CN116615203A - 改进的益生元制剂 - Google Patents
改进的益生元制剂 Download PDFInfo
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- CN116615203A CN116615203A CN202180083213.3A CN202180083213A CN116615203A CN 116615203 A CN116615203 A CN 116615203A CN 202180083213 A CN202180083213 A CN 202180083213A CN 116615203 A CN116615203 A CN 116615203A
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- solid product
- fucosyllactose
- prebiotic
- prebiotic solid
- product
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- A—HUMAN NECESSITIES
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Abstract
公开的方法包括:还原包括2’‑岩藻糖基乳糖的发酵液,以产生包括2’‑岩藻糖基乳糖和2’‑岩藻糖基乳糖醇的经处理的发酵液;从经处理的发酵液中分离包括2’‑岩藻糖基乳糖和2’‑岩藻糖基乳糖醇的料流;纯化经分离的料流;浓缩经纯化和分离的料流;对经浓缩、纯化和分离料流进行脱水,从而形成包括2’‑岩藻糖基乳糖和0.2至6.0wt.%的2’‑岩藻糖基乳糖醇的益生元固体产品,上述含量是基于益生元固体产品总重量的wt.%,其中浓缩步骤和脱水步骤可以按任何顺序进行。
Description
技术领域
本发明涉及改进的益生元(prebiotic)制剂。更具体地,本发明涉及包括2’-岩藻糖基乳糖和2’-岩藻糖基乳糖醇的益生元制剂。
背景技术
母乳含有一系列独特的寡糖,称为人乳寡糖(HMO),它们是结构多样的非共轭多糖。尽管HMO是母乳中第三丰富的固体成分(仅次于乳糖和脂肪),但人类婴儿无法消化HMO。相反,它们起到益生元的作用,帮助建立共生菌。益生元或不易消化的碳水化合物用于增强特定的有益微生物物种。例如,天然存在于人类母乳中的2’-岩藻糖基乳糖(2’-FL)是一种已知的益生元,其刺激双歧杆菌属特定的有益微生物群的生长。2’-FL不能被人类内源性酶消化,但被婴儿肠道中的共生生物共生细菌用作能量来源,以选择性地支持有益细菌的生长(益生元作用)。它与可能>200种类似的人类寡糖一起从哺乳期妇女的乳腺上皮细胞分泌到其乳汁中。HMO的α1,2/3/4岩藻糖基部分,包括2’-FL的α1,2-连接的岩藻糖,倾向于保护HMO免于消化,除非这些位于非还原端的键首先被切割。因此,2’-FL的益生元作用取决于细菌酶的若干种活性,例如裂解岩藻糖并释放乳糖的α1,2-岩藻糖苷酶活性;将释放的岩藻糖代谢成乳酸和1,2-丙二醇的活性;代谢不被人类宿主细胞使用的乳糖比例的活性;和一些其它活性。支持婴儿健康消化道的发育有助于他们免疫系统的发育,因为婴儿的大部分免疫系统都在消化道中。这些复杂寡糖的出现和浓度是人类特有的,在其它哺乳动物如家养产奶动物的乳汁中没有大量发现。人们一直在努力开发用于制造HMO的改进系统,如EP14827224.8、WO2019/003133、WO2019/003135、U.S.2017/0304375和WO2019/003136。
因此,已知的是,均衡的微生物群组成有益于整体健康和福祉。乳糖醇是一种已知的益生元,其增强肠道中乳杆菌(以及在较小程度上双歧杆菌)属种的微生物,以及增加短链脂肪酸的水平。包括2’-岩藻糖基乳糖醇(2’-FLol)的组合物将会刺激范围广泛的有益微生物群,从而导致肠道平衡更好,因为2’-FLol易于被肠道微生物群(双歧杆菌)产生的特定岩藻糖苷酶水解,释放出乳糖醇和岩藻糖。此外,乳糖醇不被人类消化酶消化,而乳糖则可以。因此,据信比起单独的2’-FL,2’-FL和2’-FLol的混合物提供更加强健和通用的益生元系统,因为它们的作用是互补的;例如,如果2’-FL在储存或膳食准备过程中被过快水解,则在混合系统中2’-FLol或乳糖醇仍然存在。此外,乳糖醇的热值为2kcal/g,而乳糖的热值为3.94kcal/g。
2’-FL通常在微生物发酵反应器中产生;然而,此类常规工艺仅产生低水平的2’-FLol作为副产品。对于制造2’-FLol以增加的水平存在的含有2’-FL和2’-FLol的组合物的方法存在需求。
发明内容
出人意料地发现了一种制造2’-FLol以增加的水平存在的含有2’-FL和2’-FLol的混合物的方法,其中2’-FL在经历还原条件以产生2’-FLol的微生物发酵中产生。
在一实施方式中,本公开提供一种方法,其包括:还原包括2’-岩藻糖基乳糖的发酵液,以产生包括2’-岩藻糖基乳糖和2’-岩藻糖基乳糖醇的经处理的发酵液;从经处理的发酵液中分离包括2’-岩藻糖基乳糖和2’-岩藻糖基乳糖醇的料流(stream);纯化经分离的料流;浓缩经纯化和分离的料流;对经浓缩、纯化和分离的料流进行脱水,从而形成益生元固体产品,其包括2’-岩藻糖基乳糖和以所述益生元固体产品总wt.%计为0.2至6.0wt.%的2’-岩藻糖基乳糖醇的益生元固体产品,其中浓缩步骤和脱水步骤可以按任何顺序进行。
