CN103582485A - 治疗急性呼吸道感染的寡糖组合物 - Google Patents
治疗急性呼吸道感染的寡糖组合物 Download PDFInfo
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- CN103582485A CN103582485A CN201180056475.7A CN201180056475A CN103582485A CN 103582485 A CN103582485 A CN 103582485A CN 201180056475 A CN201180056475 A CN 201180056475A CN 103582485 A CN103582485 A CN 103582485A
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- lactose
- oligosaccharide
- sialyllactose
- acute respiratory
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Abstract
本发明公开了包含至少一种N-乙酰乳糖胺、至少一种唾液酰寡糖和至少一种岩藻糖化的寡糖的组合物,其用于预防急性呼吸道感染(ARI)和/或减轻所述ARI感染的症状。优选地,所述组合物是一段婴儿配方食品。所述急性呼吸道感染特别是细支气管炎或耳炎。
Description
发明领域
本发明涉及用于预防急性呼吸(道)感染(ARI)和/或减轻所述ARI的症状的组合物。
发明背景
呼吸道感染非常常见,尤其是在婴儿和幼儿当中。例如,在一岁以内,婴儿通常会经历三到六次此类感染。此类感染通常开始是细菌感染,且经常随后是病毒感染,例如流行性感冒。呼吸道细菌感染的实例包括肺炎、细支气管炎、鼻窦炎、咽炎和中耳炎。
急性呼吸道感染(ARI)是继发性细菌感染(与上呼吸道感染相反)。其可以导致中耳感染、支气管炎、细支气管炎、肺炎、鼻窦炎、咽炎、耳炎或脓毒性咽喉炎。患有慢性肺病、哮喘、糖尿病或免疫系统减弱的人群更容易产生此类并发症。
多发的急性呼吸道感染(ARI)通常与急性中耳炎相关联。其为中耳的感染,其中连接中耳腔和经口腔的外部环境的咽鼓管变得发炎并随后堵塞,将细菌包埋在中耳内。在严重的情况下,鼓膜可能在压力下爆裂,使得感染的液体进入内耳。这是非常危险的状况,如果不进行治疗将可能导致永久性听力损伤。
急性中耳炎显示出与通常在鼻咽腔的固有微生物群中发现的致病菌的活性相关。数量上而言,最显著的病原体是肺炎链球菌(Streptococcuspneumoniae)(35%的情况)、无法归类的流感嗜血菌(Haemophilus influenzae)(30%的情况)和粘膜炎莫拉菌(Moraxella catarrhalis)(10%的情况)。
50%的儿童在一岁以内有过至少一次急性中耳炎发作,且35%的儿童在一至三岁期间有过急性中耳炎的复发。
细支气管炎是另一种由影响通往肺部的微小气道(称为细支气管)的感染引起的常见呼吸道疾病。由于这些气道发炎,其肿胀且充满粘液,使得呼吸困难。
尽管其通常是温和的疾病,某些婴儿还是面临需要住院治疗的更严重疾病的风险。增加罹患严重细支气管炎风险的病症包括早产、早期慢性心脏病或肺部疾病,以及由于疾病或药物治疗引起的免疫系统减弱。
患有细支气管炎的幼儿更可能在日后发展为哮喘,但是否该疾病引发或触发哮喘或者是否最终发展为哮喘的儿童单纯地更易于在婴儿时期患有细支气管炎尚不明确。
细支气管炎通常是由病毒感染引发,其一般而言是由呼吸道合胞病毒(RSV)引发。超过半数的细支气管炎病例都是由RSV感染引起,且在冬季和早春季最广泛。其它与细支气管炎相关的病毒包括鼻病毒、流感病毒和人变性肺病毒。
根据上文,可以发现需要预防ARI感染和/或减轻ARI症状,特别是细支气管炎和急性中耳炎(或耳炎)的症状的有效方法。
总体而言,人乳寡糖(HMO)是人乳中在乳糖和脂肪之后的第三大固体成分。HMO通常包含在还原末端的乳糖与在非还原末端通常包含岩藻糖或唾液酸的碳水化合物核心。已经分离并鉴定了大约一百种人乳寡糖,然而这些仅代表了还未鉴定的总数量中的非常小的部分。
在过去,出于不同目的,婴儿配方食品开始发展使用HMO组分,例如岩藻糖化的寡糖、乳糖-N-四糖、乳糖-N-新四糖或唾液酰寡糖。
