CN111465331A - 喷雾干燥的3-岩藻糖基乳糖 - Google Patents
喷雾干燥的3-岩藻糖基乳糖 Download PDFInfo
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- CN111465331A CN111465331A CN201880079310.3A CN201880079310A CN111465331A CN 111465331 A CN111465331 A CN 111465331A CN 201880079310 A CN201880079310 A CN 201880079310A CN 111465331 A CN111465331 A CN 111465331A
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- fucosyllactose
- spray
- dried powder
- hmo
- nutritional composition
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Abstract
本发明公开了一种用于制备基本上由3‑岩藻糖基乳糖组成的喷雾干燥粉末的方法、所述喷雾干燥粉末、其用于制备营养组合物的用途以及包含所述喷雾干燥粉末的营养组合物。
Description
本发明涉及人乳低聚糖的制品。更具体地,本发明涉及人乳低聚糖的固体制品并且涉及制备所述人乳低聚糖的固体制品的方法。
背景技术
人类母乳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。除乳糖外,1升人类母乳还含有多达20g/L低聚糖,即所谓的“人乳低聚糖(HMO)”。HMO代表了人类母乳的排第三的最丰富的成分。据推测,人乳中存在超过150种结构上不同的低聚糖。人乳通常包含10至13种主要HMO,其以每升数克至几百毫克的浓度存在(Thurl et al.,(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。表1中显示了最重要的HMO。这些低聚糖的结构复杂性和丰富度是人乳特有的,在其他哺乳动物(例如,驯化的乳业动物)的乳中尚未发现。
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。HMO的益生元效应已在一百多年前被发现。HMO能够通过喂食有益细菌来调节人体肠道微生物组。近年来,对HMO的其他几种功能性作用进行了研究,尤其是它们对新生儿发育的作用。已知HMO充当诱饵,以减少被细菌和病毒病原体感染的风险,细菌和病毒病原体通过与细胞表面糖蛋白结合而粘附于人类细胞。另外,各种HMO具有抗炎作用并充当免疫调节剂。因此,提出HMO降低了发展食物过敏的风险。唾液酸化的HMO对新生儿脑发育的积极作用得到了广泛的讨论(在“Prebiotics and Probiotics in Human Milk,Origins and functions ofmilk-borne oligosaccharides and bacteria”,Academic Press(2017)editors:McGuireM.,McGuire M.,and Bode L中进行了综述)。
一种HMO是3-岩藻糖基乳糖(Gal(β1-4)[Fuc(β1-3)]Glc)。1958年首次从乳中分离出3-岩藻糖基乳糖(3-FL),并于1977年首次从O型血、非分泌型、妊娠期和哺乳期的女性的尿液中分离出3-岩藻糖基乳糖(3-FL)。3-岩藻糖基乳糖可抵抗婴儿胃肠道中的酶水解。推测3-岩藻糖基乳糖到达大肠,在大肠中被细菌内化和代谢。
利用HMO对奶瓶喂养的婴儿的有益效果的第一步是向婴儿配方物中添加各个HMO。但是,给婴儿配方物补充包含结构上不同的HMO的组合会更好,因为结构上不同的HMO的组合所产生的作用与其原始来源(人乳)的作用更相似,并且不能由各个HMO产生。
用于补充婴儿配方物的各个HMO的有限供应,首先导致了HMO的化学合成的发展,其次是使用纯化酶的生物催化方法。如今,遗传工程化细菌细胞的发酵被用于产生商业规模的不同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可以从发酵液或细胞裂解物中纯化,以获得基本上纯的HMO制品,使得它们可以用于人类食品(特别是婴儿食品)中。
在其纯化期间,3-岩藻糖基乳糖通常以液体工艺流(process stream)的形式存在。随着纯化,工艺流中的3-岩藻糖基乳糖的浓度增加。但是,3-岩藻糖基乳糖的水溶液非常容易受到细菌或真菌的污染。因此,优选提供水含量低的干燥产物形式的3-岩藻糖基乳糖,使得微生物不可能生长。
通常,通过结晶获得固体形式的糖。已经记载了各个HMO的结晶:3-岩藻糖基乳糖(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(WO 2014/094783 A)。HMO的结晶涉及使用有机溶剂,例如醇(主要是乙醇或甲醇),或有机酸(例如冰醋酸)。但是,如果将HMO用作食品成分,则不适合将使用有机溶剂来结晶HMO作为获得固体形式最终产物的方法的最后一步。另外,有机溶剂对环境和对任何操作它们的个人都是有害的。因此,有机溶剂的使用需要职业安全措施和适当处理,这使得使用有机溶剂的成本很高。因此,在工业规模的HMO生产中,必须认为结晶HMO以提供固体形式的HMO是不利的。
因此,需要提供固体形式的HMO(尤其是3-岩藻糖基乳糖)的方法,其可用于HMO的工业规模生产,并且在纯化方案结束时不涉及使用有机溶剂来提供所述HMO的固体制品。