在另一实施方式中,本公开提供一种方法,其包括将有效量的益生元固体产品组合物施用于有需要的受试者,从而产生乳糖醇的体内供应。
在再另一实施方式中,本公开提供一种制造食品、成长奶、膳食补充剂或药物的方法,其中该方法包括:制造益生元固体产品;和将益生元固体产品与一种或多种适合于食品、成长奶、膳食补充剂或药物的成分混合。
在另一实施方式中,本公开提供一种制造食品、成长奶、膳食补充剂或药物的制作方法,其中该方法包括:制造益生元固体产品;将益生元固体产品溶解在溶剂中;和将溶解的益生元固体产品与一种或多种适合于食品、成长奶、膳食补充剂或药物的成分混合。
在再另一实施方式中,本公开提供一种制造婴儿配方奶粉(infant formula)的方法,其中该方法包括:制造益生元固体产品,和将益生元固体产品与至少一种婴儿配方奶粉成分混合。
在一实施方式中,本公开提供一种制造婴儿配方奶粉的方法,其中该方法包括:制造益生元固体产品,将益生元固体产品溶解在溶剂中;和将溶解的益生元固体产品与至少一种婴儿配方奶粉成分混合。
在另一实施方式中,本公开提供由以下方法获得的食品、成长奶、膳食补充剂或药物:该方法包括制造益生元固体产品;和将益生元固体产品与至少一种婴儿配方奶粉成分混合,或者首先将益生元固体产品溶解在溶剂中,和将溶解的益生元固体产品与至少一种婴儿配方奶粉成分混合。
附图说明
通过结合附图的以下详述,将更充分地理解本公开的主题,其中:
图1是说明益生元固体料流的分离和纯化的工艺流程图。
图2说明在37℃、pH 6.5的125mM磷酸钠缓冲液中,组合物2(47mM 2’-FL和2mM 2’-FLol)被12μg/ml来自长双歧杆菌(Bifidobacterium longum)的岩藻糖苷酶分别水解为乳糖和乳糖醇。实线,2’-FLol(实心圆)及其衍生产物乳糖醇(空心圆);虚线,2’-FL(实心方块)及其衍生产物乳糖(空心方块)。
图3说明在37℃、pH 6.5的125mM磷酸钠缓冲液中,组合物2(47mM 2’-FL和2mM 2’-FLol)被12μg/ml来自双歧杆菌属(Bifidobacterium sp.)的岩藻糖苷酶分别水解为乳糖和乳糖醇。实线,2’-FLol(实心圆)及其衍生产物乳糖醇(空心圆);虚线,2’-FL(实心方块)及其衍生产物乳糖(空心方块)。
图4说明在37℃、pH 6.5的125mM磷酸钠缓冲液中,组合物2(47mM 2’-FL和2mM 2’-FLol)被2μg/ml来自长双歧杆菌(Bifidobacterium longum)的岩藻糖苷酶分别水解为乳糖和乳糖醇。实线,2’-FLol(实心圆)及其衍生产物乳糖醇(空心圆);虚线,2’-FL(实心方块)及其衍生产物乳糖(空心方块)。
图5说明在37℃、pH 6.5的125mM磷酸钠缓冲液中,组合物2(47mM 2’-FL和2mM 2’-FLol)被2μg/ml来自双歧杆菌属(Bifidobacterium sp.)的岩藻糖苷酶分别水解为乳糖和乳糖醇。实线,2’-FLol(实心圆)及其衍生产物乳糖醇(空心圆);虚线,2’-FL(实心方块)及其衍生产物乳糖(空心方块)。
图6说明在37℃、pH 6.5的125mM磷酸钠缓冲液中,组合物2(47mM 2’-FL和2mM 2’-FLol)与水的无酶对照孵育。实线,2’-FLol(实心圆)及其衍生产物乳糖醇(空心圆);虚线,2’-FL(实心方块)及其衍生产物乳糖(空心方块)。
具体实施方式
本公开的特征在于产生、分离和纯化改进的益生元固体产品的方法。在一实施方式中,本公开提供一种方法,其包括:还原包括2’-FL的发酵液,以产生包括2’-FL和2’FLol的经处理的发酵液;从经处理的发酵液中分离包括2’-FL和2’FLol的料流;纯化经分离的料流;浓缩经纯化和分离的料流;对经浓缩、纯化和分离的料流进行脱水,从而形成益生元固体产品,其包括2’-岩藻糖基乳糖和以益生元固体产品总wt.%计为0.2至6.0wt.%的2’-岩藻糖基乳糖醇,其中浓缩步骤和脱水步骤可以按任何顺序进行。出于本说明书的目的,术语益生元是指一种选择性发酵的成分,其导致胃肠道微生物群的组成和/或活性发生特定变化,从而为宿主的健康带来益处。益生元的特征包括:(i)它应该对胃的酸性pH具有抗性,(ii)它不能被哺乳动物酶水解,(iii)它不应该被胃肠道吸收,(iv)它可以通过肠道微生物群发酵,和(iii)肠道细菌的生长和/或活性可以被这种化合物选择性地刺激,并且这一过程可以改善宿主的健康。
发酵步骤
发酵可以在任何合适的发酵培养基中进行,例如化学成分确定的发酵培养基。发酵培养基可以基于所使用的微生物有机体而变化。
优选地,在发酵步骤中,将糖、乳糖和发酵营养物供给经遗传修饰以产生2’-FL的微生物培养物,然后发酵,以产生2’-FL和其它碳水化合物如二岩藻糖基乳糖、2’-岩藻糖基-d-乳果糖、乳糖/异乳糖、3’-岩藻糖基乳糖、岩藻糖基半乳糖。发酵培养基可以补充有痕量矿物质和维生素,比如泛酸钙、生物素、烟酸、myo-肌醇、盐酸硫胺素、对氨基苯甲酸。也可以使用食品级加工助剂,比如消泡剂和pH控制剂。发酵步骤的温度通常为10至50℃,优选25至35℃,更优选28至32℃。发酵步骤的pH通常为3至8,优选5至7,更优选5.5至6.5。在发酵步骤结束时,可以对发酵液进行热处理步骤,以在下游处理步骤之前使微生物失活。