来自雅培公司(Abbott Laboratories)的EP0975235B1描述了包含一种或多种人乳寡糖的合成的营养组合物,其中组合物中的HMO是选自八种HMO(3-岩藻糖基乳糖、乳糖-N-岩藻五糖III、乳糖-N-岩藻五糖II、二岩藻糖基乳糖、2’-岩藻糖基乳糖、乳糖-N-岩藻五糖I、乳糖-N-新四糖和乳糖-N-岩藻五糖V),其中所述组合物预期用于正常的健康婴儿、儿童、成人或有特殊需要的个体(例如那些伴有某些病理学病症的个体)。总而言之,该欧洲专利陈述了寡糖类保护婴儿避免呼吸道、胃肠道和泌尿生殖道的病毒和细菌感染。
根据上文,可以发现需要预防急性呼吸道感染和/或减轻急性呼吸道感染症状、特别是针对婴儿和幼儿的感染和/或症状且可以方便和安全施用的有效的营养组合物。
需要在易感个体,尤其是婴儿,更尤其是呈现出此类病史或风险因素的婴儿中,减轻ARI(特别是耳炎或细支气管炎)的症状和/或降低严重性、复发率、发病率和/或持续时间。
需要这类干预,其可保持脆弱个体的代谢平衡,并因此不会伴随副作用,例如干扰免疫系统或炎症状态改变。
需要与脆弱个体如婴儿或儿童相容的非基于药物的干预方法来改善症状并减轻通常与急性呼吸道感染相关的状况,特别是耳炎和细支气管炎。这些状况可以包括对睡眠质量和/或数量、疼痛、活动过度或活动减退和/或哭泣时间的作用。
发明简述
令人吃惊地,发明人已经发现包含特定的人寡糖混合物的组合物对于用以预防急性呼吸道感染(ARI)和/或减轻急性呼吸道感染的症状特别有效,特别是在预防和/或减轻细支气管炎或耳炎的症状中有效。
因此,本发明提供了包含至少一种N-乙酰乳糖胺、至少一种唾液酰寡糖和至少一种岩藻糖基寡糖的组合物,其用于预防急性呼吸道感染和/或减轻急性呼吸道感染症状。
发明详述
如本文所用,以下术语具有下列含义。
术语“婴儿”的含义是12个月以内的儿童。
术语“幼儿”的含义是一至三岁之间的儿童。
术语“婴儿配方食品”的含义是预期用于出生后最初四个月至六个月期间婴儿特殊营养使用且其自身满足该阶段人群的营养需求的食品(1991年5月14日欧委会导则91/321/EEC关于婴儿配方食品和后续配方食品的内容的条款1.2)。
术语“后续配方食品”的含义是预期用于四个月以上婴儿的特殊营养使用且包含该阶段人群的逐渐多样化膳食中的主要液体成分的食品。
术语“一段婴儿配方食品”的含义是预期用于出生后最初四个月以内婴儿的特殊营养使用的食品。
术语“婴儿食品”的含义是预期用于出生后最初几年的婴儿特殊营养使用的食品。
术语“婴儿谷物组合物”的含义是预期用于出生后最初几年的婴儿特殊营养使用的食品。
术语“成长牛奶”的含义是适用于幼儿特定营养需要的基于牛奶的饮料。
术语“断奶期”的含义是母乳由婴儿膳食中的其它食物代替的时期。
术语“预防ARI”的含义是预防和降低ARI,特别是耳炎和细支气管炎的复发率和/或发病率和/或严重性和/或持续时间。发病率是有关任何ARI的发病次数。复发率是有关相同ARI的发病次数。该预防包括在以后生活中降低所述ARI的复发率和/或严重性。术语“在以后生活中”包含在终止该干预后的作用。“在以后生活中”中的作用可以优选在终止所述干预后2-4周、2-12个月或数年(例如2、5、10年)。
术语“减轻ARI的症状”的含义是减少ARI的症状,尤其是细支气管炎或耳炎的症状,以及特别是使患有ARI的婴儿和幼儿的呼吸过程容易和/或减轻疼痛和/或促进睡眠和/或稳定活动性。
术语“营养组合物”的含义是向个体提供营养的组合物。该营养组合物通常经口服或静脉内摄入,且通常包含脂质或脂肪来源和蛋白质来源。
术语“合成混合物”的含义是通过化学和/或生物学方法获得的混合物,其可以与哺乳动物乳中天然存在的混合物在化学上相同。
术语“低变应原的营养组合物”的含义是不容易引发过敏反应的营养组合物。
术语“唾液酰寡糖”的含义是带有唾液酸残基的寡糖。
术语“岩藻糖化的寡糖”的含义是带有岩藻糖残基的寡糖。
术语“益生元”的含义是不可消化的碳水化合物,其通过选择性地刺激人类结肠内的健康细菌例如双歧杆菌的生长和/或活性从而有利地作用于个体(Gibson GR,Roberfroid MB.Dietary modulation of the humancolonic microbiota:introducing the concept of prebiotics.J Nutr.1995;125:1401-12)。