通过用于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HMO的水溶液喷雾干燥。
发明内容
在第一方面,提供了基本上由3-岩藻糖基乳糖组成的喷雾干燥粉末,提供了方法。
在第二方面,提供了用于制备基本上由3-岩藻糖基乳糖组成的喷雾干燥粉末的方法。
在第三方面,提供了基本上由3-岩藻糖基乳糖组成的喷雾干燥粉末用于制备营养组合物的用途。
在第四方面,提供了包含基本上由3-岩藻糖基乳糖组成的喷雾干燥粉末的营养组合物。
附图说明
图1示出了举例说明喷雾干燥的3-岩藻糖基乳糖的X射线粉末衍射结果的图。
图2示出了举例说明喷雾干燥的乳-N-四糖的X射线粉末衍射结果的图。
图3示出了举例说明喷雾干燥的6’-唾液酸乳糖的X射线粉末衍射结果的图。
图4示出了举例说明喷雾干燥的3’-唾液酸乳糖的X射线粉末衍射结果的图。
图5示出了举例说明2'-岩藻糖基乳糖和乳-N-四糖的喷雾干燥混合物的X射线粉末衍射结果的图。
图6示出了举例说明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'-唾液酸乳糖的喷雾干燥混合物的X射线粉末衍射结果的图。
具体实施方式
根据第一方面,提供了基本上由通过微生物发酵产生的3-岩藻糖基乳糖组成的喷雾干燥粉末。
如本文所述,3-岩藻糖基乳糖是通过微生物发酵产生的。如本文所用,术语“基本上由...组成”是指喷雾干燥粉末由3-岩藻糖基乳糖和-任选地-副产物组成,所述副产物是在用于生产3-岩藻糖基乳糖的微生物发酵过程中产生,但是可以尚未从微生物发酵获得的工艺流中去除。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3-岩藻糖基乳糖组成的喷雾干燥粉末。
在额外的和/或替代的实施方案中,3-岩藻糖基乳糖是以无定形形式存在于喷雾干燥粉末中。
在额外的和/或替代的实施方案中,喷雾干燥粉末包含≤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。
在额外的和/或替代的实施方案中,喷雾干燥粉末不含遗传工程化微生物和源自遗传工程化微生物的核酸分子。
根据第二方面,提供了用于制备基本上由通过微生物发酵产生的3-岩藻糖基乳糖组成的喷雾干燥粉末的方法。该方法包括以下步骤:
a)从发酵液中纯化3-岩藻糖基乳糖;
b)提供含有步骤a)的3-岩藻糖基乳糖的水溶液;和
c)对步骤b)的溶液进行喷雾干燥。
在额外的和/或替代的实施方案中,从发酵液中纯化3-岩藻糖基乳糖包括以下步骤中的一步或多步:
i)从发酵液中去除微生物细胞,以获得澄清的工艺流;
ii)对澄清的工艺流进行至少一次超滤;
iii)将澄清的工艺流用阳离子交换树脂处理至少一次和/或用阴离子交换树脂处理至少一次;
iv)对澄清的工艺流进行至少一次纳滤(nanofiltration);
v)对澄清的工艺流进行至少一次电渗析;
vi)将澄清的工艺流用活性炭处理至少一次;和/或
vii)对澄清的工艺流进行至少一次结晶和/或沉淀步骤。
可以通过微生物发酵来产生3-岩藻糖基乳糖,其中将能够合成3-岩藻糖基乳糖的遗传工程化微生物在培养基(发酵液)中并且在允许通过所述遗传工程化微生物合成3-岩藻糖基乳糖的条件下进行培养。由微生物发酵产生的3-岩藻糖基乳糖的纯化包括从发酵液中分离微生物细胞以获得澄清的工艺流的步骤,该澄清的工艺流基本上不含细胞且含有3-岩藻糖基乳糖。此步骤是纯化所需低聚糖的方法中的第一步。
从发酵液中分离微生物细胞的合适方法包括离心,其中获得的微生物细胞为沉淀且发酵液为上清液。在额外的和/或替代的实施方案中,通过过滤将微生物细胞从发酵液中分离出来。用于从发酵液中分离细胞的合适过滤方法包括微滤和超滤。
这样的微滤是一种物理过滤方法,其中使含颗粒的流体通过具有特殊的孔径大小的膜以将颗粒从流体中分离出来。如本文所用,术语“微滤”是指将细胞从发酵液中分离出来的物理过滤方法。
超滤是膜过滤的一种变型且没有根本的不同。在超滤中,诸如压力或浓度梯度之类的力导致通过半透膜的分离。细胞、悬浮的固体和高分子量的溶质被保留在所谓渗余物中,而水和低分子量的溶质(如所需的唾液酸化低聚糖)则通过膜进入渗透液(滤液)中。
超滤膜由所使用的膜的分子量截留值(MWCO)限定。超滤以错流或死端模式应用。
通常,微生物细胞在细胞内合成3-岩藻糖基乳糖,并将其分泌到发酵液中。如此产生的3-岩藻糖基乳糖最后在发酵液中,然后如下文所述,对其进行进一步的工艺步骤以纯化3-岩藻糖基乳糖。
尽管该方法被用于纯化通过微生物发酵产生的3-岩藻糖基乳糖,但是所述方法也可以用于纯化通过体外酶催化产生的3-岩藻糖基乳糖。可以在生物催化反应结束时从反应混合物中纯化3-岩藻糖基乳糖。所述反应混合物作为澄清的工艺流进行纯化处理。
澄清的工艺流含有3-岩藻糖基乳糖以及副产物和不需要的杂质,例如单糖、二糖、不需要的低聚糖副产物、离子、氨基酸、多肽、蛋白质和/或核酸。
在额外的和/或替代的实施方案中,3-岩藻糖基乳糖的纯化方法包括至少一次阳离子交换处理的步骤,以从澄清的工艺流中去除荷正电的化合物。
用于去除荷正电的化合物的合适的阳离子交换树脂包括Lewatit S2568(H+)(Lanxess AG,Cologne,DE)。
在额外的和/或替代的实施方案中,3-岩藻糖基乳糖的纯化方法包括阴离子交换处理的步骤,以从澄清的工艺流中去除不期望的荷负电的化合物。
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 1×2(200-400目)、Dowex 1×8(100-200目)、Purolite Chromalite CGA100×4(Purolite GmbH,Ratingen,DE)、DowAmberlite FPA51(Dow Chemicals,Ml,USA)。