优选地,微生物有机体是遗传修饰的酵母,比如酵母属(Saccharomyces)菌株、假丝酵母属(Candida)菌株、汉逊酵母属(Hansenula)菌株、克鲁维酵母属(Kluyveromyces)菌株、毕赤酵母属(Pichia)菌株、裂殖酵母属(Schizosaccharomyces)菌株、许旺酵母属(Schwanniomyces)菌株、有孢圆酵母属(Torulaspora)菌株、耶氏酵母属(Yarrowia)菌株或接合酵母属(Zygosaccharomyces)菌株。更优选地,酵母为酿酒酵母(Saccharomycescerevisiae)、多形汉逊酵母(Hansenula polymorpha)、乳酸克鲁维酵母(Kluyveromyceslactis)、马克斯克鲁维酵母(Kluyveromyces marxianus)、巴斯德毕赤酵母(Pichiapastoris)、甲醇毕赤酵母(Pichia methanolica)、树干毕赤酵母(Pichia stipites)、博伊丁假丝酵母(Candida boidinii)、粟酒裂殖酵母(Schizosaccharomyces pombe)、西方许旺酵母(Schwanniomyces occidentalis)、戴尔有孢圆酵母(Torulaspora delbrueckii)、解脂耶氏酵母(Yarrowia lipolytica)、鲁氏接合酵母(Zygosaccharomyces rouxii)或拜氏接合酵母(Zygosaccharomyces bailii)。
优选地,微生物有机体还可以选自细菌属双歧杆菌属(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)、真杆菌属(Eubacterium)、韦荣氏球菌属(Veilonella)、梭杆菌属(Fusobacterium)、厌氧杆菌属(Bacterioides)、普氏菌属(Prevotella)、埃希氏杆菌属(Escherichia)或丙酸杆菌属(Propionibacterium)。更优选地,细菌物种是青春双歧杆菌(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)、乳酸双歧杆菌(B.lactis)、长双歧杆菌(B.longum);屎肠球菌(Enterococcus faecium);大肠杆菌(Escherichia coli);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)、约氏乳杆菌(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)、唾液乳杆菌(L.salivarius)、沙克乳杆菌(L.sakel)、乳酸乳球菌(Lactococcus lactis)(包括但不限于乳酸亚种、乳脂亚种和二乙酰乳酸亚种);肠系膜明串珠菌(Leuconostoc mesenteroides)(包括但不限于肠系膜亚种);乳酸片球菌(Pedicoccus acidilactici)、戊糖片球菌(P.pentosaceus);产丙酸丙酸杆菌(Propionibacterium acidipropionici)、费氏丙酸杆菌费氏亚种(P.freudenreichiissp.shermanii);肉葡萄球菌(Staphylococcus carnosus);和嗜热链球菌(Streptococcusthermophilus)。发酵液还可以包括发酵过程的其它产物,例如细胞(生物质)、发酵培养基、残留底物材料和发酵过程中产生的任何分子/副产物。
任选地,可以对发酵液进行热处理步骤,以杀灭可以任何显著程度存在的细菌或其它不需要的微生物。
还原步骤
对包括2’-岩藻糖基乳糖的发酵液进行还原,以产生包括2’-岩藻糖基乳糖和2’-岩藻糖基乳糖醇的经处理的发酵液。在该还原过程中,2’-岩藻糖基乳糖醇通过以下两种途径中的至少一种形成:
途径#1
-乳糖+2H++2e-→乳糖醇
-乳糖醇+GDP-岩藻糖→2'-盐藻糖基乳糖醇+GDP途径#2
-乳糖+GDP-岩藻糖→2'-盐藻糖基乳糖+GDP
2'-盐藻糖基乳糖+2H++2e-→盐藻糖基乳糖醇
在这些途径中,术语“2H++2e-”代表还原当量,通常以NAD(H)、NADP(H)、FAD(H)或中间体形式存在。在这两种途径中,反应都是由微生物酶催化的,并且这些反应将会在微生物内部发生。这些途径涉及还原反应,因此需要还原当量(H++e-)。2’-岩藻糖基乳糖醇的产生程度会受到以下因素影响:氧气流量,氧气浓度降低会增强还原条件;乳糖的相对流量,其在途径#1中直接还原为乳糖醇;作为碳源和电子载体的蔗糖的相对流量;或2’-岩藻糖基乳糖从微生物细胞输出的变化。另外可选地,还原在发酵过程中自发发生。还原步骤的温度和压力与发酵步骤的相同。