术语“益生菌”的含义是对宿主健康或幸福具有有利作用的微生物细胞制剂或微生物细胞的组分。(Salminen S,Ouwehand A.Benno Y.等人“Probiotics:how should they be defined”Trends Food Sci.Technol.1999:10107-10)。
“过敏症”是可以由医师检查到且可以临时治疗或以更加持久的方式治疗的过敏症。
除非另外指明,全部百分比都是重量百分比。
本发明的组合物优选地是低变应原的营养组合物。
所述组合物包含至少一种N-乙酰乳糖胺。即,其包含N-乙酰乳糖胺和/或包含含有N-乙酰乳糖胺的寡糖。适合的含有N-乙酰乳糖胺的寡糖包括乳糖-N-四糖(LNT)和乳糖-N-新四糖(LNnT)。
因此,根据本发明,N-乙酰乳糖胺优选地选自乳糖-N-四糖(LNT)和乳糖-N-新四糖(LNnT)。
LNT和LNnT可以使用例如US专利号5,288,637和WO96/10086中所述的糖基转移酶将来自供体部分的糖单元经酶转移至受体部分来进行化学合成。或者,LNT和LNnT可以如Wrodnigg,T.M.;Stutz,A.E.(1999)Angew.Chem.Int.Ed.38:827-828中所述,通过将游离的(例如果糖)或与寡糖结合的酮基-己糖类(例如乳果糖)化学转化为N-乙酰己糖胺或包含N-乙酰己糖胺的寡糖来制备。按照该方法制备的N-乙酰乳糖胺随后可以转移至作为受体部分的乳糖。
优选地,本发明的组合物包含每100g组合物为0.1-3g的N-乙酰乳糖胺乳糖(基于干重)。
根据本发明,唾液酰寡糖选自3’-唾液酰乳糖和6’-唾液酰乳糖。优选地,3’-唾液酰乳糖和6’-唾液酰乳糖都存在于所述组合物中。在该实施方案中,3’-唾液酰乳糖和6’-唾液酰乳糖的比例优选地为5:1和1:2之间。
唾液酰乳糖的3’-和6’-形式可以通过色谱或过滤技术从天然来源例如动物乳中分离。或者,它们可以通过生物技术方法使用特定的唾液酸转移酶或唾液酸酶、神经氨酸酶,或者通过基于酶的发酵技术(重组或天然酶类)、通过化学合成或微生物发酵技术来制备。在后一种情况中,微生物可以表达其天然酶类和底物,或者可以经基因操作用于制备各自的底物和酶类。可以使用单一微生物培养物或混合培养物。可以由受体底物从任何DP=1以上的聚合水平(DP)开始,引发形成唾液酰寡糖。或者,唾液酰乳糖可以经化学合成方法从乳糖和游离N’-乙酰神经氨酸(唾液酸)制备。唾液酰乳糖也可以从市场获得,例如购自日本的Kyowa Hakko Kogyo公司。
优选地,本发明的组合物包含每100g基于干重的组合物中0.05-2g,更加优选0.1-2g的唾液酰寡糖。
所述岩藻糖化的寡糖可以选自2’-岩藻糖基乳糖、3-岩藻糖基乳糖、二岩藻糖基乳糖、乳糖-N-岩藻五糖(即乳糖-N-岩藻五糖I、乳糖-N-岩藻五糖II、乳糖-N-岩藻五糖III和乳糖-N-岩藻五糖V)、乳糖-N-二岩藻六糖I、岩藻糖基乳糖-N-六糖、二岩藻糖基乳糖-N-六糖I和二岩藻糖基乳糖-N-新六糖II。特别优选的岩藻糖化的寡糖是2’-岩藻糖基乳糖(2-FL)。
所述岩藻糖化的寡糖可以经色谱或过滤技术从天然来源例如动物乳中分离。或者,它们可以经生物技术方法使用特定的岩藻糖基转移酶和/或岩藻糖苷酶,或者使用基于酶的发酵技术(重组或天然酶类)或微生物发酵技术来制备。在后一种情况中,微生物可以表达其天然酶类和底物,或者可以经基因操作用于制备各自的底物和酶类。可以使用单一微生物培养物或混合培养物。可以由受体底物从任何DP=1以上的聚合水平(DP)开始,引发形成岩藻糖化的寡糖。或者,岩藻糖化的寡糖可以经化学合成方法从乳糖和游离岩藻糖制备。岩藻糖化的寡糖也可以从市场获得,例如购自日本的Kyowa Hakko Kogyo公司。
优选地,本发明的组合物包含每100g基于干重的组合物中0.1-3g岩藻糖化的寡糖。
在优选的实施方案中,本发明的组合物包含每100g组合物中0.05-3g总量的N-乙酰乳糖胺、唾液酰寡糖和岩藻糖化的寡糖。
本发明组合物可以进一步包含至少一种益生菌菌株,所述益生菌菌株优选地是双歧杆菌属(Bifidobacteria)和/或乳杆菌属(Lactobacilli)。
