CN108541221B - Hmo的混合物 - Google Patents
Hmo的混合物 Download PDFInfo
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- CN108541221B CN108541221B CN201680073344.2A CN201680073344A CN108541221B CN 108541221 B CN108541221 B CN 108541221B CN 201680073344 A CN201680073344 A CN 201680073344A CN 108541221 B CN108541221 B CN 108541221B
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Abstract
一种人乳寡糖(HMO)的合成混合物,其基本上由乳‑N‑新四糖(LNnT),乳‑N‑四糖(LNT),2’‑岩藻糖基乳糖(2’FL),3’‑O‑唾液酸基乳糖(3’‑SL),6’‑O‑唾液酸基乳糖(6’‑SL),二岩藻糖基乳糖(DFL)或3‑岩藻糖基乳糖(3‑FL)(优选DFL),和任选的乳糖组成。所述合成组合物可用于:治疗或预防非婴儿人类中的病毒和/或细菌感染;调节非婴儿人类中的微生物群;和/或改善非婴儿人类的认知功能,以及作为药物或营养组合物。
Description
技术领域
本发明涉及人乳寡糖(“HMO”)的合成混合物,特别是LNnT、LNT、2’-FL、3’-SL、6’-SL和DFL或3-FL的混合物,以及混合物在人类健康中的应用。
背景技术
HMO已经成为近年来极为关注的课题,因为其在人类机体中发生的许多生物学过程中发挥作用。哺乳动物乳汁包含这些复杂的寡糖中的至少130种(Urashima等,MilkOligosaccharides,Nova Biomedical Books,New York,2011,ISBN:978-1-61122-831-1)。
此前,HMO的唯一来源是主要包含水、以及55-70g/l乳糖、24-59g/l脂质、约13g/l蛋白质、5-15g/l HMO和约1.5g/l矿物质的哺乳动物乳汁。
然而,由于HMO在许多人类生物学过程中的作用,近年来已经开发出几种合成HMO的方法。在这方面,已经开发出通过微生物发酵、酶法、化学合成或这些技术的组合来制备HMO的方法。例如,通过化学方法,可以如WO2011/100980和WO2013/044928中所述制备Galpβ1-4GlcNAcpβ1-3Galpβ1-4Glc或乳-N-新四糖(“LNnT”);可以如WO 2012/155916和WO 2013/044928中所述合成Galpβ1-3GlcNAcpβ1-3Galpβ1-4Glc或乳-N-四糖(“LNT”);可以如WO2011/100979中所述合成6’-O-唾液酸基乳糖(“6’-SL”);可以如WO 2013/091660中所述制备LNT和LNnT的混合物;可以如WO 2010/115934和WO 2010/115935中所述制备2’-O-岩藻糖基乳糖(“2’-FL”);可以如WO 2013/139344中所述制备3-岩藻糖基乳糖(“3-FL”);以及可以如WO 2010/100979中所述制备6’-SL。作为生物技术方法的实例,WO 01/04341和WO 2007/101862描述了如何使用基因修饰的大肠杆菌(E.coli)制备任选被岩藻糖或唾液酸取代的核心人乳寡糖,包括LNnT、6’-SL和3’-O-唾液酸基乳糖(“3’-SL”);以及WO 2015/032412描述了使用基因修饰的大肠杆菌制备2’-FL和二岩藻糖基乳糖或Fuc(α1-2)Gal(β1-4)[Fuc(α1-3)]Glc(“DFL”)。作为酶法的实例,可以如EP-A-577580中所述制备唾液酸化的寡糖。
还已经致力于开发用于酶法合成HMO寡糖的混合物,而不必如WO 2012/156897和WO 2012/156898中所述合成混合物的所有寡糖组分的方法。这些方法已经提供了包含多种不同寡糖的反应混合物。
越来越多的证据表明,人类消化道中被称为微生物群的微生物的定居群落在健康和疾病中起着重要作用。当肠道微生物群的组成失去平衡时,人类宿主可能会遭受后果。最近的研究涉及到例如癌症、肥胖、炎性肠病、银屑病、哮喘、以及甚至可能是自闭症的各个病症中的肠道微生物群的失衡。包括HMO在内的各个不易消化纤维被认为有益于调节微生物群,并且对于将它们用于治疗一种或多种此类病症的关注日益增加。然而,许多可消化的纤维非特异性地调节微生物群,而另一些不能够提供足够广泛的调节但能够提供特异性调节。
因此,需要对微生物群进行特异性的调节,以便以不同方式解决各个病症,并同时解决多种病症。具体而言,需要一种组合物,该组合物尤其可用于治疗和/或预防细菌和病毒感染,特别是在肠道和呼吸道中的细菌和病毒感染,改善认知功能和/或增加抗癌剂对抗肿瘤的功效。
发明内容
本发明的第一方面涉及HMO的合成混合物,其基本上由LNnT、LNT、2’-FL、3’-SL、6’-SL和DFL或3-FL(优选DFL)组成。该混合物可任选地包括乳糖。HMO混合物优选基本上由以下组成:
i.约55wt%至约75wt%的2’-FL,更优选约60wt%至约70wt%的2’-FL;
ii.约2wt%至约10wt%的LNnT,更优选约3wt%至约7wt%的LNnT;