在发酵液的发酵和还原之后,这些步骤的产物经过各种步骤,以分离和纯化2’-FL和2’-FLol的干燥混合物。这些步骤如图1所示。分离步骤用于将2’-FL和2’-FLol从发酵液中含有的其它材料中分离出来。这样的分离步骤可以包括离心、如下所述的常规过滤和微滤,其产生富含2’-FL和2’-FLol的分离的料流。在分离步骤之后,分离的;对经分离的料流进行纯化步骤,其可以包括超滤、纳滤(nanofiltration)、阴离子交换、阳离子交换和脱色,以形成经分离和纯化的料流。然后在浓缩步骤和脱水步骤中对经分离和纯化的料流进行处理。这些步骤可以按任何顺序进行。换言之,可以首先在浓缩步骤中对经分离和纯化的料流进行处理,然后将浓缩产物送至脱水步骤。另外可选地,可以首先对经分离和纯化的料流进行脱水步骤,然后可将该脱水步骤的产物送至浓缩步骤。浓缩步骤可以包括蒸发、反渗透过滤和纳滤。蒸发过程可以包括,例如,降膜蒸发、升膜蒸发和旋转蒸发,以形成经分离、纯化和浓缩的料流。脱水步骤可以包括结晶、干燥、蒸发和常规过滤中的至少一种,以形成益生元固体产品。
在本公开的分离/纯化工艺步骤中使用的各种单元操作说明如下。可以根据所需的纯度水平使用这些单元操作的组合。有可能一些单元操作,如离心分离和常规过滤也可以既用于分离也用于浓缩步骤。
发酵液的分离和纯化操作
常规过滤
出于本说明书的目的,术语常规过滤是指使用板框式过滤、凹腔式过滤(recessedchamber filtration)、带式过滤(belt filtration)、真空过滤、水平金属叶过滤(horizontal metal leaf filtration)、竖直金属叶过滤(vertical metal-leaffiltration)、层叠盘式过滤(stacked-disc filtration)、旋转真空过滤及其组合的方法。
离心
离心可用于去除悬浮物质,比如生物质。所需的益生元固体产品包含在没有通过离心留住的液体中。优选地,离心是连续操作的。
微滤
错流(cross flow)过滤过程可以用于用作保护滤器,以去除离心步骤中未去除的残余生物质。通常,微滤具有10微米的截留,优选5微米的截留,更优选0.2微米的截留。产物流是液体渗透物。
超滤
错流超滤可以用于从发酵产物中去除蛋白质和其它高分子量化合物,比如DNA和大的多糖。超滤膜的孔径范围为约200kD截留分子量(“MWCO”)或更小至约1kD MWCO。产物流为渗透物。优选地,在超滤步骤后,渗透物中所需益生元固体的产率大于50%、大于60%、大于70%、大于80%、大于90%、大于91%、大于92%、大于93%、大于94%、大于95%、大于96%、大于97%、大于98%或大于99%。
纳滤
错流纳滤可以用于去除分子量小于所需益生元固体的低分子量分子,比如单糖和二糖、肽、小的有机酸和盐。纳滤膜的孔径为约500道尔顿(Da)或更小的截留分子量至200DaMWCO或更小。优选地,截留分子量为500道尔顿(Da)或更小、450Da MWCO、400Da MWCO、350DaMWCO、300Da MWCO、250Da MWCO或200Da MWCO或更小。产物流为渗余物。优选地,在纳滤步骤后,滞留物中所需益生元固体的产率大于50%、大于60%、大于70%、大于80%、大于90%、大于91%、大于92%、大于93%、大于94%、大于95%、大于96%、大于97%、大于98%或大于99%。
阳离子交换(CEX)
离子交换色谱可以用于从含有益生元固体的料流中分离带电分子。CEX固定相通常含有在水溶液中带负电荷的脂肪族磺酸基团,其紧密结合任何强碱性分析物。该步骤去除带正电荷的成分,例如残留的氨、金属和肽。所用树脂的结合能力一般为1.2至2.2mmeq/L。典型的用于阳离子交换的树脂包括Dow Dowex 88、Resindion JC系列(如JC603)和Resindion PK等级(如PK216)。
脱色
可以执行脱色步骤,以去除含颜色的组分。该步骤可使用活性炭比如Norit CA1活性炭、疏水相互作用色谱(HIC)或另一种可官能化的吸附树脂比如Resindion Relite RAD/F进行。脱色可以在阴离子交换步骤之前或之后进行。
阴离子交换
阴离子交换步骤可以用于分离带电分子。在阴离子交换柱中,填料带正电,因此通过库仑相互作用保留带负电的分子。该步骤去除带负电的成分,例如硫酸盐、磷酸盐、有机酸和带负电的颗粒。所用树脂的结合能力一般为0.8至2.0mmeq/L。典型的用于阴离子交换的树脂包括Resindion Relite系列如RAM2、D182、JA100,和Diaion WA系列如WA20。
浓缩
使用蒸发、反渗透过滤和纳滤,浓缩步骤可以用于从含益生元固体的料流中经济地去除大量液体。蒸发过程可以包括,例如,降膜蒸发、升膜蒸发和旋转蒸发。进入该过程的固体浓度为约5至30wt%。从该过程离开的固体浓度通常大于30wt%。优选大于50wt%。更优选地,离开脱水操作的固体浓度为60至80wt%。回收材料的固体部分大于80wt.%益生元固体,其余杂质主要是醛醇(alditol)或二糖或三糖。
热处理
热处理步骤可以用于杀灭可以任何显著程度存在的细菌或其它不期望的微生物,并且基本上为巴氏灭菌过程。任何可接受的巴氏灭菌条件都是可以的,例如从62.8℃持续30分钟到72℃持续20秒到100℃持续0.01秒。
干燥