在其他/或替代实施方案中,纯化3-岩藻糖基乳糖的方法包括纳滤和/或渗滤步骤,以去除具有较低分子量的杂质,并浓缩所需的低聚糖。
渗滤包括向溶液中添加淡水,以去除(洗出)膜可渗透的组分。渗滤可用于通过使用合适的膜基于组分的分子大小和电荷来分离组分,其中一种或多种物质被有效地保留,而其他物质是膜可渗透的。特别地,使用纳滤膜的渗滤可有效分离低分子量化合物(如小分子)和盐。纳滤膜的分子量截留值通常为150-1000道尔顿。纳滤在乳品行业中广泛用于乳清的浓缩和脱矿质。
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)。
已经发现,使用纳滤膜进行的渗滤可有效地作为预处理,以在对含有低聚糖的溶液进行电渗析处理之前去除大量污染物。在纯化HMO的过程中,使用纳滤膜进行浓缩和渗滤可实现较低的能源和加工成本,以及更好的产物质量(由于热暴露减少),导致美拉德反应和羟醛反应减少。
在额外的和/或替代的实施方案中,用于纯化3-岩藻糖基乳糖的方法包括至少一次电渗析步骤。
电渗析(ED)结合了渗析和电解,并可用于基于离子通过半透膜的选择性电迁移而分离或浓缩溶液中的离子。
电渗析的基本原理是由一个电解池组成,该电解池包括一对浸没在电解液中用于传导离子的电极,该电极与直流发生器相连。连接到直流发电机的正极的电极是阳极,连接到负极的电极是阴极。然后电解液支持电流流动,该电流是由于负离子和正离子分别朝着阳极和阴极移动而产生的。用于电渗析的膜基本上是具有负或正电荷基团的多孔离子交换树脂片,因此分别描述为阳离子膜或阴离子膜。离子交换膜通常是由带有与二乙烯基苯交联的合适的官能团(例如用于阳离子膜的磺酸或用于阴离子膜的季铵基)的聚苯乙烯组成。电解液可以是例如氯化钠、乙酸钠、丙酸钠和/或氨基磺酸。然后以如下方式组装电渗析堆(stack):使阴离子膜和阳离子膜平行,如同在压滤机中的两个电极块之间一样,以使进行离子耗竭的料流与进行离子富集的料流充分分离(两种溶液也称为稀释液(进行离子耗竭)和浓缩液(进行离子富集))。电渗析过程的核心是膜堆,其由安装在两个电极之间的由垫片(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,阴离子和阳离子将跨膜向电极迁移。
在额外的和/或替代的实施方案中,纯化3-岩藻糖基乳糖的方法还包括连续色谱法的步骤,例如模拟移动床(SMB)色谱法。
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色谱已经用于从果糖-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方法使用例如含钙、交联的聚苯乙烯树脂,亚硫酸氢盐形式的阴离子树脂(Bechthold M et al.,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,Bala Cynwyd,USA)。
考虑到连续的操作模式、流动相的回收再用以及使用大型柱的潜力,SMB系统原则上可以放大(scale)以实现数百吨的生产量。
模拟移动床色谱法的方法步骤的优点在于该方法步骤允许进一步去除与所需低聚糖在结构上密切相关的低聚糖。
在额外的和/或替代的实施方案中,用于纯化3-岩藻糖基乳糖的方法包括用活性炭处理工艺流以从工艺流中去除污染物质,例如色素。
在额外的和/或替代的实施方案中,用于纯化3-岩藻糖基乳糖的方法包括至少一个从澄清的工艺流中结晶或沉淀3-岩藻糖基乳糖的步骤。从澄清的工艺流中结晶或沉淀3-岩藻糖基乳糖可通过将适量的与水混溶的有机溶剂添加到含有3-岩藻糖基乳糖的工艺流中来实现。有机溶剂可以选自C1-至C6-醇和C1-至C4-碳酸。
在用于纯化3-岩藻糖基乳糖的方法的额外的和/或替代的实施方案中,包括无菌过滤和/或内毒素去除的步骤,优选地通过使工艺流过滤通过3kDa过滤器或6kDa过滤器。
在额外的和/或替代的实施方案中,用于纯化3-岩藻糖基乳糖的方法包括增加工艺流中3-岩藻糖基乳糖的浓度的步骤。可通过对工艺流进行真空蒸发、反渗透或纳滤(例如,具有尺寸排阻极限的纳滤膜的纳滤)来提高工艺流中3-岩藻糖基乳糖的浓度。或者,将结晶或沉淀的3-岩藻糖基乳糖溶解在水中,以获得具有所需浓度的3-岩藻糖基乳糖的3-岩藻糖基乳糖溶液。
在额外的和/或替代的实施方案中,所得的工艺流是含有3-岩藻糖基乳糖的水溶液,其浓度≥20g/L、≥25g/L、≥30g/L、≥40g/L、≥60g/L、≥100g/L、≥200g/L或甚至≥300g/L。
在额外的和/或替代的实施方案中,相对于溶液中干物质/溶质的重量计,水溶液含有3-岩藻糖基乳糖,其纯度为至少80%、至少85%、至少90%、至少93%、至少95%或至少98%。
所获得的含有纯化的3-岩藻糖基乳糖的浓缩物可以在适当的条件下贮藏。
用于纯化3-岩藻糖基乳糖的方法具有成本效益,并且易于放大,使其适合作为数吨规模制备工艺的基础。
用于纯化3-岩藻糖基乳糖的方法的优点还在于水溶液不含遗传工程化微生物和源自遗传工程化微生物的核酸分子。另外,水溶液中不含蛋白质。蛋白质的全部去除消除了对潜在的消费者造成过敏的风险。
用于制备喷雾干燥粉末的方法包括提供含有3-岩藻糖基乳糖的水溶液的步骤。
在额外的和/或替代的实施方案中,水溶液含有3-岩藻糖基乳糖,其量为至少20%(w/v)、30%(w/v)、35%(w/v),至多45%(w/v)、50%(w/v)、60%(w/v)。
在额外的和/或替代的实施方案中,相对于溶液中干物质/溶质的重量计,水溶液含有3-岩藻糖基乳糖,其纯度为至少80%、至少85%、至少90%、至少93%、至少95%或至少98%。
在额外的和/或替代的实施方案中,水溶液不含遗传工程化微生物、源自遗传工程化微生物的核酸分子,以及蛋白质。
在喷雾干燥粉末的制备过程中,对含有3-岩藻糖基乳糖的水溶液进行喷雾干燥。