iii.约10wt%至约20wt%的LNT,更优选约12wt%至约18wt%的LNT;
iv.约1wt%至约15wt%的DFL或3-FL,更优选约1wt%至约10wt%、甚至更优选约2wt%至约10wt%的DFL或3-FL,例如约2wt%至约8wt%;
v.约1wt%至约10wt%的3’-SL,更优选约2wt%至约8wt%的3’-SL;和
vi.约1wt%至约15wt%的6’-SL,优选约5wt%至约15wt%的6’-SL,更优选约7wt%至约13wt%的6’-SL。
本发明的第二方面涉及包含根据本发明第一方面的HMO合成混合物的营养或药物组合物。
本发明的第三方面涉及HMO的合成混合物或包含HMO的合成混合物的组合物,其用于:i)预防和/或治疗非婴儿人类中的病毒和/或细菌感染;ii)特异性调节非婴儿人类的固有(indigenous)微生物群;和/或iii)改善非婴儿人类的认知功能。如上所述,HMO的合成混合物基本上由LNnT,LNT,2'-FL,3'-SL,6'-SL,DFL或3-FL之一(优选DFL),和任选的乳糖组成。合成HMO混合物或包含它的营养或药物组合物含有具有新的性质和生物活性组合的多种不同HMO。该组合物通过增加双歧杆菌(Bifidobacterium)来特异性调节肠道微生物群,通过调节病毒和致病细菌与肠上皮细胞的肠道结合以及通过改善肠道屏障功能,而特别适用于对抗病毒和细菌性肠道感染。该组合物通过抑制病原体与人上皮细胞结合还特别适用于对抗病毒和细菌性呼吸道感染。
本发明的第四方面涉及一种调节非婴儿人类的固有微生物群以增加双歧杆菌的丰度,以便提高抗癌剂在非婴儿人类患者中对抗肿瘤的功效的方法。该方法包括向非婴儿人类施用如上所述根据本发明第一方面的HMO合成混合物或根据本发明的第二方面的营养或药物组合物。双歧杆菌可以作为免疫增强剂,因此其丰度的增加可以增强癌症患者对抗癌剂的响应。这种性质使混合物适合作为癌症治疗的助剂。
本发明的第五方面涉及一种调节非婴儿人类的固有肠道微生物群以增加双歧杆菌和/或Barnesiella的丰度并且还减少活泼瘤胃球菌(Ruminococcus gnavus)的丰度的方法。该方法包括向非婴儿人类施用如上所述根据本发明第一方面的HMO合成混合物或根据本发明第二方面的营养或药物组合物。双歧杆菌和/或Barnesiella的丰度增加和活泼瘤胃球菌的丰度减少使得非婴儿人类肠道环境不易发生炎症并提供改善的肠道屏障功能。这些作用可以预防和/或治疗如炎性肠病、肠易激综合征的病症,以及与炎症和肠道屏障功能受损相关的其他病症。
本发明的第六方面涉及一种调节非婴儿人类的固有微生物群以增加双歧杆菌属丰度并至少保持栖粪杆菌(Faecalibacterium)丰度的方法。该方法包括向非婴儿人类施用如上所述根据本发明第一方面的HMO合成混合物或根据本发明第二方面的营养或药物组合物。增加双歧杆菌丰度并且至少保持栖粪杆菌丰度使得非婴儿人类肠道环境不易发炎,并提供改善的肠道屏障功能。优选地,活泼瘤胃球菌的丰度减少。这些作用可以预防和/或治疗如炎性肠病、肠易激综合征的病症,以及与炎症和肠道屏障功能受损相关的其他病症。
在本发明的第五和第六方面中,优选变形菌门的丰度也减少。
本发明的第七方面涉及预防或治疗非婴儿人类的病毒和/或细菌感染,尤其是肠道感染和呼吸道感染的方法。所述方法包括向非婴儿人类施用如上所述根据本发明第一方面的HMO合成混合物或根据本发明第二方面的营养或药物组合物。
本发明的第八方面涉及一种改善非婴儿人类的认知功能的方法。该方法包括向非婴儿人类施用如上所述根据本发明第一方面的HMO合成混合物或根据本发明第二方面的营养或药物组合物。
具体实施方式
根据本发明,以下术语优选具有以下含义:
“非婴儿人类”或“非婴儿”优选是指3岁及以上的人。因此,非婴儿人类是任何年龄在3岁以上的人,例如,可以是小孩、青少年、成年人或老年人。
“HMO的合成混合物”是指人工制备的混合物,并且优选是指其中至少一种HMO是以化学方式和/或生物学方式(例如通过化学反应、酶促反应或重组)离体产生的混合物。更优选地,混合物中的所有HMO都是以化学方式和/或生物学方式离体产生的。在一些实施方式中,本发明的合成混合物可以与天然存在的混合物相同,但优选不与其相同。
“微生物群”、“微生物区系”和“微生物组”是指通常栖息于身体器官或部分、特别是非婴儿人类的胃肠器官的活微生物群体。胃肠微生物群的最主要成员包括以下的微生物,在门水平的厚壁菌门(Firmicutes)、拟杆菌门(Bacteroidetes)、放线菌门(Actinobacteria)、变形菌门(Proteobacteria)、互养菌门(Synergistetes)、疣微菌门(Verrucomicrobia)、梭杆菌门(Fusobacteria)和广古菌门(Euryarchaeota);在属水平的拟杆菌属(Bacteroide)、栖粪杆菌属(Faecalibacterium)、双歧杆菌属(Bifidobacterium)、罗斯氏菌属(Roseburia)、Alistipes、柯林斯氏菌(Collinsella)、布劳特氏菌属(Blautia)、粪球菌属(Coprococcus)、瘤胃球菌属(Ruminococcus)、真杆菌属(Eubacterium)和多尔氏菌属(Dorea);在种水平的单形拟杆菌(Bacteroides uniformis)、Alistipes putredinis、Parabacteroides merdae、布氏瘤胃球菌(Ruminococcusbromii)、Dorea longicatena、粪拟杆菌(Bacteroides caccae)、多形拟杆菌(Bacteroidesthetaiotaomicron)、霍氏真杆菌(Eubacterium hallii)、扭链瘤胃球菌(Ruminococcustorques)、Faecalibacterium prausnitzii、酸奶瘤胃球菌(Ruminococcus lactaris)、产气柯林斯菌(Collinsella aerofaciens)、Dorea formicigenerans、普通拟杆菌(Bacteroides vulgatus)和罗斯拜瑞氏菌(Roseburia intestinalis)。