干燥可以在间接干燥过程中通过间接干燥器进行,或者在直接干燥过程中通过直接干燥器进行。出于本说明书的目的,术语间接干燥器包括不利用待干燥材料与用于加热的工艺气体的直接接触进行干燥,而是依赖于通过干燥器的壁(例如,在滚筒干燥器的情况下,通过壳体壁)或另外可选地通过桨叶干燥器的中空桨叶的壁的热传递的那些装置,因为它们旋转通过固体,同时传热介质在桨叶的中空内部循环。间接干燥器的其它实例包括接触干燥器和真空滚筒干燥器。传热介质优选为蒸汽或传热油。更优选地,传热介质为蒸汽。术语直接干燥器包括热工艺气体移动通过容器、直接接触循环固体的过程,例如喷雾干燥器。急骤干燥器或流化床干燥器是此类直接干燥方法的其它实例。优选地,当使用直接干燥时,其通过在喷雾干燥器中的喷雾干燥进行。优选地,干燥方法为间接干燥。优选地,间接干燥方法为滚筒干燥。在滚筒干燥中,加热表面是旋转的水平金属圆筒的外壳。圆筒优选被在内部冷凝的蒸汽加热,使筒壁的温度达到110-155℃。优选地,益生元固体材料在干燥器上的停留时间小于3分钟。湿的材料作为相对较薄的层施加到滚筒表面上。干燥的产品在刀片或绳(string)的帮助下从滚筒中取出。随后,可以使用研磨和筛分步骤,以获得所需的粒度范围。
研磨
如果需要研磨步骤,一般来说可以使用任何适合于固体类型和目标粒度的研磨方法。此类研磨设备可以包括,例如,球磨机、锤磨机、SAG磨机、棒磨机、雷蒙(Raymond)磨机和立式磨机。
结晶
通过首先在过饱和溶液中形成益生元固体核,然后生长晶体,结晶过程可以用于使纯化的益生元固体材料脱水。这样的过程可以是分批的或连续的。典型的用于结晶的条件显示在WO 2018/164937中,其公开内容并入本文以供参考。该过程涉及将含有益生元固体的起始溶液浓缩至过饱和状态,然后从过饱和溶液中沉淀益生元固体晶体,同时优选将过饱和溶液置于至少55℃的温度下。优选地,溶液具有至少60wt.%且小于约98wt.%的益生元固体含量。随着益生元固体晶体百分比的增长,结晶通常受到粘度的限制,优选地,具有约30wt.%晶体的典型终点。
益生元固体产品
益生元固体产品含有0.2至6.0wt.%的2’-FLol、86.0至94.0wt.%的2’-FL和0至13.8wt.%的碳水化合物副产物。出于本说明书的目的,术语“碳水化合物副产物”包括二岩藻糖基乳糖、2’-岩藻糖基-d-乳果糖、乳糖/异乳糖、3’-岩藻糖基乳糖、岩藻糖基半乳糖、葡萄糖/半乳糖和果糖。这些材料的量使用Dionex Carbopac PA1柱使用离子色谱脉冲安培法检测确定。
优选地,益生元固体含有0.5至6.0wt.%、更优选0.5至3.5wt.%的2’-FLol,相应水平的其它碳水化合物分别为0至13.5wt.%和2.5至13.5wt.%。在这两种情况下,2’-FL均以86.0至94.0wt.%的量存在。
在另一实施方式中,益生元固体含有2.0至4.5wt.%、更优选2.0至4.0wt.%的2’-FLol,相应水平的碳水化合物副产物分别为1.5至12.0wt.%和2.0至12.0wt.%。在这两种情况下,2’-FL均以86.0至94.0wt.%的量存在。
在另一实施方式中,益生元固体含有0.2至10.0wt.%的2’-FLol、86.0至90.0wt.%的2’-FL和0至13.8wt.%的碳水化合物副产物。
优选地,2’-FL/2’-FLol的比率为14.3至470。
在另一实施方式中,本公开提供一种方法,其包括将有效量的益生元固体产品组合物施用于有需要的受试者,从而产生乳糖醇的体内供应。如上所述,在肠道中,2’-FLol被水解为岩藻糖和乳糖醇。
在另一实施方式中,本公开提供一种制造食品、成长奶、膳食补充剂或药物的方法,其中该方法包括:制造益生元固体产品;将益生元固体产品与一种或多种适合于食品、成长奶、膳食补充剂或药物的成分混合。
在再另一实施方式中,本公开提供一种制造食品、成长奶、膳食补充剂或药物的方法,其中该方法包括制造益生元固体产品;将益生元固体产品溶解在溶剂中;将溶解的益生元固体产品与一种或多种适合于食品、成长奶、膳食补充剂或药物的成分混合。
在另一实施方式中,本公开提供一种制造婴儿配方奶粉的方法,其中该方法包括制造益生元固体产品并将益生元固体产品与至少一种婴儿配方奶粉成分混合。
在一实施方式中,本公开提供一种制造婴儿配方奶粉的方法,其中该方法包括制造益生元固体产品并将益生元固体产品溶解在溶剂中;将溶解的益生元固体产品与至少一种婴儿配方奶粉成分混合。
在另一实施方式中,本公开提供从以下方法获得的食品、成长奶、膳食补充剂或药物,其中该方法包括:制造益生元固体产品;和将益生元固体产品与至少一种婴儿配方奶粉成分混合,或者首先将益生元固体产品溶解在溶剂中,将溶解的益生元固体产品与至少一种婴儿配方奶粉成分混合。
出于本说明书的目的,术语“婴儿配方奶粉”是指根据适用的国际食品法典委员会(Codex Alimentarius)和美国食品和药物管理局标准(i)满足从出生到4至6月龄的婴儿的全部正常营养需求,并适应其生理特征和/或除其它食物以外还喂养直至约1岁及以上的婴儿,或(ii)满足早产儿的正常营养需求的工业配制的母乳替代品。术语“婴儿”是指从出生到大约一岁的儿童。术语“成长奶(GUM)”是指营养增强型奶、植物、氨基酸和/或豆奶类液体产品,或用于重构为液体产品的粉末产品,在每种情况下都意在用作饮品,销售并意在用于十二(12)个月至三十六(36)个月的儿童,以及用于最大并包括六(6)岁的儿童。