喷雾干燥是获得干燥粉末的方法,其中首先将含有目的物质(即3-岩藻糖基乳糖)的溶液喷雾成液滴,通过热空气将液滴迅速干燥。喷雾干燥非常快,待干燥的物质暴露于高温的时间很短。
在额外的和/或替代的实施方案中,已经从发酵液或工艺流中纯化的含有3-岩藻糖基乳糖的水溶液在至少110℃、优选至少120℃、更优选至少125℃,且低于150℃、优选低于140℃、更优选低于135℃的喷嘴温度下喷雾干燥。
在额外的和/或替代的实施方案中,已经从发酵液或工艺流中纯化的含有3-岩藻糖基乳糖的水溶液在至少60℃、优选至少65℃,且低于80℃、优选低于70℃的出口温度下喷雾干燥。在特别优选的实施方案中,将含有3-岩藻糖基乳糖的水溶液在约68℃至约70℃的喷嘴温度下喷雾干燥。
含有3-岩藻糖基乳糖的水溶液的喷雾干燥提供了低吸湿性的粉末,其中3-岩藻糖基乳糖以无定形形式存在,并且其中粒度是均匀的。
根据第三方面,提供了包含已经从工艺流中纯化的3-岩藻糖基乳糖的喷雾干燥粉末用于制备营养组合物的用途。基本上由3-岩藻糖基乳糖组成的喷雾干燥粉末适用于人类食用(consumption),因此可以包含在用于人类食用的制品中,例如药物制剂、婴儿配方物、乳制品饮料或膳食补充剂。
根据第四方面,提供了营养组合物,其包含根据第二方面制备的如第一方面所述的喷雾干燥粉末。
在额外的和/或替代的实施方案中,营养组合物包含至少一种非3-岩藻糖基乳糖的额外HMO。所述至少一种额外HMO可以是中性HMO,优选地选自2'-岩藻糖基乳糖(2'-FL)、乳-N-四糖(LNT)、乳-N-新四糖(LNnT)和乳-N-岩藻戊糖I(LNFPI)。在额外的和/或替代的实施方案中,所述至少一种额外HMO可以是唾液酸化的HMO,优选地选自3'-唾液酸乳糖(3'-SL)、6'-唾液酸乳糖(6'-SL)、唾液酸乳-N-四糖(LST)-a、LST-b、LST-c和二唾液酸乳-N-四糖(DSLNT)。
在额外的和/或替代的实施方案中,营养组合物包含基本上由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中提供了包含优选量的每种所述化合物的营养组合物。
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
根据表1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以包含具有表1第三列中指定的浓度的混合物的化合物。
在额外的和/或替代的实施方案中,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、麦芽糊精、淀粉、蔗糖、肌醇等),蛋白质(来自脱脂乳、乳清、酪蛋白(源自任何驯化的乳业动物)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),矿物质和微量元素(钠、钾、氯化物、钙、磷、镁、铁、锌、锰、氟化物、硒、碘、铜)。
在优选的实施方案中,包含喷雾干燥的人乳低聚糖或人乳低聚糖混合物或人乳低聚糖与功能性单糖的混合物或人乳低聚糖与其他纤维的混合物的营养组合物是满足法规(EU)2016/127和/或联邦法规(USA)标题21 107.100(营养规范)中提出的成分要求的婴儿配方物。表2和表3列出了婴儿配方物的代表性组合物。
婴儿配方物:脱脂乳
植物油(棕榈油、菜籽油、葵花籽油)
人乳低聚糖
3-岩藻糖基乳糖
脱脂奶粉
高山被孢霉(Mortierella alpine)的油
鱼油
碳酸钙
氯化钾
维生素C
氯化钠
维生素E
醋酸亚铁
硫酸锌
烟酸
D-泛酸钙
硫酸铜
维生素A
维生素B1
维生素B6
硫酸镁
碘酸钾
叶酸
维生素K
亚硒酸钠
维生素D
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。终浓度基于在90ml水中的13.5g粉末的制品计。
在额外的和/或替代的实施方案中,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,优选的微生物源自健康人的微生物组或可在健康人的微生物组中找到。优选地,但不限于,微生物选自双歧杆菌属(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)、梭菌属(Clostridium)、真细菌属(Eubacterium)、Veilonella、梭杆菌属(Fusobacterium)、拟杆菌属(Bacterioides)、普氏菌属(Prevotella)、埃希氏菌属(Escherichia)、丙酸杆菌属(Propionibacterium)和酵母菌属(Saccharomyces)。在额外的和/或替代的实施方案中,微生物选自:青春双岐杆菌(Bifidobacterium adolescentis)、动物双歧杆菌(B.animalis)、两岐双岐杆菌(B.bifidum)、短双歧杆菌(B.breve)、婴儿双岐杆菌(B.infantis)、乳糖双歧杆菌(B.lactis)、长双歧杆菌(B.longum);屎肠球菌(Enterococcus faecium);大肠杆菌(Escherichia coli);马克思克鲁维酵母(Klyveromyces marxianus);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)、加氏乳杆菌(L.gasseri)、瑞士乳杆菌(L.helveticus)、约翰逊乳酸杆菌(L.johnsonii)、副干酪乳杆菌(L.paracasei)、胚芽乳杆菌(L.plantarum)、胚芽乳杆菌(L.reuteri)、鼠李糖乳杆菌(L.rhamnosus)、唾液乳杆菌(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)亚种、乳脂(cremoris)亚种和双乙酰基乳酸(diacetylactis)亚种);肠膜样明串珠菌(Leuconostoc mesenteroides)(包括但不限于肠膜样(mesenteroides)亚种);乳酸片球菌(Pedicoccus acidilactici)、戊糖片球菌(P.pentosaceus);丙酸丙酸杆菌(Propionibacterium acidipropionici)、费氏丙酸杆菌谢氏亚种(P.freudenreichiissp.Shermanii);肉葡萄球菌(Staphylococcus carnosus);和嗜热链球菌(Streptococcusthermophilus)。