胃肠微生物群包括位于或附着于覆盖胃肠道上皮的粘液层的粘膜-相关的微生物群、和在胃肠道腔中发现的腔(luminal)-相关的微生物群。
“调节微生物群”是指对微生物群施加改造或控制影响,特别是引起双歧杆菌、Barnesiella和/或栖粪杆菌的固有肠丰度增加以及活泼瘤胃球菌和/或变形菌门的肠丰度减少的影响。
“变形菌”是一种革兰氏阴性菌门,并且包括各种病原菌,比如埃希氏菌属(Escherichia)、沙门氏菌属(Salmonella)、弧菌属(Vibrio)、螺杆菌属(Helicobacter)、耶尔森氏菌属(Yersinia)和许多其它值得注意的属。
“治疗”是指为减轻或消除疾病的症状或病理状态而给予的治疗或采取的行动。
本文中的“预防性治疗”或“预防”是指为减少疾病发作或复发的风险而给予的治疗或采取的行动。
本文中的“病毒感染”是指由通常导致炎症反应的病毒引起的胃肠或胃肠道任何其他部分的感染,通常称为肠胃感冒。症状可以包括以下一项或多项:水样腹泻、恶心呕吐、头痛、肌肉疼痛、关节疼痛发热、寒战、出汗、皮肤湿冷、腹部绞痛和疼痛、食欲不振、体重减轻。病毒性胃感染的实例包括但不限于由轮状病毒或诺如病毒引起的病毒性胃肠道感染。
本文中的“细菌感染”是指由致病细菌引起的胃肠或胃肠道的任何其它部分的感染,通常称为细菌性肠炎。症状可以包括以下一项或多项:食欲不振、恶心呕吐、腹泻、腹部疼痛和绞痛、便血、发热。细菌感染的实例包括但不限于耶尔森氏菌属、葡萄球菌属(Staphylococcus)、志贺氏菌属(Shigella)、沙门氏菌属、弯曲杆菌属(Campylobacter)和大肠杆菌的致病菌株的胃肠道感染。
“呼吸道感染”是指上呼吸道和下呼吸道的任何病毒和/或细菌感染,即鼻窦、咽喉、气道或肺部的感染。
“癌症”优选是指例如以下一者或多者的任何部分的肿瘤:呼吸道、胃肠道、泌尿道或肝脏。
“口服给药”是指通过口腔递送组合物的任何常规形式。因此,口服给药是肠内给药的一种形式。
“认知功能”是指引起知晓的大脑活动,包括获取信息的所有手段和机制。认知功能包括推理、记忆、注意力和语言,并且直接引起信息的获得和由此的知晓。
根据本发明,令人惊讶地发现,基本上由LNnT、LNT、2'-FL、3'-SL、6'-SL和DFL或3-FL(优选DFL)以及任选的乳糖组成的合成HMO混合物可以提供一种抗感染组合物,其用于通过在非婴儿人类中特异性调节肠道微生物群、结合病毒、减少致病性易位和改善肠道屏障功能来预防或治疗细菌或病毒感染。此外,本发明的HMO混合物充当诱饵受体并结合轮状病毒以防止轮状病毒附着于人肠细胞。这些性质,加上肠道屏障功能的改善,使得HMO混合物适用于预防和治疗肠道感染。
还发现本发明的HMO混合物可增加脑神经节苷脂和糖蛋白唾液酸浓度,并通过迷走神经增强海马长时程增强作用,导致非婴儿人类的突触发生和神经发育增加。这使得HMO混合物适合施用至非婴儿人类以改善其认知功能。
本发明的HMO混合物在非婴儿人类中还可以:
i)增加双歧杆菌的固有肠道丰度,和
ii)增加Barnesiella的肠道丰度,和/或至少保持栖粪杆菌的肠道丰度,且
iii)减少活泼瘤胃球菌和/或变形菌门的肠道丰度。
这些作用可以使肠道环境不易发炎。加上肠屏障功能的改善,HMO混合物的这些作用可以预防和/或治疗如炎性肠病、肠易激综合征的病症,以及其他与炎症和屏障功能受损相关的病症。
令人惊讶的是,由本发明的HMO混合物诱导的肠道中双歧杆菌的增加提高了抗癌剂对抗肿瘤的功效。双歧杆菌用作为免疫助剂,加强癌症患者对抗癌剂的响应。该性质使得HMO混合物适合作为癌症治疗中的助剂。
优选本发明的HMO混合物包含:i)约55wt%至约75wt%的2’-FL,更优选约60wt%至约70wt%;ii)约2wt%至约10wt%的LNnT,更优选约3wt%至约7wt%;iii)约10wt%至约20wt%的LNT,更优选约12wt%至约18wt%;iv)约1wt%至约15wt%的DFL或3-FL,优选约1wt%至约10wt%,甚至更优选约2wt%至约10wt%;v)约1wt%至约10wt%的3’-SL,更优选约2wt%至约8wt%;和vi)约1wt%至约15wt%的6’-SL,优选约5wt%至约15wt%,更优选约7wt%至约13wt%。本发明的HMO混合物还可以含有乳糖,但它不被认为是混合物的活性成分。
合成HMO混合物可以以任何合适的形式施用于非婴儿人类,如营养组合物或药物组合物,例如单位剂型(例如片剂、胶囊、粉末的小袋(sachet)等)。
营养组合物或药物组合物由基本上由LNnT,LNT,2'-FL,3'-SL,6'-SL,DFL或3-FL之一,以及任选的乳糖组成的HMO合成混合物和合适的赋形剂组成。营养或药物组合物不包含除上述这些之外的任何其他HMO。