已知有许多不同来源和类型的碳水化合物、脂肪、蛋白质、矿物质和维生素,其可以用作当前主题中说明的婴儿配方奶粉或GUM中的配方成分,其条件是这些营养素与所选制剂中的添加成分相容,并且还适用于婴儿配方奶粉。
适用于婴儿配方奶粉的碳水化合物可以是简单的或复杂的、含乳糖的或不含乳糖的,或其组合,其非限制性实例包括水解的、完整的、天然的和/或化学改性的玉米淀粉、麦芽糖糊精、葡萄糖聚合物、蔗糖、玉米糖浆、玉米糖浆固体、大米或马铃薯来源的碳水化合物、葡萄糖、果糖、乳糖、高果糖玉米糖浆和难消化的寡糖,例如3’-岩藻糖基乳糖、2’,3’-二岩藻糖基乳糖、乳-N-三糖II、乳-N-四糖、乳-N-新四糖、乳-N-岩藻五糖I、乳-N-新岩藻五糖、乳-N-岩藻五糖II、乳-N-岩藻五糖III、乳-N-岩藻五糖V、乳-N-新岩藻五糖V、乳-N-二岩藻六糖I、乳-N-二岩藻六糖II、6’-半乳糖基乳糖、3’-半乳糖基乳糖、乳-N-六糖和乳-N-新六糖、唾液酸基-乳-N-四糖a、唾液酸基乳-N-四糖b、唾液酸基乳-N-四糖c、二唾液酸基乳-N-四糖、3’和6’唾液酸基乳糖、乳-N-四糖、二岩藻糖基乳糖、乳-N-新四糖、低聚果糖(FOS)、低聚半乳糖(GOS)及其组合。
适用于婴儿配方奶粉的蛋白质包括水解的、部分水解的和未水解的或完整的蛋白质或蛋白质来源,其可以衍生自任何已知的或其它合适的来源,例如牛奶(例如酪蛋白、乳清)、动物(例如肉、鱼)、谷物(例如大米、玉米)、植物(例如大豆)或其组合。用于本文的蛋白质还可以包括已知用于或以其它方式适用于婴儿配方奶粉的游离氨基酸,或者完全或部分被其替代,其非限制性实例包括丙氨酸、精氨酸、天冬酰胺、肉碱、天冬氨酸、胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、牛磺酸、苏氨酸、色氨酸、牛磺酸、酪氨酸、缬氨酸及其组合。这些氨基酸最典型地以其L型使用,尽管当营养上等同时也可以使用相应的D型异构体。也可以使用外消旋或异构混合物。
适用于婴儿配方奶粉的脂肪包括椰子油、大豆油、玉米油、橄榄油、红花油、高油酸红花油、海藻油、MCT油(中链甘油三酯)、向日葵油、高油酸向日葵油、棕榈和棕榈仁油、棕榈油精、菜籽油、海产油(marine oil)、棉籽油及其组合。
适用于本发明婴儿配方奶粉的维生素和类似的其它成分包括维生素A、维生素D、维生素E、维生素K、硫胺素、核黄素、吡哆醇、维生素B12、烟酸、叶酸、泛酸、生物素、维生素C、胆碱、肌醇其盐和衍生物及其组合。
适用于婴儿配方奶粉的矿物质包括钙、磷、镁、铁、锌、锰、铜、铬、碘、钠、钾、氯化物及其组合。优选地,将上述营养素掺入婴儿配方奶粉中,其符合针对适当地理和用户人口统计的公认指南,例如,如21U.S.C.§350a(2018)中所说明。
婴儿配方奶粉或GUM可以进一步包括其他任选的成分,该成分可以改变组合物的物理、化学、美学或加工特性,或者在用于目标婴儿人群时用作药物或额外的营养成分。此类任选的成分的非限制性实例包括防腐剂、额外的抗氧化剂、乳化剂、缓冲剂、着色剂、调味剂、核苷酸和核苷、益生菌、益生元、乳铁蛋白和相关衍生物、增稠剂和稳定剂等。
实施例
以下实施例进一步详述和解释本发明方法的性能。本领域技术人员将认识到在本发明的精神和权利要求的范围内的许多变化。
分析方法
样品和标准品在适当稀释后使用高效阴离子交换色谱(HPAEC)与脉冲安培检测(PAD)联用进行分析。在Thermo Dionex ICS3000系统上注入样品和标准品(10uL)。在配备Thermo Dionex Carbopac PA1保护柱(50x4 mm)的Thermo Dionex Carbopac PA1柱(250x4mm)上进行分离。所关注的化合物,即乳糖醇、2’-岩藻糖基乳糖(2’-FL)、乳糖和2’-岩藻糖基乳糖醇(2’-FLol)用100mM NaOH作为流动相以1.5mL/min的流速洗脱10分钟。乳糖醇、2’-FL和乳糖的定量用市售参考材料使用外部校准进行。在没有2’-FLol参考材料的情况下,假设乳糖醇和2’-FLol对PAD的响应相同,基于乳糖醇参考材料通过外部校准对2’-FLol进行定量。
比较例
使用所述分析方法对几种市售2’-岩藻糖基乳糖产品中2’-岩藻糖基乳糖醇存在的量进行分析,并与组合物1和组合物2代表的本发明材料进行比较。
表1
样品 | 2’-岩藻糖基乳糖醇(wt%) |
组合物1 | 2.2 |
组合物2 | 3.86 |
Friesland Campina | 0.19 |
Dupont | 未检测到 |
Glycom | 0.01 |
Jennewein Biotechnologie GmbH | 0.1 |
2’-岩藻糖基乳糖醇被有益肠道细菌酶促水解
为了模拟2’-岩藻糖基乳糖醇被肠道细菌有效水解,释放乳糖醇,以1ml的总体积进行了体外酶促水解实验。以12μg/ml应用来自长双歧杆菌和双歧杆菌属的市售岩藻糖苷酶,用于水解存在于800μl 125mM pH 6.5磷酸钠缓冲液中的49mM的2-FL(对照,Care4U,Dupont)或47mM 2’-FL和2mM 2’-FLol(组合物2),加入200μl酶溶液,在37℃和1000rpm条件下(在来自Eppendorf的热混合器中)保持24小时。
表2
2小时后取出125μl样品,并立即在95℃下加热5分钟,使酶失活,然后如上所述通过HPAEC-PAD进行分析。