适合的益生菌菌株包括购自芬兰Valio Oy的商标为LGG的鼠李糖乳杆菌(Lactobacillus rhamnosus)ATCC53103;鼠李糖乳杆菌CGMCC1.3724、副干酪乳杆菌(Lactobacillus paracasei)CNCM I-2116、售自BioGaia A.B的商标为Reuteri的罗伊乳杆菌(Lactobacillus reuteri);约氏乳杆菌(Lactobacillus johnsonii)CNCM I-1225、售自新西兰BLISTechnologies Limited的命名为K12的唾液链球菌(Streptococcus salivarius)DSM13084;尤其是售自丹麦Christian Hansen公司的商标为Bb12的乳双歧杆菌(Bifidobacterium lactis)CNCM1-3446;售自日本Morinaga MilkIndustry有限公司的商标为BB536的长双歧杆菌(Bifidobacterium longum)ATCC BAA-999;售自Danisco的商标为Bb-03的短双歧杆菌(Bifidobacterium breve);售自Morinaga的商标为M-16V的短双歧杆菌;售自Procter & GambIe公司的商标为Bifantis的婴儿双歧杆菌(Bifidobacterium infantis)和售自Institut Rosell(Lallemand)的商标为R0070的短双歧杆菌。
优选地,本发明组合物包含每g基于干重的组合物为10e3-10e12cfu的益生菌菌株,更加优选10e7-10e12cfu。
本发明的组合物可以进一步包含至少一种益生元,通常包含0.3-10%组合物重量的量。
益生元通常是不可消化的,在某种程度上它们在胃或小肠内不能降解和吸收,并因此当它们进入结肠时保持完整,在其中它们可以选择性的被有益菌发酵。益生元的实例包括某些寡糖,例如寡聚果糖(FOS)和寡聚半乳糖(GOS)。可以使用的益生元组合例如90%GOS与10%短链寡聚果糖,例如售自BENEO-Orafti的商标为果糖的产品(以前为),或10%菊糖,例如售自BENEO-Orafti的商标为菊糖(以前为)的产品。特别优选的益生元组合是70%短链寡聚果糖和30%菊糖,其是售自BENEO-Orafti的商标为“Prebio1”的产品。
本发明组合物可以进一步包含至少一种噬菌体(细菌噬菌体)或噬菌体混合物,优选地针对致病性的链球菌属(Streptococci)、嗜血菌属(Haemophilus)、莫拉菌属(Moraxella)、葡萄球菌属(Staphylococci)。
本发明的组合物优选地是合成营养组合物。在此情况下,其可以是一段婴儿配方食品、婴儿配方食品、婴儿食品、婴儿谷物组合物、后续配方食品或成长牛奶,且所述组合物优选地是一段婴儿配方食品。
根据优选的实施方案,本发明的组合物用于罹患ARI的婴儿和幼儿。
本发明的组合物可以用于断奶期之前和/或期间使用。
本发明组合物可以进一步包含至少一种噬菌体或噬菌体混合物,例如针对致病性的链球菌属、嗜血菌属、莫拉菌属、葡萄球菌属。
因此,优选地本发明组合物是用于使患有ARI或具有ARI早期症状的婴儿呼吸过程容易、减轻疼痛、改善睡眠和/或减轻症状。
ARI特别是细支气管炎或耳炎。
本发明还包括包含至少一种N-乙酰乳糖胺、至少一种唾液酰寡糖和至少一种岩藻糖化的寡糖的组合物作为合成营养物用于预防和/或治疗急性呼吸道感染、优选细支气管炎或耳炎的用途。
该用途包括所述组合物是补充剂的情况,优选以单位剂量形式提供。
上文所述的全部用途特别预期用于婴儿和幼儿。本发明的组合物和用途特别适用于有罹患呼吸道感染和/或炎症风险、具有呼吸道感染或炎症家族史或者已经经历过呼吸道感染或炎症(和/或呼吸道过敏)的某些发作的婴儿和幼儿。在一项实施方案中,本发明组合物和用途适用于有罹患呼吸道感染或炎症风险或已经经历过呼吸道感染或炎症(和/或呼吸道过敏)的发作的青少年或成人。
不希望被理论束缚,发明人相信上文所述寡糖的组合在预防ARI和/或减轻ARI症状中的效力可以是由上文所述寡糖组合所引发的协同作用的结果。一方面,促进了共生的口咽部微生物群,并且另一方面有效地抑制了致病的微生物群。例如,已知大量的口咽病原体的粘附被特定的可溶的乳寡糖(见上文)减缓。认为这种促进和抑制的组合导致了口咽部微生物群的建立,其具有最佳的和平衡的(i)生态位占据、(ii)微生物群-宿主相互作用、以及(iii)生态稳定性。这意味着(i)即使面临外源性的非生物和生物挑战,仍然保持稳定的口咽部生态平衡。因此,在干预期之外潜在感染物被竞争抑制,并且不容易建立和引发ARI疾病。