在一个实施方式中,本发明的HMO混合物可以是营养组合物的形式。例如,营养组合物可以是用于老年个体或免疫受损个体的食物组合物、补液或饮食维持或补充剂。营养组合物可以含有蛋白质、脂质和/或可消化的碳水化合物的来源,并且可以是粉末或液体形式。该组合物可以设计成营养的唯一来源或营养补充剂。
合适的蛋白质来源包括乳蛋白、大豆蛋白、大米蛋白、豌豆蛋白和燕麦蛋白、或其混合物。乳蛋白可以是乳蛋白浓缩物、乳蛋白分离物、乳清蛋白或酪蛋白、或两者混合物的形式。蛋白质可以是全蛋白质或者部分水解或深度水解的水解蛋白质。水解蛋白质提供易消化的优点,这对于患有发炎胃肠道的非婴儿可以是重要的。蛋白质也能够以游离氨基酸的形式提供。蛋白质能够包括营养组合物的大约5%至大约30%的能量,通常为大约10%至20%。
蛋白质来源可以是谷氨酰胺、苏氨酸、半胱氨酸、丝氨酸、脯氨酸或这些氨基酸的组合的来源。谷氨酰胺来源可以是谷氨酰胺二肽和/或富含谷氨酰胺的蛋白质。谷氨酰胺由于肠上皮细胞使用谷氨酰胺作为能量来源而能够包括在内。苏氨酸、丝氨酸和脯氨酸是产生粘蛋白的重要氨基酸。粘蛋白覆盖胃肠道,可以改善粘膜愈合。半胱氨酸是对于身体的抗氧化防御来说至关重要的谷胱甘肽的主要前体。
合适的可消化碳水化合物包括麦芽糖糊精、水解或改性的淀粉或玉米淀粉、葡萄糖聚合物、玉米糖浆、玉米糖浆固体、高果糖玉米糖浆、源自大米的碳水化合物、源自豌豆的碳水化合物、源自马铃薯的碳水化合物、木薯粉、蔗糖、葡萄糖、果糖、蔗糖、乳糖、蜂蜜、糖醇(例如麦芽糖醇、赤藓糖醇、山梨糖醇)、或其混合物。优选地,该组合物不含添加的乳糖。通常,可消化碳水化合物提供营养组合物的大约35%至大约55%的能量。特别合适的可消化碳水化合物是低葡萄糖当量(DE)麦芽糖糊精。
合适的脂质包括中链甘油三酯(MCT)和长链甘油三酯(LCT)。优选地,脂质是MCT和LCT的混合物。例如,MCT可以包含约30重量%至约70重量%的脂质,更具体地约50重量%至约60重量%。MCT提供易消化的优点,这对于患有发炎胃肠道的非婴儿可以是重要的。通常,脂质提供营养组合物的约35%至约50%的能量。脂质可以包含必需脂肪酸(ω-3和ω-6脂肪酸)。优选地,这些多不饱和脂肪酸提供小于脂质来源总能量的约30%。认为降低这些多不饱和脂肪酸的水平会降低对过氧化作用的敏感性;这对于患有炎症状况的非婴儿可以是有益的。
长链甘油三酯的合适来源是菜籽油、葵花籽油、棕榈油、大豆油、乳脂、玉米油、高油酸油和大豆卵磷脂。分馏椰子油是中链甘油三酯的合适来源。营养组合物的脂质特征优选设计为具有约4:1至约10:1的多不饱和脂肪酸ω-6(n-6)比ω-3(n-3)的比率。例如,n-6与n-3脂肪酸比率可以是约6:1至约9:1。
营养组合物还可以包括维生素和矿物质。如果意在将营养组合物作为唯一的营养来源,其优选地包括完整的维生素和矿物质图谱。维生素的实例包括维生素A、B-复合维生素(例如B1、B2、B6和B12)、维生素C、D、E和K、烟酸和酸类维生素例如泛酸、叶酸和生物素。矿物质的实例包括钙、铁、锌、镁、碘、铜、磷、锰、钾、铬、钼、硒、镍、锡、硅、钒和硼。
营养组合物还可以包括类胡萝卜素,例如叶黄素、番茄红素、玉米黄质和β-胡萝卜素。包括的类胡萝卜素的总量可以从大约0.001μg/ml至大约10μg/ml变化。包括的叶黄素的量可以为大约0.001μg/ml至大约10μg/ml、优选大约0.044μg/ml至大约5μg/ml叶黄素。包括的番茄红素的量可以为大约0.001μg/ml至大约10μg/ml、优选大约0.0185μg/ml至大约5μg/ml番茄红素。包括的β-胡萝卜素可以为大约0.001μg/ml至大约10mg/ml、例如大约0.034μg/ml至大约5μg/ml的β-胡萝卜素。
营养组合物优选还包含降低浓度的钠;例如约300mg/l至约400mg/l。剩余的电解质可以以满足需要的浓度存在,而不会提供肾功能的过度肾溶质负担。例如,钾优选以约1180至约1300mg/l的范围存在;并且氯化物优选以约680至约800mg/l的范围存在。
营养组合物还可以包含各种其它常规成分,比如防腐剂、乳化剂、增稠剂、缓冲剂、纤维和益生元(例如低聚果糖、低聚半乳糖)、益生菌(例如动物双歧杆菌乳双歧亚种(B.animalis subsp.lactis)BB-12、乳双歧杆菌(B.lactis)HN019、乳双歧杆菌Bi07、婴儿双歧杆菌(B.infantis)ATCC 15697、鼠李糖乳杆菌(L.rhamnosus)GG、鼠李糖乳杆菌HNOOl、嗜酸乳杆菌(L.acidophilus)LA-5、嗜酸乳杆菌NCFM、发酵乳杆菌(L.fermentum)CECT5716、长双歧杆菌(B.longum)BB536、长双歧杆菌AH1205、长双歧杆菌AH1206、短双歧杆菌(B.breve)M-16V、罗伊氏乳杆菌(L.reuteri)ATCC 55730、罗伊氏乳杆菌ATCC PTA-6485、罗伊氏乳杆菌DSM 17938)、包括生育酚、类胡萝卜素、抗坏血酸/维生素C、抗坏血酸棕榈酸酯、多酚、谷胱甘肽和超氧化物歧化酶(甜瓜)的抗氧化剂/抗炎化合物、其它生物活性因子(例如生长激素、细胞因子、TFG-β)、着色剂、香料、和稳定剂、润滑剂等等。
营养组合物可以配制为可溶性粉末、液体浓缩物或即用型制剂。组合物可以经由鼻胃管或口服供应给需要的人。各种香料、纤维和其它添加剂也可以存在。