除了组合活的生物体之外,营养组合物还可以包含死细胞培养物。在益生菌领域中,有时使用灭活的细胞培养物(例如间歇灭菌的(tyndalized)细菌)。这些灭活的培养物可以提供蛋白质、肽、低聚糖、细胞外壁片段和天然产物,导致对免疫系统的短期刺激。
在营养组合物中包含益生菌微生物特别有利,特别是在存在HMO的情况下,因为它还促进建立健康的肠道微生物组。
在额外的和/或替代的实施方案中,营养组合物还包含益生元,例如低聚半乳糖(GOS)、低聚果糖(FOS)、菊粉或其组合。
营养组合物以固体形式存在,包括但不限于粉末、颗粒、薄片、小丸(pellet)或其组合。
在额外的实施方案中,营养组合物选自药物制剂、婴儿配方物、乳制品饮料和膳食补充剂。
作为药物制剂,营养组合物可以用于改善认知表现,特别是用于改善注意力、学习和/或记忆。
将参考特定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,而不必是为了描述时间、空间、排行或任何其他方面的顺序。应当理解,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示出的其他顺序来操作。
应当注意,权利要求中使用的术语“包括”不应解释为限于其后列出的手段;它不排除其他元素或步骤。因此,应将其理解为指定所提及的所述特征、整数、步骤或组件的存在,但并不排除一个或多个其他特征、整数、步骤或组件或其组的存在或增加。因此,表述“包括组件A和B的设备”的范围不应限于仅由组件A和B组成的设备。这意指相对于本发明,设备的唯一相关组件是A和B。
在整个说明书中,对“一个实施方案(one embodiment)”或“一个实施方案(anembodiment)”的引用是指结合该实施方案描述的特定特征、结构或特性包括在本发明的至少一个实施方案中。因此,在本说明书全文的各处出现的短语“在一个实施方案中”或“在一个实施方案中”并不必然总是指相同的实施方案。此外,在一个或多个实施方案中,特定特征、结构或特性可以以任何合适的方式组合,对于本领域的普通技术人员来说,根据本公开内容这将是显而易见的。
类似地,应当理解,在本发明的代表性实施方案的描述中,有时将本发明的各个特征组合在单个实施方案、附图或其描述中,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被解释为反映以下意图:所要求保护的发明需要比每个权利要求中明确列出的特征更多的特征。而是,如以下权利要求所反映的,本发明的方面可能需要少于任何前述公开的实施方案的所有特征的特征。因此,在详细说明后的权利要求在此明确纳入该详细说明中,其中每个权利要求独立地作为本发明的单独的实施方案。
此外,尽管本文描述的一些实施方案包括其他实施方案中包括的一些特征但不包括其他特征,但是不同实施方案的特征的组合意在落入本发明的范围内,并且形成不同的实施方案,如本领域技术人员将理解的那样。例如,在下文的权利要求中,任何要求保护的实施方案都可以任何组合使用。
此外,一些实施方案在本文中被描述为可以通过计算机系统的处理器或通过执行该功能的其他手段来应用的方法或方法要素(element)的组合。因此,具有用于执行这种方法或方法要素的必要指令的处理器构成用于执行该方法或方法要素的手段。此外,本文描述的装置实施方案的元件(element)是用于实施由该元件执行的功能,以实施本发明的手段的实例。
在本文提供的说明书和附图中,阐述了许多具体细节。然而,应当理解,可以在没有这些具体细节的情况下实施本发明的实施方案。在其他情况下,未详细示出公知的方法、结构和技术,以促进对说明书和附图的理解。
现在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,可以根据本领域技术人员的知识来配置本发明的其他实施方案,本发明仅由所附权利要求的条款来限制。
实施例1:从发酵液中纯化2'-岩藻糖基乳糖
如欧洲专利申请16196486.1中所述,通过使用遗传修饰的大肠杆菌菌株进行发酵来产生2'-岩藻糖基乳糖。如WO 2015/106943 A1中所述,通过过滤、离子交换色谱、纳滤、渗滤或电渗析并用活性炭处理从发酵液中纯化2'-岩藻糖基乳糖。对所得的含有2'-岩藻糖基乳糖的溶液进行喷雾干燥,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
如欧洲专利申请16196486.1中所述,通过使用遗传修饰的大肠杆菌菌株进行发酵来产生3-岩藻糖基乳糖。