所述寡糖可以在同一组合物中施用或者依次施用。
如果所述年龄段是0-12个月,那么该组合物优选地是以液态形式施用的营养组合物。其可以是营养完全的配方食品例如婴儿配方食品、后续配方食品或成长牛奶。或者,对于幼儿组,该组合物可以是例如果汁饮料或其它冷藏或耐储存的饮料或汤,或婴儿食品,或婴儿谷物组合物。
本发明的组合物还包含蛋白质来源,优选为每100kcal低于2.0g的量,甚至更加优选每100kcal低于1.8g的量。蛋白质的类型对于本发明不是决定性的,条件是要满足必需氨基酸含量的最低需求并保证满意生长。因此,可以使用的蛋白质来源是基于乳清、酪蛋白及其混合物,以及基于大豆的蛋白质来源。当考虑乳清蛋白时,该蛋白质来源可以基于酸乳清或甜乳清或其混合物,且可以包含以任何期望比例的α-乳清蛋白和β-乳球蛋白。
所述蛋白质可以是完整的或水解的或者完整和水解的蛋白质的混合物。可以期望提供部分水解的蛋白质(水解程度在2-20%之间),例如用于认为具有发生牛奶过敏风险的婴儿。一般而言,水解蛋白可以降低过敏(对牛奶或对其它变应原)的风险。如果需要水解蛋白,该水解过程可以如期望的和如本领域已知的方法进行。例如,乳清蛋白水解物可以以一个或多个步骤将乳清部分酶水解进行制备。如果用作起始原料的乳清部分是基本上不含乳糖的,发现在水解过程中该蛋白质经受更少的赖氨酸阻断。这使得赖氨酸阻断的程度从大约赖氨酸总重的15%减少至低于赖氨酸重量的10%;例如,大约7%赖氨酸重量,其大大地提高了所述蛋白质来源的营养质量。
本发明的组合物一般包含碳水化合物来源。特别优选本发明的营养组合物是婴儿配方食品。在此情况下,通常在婴儿配方食品中发现的任何碳水化合物来源例如乳糖、蔗糖、麦芽糊精、淀粉及其混合物都可以使用,但优选的碳水化合物来源是乳糖。
本发明的组合物一般包含脂质来源。如果所述本发明营养组合物是婴儿配方食品时,其特别相关。在此情况下,所述脂质来源可以是任何适用于婴儿配方食品的脂质或脂肪。优选的脂肪来源包括棕榈油、高油酸葵花籽油和高油酸红花油。还可以加入必需脂肪酸亚油酸和α-亚麻酸,以及少量包含大量形成的花生四烯酸和二十二碳六烯酸的油类,例如鱼油或微生物油类。脂肪来源优选地具有n-6与n-3脂肪酸约5:1至约15:1的比例;例如约8:1至约10:1。
本发明的营养组合物还优选地包含被认为是每日膳食所必需的营养上有意义的量的所有维生素和矿物质。已经确定了某些维生素和矿物质的最小需求量。任选地存在于本发明组合物中的矿物质、维生素和其它营养物的实例包括维生素A、维生素B1、维生素B2、维生素B6、维生素B12、维生素E、维生素K、维生素C、维生素D、叶酸、肌醇、烟酸、生物素、泛酸、胆碱、钙、磷、碘、铁、镁、铜、锌、锰、氯、钾、钠、硒、铬、钼、牛磺酸和L-肉碱。矿物质通常以盐的形式加入。特定矿物质以及其它维生素的存在和量将根据预期的人群而不同。
如果必要,本发明组合物可以包含乳化剂和稳定剂,例如大豆、卵磷脂、柠檬酸单甘油酯或二甘油酯等。
本发明组合物还可以包含其它可以具有有利作用的物质,例如乳铁蛋白、核苷酸类、核苷类等。
现将本发明组合物以举例的方式进行描述。
该配方食品可以以任何适合的方法制备。例如,其可以通过将蛋白质、碳水化合物来源和脂肪来源一起以合适的比例混合来制备。如果使用,可以在此时包含乳化剂。可以在此时加入维生素和矿物质,但通常较晚加入以避免热降解。任何亲脂性维生素、乳化剂等可以在混合前预先溶于脂肪来源中。水(优选的水是经过反渗透的)可以随后混入,以形成液态混合物。水的温度方便地处于大约50°C至大约80°C之间,以有助于成分的扩散。可以使用市场可获得的液化器形成液态混合物。如果终产物具有液态形式时,可以在该阶段加入N-乙酰乳糖胺、唾液酰寡糖和岩藻糖化的寡糖。如果终产物是粉末,在需要时,寡糖类同样可以在该阶段加入。随后将液态混合物均质化,例如分两个阶段。
随后可将该液态混合物热处理以减少细菌荷载量,例如通过将该液态混合物快速加热至约80°C至约150°C持续约5秒至约5分钟。其可以通过蒸汽注入、高压釜或热交换器(例如板式热交换器)的方式来进行。
随后,将该液态混合物冷却至约60°C至约85°C,例如通过瞬时冷却法冷却。然后将该液态混合物再次均质化,例如分两阶段进行,第一阶段在约10Mpa和约30Mpa之间,第二阶段在约2Mpa和约10Mpa之间。该均质化的混合物随后进一步冷却,以加入热敏感的成分,例如维生素和矿物质。该均质化的混合物的pH和固体含量在此时方便地调整。