营养组合物可以通过用于制备固体或液体形式的营养组合物的任何常用制造技术来制备。例如,组合物可以通过组合各种供给溶液来制备。脂肪包蛋白质供给溶液可以通过加热和混合脂质来源、然后在加热和搅拌的同时添加乳化剂(例如卵磷脂)、脂溶性维生素和蛋白质来源的至少一部分来制备。然后碳水化合物供给溶液通过在加热和搅拌的同时向水中加入矿物质、痕量和超痕量矿物质、增稠剂或混悬剂来制备。在加入碳水化合物(例如HMO和可消化的碳水化合物来源)之前,持续加热和搅拌所得溶液保持10分钟。然后将所得的供给溶液在加热和搅拌的同时混合在一起,并将pH调节至6.6-7.0,然后将组合物进行高温短时加工,在此期间将组合物热处理、乳化并均化,然后允许冷却。加入水溶性维生素和抗坏血酸,如果需要将pH调节至所需范围,加入香料,并加入水以达到所需的总固体水平。
对于液体产品,然后可以将所得溶液无菌包装以形成无菌包装的营养组合物。以这种形式,营养组合物可以是即食型或浓缩型液体形式。或者,该组合物可以喷雾干燥并作为可重构粉末加工和包装。
当营养产品是即食型营养液时,以液体重量计,液体中HMO的总浓度可优选为约0.0001%至约2.0%,包括约0.001%至约1.5%,包括约0.01%至约1.0%。当营养产品是浓缩营养液时,以液体重量计,液体中HMO的总浓度可优选为约0.0002%至约4.0%,包括约0.002%至约3.0%,包括约0.02%至约2.0%。
在其他实施方式中,本发明的HMO混合物可以包含在药物组合物中。药物组合物可以包含药学上可接受的载体,例如磷酸盐缓冲盐溶液、乙醇在水中的混合物、水和乳液如油/水或水/油乳液,以及各种润湿剂或赋形剂。该药物组合物还可以含有在施用于非婴儿时不产生不良、过敏或其它不希望的反应的其它物质。载体和其它材料可以包括溶剂、分散剂、包衣、吸收促进剂、控释剂和一种或多种惰性赋形剂,例如淀粉、多元醇、成粒剂、微晶纤维素、稀释剂、润滑剂、粘合剂和崩解剂。如果需要,抗感染组合物的片剂剂量可以通过标准的水性或非水性技术进行包衣。
药物组合物可以口服施用,例如作为包含预定量的片剂、胶囊或小丸,或者作为包含预定浓度的粉末或颗粒剂,或包含预定浓度的以含水液体或无水液体的凝胶、糊剂、溶液剂、混悬剂、乳剂、糖浆剂、大丸剂(bolus)、药糖剂、或浆剂。口服施用组合物可以包括粘合剂、润滑剂、惰性稀释剂、调味剂和湿润剂。口服施用组合物比如片剂可以任选地进行包衣并且可以进行配制以提供其中混合物的持续、延迟或控制释放。
药物组合物还可以通过直肠栓剂、气溶胶管、鼻胃管或直接输注到胃肠道或胃中来施用。
药物组合物还可以包括治疗剂,例如抗病毒剂、抗生素、益生菌、止痛剂和抗炎剂。基于诸如免疫状态、体重和年龄的因素,可以以常规方式确定这些组合物用于非婴儿人类的合适剂量。在某些情况下,剂量浓度将与人母乳中的HMO类似。所需量通常为每天约200mg至约20g,在某些实施方式中为每天约300mg至约15g,每天约400mg至约10g,在某些实施方式中为每天约500mg至约10g,在某些实施方式中为每天约1g至约10g。适当的剂量方案可以通过常规方法来确定。
本发明的药物组合物可以与用于有关疾病的其他药物结合用于治疗所述疾病,例如,与抗糖尿病药物或抗生素治疗结合。
在另一个实施方式中,包含本发明的HMO混合物的组合物是单位剂型。该单位剂型可以包含可接受的载体,例如,磷酸盐缓冲盐溶液、乙醇在水中的混合物、水和乳液如油/水或水/油乳液,以及各种润湿剂或赋形剂。单位剂型还可以含有在施用于患者时不产生不良、过敏或其它不希望的反应的其它材料。载体和其它材料可以包括溶剂、分散剂、包衣、吸收促进剂、控释剂和一种或多种惰性赋形剂,例如淀粉、多元醇、成粒剂、微晶纤维素、稀释剂、润滑剂、粘合剂和崩解剂。如果需要,组合物的片剂剂量可以通过标准的水性或非水性技术进行包衣。
本发明的单位剂型可以口服施用,例如作为包含预定量的混合物的片剂、胶囊或小丸,或者作为包含预定浓度的混合物的粉末或颗粒剂,或包含预定浓度的混合物的以含水液体或无水液体的凝胶、糊剂、溶液剂、混悬剂、乳剂、糖浆剂、大丸剂(bolus)、药糖剂、或浆剂。口服施用组合物可以包括一种或多种粘合剂、润滑剂、惰性稀释剂、调味剂和湿润剂。口服施用组合物比如片剂可以任选地进行包衣并且可以进行配制以提供其中HMO混合物的持续、延迟或控制释放。
本发明的单位剂型还可以通过直肠栓剂、气溶胶管、鼻胃管或直接输注到胃肠道或胃中来施用。
本发明的单位剂型还可以包括治疗剂,例如抗病毒剂、抗生素、益生菌、止痛剂和抗炎剂。基于如患者的免疫状态、体重和年龄的因素,可以以常规方式确定用于患者的这种组合物的适当剂量。在某些情况下,剂量浓度将与人母乳中的组合物的HMO类似。所需量通常为每天约200mg至约20g,在某些实施方式中为每天约300mg至约15g,每天约400mg至约10g,在某些实施方式中为每天约500mg至约10g,在某些实施方式中为每天约1g至约10g。适当的剂量方案可以通过本领域技术人员已知的方法确定。
实施例
实施例1
总共招募50名健康男性和女性受试者参与研究。经筛查访视和磨合期(run-in)1-2周后,选择受试者并随机分为2组,每组25名受试者。一组施用含有5g下述本发明HMO混合物的治疗产品:
i)14.2wt%的LNT
ii)5.3wt%的LNnT
iii)63.7wt%的2’-FL
iv)4.2wt%的DFL
v)3.7wt%的3’-SL和
