖基转移酶(N-acetylglucosamine glycosyltransferase)(来自脑膜炎双球菌(Neisseriameningitidis)MC58的lgtA)、β-1，3-半乳糖基转移酶(来自肠道沙门氏菌萨拉姆亚种(Salmonella enterica subsp.salamae)血清变型Greenside的wbdO)、来自大肠杆菌K12的lacY、均来自大肠杆菌K12的UDP-葡萄糖-4-差向异构酶galE和UTP-葡萄糖-1-磷酸尿苷酰转移酶galU。另外，编码氨基葡萄糖-6-磷酸合酶的galS基因超表达。为了发酵制备乳-N-四糖，所述菌株在包含2％葡萄糖作为碳源的特定无机盐培养基中生长。必要时添加消泡剂。使用25％氨溶液控制pH。逐步添加乳糖使216g/L乳糖原料至最终浓度为15mM，除发酵过程外，培养基中的乳糖浓度保持恒定。在过程中作为副产物累积的残留乳糖和乳-N-四糖II被添加到发酵罐中的第二大肠杆菌水解。该菌株表达了功能性β-内酰胺酶、β-N-乙酰基己糖胺酶(来自两歧双歧杆菌JCM1254的bbhl)和用于降解单糖的功能性半乳糖操纵子(gal-operon)(EP 2 845 905 A)。
将细胞从发酵液中分离，并根据实施例2中所述的步骤，将包含乳-N-四糖的流体纯化至纯度为75-80％，通过质量平衡确定。
根据WO 2015/049331，使用模拟移动床(SMB)色谱通过色谱法除去因低效的酶促降解和代谢而产生的污染性碳水化合物副产物。或者，通过用异丙醇结晶来纯化乳-N-四糖。为了结晶，将包含乳-N-四糖的溶液通过蒸发浓缩至浓度为20％并进行喷雾干燥。使用NUBILOSALTC-GMP喷雾干燥器(NUBILOSA，Konstanz，Germany)，使溶液在氮气流下通过入口温度为130℃的喷雾干燥器喷嘴，同时控制产物流量以保持出口温度为67℃至68℃。
将固体材料以1kg粉末于12L异丙醇/水中的比例加入到异丙醇和水(3∶1(体积/体积))的混合物中。将悬浮液剧烈搅拌，然后将不溶的乳-N-四糖过滤并在40℃下干燥。以73-89％纯的材料开始，将结晶的乳-N-四糖纯化至约95％，其回收率为85％。将糖溶解于水中至浓度为25％，然后依次通过6kDa过滤器(Pall Microza超滤模块SIP-2013，PallCorporation，Dreieich，Germany)和0.2μm无菌过滤器。通过在上述条件下喷雾干燥无菌材料而获得固体材料。
实施例4：从发酵液中纯化3′-唾液酸乳糖和6′-唾液酸乳糖
为了制备3′-唾液酸乳糖和6′-唾液酸乳糖，使用重组大肠杆菌BL21(DE3)ΔlacZ菌株。所述菌株具有共有的遗传修饰：来自大肠杆菌的氨基葡萄糖-6-磷酸合酶GlmS的染色体组成型表达；来自集胞藻属(Synechocystis sp.)的N-乙酰氨基葡萄糖2-差向异构酶Slr1975的染色体组成型表达；来自酿酒酵母(Saccharomyces cerevisiae)的氨基葡萄糖6-磷酸N-乙酰基转移酶Gna1的染色体组成型表达；来自大肠杆菌的磷酸烯醇丙酮酸合酶PpsA的染色体组成型表达；均来自空肠弯曲杆菌(Campylobacter jejuni)的N-乙酰神经氨酸合酶(N-acetylneuraminatesynthase)NeuB和CMP-唾液酸合酶NeuA的染色体组成型表达。此外，将以下基因整合到BL21菌株的基因组中并组成性地表达：编码来自大肠杆菌的乳糖通透酶LacY的基因；编码来自大肠杆菌W的cscB(蔗糖通透酶)、cscK(果糖激酶)、cscA(蔗糖水解酶)和cscR(转录调控因子)的基因；以及功能性半乳糖操纵子，所述功能性半乳糖操纵子由来自大肠杆菌K12的基因galE(UDP-葡萄糖-4-差向异构酶)、galT(半乳糖-1-磷酸尿苷酰转移酶)、galK(半乳糖激酶)和galM(半乳糖-1-差向异构酶)组成。
合成3′-唾液酸乳糖的菌株携带来自弧菌属(Vibrio sp.)JT-FAJ-16的a-2，3-唾液酸转移酶基因，而产生6′-唾液酸乳糖的菌株包含来自鳆发光杆菌(Photobacteriumleiognathi)JT-SHIZ-119的α-2，6-唾液酸转移酶plsT6。
产生唾液酸乳糖的菌株在包含2％蔗糖作为碳源的特定无机盐培养基中生长。在分批补料阶段进给的蔗糖进料(500g/L)中补充有8mM MgSO4、0.1mM CaCl2、微量元素和5g/LNH4Cl。