将该均质化的混合物转移至合适的干燥设备例如喷雾干燥器或冷冻干燥器中并转化为粉末。该粉末应当具有低于约5%重量的含水量。在该阶段通过干燥混合或者通过将它们混入晶体的糖浆形式中来加入N-乙酰乳糖胺、唾液酰寡糖和岩藻糖化的寡糖,并且如果使用的话,同时加入益生菌菌株,并喷雾干燥(或冷冻干燥)。
如果优选液态组合物,可以将该均质化的混合物灭菌,随后无菌填装入适合的容器中,或先装入容器中并随后蒸馏。
在另一项实施方案中,本发明组合物可以是补充剂,其包含足够达到个体中所需效果的量的N-乙酰乳糖胺、唾液酰寡糖和岩藻糖化的寡糖。该施用形式更加适合于较大儿童和成人。优选地,N-乙酰乳糖胺的每日剂量是0.1-3g,唾液酰寡糖的每日剂量是0.1-2g,以及岩藻糖化的寡糖的每日剂量是0.1-3g。
包含在补充剂中的寡糖的量根据所述补充剂的施用方式来选择。例如,如果该补充剂每天施用两次,则每次补充剂可包含0.05-1.5g的N-乙酰乳糖胺、0.05-1g的唾液酰寡糖和0.05-1.5g的岩藻糖化的寡糖。
例如,所述补充剂可以是片剂、胶囊、锭剂或液体形式。该补充剂可以进一步包含保护性的水胶体(例如树胶、蛋白质、变性淀粉)、粘合剂、薄膜成型剂、包封剂/材料、外壁/外壳材料、基质化合物、包衣、乳化剂、表面活性剂、增溶剂(油类、脂肪、蜡类、卵磷脂类等)、吸附剂、载体、填充剂、辅助化合物、分散剂、润湿剂、加工助剂(溶剂)、助流剂、味道掩蔽剂、增重剂、胶结剂和凝胶成型剂。该补充剂还可以包含常规药用添加剂和佐剂、赋形剂和稀释剂,包括但不限于水、任何来源的明胶、植物胶、木素磺酸盐、滑石粉、糖、淀粉、阿拉伯胶、植物油、聚亚烷基二醇类、矫味剂、防腐剂、稳定剂、乳化剂、缓冲剂、润滑剂、着色剂、润湿剂、填充剂等。
此外,依照政府机构的推荐,例如USRDA,该补充剂可以包含适用于口服或胃肠外施用的有机或无机载体材料以及维生素、矿物质微量元素和其它微量营养物。
根据本发明的婴儿配方食品组合物的实例见下文。该组合物仅用于解释说明。另一个实例是基于市售的NAN和/或Lactogen婴儿配方食品(来自雀巢公司,瑞士),其中所加入的本发明的特定寡糖的量如下文所述。
实验数据:
已经进行了与本发明相关的以下实验性研究(研究模型1和2)。
下文所概括的发现显示特定寡糖的混合物可以提高乳酸菌(长双歧杆菌婴儿亚种(Bifidobacterium longum subsp infantis))的代谢活性,从而产生对模式病原体更强的抑制。在婴儿中,母乳中该寡糖混合物的量越多,则伴随较少的呼吸道感染。
汇总结果说明,特定的寡糖混合物与特定的婴儿共生菌协同性地作用,从而减少呼吸道感染。
研究模型1:条件培养基对长双歧杆菌婴儿亚种的刺激和对病原体的抑制
方法:
将长双歧杆菌婴儿亚种(ATCC15697)在添加了1%(w/v)葡萄糖或1%(w/v)2’岩藻糖基乳糖(2FL)或1%(w/v)乳糖-N-新四糖(LNnT)或1%(w/v)6’唾液酰乳糖(6SL)或1%(w/v)等量的2FL、LNnT和6SL的组合的API生长培养基中在缺氧情况下生长。将每次过夜的培养物稀释,使其具有在包含作为碳源的0.1%葡萄糖的DMEM(达尔伯克改良伊格尔培养基)中0.1的起始OD600。该培养基不经任何进一步的碳水化合物添加直接使用,或者另外加入1%(w/v)葡萄糖或1%(w/v)2’岩藻糖基乳糖(2FL)或1%(w/v)乳糖-N-新四糖(LNnT)或1%(w/v)6’唾液酰乳糖(6SL)或1%(w/v)等量的2FL、LNnT和6SL的组合。因此,DMEM培养基的条件培养是在37°C缺氧情况下进行。
再培养一夜后,将条件培养基离心,并经0.22微米滤器过滤上清以除去细菌。经HPLC用Hi-Plex H柱和UV检测器将乙酸盐定量。
因此,用NaOH将条件培养的DMEM培养基调至pH约6-7,与10e6cfu/ml的过夜生长的模式病原体鼠伤寒沙门菌(Salmonella typhimurium)SL1344孵育。在37°C孵育2小时,将病原体涂布于LB琼脂上并在37°C孵育过夜后定量。
图1说明了实验结果所显示的在DMEM培养基中不另外添加碳水化合物,或者另外加入葡萄糖(Glc)或乳糖-N-新四糖(LNnT)或2’岩藻糖基乳糖(2FL)或6’唾液酰乳糖(6SL)或LNnT、6SL和2FL的混合物的情况下对双歧杆菌(长双歧杆菌婴儿亚种)的代谢刺激。(n=6;显示了平均值与SEM;通过ANOVA指示显著性)。注:仅有LNnT、6SL和2FL的混合物显著地刺激了乙酸盐的产生。