vi)8.9wt%的6’-SL,
另一组施用安慰剂(含2克葡萄糖)。治疗产品和安慰剂在单位剂量容器中呈粉末形式。
如果受试者至少18岁,则有资格参加。所有被招募的受试者都能够并愿意理解并遵守研究程序。如果有以下情况,则将受试者排除:在筛查访视前一个月内已经参加了临床研究;在筛查测试中具有在临床上与参加研究有关的异常结果;正患有严重的疾病,如恶性肿瘤、糖尿病、严重冠心病、肾脏疾病、神经***疾病或严重的精神疾病或任何可能混淆研究结果的病症;在研究前使用高剂量的益生菌补充剂(允许使用酸奶)3个月;在研究前服用抗生素药物3个月;在研究前2周内定期服用任何可能干扰症状评估的药物;以及怀孕或泌乳。
在筛查访视时,登记病史和伴随药物,并收集血液样本用于安全性分析。分发粪便样本试剂盒。要求受试者将样本保存在冰箱中,直到下一次访视。
在第二次访视时,检查资格标准,并且将合格的受试者随机分配到试验中的两组(arm)。收集粪便样本并分发用于新样本的装置。让受试者熟悉交互式互联网支持***(interactive internet enabled system),其每天记录数据,并提供治疗或安慰剂产品。提醒受试者在研究过程中不要改变他们惯常的饮食。收集血液样本用于生物标志物研究。将粪便样本储存在-80℃直到分析。对粪便样本进行16S rRNA测序分析。
该研究进行8周,受试者每天服用安慰剂或治疗产品。受试者被指示在早晨与早餐一起服用产品。通过交互式互联网支持***监控依从性(compliance)。受试者还使用该***记录:
-Bristol粪便性状(Bristol Stool Form)(BSF)量表信息,
-症状信息如腹痛、腹部不适、腹部绞痛、腹胀和腹部饱胀感,
-额外的胃肠症状评分量表(Gastrointestinal Symptom Rating Scale)(GSRS)信息。
该调查问卷包括15个项目,覆盖五个维度(腹痛、消化不良、反流、腹泻、便秘),并使用七级Likert量表。
在研究结束时,每名受试者都有医疗团队的退出访问。像之前一样收集粪便样本和血液样本并进行分析。
粪便分析表明用本发明的HMO混合物治疗的受试者具有增加的双歧杆菌和Barnesiella的丰度以及降低的厚壁菌门特别是梭状芽孢杆菌(Clostridia)和活泼瘤胃球菌的丰度。这些受试者中栖粪杆菌的丰度不变。这些受试者中变形菌门的丰度降低。
实施例2
总共招募50名健康男性和女性受试者参与研究。经筛查访视和磨合期1-2周后,选择受试者并随机分为2组,每组25名受试者。一组施用含有5g下述本发明HMO混合物的治疗产品:
i)14.2wt%的LNT
ii)5.3wt%的LNnT
iii)63.7wt%的2’-FL
iv)4.2wt%的3-FL
v)3.7wt%的3’-SL和
vi)8.9wt%的6’-SL,
另一组施用安慰剂(含2克葡萄糖)。治疗产品和安慰剂在单位剂量容器中呈粉末形式。
如果受试者至少18岁,则有资格参加。所有被招募的受试者都能够并愿意理解并遵守研究程序。如果有以下情况,则将受试者排除:在筛查访视前一个月内已经参加了临床研究;在筛查测试中具有在临床上与参加研究有关的异常结果;正患有严重的疾病,如恶性肿瘤、糖尿病、严重冠心病、肾脏疾病、神经***疾病或严重的精神疾病或任何可能混淆研究结果的病症;在研究前使用高剂量的益生菌补充剂(允许使用酸奶)3个月;在研究前服用抗生素药物3个月;在研究前2周内定期服用任何可能干扰症状评估的药物;以及怀孕或泌乳。
在筛查访视时,登记病史和伴随药物,并收集血液样本用于安全性分析。分发粪便样本试剂盒。要求受试者将样本保存在冰箱中,直到下一次访视。
在第二次访视时,检查资格标准,并且将合格的受试者随机分配到试验中的两组(arm)。收集粪便样本并分发用于新样本的装置。让受试者熟悉交互式互联网支持***,其每天记录数据,并提供治疗或安慰剂产品。提醒受试者在研究过程中不要改变他们惯常的饮食。收集血液样本用于生物标志物研究。将粪便样本储存在-80℃直到分析。对粪便样本进行16S rRNA测序分析。
该研究进行8周,受试者每天服用安慰剂或治疗产品。受试者被指示在早晨与早餐一起服用产品。通过交互式互联网支持***监控依从性。受试者还使用该***记录:
-Bristol粪便性状(BSF)量表信息,
-症状信息如腹痛、腹部不适、腹部绞痛、腹胀和腹部饱胀感,
-额外的胃肠症状评分量表(GSRS)信息。
该调查问卷包括15个项目,覆盖五个维度(腹痛、消化不良、反流、腹泻、便秘),并使用七级Likert量表。
在研究结束时,每名受试者都有医疗团队的退出访问。像之前一样收集粪便样本和血液样本并进行分析。
粪便分析表明用本发明的HMO混合物治疗的受试者具有增加的双歧杆菌和Barnesiella的丰度以及降低的厚壁菌门特别是梭状芽孢杆菌和活泼瘤胃球菌的丰度。这些受试者中栖粪杆菌的丰度不变。这些受试者中变形菌门的丰度降低。
实施例3
将二十只7周龄的C57BL/6J雌性小鼠各自独立饲养以避免小鼠之间的污染并提供经辐照的食物和水。将小鼠分成2组,每组10只小鼠。
用饮用水中的氨苄青霉素(0.5g/L)处理小鼠,饮用水每3天更换一次。1周后,终止在饮用水中添加氨苄青霉素。之后,给1组施用含有以下本发明的HMO混合物的治疗产品:
14.2wt%的LNT
5.3wt%的LNnT
63.7wt%的2’-FL
4.2wt%的DFL
3.7wt%的3’-SL和
8.9wt%的6’-SL。