通过超滤(截留值(cut-off)为0.05μm)(CUT membrane technology,Erkrath,Germany),然后通过MWCO为150kDa的错流过滤器(Microdyn-Nadir,Wiesbaden,Germany)从培养基中分离细胞。将含有约30g/L 3-岩藻糖基乳糖的无细胞发酵培养基通过H+形式的强阳离子交换剂(Lewatit S 2568(Lanxess,Cologne,Germany),以去除荷正电的污染物。然后用氢氧化钠将溶液的pH设置为7.0,并应用于氯化物形式的阴离子交换剂(LewatitS6368 A,Lanxess)。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)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。将电导率约为15mS cm-1的浓缩溶液过滤(10kDa;Microdyn-Na dir,Wiesbaden,Germany)、通过活化的活性炭(CAS:7440-44-0,Carl Roth,Karlsruhe,Germany)澄清并通过电渗析来去离子。为此使用具有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的氨基磺酸作为电解液。为了减少由美拉德反应和源自发酵过程的羟醛产物导致的棕褐色,使用如前所述的Na+和Cl-形式的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。在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。为了进一步的脱色,将溶液与活性炭(CAS:7440-44-0,Carl Roth,Karlsruhe,Germany)混合,并通过过滤获得几乎无色的溶液。
实施例3:从发酵液中纯化乳-N-四糖
使用遗传修饰的大肠杆菌BL21(DE3)ΔlacZ菌株进行乳-N-四糖的发酵生产,其基因组整合的基因是乳-N-四糖的体内合成所必需的,即N-乙酰基葡糖胺糖基转移酶(来自脑膜炎奈瑟氏球菌(Neisseria meningitidis)MC58的lgtA)、β-1,3-半乳糖基转移酶(来自肠炎沙门菌亚属沙门菌血清型Greenside(Salmonella enterica subsp.salamae serovarGreenside)的wbdO)、来自大肠杆菌K12的lacY、UDP-葡萄糖-4-差向异构酶galE和UTP-葡萄糖-1-磷酸尿苷转移酶galU(两者均来自大肠杆菌K12)。另外,编码葡糖胺-6-磷酸合酶的galS基因被过表达。为了发酵产生乳-N-四糖,将菌株在包含2%葡萄糖作为碳源的确定成分的矿物盐培养基中生长。必要时加入消泡剂。用25%氨溶液控制pH。从216g l-1的乳糖储液中逐步添加乳糖至终浓度为15mM,培养基中的乳糖浓度在发酵过程中保持恒定。在所述过程中作为副产物积累的残留乳糖和乳-N-丙糖II被添加到发酵罐中的第二种大肠杆菌菌株水解。该菌株表达了功能性β-内酰胺酶、β-N-乙酰基己糖胺酶(来自两岐双歧杆菌(Bifidobacterium bifidum)JCM1254的bbhl)和用于降解单糖的功能性gal操纵子(EP2845905A)。
根据实施例2中所述的方法从发酵液中分离细胞,并将通过质量平衡测定的含乳-N-四糖的流体纯化至75-80%的纯度。
根据WO 2015/049331,通过使用模拟移动床(SMB)色谱的色谱法去除了由无效的酶促降解和代谢产生的污染性碳水化合物副产物。或者,通过用异丙醇的结晶来纯化乳-N-四糖。为了结晶,将含乳-N-四糖的溶液通过蒸发浓缩至浓度为20%并喷雾干燥。使用NUBILOSA LTC-GMP喷雾干燥器(NUBILOSA,Konstanz,Germany)使溶液在氮气流下通过喷雾干燥器喷嘴,入口温度为130℃,同时控制产物流以保持出口温度为67℃至68℃。
将固体材料加入到异丙醇和水(3:1(体积/体积))的混合物中,比率为在12L异丙醇/水中的1kg粉末。剧烈搅拌该悬液,然后将不溶的乳-N-四糖过滤并在40℃下干燥。以73-89%的纯原料开始,将结晶的乳-N-四糖纯化至约95%,回收率为85%。将糖溶解在水中至浓度为25%,然后依次通过6kDa过滤器(Pall Microza ultrafiltration module SIP-2013,Pall Corporation,Dreieich,Germany)和0.2μm无菌过滤器。通过在上述条件下将无菌材料喷雾干燥来获得固体材料。
实施例4:从发酵液中纯化3'-和6'-唾液酸乳糖
为了生产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。这些菌株具有常见的遗传修饰:来自大肠杆菌的葡糖胺-6-磷酸合酶GlmS的染色体组成型表达、来自集胞藻属种(Synechocystis sp.)的N-乙酰葡糖胺2-差向异构酶Slr1975、来自酿酒酵母(Saccharomyces cerevisiae)的葡糖胺6-磷酸N-乙酰转移酶Gna1、来自大肠杆菌的磷酸烯醇丙酮酸合酶PpsA、N-乙酰神经氨酸合酶NeuB和CMP-唾液酸合成酶NeuA(后两者均来自空肠弯曲杆菌(Campylobacter jejuni))。此外,将编码以下的基因整合到BL21菌株的基因组中并组成型表达:来自大肠杆菌的乳糖通透酶LacY,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(转录调节因子),以及功能性gal操纵子,其由来自大肠杆菌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'-唾液酸乳糖的菌株带有来自弧菌属种(Vibrio sp.)JT-FAJ-16的α-2,3-唾液酸转移酶基因,而产生6'-唾液酸乳糖的菌株含有来自发光细菌属(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含有2%蔗糖作为碳源的确定成分的矿物盐培养基中生长。在分批补料阶段补料的蔗糖进料(500g l-1)中补充有8mM MgSO4、0.1mM CaCl2、痕量元素和5g l-1NH4Cl。