图2说明了实验结果所显示的在培养基中不另外添加碳水化合物,或者另外加入葡萄糖(Glc)或乳糖-N-新四糖(LNnT)或2’岩藻糖基乳糖(2FL)或2’岩藻糖基乳糖(2FL)或6’唾液酰乳糖(6SL)或LNnT、6SL和2FL的混合物的情况下双歧杆菌(长双歧杆菌婴儿亚种)的体外生长。(n=4;显示了平均值与SEM;通过ANOVA用小写字母指示显著性(p<0.01))。
结果:
令人吃惊地发现,包含等量的岩藻糖化的寡糖(如2’FL)、N-乙酰基寡糖(如LNnT)和唾液酰寡糖(如6SL)的寡糖混合物可以显著地提高乳酸菌(例如双歧杆菌)的代谢活性,如乙酸盐的形成所示(图1)。
此外,与单独用各寡糖或葡萄糖条件培养的培养基相比较,用双歧杆菌和所述的寡糖混合物条件培养的培养基还显著地且协同性地抑制模式病原体(图2)。
该抑制作用的准确性质目前尚不清楚,但我们认为,2FL、LNNT和6SL的寡糖混合物与双歧杆菌在体外实验中协同发挥抗病原体作用,所述的病原体不仅仅是本文所检测的模式病原体。
研究模型2:母乳样品的追溯性流行病学分析和2岁以内的呼吸道感染的发病率
方法:
从约270对婴儿和母亲的群体中,我们分析了早期乳样品中特定寡糖存在的量。为此目的,将脱脂的乳样品在水中稀释10-100倍,并用装有CarboPac PA1柱(Dionex)和电化学检测器的HPAEC(Dionex)进行分析。用经认证的寡糖标准物对寡糖进行定性和定量。我们绘图表示了饲喂含有(i)低含量(低于2g/l)和(ii)高含量(高于2g/l)的寡糖混合物(包含2FL、LNnT和6SL)的奶的婴儿的呼吸道感染的次数。
图3说明了实验结果显示喂食了包含低量(<2g/l)的或者高量(≥2g/l)的含有2FL、LNnT和6SL的寡糖混合物的奶的2岁以内的婴儿的呼吸道感染次数。(显示了统计学意义)。
结果:
令人吃惊地发现,喂食包含高含量的寡糖混合物的奶显著地降低了婴儿呼吸道感染的次数。
Claims (14)
1.包含至少一种N-乙酰乳糖胺、至少一种唾液酰寡糖和至少一种岩藻糖化的寡糖的组合物,其用于预防急性呼吸道感染和/或减轻急性呼吸道感染的症状。
2.如上述权利要求所述的组合物,其中N-乙酰乳糖胺是选自乳糖-N-四糖和乳糖-N-新四糖。
3.如上述权利要求中任一项所述的组合物,其中唾液酰寡糖是选自3’-唾液酰乳糖和6’-唾液酰乳糖,并且优选地所述组合物同时包含3’-唾液酰乳糖和6’-唾液酰乳糖,3’-唾液酰乳糖和6’-唾液酰乳糖的比例优选地为5:1至1:2之间。
4.如上述权利要求中任一项所述的组合物,其中岩藻糖化的寡糖选自2’-岩藻糖基乳糖、3-岩藻糖基乳糖、二岩藻糖基乳糖、乳糖-N-岩藻五糖(即,乳糖-N-岩藻五糖I、乳糖-N-岩藻五糖II、乳糖-N-岩藻五糖III和乳糖-N-岩藻五糖V)、乳糖-N-二岩藻六糖I、岩藻糖基乳糖-N-六糖、二岩藻糖基乳糖-N-六糖I和二岩藻糖基乳糖-N-新六糖II,并且优选地,岩藻糖化的寡糖是2’-岩藻糖基乳糖(2-FL)。
5.如上述权利要求中任一项所述的组合物,其中所述组合物还进一步包含至少一种益生菌菌株,所述益生菌菌株优选双歧杆菌属(Bifidobacteria)和/或乳杆菌属(Lactobacilli)。
6.如上述权利要求中任一项所述的组合物,其中所述组合物进一步包含至少一种益生元。
7.如上述权利要求中任一项所述的组合物,其中所述组合物进一步包含至少一种噬菌体或噬菌体混合物。
8.如上述权利要求中任一项所述的组合物,其中所述组合物是一段婴儿配方食品、婴儿配方食品、后续配方食品、婴儿食品配方、婴儿谷物配方食品或成长牛奶,且所述组合物优选地是一段婴儿配方食品。
9.如上述权利要求中任一项所述的组合物,其用于罹患急性呼吸道感染的婴儿和幼儿。
10.如上述权利要求中任一项所述的组合物,其在断奶期前和/或断奶期间使用。
11.如上述权利要求中任一项所述的组合物,其用于使患有ARI或具有ARI早期症状的婴儿呼吸过程容易、减轻疼痛、改善睡眠和/或减轻症状。
12.包含至少一种N-乙酰乳糖胺、至少一种唾液酰寡糖和至少一种岩藻糖化的寡糖的组合物作为合成营养物用于预防和/或治疗急性呼吸道感染、优选细支气管炎或耳炎的用途。
13.如上述权利要求所述的用途,其中该组合物是补充剂,优选以单位剂量形式提供。