为了形成唾液酸乳糖，使用216g/L的乳糖进料。通过使用氨溶液(25％v/v)控制pH。在恒定通气和搅拌下，在30℃下进行分批补料发酵。为了在发酵结束时除去残留的乳糖，向发酵罐中加入β-半乳糖苷酶。所得的单糖被生产菌株代谢。
然后通过离子交换色谱将无细胞液体去离子。首先，将阳离子污染物在H+形式的体积为200L的强阳离子交换剂(Lewatit S 2568(Lanxess，Cologne，Germany))上去除。使用NaOH将所得溶液的pH设为7.0。在第二步中，使用氯化物形式的强阴离子交换剂LewatitS 6368 S(Lanxess，Cologne，Germany)将阴离子和不希望的着色剂从溶液中去除。所述离子交换剂具有200L的床体积。在错流过滤器(截留值为150kDa)(Microdyn-Nadir，Wiesbaden，Germany)上采用第二过滤步骤，将源自酸化溶液的沉淀物去除。为了浓缩糖，将溶液在Dow FILMTECH NF270-4040(Inaqua，
Germany)上或者在Trisep 4040-XN45-TSF膜(截留值为0.5kDa)(Microdyn-Nadir，Wiesbaden，Germany)上进行纳滤。使用Trisep 4040-XN45-TSF膜，将源自发酵过程并且污染唾液酸乳糖溶液的单糖N-乙酰氨基葡萄糖从产物中分离。然后使用活性炭(CAS：7440-44-0，Carl Roth，Karlsruhe，Germany)处理浓缩的唾液酸乳糖溶液以除去着色剂，例如美拉德反应产物和醛醇缩合反应产物。为了将唾液酸乳糖从源自发酵过程的副产物(如唾液酸和N-乙酰氨基葡萄糖)中分离，将所述溶液用截留值为1kDa的膜GE4040F30(GE water&processtechnologies，Ratingen，Germany)过滤，并渗滤至电导率为0.6至0.8mS cm-1。将稀释的溶液在旋转蒸发仪上浓缩至浓度为约300g/L。在最终的色谱分离中，除去了其他污染性糖，如二唾液酸乳糖。因此，将浓缩的溶液施加到乙酸盐形式的弱阴离子交换树脂(AmberliteFPA51，Dow Chemical，Michigan，USA)上。虽然唾液酸乳糖几乎不与树脂结合，但二唾液酸乳糖被吸附。因此，唾液酸乳糖用10mM乙酸铵洗脱，而二唾液酸乳糖用1M乙酸铵洗脱。为了除去乙酸铵，用10倍过量的乙醇沉淀唾液酸乳糖。将固体级分过滤并干燥。
通过使20％的唾液酸乳糖溶液依次通过6kDa过滤器(Pall Microza超滤模块SIP-2013，Pall Corporation，Dreieich，Germany)和0.2μm无菌过滤器来最终化产物。
使用Büchi喷雾干燥器(Büchi Mini Spray Dryer B-290)(Biichi，Essen，Germany)将一部分溶液进行喷雾干燥，采用以下参数：入口温度：130℃，出口温度67℃-71℃，气流670L/h，吸气器100％。
喷雾干燥的6′-唾液酸乳糖具有的纯度为91％，而3′-唾液酸乳糖材料具有的纯度为93％。
实施例5：HMO混合物的制备
由固体产物制备HMO的混合物。因此，将单个HMO进行喷雾干燥并混合粉末。HMO-混合物I包含比例为70％至30％的2′-岩藻糖基乳糖和乳-N-四糖；HMO-混合物II包含2′-岩藻糖基乳糖(52％)、3-岩藻糖基乳糖(13％)、乳-N-四糖(26％)、3′-唾液酸乳糖(4％)和6′-唾液酸乳糖(5％)。将混合粉末溶解于水中以得到20％糖的溶液，并使用如实施例4中所述的Biichi喷雾干燥器再次进行喷雾干燥。
实施例6：喷雾干燥的人乳寡糖的表征
6.1差示扫描量热法(DSC)
采用差示扫描量热法(DSC)在Mettler Toledo 821e(Mettler Toledo，Giessen，Germany)上分别测定以下物质的热事件(thermal event)：喷雾干燥的人乳寡糖(即3-岩藻糖基乳糖、6′-唾液酸乳糖、3′-唾液酸乳糖、乳-N-四糖)；和喷雾干燥的人乳寡糖的混合物；2′-岩藻糖基乳糖/乳-N-四糖的混合物(HMO-混合物I)；以及2′-岩藻糖基乳糖、3-岩藻糖基乳糖、乳-N-四糖、6′-唾液酸乳糖、3′-唾液酸乳糖的混合物(HMO混合物II)。
Mettler Toledo 821e(Mettler Toledo，Giessen，Germany)用于测定喷雾干燥的产物的热事件(玻璃化转变温度(Tg)、其他放热和吸热事件)。