将治疗产品以40mg/ml的总浓度添加到1组的饮用水中。另一组接受具有40mg/ml葡萄糖的饮用水。每天施用新鲜的水,并且所有小鼠都可以自由获取饮用水。用啮齿动物食物喂养小鼠,每天给予新鲜的食物。
在终止用氨苄青霉素处理两天后,每组的小鼠通过口服灌胃万古霉素抗性屎肠球菌(Enterococcus faecium)菌株(VRE)而被感染。在不同时间点收集新鲜粪便颗粒以确定VRE水平。VRE通过在具有万古霉素的肠球菌琼脂板上铺覆连续稀释的粪便颗粒来定量。通过外观识别VRE菌落并通过革兰氏染色证实。使用赋予万古霉素抗性的vanA基因的PCR来确认受感染小鼠中VRE的存在。
监测小鼠2周,然后使其安乐死。收集髂骨、盲肠和结肠的腔内容物并立即冷冻并储存在-80℃下。使用96孔PowerSoil DNA分离试剂盒(MO-BIO)提取DNA。在PCR期间每个板最少一个样本-孔保持为空,以用作阴性对照。使用附带的Illumina适配器用正向引物S-D-Bact-0341-b-S-17和反向引物S-D-Bact-0785-a-A-21(Klindworth等Nucleic AcidsRes.41,e1(2013))进行PCR。这些是靶向V3-V4区域的通用细菌16S rDNA引物。使用以下PCR程序:98℃进行30秒,25×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证扩增。在使用Nextera Index Kit V2(Illumina)的巢式PCR中加入条形码(barcode),使用以下PCR程序:98℃进行30秒,8×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证引物的附着。
使用SequalPrep Normalization Plate试剂盒对来自巢式PCR的产物进行标准化和合并。通过蒸发将合并的基因库浓缩,并使用Qubit High Sensitivity Assay试剂盒(Thermo Fisher Scientific)在Qubit荧光计上测量所合并的基因库的DNA浓度。使用用于2×300bp配对末端测序的MiSeq Reagent试剂盒V3(Illumina)在MiSeq桌面测序仪上进行测序。使用64位版本的USEARCH(Edgar,2013)用于序列数据的生物信息学分析。
在用本发明的HMO混合物处理的小鼠中,VRE定植在14天内减少到不可检测的水平。VRE的密度在5天内减少。用HMO混合物处理的小鼠还显示出更高的紫单胞菌科(Porphyromonadaceae)丰度,特别是Barnesiella丰度。未经处理的小鼠在整个肠中继续携带大量的VRE。
实施例4
将二十只7周龄的C57BL/6J雌性小鼠各自独立饲养以避免小鼠之间的污染并提供经辐照的食物和水。将小鼠分成2组,每组10只小鼠。
用饮用水中的氨苄青霉素(0.5g/L)处理小鼠,饮用水每3天更换一次。1周后,终止在饮用水中添加氨苄青霉素。之后,给1组施用含有以下本发明的HMO混合物的治疗产品:
14.2wt%的LNT
5.3wt%的LNnT
63.7wt%的2’-FL
4.2wt%的3-FL
3.7wt%的3’-SL和
8.9wt%的6’-SL。
将治疗产品以40mg/ml的总浓度添加到1组的饮用水中。另一组接受具有40mg/ml葡萄糖的饮用水。每天施用新鲜的水,并且所有小鼠都可以自由获取饮用水。用啮齿动物食物喂养小鼠,每天给予新鲜的食物。
在终止用氨苄青霉素处理两天后,每组的小鼠通过口服灌胃万古霉素抗性屎肠球菌菌株(VRE)而被感染。在不同时间点收集新鲜粪便颗粒以确定VRE水平。VRE通过在具有万古霉素的肠球菌琼脂板上铺覆连续稀释的粪便颗粒来定量。通过外观识别VRE菌落并通过革兰氏染色证实。使用赋予万古霉素抗性的vanA基因的PCR来确认受感染小鼠中VRE的存在。
监测小鼠2周,然后使其安乐死。收集髂骨、盲肠和结肠的腔内容物并立即冷冻并储存在-80℃下。使用96孔PowerSoil DNA分离试剂盒(MO-BIO)提取DNA。在PCR期间每个板最少一个样本-孔保持为空,以用作阴性对照。使用附带的Illumina适配器用正向引物S-D-Bact-0341-b-S-17和反向引物S-D-Bact-0785-a-A-21(Klindworth等Nucleic AcidsRes.41,e1(2013))进行PCR。这些是靶向V3-V4区域的通用细菌16S rDNA引物。使用以下PCR程序:98℃进行30秒,25×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证扩增。在使用Nextera Index Kit V2(Illumina)的巢式PCR中加入条形码(barcode),使用以下PCR程序:98℃进行30秒,8×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证引物的附着。
使用SequalPrep Normalization Plate试剂盒对来自巢式PCR的产物进行标准化和合并。通过蒸发将合并的基因库浓缩,并使用Qubit High Sensitivity Assay试剂盒(Thermo Fisher Scientific)在Qubit荧光计上测量所合并的基因库的DNA浓度。使用用于2×300bp配对末端测序的MiSeq Reagent试剂盒V3(Illumina)在MiSeq桌面测序仪上进行测序。使用64位版本的USEARCH(Edgar,2013)用于序列数据的生物信息学分析。