14.如权利要求1-10中任一项所述的组合物,其中所述组合物包含水解和/或部分水解的蛋白质,优选其为足够或能够降低过敏症的风险的量。
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- 2011-11-21 MX MX2013005727A patent/MX343321B/es active IP Right Grant
- 2011-11-21 AU AU2011340882A patent/AU2011340882B2/en active Active
- 2011-11-21 CN CN201180056475.7A patent/CN103582485A/zh active Pending
- 2011-11-21 BR BR112013012598A patent/BR112013012598A2/pt not_active IP Right Cessation
- 2011-11-21 SG SG2013038179A patent/SG190323A1/en unknown
- 2011-11-21 RU RU2013128570/15A patent/RU2593321C2/ru active
- 2011-11-21 CA CA2818012A patent/CA2818012A1/en not_active Abandoned
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107405354A (zh) * | 2015-03-05 | 2017-11-28 | 格礼卡姆股份公司 | 治疗急性呼吸道感染的组合物和方法 |
CN108541221A (zh) * | 2015-12-15 | 2018-09-14 | 格礼卡姆股份公司 | Hmo的混合物 |
CN105725216A (zh) * | 2016-03-15 | 2016-07-06 | 天津普生源科技发展有限公司 | 一种含有gaba的助眠功能食品及其制备方法 |
CN109640702A (zh) * | 2016-09-07 | 2019-04-16 | 雀巢产品技术援助有限公司 | 用于婴儿和/或幼儿的包含低聚糖的营养组合物 |
CN113423288A (zh) * | 2019-02-04 | 2021-09-21 | N·V·努特里奇亚 | 用于睡眠改善的含有不可消化的低聚糖的发酵配方物 |
CN115066188A (zh) * | 2020-01-20 | 2022-09-16 | 森永乳业株式会社 | 组合物 |
Also Published As
Publication number | Publication date |
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IL226348A0 (en) | 2013-07-31 |
AU2011340882A1 (en) | 2013-05-30 |
CL2013001433A1 (es) | 2013-12-13 |
CA2818012A1 (en) | 2012-06-14 |
BR112013012598A2 (pt) | 2016-08-09 |
MX343321B (es) | 2016-11-01 |
RU2593321C2 (ru) | 2016-08-10 |
RU2013128570A (ru) | 2014-12-27 |
TW201302205A (zh) | 2013-01-16 |
WO2012076323A1 (en) | 2012-06-14 |
EP2643006A1 (en) | 2013-10-02 |
AU2011340882B2 (en) | 2016-10-20 |
EP2465509A1 (en) | 2012-06-20 |
SG190323A1 (en) | 2013-06-28 |
MX2013005727A (es) | 2013-07-03 |
US20130236424A1 (en) | 2013-09-12 |
US9763465B2 (en) | 2017-09-19 |
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