在卷曲的铝坩埚(Mettler Toledo，Giessen，Germany)中分析约25mg喷雾干燥的人乳寡糖。将样品以10K/min的速率冷却至0℃并以10K/min的扫描速率重新加热至100℃。在第二个加热周期中将样品冷却至0℃之后，将样品重新加热至150℃。在加热扫描期间基线的吸热位移的中点被视为玻璃化转变温度(Tg)。通过峰值温度和事件的归一化能量记录放热峰和吸热峰。
正如在约48-58℃范围内的一个主要阶梯转变(step transition)所证明的，所有样品的第一次加热扫描都显示出总热流量(heat flow)中一个主要玻璃化转变事件，在大多数样品中，在第一次加热扫描中观察到的主要玻璃化转变事件在第二次加热扫描中再次发生。DSC分析的结果总结于表4中。
| 样品 | 第1次加热扫描 | 第2次加热扫描 |
| Tg[℃] | Tg[℃] | |
| 3-岩藻糖基乳糖 | 57.6 | 59.9 |
| 乳-N-四糖 | 49.9 | 79.4 |
| 6′-唾液酸乳糖 | 47.6 | 49.6 |
| 3′-唾液酸乳糖 | 48.8 | 54.3 |
| 2′-岩藻糖基乳糖/乳-N-四糖 | 56.3 | 59 |
| HMO混合物 | 54.2 | 55.6 |
表4：通过差示扫描量热法测定的HMO的热事件
对于3-岩藻糖基乳糖，在第一次加热扫描中在Tg之后检测到一个吸热弛豫峰。对于乳-N-四糖，在第二次加热扫描中，检测到比其他样品的Tg高得多的Tg，其为约79℃。这可能是由在第一次加热扫描期间在约89℃(-6.04J/g)下的吸热事件引起的。类似于3-岩藻糖基乳糖，对于6′-唾液酸乳糖，在Tg之后也检测到一个吸热弛豫峰，但是，在该样品中，另外在77℃(-0.22J/g)处出现吸热事件。没有检测到3′-唾液酸乳糖和HMO-混合物I的吸热事件，而对于HMO-混合物II，在第一次加热扫描期间的吸热事件在79℃(0.34J/g)处。
6.2X-射线粉末衍射(XRD)
广角X-射线粉末衍射(XRD)用于研究冻干产物的形态。使用装备有铜阳极(45kV，40mA，在波长0.154nm处的Kα1发射)和PIXcel3D检测器的X射线衍射仪Empyrean(Panalytical，Almelo，The Netherlands)。将约100mg喷雾干燥的样品在反射模式下在5-45°2θ的角度范围内进行分析，其中步长为0.04°2θ且计数时间为每步100秒。
所有单一的寡糖以及HMO混合物I和II都显示出完全无定形状态(图1至6)。对于乳-N-四糖，在9-10°附近检测到第二个(无定形)信号。
6.3激光衍射
粉末粒度通过激光衍射进行评估。该系统通过同心排列的传感器元件阵列检测散射和衍射的光。然后，软件算法通过计算到达不同的传感器元件的光强度值的z值来近似粒子计数。使用SALD-7500集料粒度仪(Shimadzu Corporation，Kyoto，Japan)定量激光衍射系统(qLD)进行分析。
将少量(刮刀尖端)的各个样品分散于2mL异辛烷中，并通过超声均质化5分钟。将分散体转移到装满异辛烷的间歇式电解槽中，并以手动模式进行分析。
数据采集设置如下：每次测量的信号平均计数：128，信号累积计数：3，以及间隔：2秒。
在测量之前，将系统用异辛烷空白。将每个样品分散体测量3次，并记录平均值和标准偏差。使用软件WING SALD II版本V3.1评估数据。由于样品的折射率是未知的，因此使用糖(二糖)颗粒的折射率(1.530)来测定粒度分布曲线。记录平均直径和中值直径的粒度值。
所有样品的平均粒度非常相似，HMO-混合物II的测量值略低。粒度特征总结于表5中。另外，粒度分布显示了所有样品均存在一个主要粒度组。
表5：通过激光衍射测定的HMO的粒度。
Claims (16)
1.一种喷雾干燥的粉末，其基本上由已通过微生物发酵制备的LNT和/或LNnT组成。
2.根据权利要求1所述的喷雾干燥的粉末，其中所述喷雾干燥的粉末包含至少80重量％、至少85重量％、至少90重量％、至少93重量％、至少95重量％或至少98重量％的LNT和/或LNnT。
3.根据权利要求1或2所述的喷雾干燥的粉末，其中所述LNT和/或LNnT以无定形形式存在。
4.根据权利要求1至3中任一项所述的喷雾干燥的粉末，其中所述喷雾干燥的粉末包含≤15重量％的水、优选≤10重量％的水、更优选≤7重量％的水、最优选≤5重量％的水。
5.根据权利要求1至4中任一项所述的喷雾干燥的粉末，其中所述喷雾干燥的粉末不含基因工程微生物和来源于基因工程微生物的核酸分子。
6.一种用于制造如权利要求1至5中任一项所定义的喷雾干燥的粉末的方法，所述方法包括以下步骤：
a)从发酵液中纯化LNT和/或LNnT；
b)提供包含步骤a)的LNT和/或LNnT的水溶液；和