为了形成唾液酸乳糖,使用216g l-1的乳糖进料。通过使用氨溶液(25%v/v)控制pH。补料分批发酵在恒定通风和搅拌下于30℃下进行。为了在发酵结束时去除残留的乳糖,将β-半乳糖苷酶加入发酵容器中。所得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,在体积为200L的H+形式的强阳离子交换剂(Lewatit S 2568(Lanxess,Cologne,Germany)上去除阳离子污染物。使用NaOH将所得溶液pH设置为7.0。在第二步中,使用氯化物形式的强阴离子交换剂Lewatit S6368S(Lanxess,Cologne,Germany)从溶液中去除阴离子和不需要的色素。离子交换剂的床体积为200L。使用在错流过滤器(截留值为150kDa)(Microdyn-Nadir,Wiesbaden,Germany)上进行的第二过滤步骤,去除源自酸化溶液的沉淀。为了浓缩糖,将溶液在Dow FILMTECHNF270-4040(Inaqua,Germany)或替代地在Trisep4040-XN45-TSFMembrane(截留值为0.5kDa)(Microdyn-Nadir,Wiesbaden,Germany)上纳滤。使用后者时,从产物中分离单糖N-乙酰葡糖胺,其源自发酵过程并污染唾液酸乳糖溶液。然后将浓缩的唾液酸乳糖溶液用活性炭(CAS:7440-44-0,Carl Roth,Karlsruhe,Germany)处理以去除色素,例如美拉德反应产物和羟醛反应产物。为了将唾液酸乳糖与源自发酵过程的副产物(如唾液酸和N-乙酰葡糖胺)分离,用截留值为1kDa的膜GE4040F30(GE water&processtechnologies,Ratingen,Germany)过滤溶液并渗滤至电导率为0.6至0.8mS cm-1。将稀释的溶液在旋转蒸发仪上浓缩至约300g/L的浓度。在最终的色谱分离中,去除了其他污染性糖,如二唾液酸乳糖。为此,将浓缩溶液施加于乙酸盐形式的弱阴离子交换树脂(AmberliteFPA51,Dow Chemical,Michigan,USA)。尽管唾液酸乳糖几乎不与树脂结合,但二唾液酸乳糖却被吸附了。因此,将唾液酸乳糖用10mM乙酸铵洗脱,而将二唾液酸乳糖用1M乙酸铵洗脱。为了去除乙酸铵,用过量10倍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 Microzaultrafiltration module SIP-2013,Pall Corporation,Dreieich,Germany)和0.2μm无菌过滤器来最终完成产物。
使用Büchi喷雾干燥器(Büchi Mini Spray Dryer B-290)(Büchi,Essen,Germany)将部分溶液喷雾干燥,应用以下参数: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'-唾液酸乳糖的纯度为91%,而3'-唾液酸乳糖的纯度为93%。
实施例5:HMO混合物的制备
从固体产物制备HMO的混合物。为此,将单个HMO喷雾干燥并将粉末混合。HMO-MixI包含2'-岩藻糖基乳糖和乳-N-四糖,比例为70%至30%;HMO-Mix 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%)。将混合的粉末溶解在水中,制成20%糖的溶液,使用Büchi喷雾干燥器再次喷雾干燥,如实施例4所述。
实施例6:喷雾干燥的人乳低聚糖的表征
6.1差示扫描量热法(DSC)
在Mettler Toledo 821e(Mettler Toledo,Giessen,Germany)上使用差示扫描量热法(DSC)分别测定喷雾干燥的人乳低聚糖(即3-岩藻糖基乳糖、6'-唾液酸乳糖、3'-唾液酸乳糖、乳-N-四糖)和人乳低聚糖的喷雾干燥混合物(2'-岩藻糖基乳糖/乳-N-四糖的混合物(HMO-Mix 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 Mix II))的热事件(thermal event)。
使用Mettler Toledo 821e(Mettler Toledo,Giessen,Germany)来测定喷雾干燥产物的热事件(玻璃化转变温度(Tg),进一步的放热和吸热事件)。
在卷曲(crimped)的铝坩埚(Mettler Toledo,Giessen,Germany)中分析了约25mg喷雾干燥的人乳低聚糖。将样品以10K/min冷却至0℃,然后以10K/min的扫描速度重新加热至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)。通过事件的峰值温度和归一化能量报告放热峰和吸热峰。
在所有样品中的第一次加热扫描均显示了总热流中的主要玻璃化转变事件,这在约48-58℃的范围内由主要阶梯转变所证明,在大多数样品中,在第一次加热扫描中观察到的主要的玻璃化转变事件,在第二次加热扫描中再次发生。DSC分析的结果总结在表4中。
样品 | 第一次加热扫描 | 第二次加热扫描 |
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 Mix | 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之后检测到了吸热弛豫峰。对于乳-N-四糖,在第二次加热扫描中检测到了比其他样品高得多的Tg,约为79℃。这可能是由于在约89℃(-6.04J/g)下的第一次加热扫描期间发生的吸热事件导致的。像3-岩藻糖基乳糖一样,对于6'-唾液酸乳糖,在Tg之后也检测到吸热弛豫峰,但是,在该样品中,在77℃(-0.22J/g)下额外发生吸热事件。对于3'-唾液酸乳糖和HMO-Mix I,未检测到吸热事件,对于HMO-Mix II,在第一次加热扫描期间的吸热事件是在79℃(0.34J/g)下。