表3
底物 | 岩藻糖苷酶 | 2’-FL(wt%) | 2’-FLol(wt%) |
Care4U | 长双歧杆菌(Bifidobacterium longum) | 0 | 未检测到 |
Care4U | 双歧杆菌属(Bifidobacterium sp.) | 3 | 未检测到 |
Care4U | 无(对照反应) | 100 | 未检测到 |
本发明组合物2 | 长双歧杆菌(Bifidobacterium longum) | 0 | 0 |
本发明组合物2 | 双歧杆菌属(Bifidobacterium sp.) | 18 | 14 |
本发明组合物2 | 无(对照反应) | 99 | 97 |
数据证实,通常存在于哺乳动物消化道中的岩藻糖苷酶能够水解2’-FL和2’-FLol。
2’-岩藻糖基乳糖醇酶促水解释放乳糖醇
为了模拟2’-岩藻糖基乳糖醇被肠道细菌有效水解和释放乳糖醇,使用来自长双歧杆菌和双歧杆菌属的市售岩藻糖苷酶以两种不同浓度(2和12μg/ml)进行体外酶水解实验。
组合物2(包括47mM 2’-FL和2mM 2’-FLol)的水解在37℃和1000rpm条件下(在来自Eppendorf的热混合器中)仔细监测24小时。将组合物2溶解在125mM pH 6.5的磷酸钠缓冲液中,并向800μl该溶液中以规定的浓度加入酶。在10分钟、30分钟、2小时、8小时和24小时后采集时间样品。取出时间样品后,立即在95℃下加热5分钟使酶失活,然后如上所述通过HPAEC-PAD进行分析。将数据向最大量进行归一化,并以百分比表示为相对量,其中时间序列中的最大量设置为100%。
表4
通过将组合物2与12μg/ml长双歧杆菌岩藻糖苷酶(图2)、12μg/ml双歧杆菌属岩藻糖苷酶(图3)、2μg/ml长双歧杆菌岩藻糖苷酶(图4)或2μg/ml双歧杆菌属岩藻糖苷酶(图5)一起孵育,本发明的包括2’-FL和2’-FLol的组合物均易于水解,分别释放乳糖和乳糖醇。相比之下,未添加酶的对照是稳定的,没有2’-FL或2’-FLol的水解(图6)。因此,数据证实,通常存在于哺乳动物消化道中的岩藻糖苷酶可以水解2’-FL和2’-FLol,从而分别释放乳糖和乳糖醇。
对普通技术人员来说,在阅读上述公开内容后,本文公开的本发明的其它特征、优点和实施方式将是显而易见的。在这方面,尽管已相当详细地描述了本发明的具体实施方式,但可以在不脱离所描述并要求保护的本发明的精神和范围的情况下,对这些实施方式进行变化和修改。
Claims (29)
1.一种方法,其包括:
a.还原包括2’-岩藻糖基乳糖的发酵液,以产生包括2’-岩藻糖基乳糖和2’-岩藻糖基乳糖醇的经处理的发酵液;
b.从经处理的发酵液中分离包括2’-岩藻糖基乳糖和2’-岩藻糖基乳糖醇的料流;
c.纯化经分离的料流;
d.浓缩经分离和纯化的料流;
e.对经分离、纯化和浓缩的料流进行脱水,从而形成益生元固体产品,其包括2’-岩藻糖基乳糖和以所述益生元固体产品总wt.%计为0.2至6.0wt.%的2’-岩藻糖基乳糖醇,
其中步骤d和e可以任何顺序进行。
2.根据权利要求1所述的方法,其中所述脱水步骤选自结晶、干燥、蒸发和常规过滤中的至少一种。
3.根据权利要求1或权利要求2所述的方法,其中所述干燥选自间接干燥、直接干燥或其组合。
4.根据权利要求3所述的方法,其中所述直接干燥是喷雾干燥。
5.根据前述权利要求中任一项所述的方法,其中所述2’-岩藻糖基乳糖醇以0.5至6.0wt.%的量存在于所述益生元固体产品中。
6.根据权利要求5所述的方法,其中所述2’-岩藻糖基乳糖醇以0.5至3.5wt.%的量存在于所述益生元固体产品中。
7.根据前述权利要求中任一项所述的方法,其中所述2’-岩藻糖基乳糖醇以2.0至4.5wt.%的量存在于所述益生元固体产品中。
8.根据权利要求7所述的方法,其中所述2’-岩藻糖基乳糖醇以2.0至4.0wt.%的量存在于所述益生元固体产品中。
9.根据前述权利要求中任一项所述的方法,其中所述发酵液还包括生物质。
10.根据前述权利要求中任一项所述的方法,其中以所述益生元固体产品总wt.%计,2’-岩藻糖基乳糖以86.0至94.0wt.%的量存在于所述益生元固体产品中。
11.根据权利要求10所述的方法,其中所述益生元固体产品中2’-岩藻糖基乳糖/2’-岩藻糖基乳糖醇的比率为14.3至470。
12.根据权利要求2-11中任一项所述的方法,其中所述脱水步骤是结晶过程。
13.根据权利要求12所述的方法,其中所述益生元固体产品是结晶产品。
14.根据权利要求4-13中任一项所述的方法,其中所述益生元固体产品是干燥粉末。
15.益生元固体产品,其通过权利要求1-14中任一项所述的方法制造。
16.一种方法,其包括将有效量的权利要求15所述的组合物施用于有需要的受试者,从而产生乳糖醇的体内供应。
17.一种制造食品、成长奶、膳食补充剂或药物的方法,其中所述方法包括:
a.根据权利要求1-14中任一项所述的方法制造益生元固体产品;和
b.将所述益生元固体产品与一种或多种适合于食品、成长奶、膳食补充剂或药物的成分混合。
18.一种制造食品、成长奶、膳食补充剂或药物的方法,其中所述方法包括:
a.根据权利要求1-14中任一项所述的方法制造益生元固体产品;
b.将益生元固体产品溶解在溶剂中;和