c)将步骤b)的溶液进行喷雾干燥。
7.根据权利要求6所述的方法，其中从发酵液中纯化LNT和/或LNnT的步骤(步骤a))包括以下的一个或多个步骤：
i)将微生物细胞从发酵液中除去，以获得澄清的工艺物料流；
ii)使澄清的工艺物料流进行至少一次超滤；
iii)使用阳离子交换树脂处理澄清的工艺物料流至少一次和/或使用阴离子交换树脂处理澄清的工艺物料流至少一次；
iv)使澄清的工艺物料流进行至少一次纳滤和/或渗滤；
v)使澄清的工艺物料流进行至少一次电渗析；
vi)使用活性炭处理澄清的工艺物料流至少一次；和/或
vii)使澄清的工艺物料流进行至少一次结晶和/或沉淀步骤。
8.根据权利要求6或7所述的方法，其中所述水溶液包含的LNT和/或LNnT的量为至少20％(w/v)、30％(w/v)、35％(w/v)且最高达45％(w/v)、50％(w/v)、60％(w/v)。
9.根据权利要求6至8中任一项所述的方法，其中将包含LNT和/或LNnT的水溶液在至少110℃、优选至少120℃、更优选至少125℃并且小于150℃、优选小于140℃且更优选小于135℃的喷嘴温度下进行喷雾干燥。
10.根据权利要求6至9中任一项所述的方法，其中将包含LNT和/或LNnT的水溶液在至少60℃、优选至少65℃并且小于80℃、优选小于70℃的出口温度下进行喷雾干燥。
11.根据权利要求1至5中任一项所述的喷雾干燥的粉末用于制造营养组合物、优选婴儿配方物的用途。
12.一种营养组合物，其包含根据权利要求1至5中任一项所述的喷雾干燥的粉末。
13.根据权利要求12所述的营养组合物，其还包含至少一种其他HMO，其中所述至少一种其他HMO为中性的HMO或唾液酸化的HMO。
14.根据权利要求12或13所述的营养组合物，其中所述至少一种中性的HMO选自2′-岩藻糖基乳糖、3-岩藻糖基乳糖、乳-N-四糖、乳-N-新四糖和乳-N-岩藻五糖I。
15.根据权利要求12至14中任一项所述的营养组合物，其中所述至少一种唾液酸化的HMO选自3′-唾液酸乳糖、6′-唾液酸乳糖、唾液酸乳糖-N-四糖(LST)-a、LST-b、LST-c和二唾液酸乳糖-N-四糖。
16.根据权利要求12至15中任一项所述的营养组合物，其中所述营养组合物包含至少一种益生菌微生物。
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| EP17206159.0 | 2017-12-08 | ||
| EP17206223.4 | 2017-12-08 | ||
| EP17206159.0A EP3494805A1 (en) | 2017-12-08 | 2017-12-08 | Spray-dried tetrasaccharides |
| EP17206124.4 | 2017-12-08 | ||
| EP17206124.4A EP3494804A1 (en) | 2017-12-08 | 2017-12-08 | Spray-dried 3-fucosyllactose |
| EP17206414.9A EP3494807A1 (en) | 2017-12-11 | 2017-12-11 | Spray-dried sialyllactose |
| EP17206414.9 | 2017-12-11 | ||
| EP18155669.7A EP3524067A1 (en) | 2018-02-08 | 2018-02-08 | Spray-dried mixture of human milk oligosaccharides |
| EP18155669.7 | 2018-02-08 | ||
| PCT/EP2018/083974 WO2019110804A1 (en) | 2017-12-08 | 2018-12-07 | Spray-dried tetrasaccharides |
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| GB2623899B (en) * | 2019-12-11 | 2024-08-07 | Mjn Us Holdings Llc | Staged nutritional compositions containing human milk oligosaccharides and uses thereof |
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