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。使用配备有铜阳极(45kV,40mA,波长为0.154nm的Kα1发射)和PIXcel3D检测器的X射线衍射仪Empyrean(Panalytical,Almelo,The Netherlands)。以反射模式分析了约100mg喷雾干燥样品,角度范围为5-45°2θ,步长为0.04°2θ,每步的计数时间为100秒。
所有单一的低聚糖以及HMO混合物I和II都显示出完全无定形状态(图1-6)。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
通过激光衍射评估粉末粒度。该系统通过同心排列的传感器元件阵列检测散射和衍射光。然后,软件算法通过计算到达不同传感器元素的光强度值的z值来近似颗粒计数。使用SALD-7500聚合粒度仪(SALD-7500Aggregate Sizer)(Shimadzu Corporation,Kyoto,Japan)定量激光衍射系统(qLD)进行分析。
将少量(刮刀尖端)的每种样品分散在2ml异辛烷中,并通过超声处理均化5分钟。将分散体转移到填充有异辛烷的批处理单元(batch cell)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(Signal Averaging Count perMeasurement):128,信号累积计数(Signal Accumulation Count):3,间隔:2秒。
在测量之前,用异辛烷使系统空白(blank)。测量每个样品的分散体3次,并报告平均值和标准偏差。使用软件WING SALD II版本V3.1评估数据。由于样品的折射率未知,因此使用糖(二糖)颗粒的折射率(1.530)来确定尺寸分布曲线。报告了均值和中值直径的尺寸值。
所有样品的平均粒度非常相似,HMO-Mix II的测量值略低。粒度特征总结在表5中。此外,粒度分布表明所有样品均存在一个主要尺寸群。
表5:通过激光衍射测定的HMO的粒度
Claims (16)
1.一种喷雾干燥粉末,其基本上由通过微生物发酵产生的3-岩藻糖基乳糖组成。
2.根据权利要求1所述的喷雾干燥粉末,其中所述喷雾干燥粉末含有至少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3-岩藻糖基乳糖。
3.根据权利要求1或2所述的喷雾干燥粉末,其中所述3-岩藻糖基乳糖以无定形形式存在。
4.根据权利要求1至3中任一项所述的喷雾干燥粉末,其中所述喷雾干燥粉末含有≤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粉末,其中所述喷雾干燥粉末不含遗传工程化微生物和源自遗传工程化微生物的核酸分子。
6.一种用于制备根据权利要求1至5中任一项所述的喷雾干燥粉末的方法,该方法包括以下步骤:
a)从发酵液中纯化3-岩藻糖基乳糖;
b)提供含有步骤a)的3-岩藻糖基乳糖的水溶液;和
c)对步骤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3-岩藻糖基乳糖的步骤(步骤a))包括以下步骤中的一步或多步:
i)从发酵液中去除微生物细胞,以获得澄清的工艺流;
ii)对澄清的工艺流进行至少一次超滤;
iii)将澄清的工艺流用阳离子交换树脂处理至少一次和/或用阴离子交换树脂处理至少一次;
iv)对澄清的工艺流进行至少一次纳滤和/或渗滤;
v)对澄清的工艺流进行至少一次电渗析;
vi)将澄清的工艺流用活性炭处理至少一次;和/或
vii)对澄清的工艺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,其中所述水溶液含有3-岩藻糖基乳糖的量为至少20%(w/v)、30%(w/v)、35%(w/v),至多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,其中将含有3-岩藻糖基乳糖的水溶液在至少110℃、优选至少120℃、更优选至少125℃,且低于150℃、优选低于140℃、更优选低于135℃的喷嘴温度下喷雾干燥。
10.根据权利要求6至9中任一项所述的方法,其中将含有3-岩藻糖基乳糖的水溶液在至少60℃、优选至少65℃,且低于80℃、优选低于70℃的出口温度下喷雾干燥。
11.根据权利要求1至5中任一项所述的喷雾干燥粉末用于制备营养组合物的用途,优选婴儿配方物。
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,其还包含至少一种额外的HMO,其中所述至少一种额外的HMO是中性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,其中至少一种中性HMO选自2'-岩藻糖基乳糖、乳-N-四糖、乳-N-新四糖和乳-N-岩藻戊糖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-N-四糖(LST)-a、LST-b、LST-c和二唾液酸乳-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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2018
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