c.将溶解的益生元固体产品与一种或多种适合于制造食品、成长奶、膳食补充剂或药物的成分混合。
19.一种制造婴儿配方奶粉的方法,其中所述方法包括:
a.根据权利要求1-14中任一项所述的方法制造益生元固体产品;和
b.将所述益生元固体产品与至少一种婴儿配方奶粉成分混合。
20.一种制造婴儿配方奶粉的方法,其中所述方法包括:
a.根据权利要求1-14中任一项所述的方法制造益生元固体产品;和
b.将所述益生元固体产品溶解在溶剂中;和
c.将溶解的益生元固体产品与至少一种婴儿配方奶粉成分混合。
21.一种食品、成长奶、膳食补充剂或药物,其由根据权利要求17或18所述的方法获得。
22.一种婴儿配方奶粉,其由根据权利要求19或20所述的方法获得。
23.根据权利要求18或20所述的方法,其中所述溶剂是水。
24.根据权利要求1-14中任一项所述的方法,其中所述还原步骤(a)在10至50℃的温度下进行。
25.根据权利要求24所述的方法,其中所述温度为25至35℃。
26.根据权利要求25所述的方法,其中所述温度为28至32℃。
27.根据权利要求1-14中任一项所述的方法,其中还原步骤(a)在3至8的pH下进行。
28.根据权利要求27所述的方法,其中pH为5至7。
29.根据权利要求28所述的方法,其中pH为5.5至6.5。
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PCT/EP2021/084563 WO2022122721A1 (en) | 2020-12-11 | 2021-12-07 | Improved prebiotic formulations |
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EP3494806A1 (en) * | 2017-12-08 | 2019-06-12 | Jennewein Biotechnologie GmbH | Spray-dried lacto-n-fucopentaose |
CN110592162A (zh) * | 2019-08-15 | 2019-12-20 | 安徽天凯生物科技有限公司 | 一种产2’-岩藻基乳糖菌株最佳发酵条件的构建方法 |
WO2020079146A1 (en) * | 2018-10-18 | 2020-04-23 | Basf Se | Crystalline form ii of 2'-o-fucosyllactose, process for its preparation, nutritional, cosmetic or pharmaceutical formulation containing the same |
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CA2822500C (en) * | 2010-12-31 | 2022-07-26 | Abbott Laboratories | Human milk oligosaccharides to promote growth of beneficial bacteria |
EP3209308B1 (en) | 2014-10-24 | 2022-08-03 | Evolve Biosystems Inc. | Activated bifidobacteria and methods of use thereof |
WO2018164937A1 (en) | 2017-03-06 | 2018-09-13 | Dupont Nutrition Biosciences Aps | Process for crystallizing 2'-fucosyllactose and related compositions |
WO2019003135A1 (en) | 2017-06-30 | 2019-01-03 | Glycom A/S | PURIFICATION OF OLIGOSACCHARIDES |
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EP3494806A1 (en) * | 2017-12-08 | 2019-06-12 | Jennewein Biotechnologie GmbH | Spray-dried lacto-n-fucopentaose |
WO2020079146A1 (en) * | 2018-10-18 | 2020-04-23 | Basf Se | Crystalline form ii of 2'-o-fucosyllactose, process for its preparation, nutritional, cosmetic or pharmaceutical formulation containing the same |
CN110592162A (zh) * | 2019-08-15 | 2019-12-20 | 安徽天凯生物科技有限公司 | 一种产2’-岩藻基乳糖菌株最佳发酵条件的构建方法 |
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