在用本发明的HMO混合物处理的小鼠中,VRE定植在14天内减少到不可检测的水平。VRE的密度在5天内减少。用HMO混合物处理的小鼠还显示出更高的紫单胞菌科丰度,特别是Barnesiella丰度。未经处理的小鼠在整个肠中继续携带大量的VRE。
实施例5
将45只6周龄雌性C57BL/6小鼠皮下注射B16黑素瘤细胞。然后将小鼠随机分为三组(每组15只小鼠),并各自独立饲养以避免小鼠之间的污染。对小鼠供应颗粒状半合成AIN76饮食(Research Diets Inc.,New Brunswick,NJ),在用于A组的饲料中具有5%的下述本发明的HMO混合物:
14.2wt%的LNT
5.3wt%的LNnT
63.7wt%的2’-FL
4.2wt%的DFL
3.7wt%的3’-SL和
8.9wt%的6’-SL;
在用于B组的饲料中具有5%的下述本发明的HMO混合物:
14.2wt%的LNT
5.3wt%的LNnT
63.7wt%的2’-FL
4.2wt%的3-FL
3.7wt%的3’-SL和
8.9wt%的6’-SL;以及
在用于C组的饲料中具有5%的玉米淀粉(对照)。
每天施用新鲜水,并且所有小鼠都可以自由获取饮用水和饲料。植入肿瘤三天后,给小鼠注射200μg CTLA-4抗体。每3天给予额外的抗体治疗直至实验结束(14天)。整个研究期间测量食物消耗、体重和肿瘤体积(直径)。在第0、4、7、10和14天收集新鲜粪便样本。立即将样本冷冻并在-80℃下储存直至进一步分析。
植入B16细胞14天后,通过颈椎脱臼使小鼠安乐死。切除肿瘤并称重。将肿瘤切片固定在4%多聚甲醛中并储存在-80℃。将盲肠和结肠的粘膜和肠内容物移除并储存在-80℃。
为了分析肿瘤浸润T细胞,将肿瘤切成小块并用0.2mg/ml DNA酶和1.67Wünsch U/ml释放酶(Roche)消化。通过40-μm尼龙细胞过滤器过滤获得的细胞悬液并裂解红血细胞。按照制造商的方案,使用CD8α(Ly-2)微珠(Miltenyi Biotec)从源自B16肿瘤的细胞悬液中纯化CD8+T细胞。将获得的细胞在1μl/ml布雷菲德菌素A的存在下孵育2小时,洗涤并用大鼠抗小鼠CD16/CD32mAb(2.4G2)孵育以阻断非特异性结合,然后用CD8α-PE-Cy5和CD69-PE染色,然后根据制造商的说明书(BD Biosciences-Pharmingen)用IFN-γ-PE-Cy7或同种型对照抗体进行细胞内染色。通过将获得的细胞总数除以肿瘤重量计算肿瘤中CD8GFP+和GFP-T细胞的密度。
为了评估微生物群特征,使用96孔PowerSoil DNA分离试剂盒(MO-BIO)从粪便样本、粘膜和肠内容物中提取DNA。在PCR期间每个板最少一个样本-孔保持为空,以用作阴性对照。使用附带的Illumina适配器用正向引物S-D-Bact-0341-b-S-17和反向引物S-D-Bact-0785-a-A-21(Klindworth等人,Nucleic Acids Res.41,e1(2013))进行PCR。这些是靶向V3-V4区域的通用细菌16S rDNA引物。使用以下PCR程序:98℃进行30秒,25×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证扩增。在使用Nextera Index Kit V2(Illumina)的巢式PCR中加入条形码,使用以下PCR程序:98℃进行30秒,8×(98℃进行10秒,55℃进行20秒,72℃进行20秒),72℃进行5分钟。通过将产物在1%琼脂糖凝胶上运行来验证引物的附着。使用SequalPrepNormalization Plate试剂盒对来自巢式PCR的产物进行标准化和合并。通过蒸发将合并的基因库浓缩,并使用Qubit High Sensitivity Assay试剂盒(Thermo Fisher Scientific)在Qubit荧光计上测量所合并的基因库的DNA浓度。使用用于2×300bp配对末端测序的MiSeq Reagent试剂盒V3(Illumina)在MiSeq桌面测序仪上进行测序。使用64位版本的USEARCH(Edgar,2013)用于序列数据的生物信息学分析。
结果显示两种HMO混合物的摄入通过增加粘膜和肠腔环境中的双歧杆菌的丰度有利地调节微生物群。此外,结果显示双歧杆菌的丰度与肿瘤微环境中浸润T细胞的致敏(priming)和累积正相关,并与肿瘤大小负相关。总的来说,这些结果表明,两种HMO混合物都可以增加双歧杆菌属的丰度,并且通过这增加了抗癌剂对抗肿瘤生长的功效。
实施例6
将小鼠(5周龄;n=30)随机分到以下组之一:A)对照组(n=10);b)1%HMO混合物(n=10);C)5%HMO混合物(n=10)。HMO混合物的组成在下表中给出。
HMO在饮用水中提供。所有动物都可以自由获取相同的饮食(KLIBA 2122)。
2周后,通过鼻内接种用流感病毒株PR8以每只小鼠100PFU的剂量攻击小鼠。接下来的14天监测小鼠,评估疾病症状的临床评分和体重减轻。
结果显示HMO混合物可防止由流感病毒感染引起的疾病症状和体重减轻。
Claims (2)
1.由乳-N-新四糖、乳-N-四糖、2’-O-岩藻糖基乳糖、3’-O-唾液酸基乳糖、6’-O-唾液酸基乳糖、二岩藻糖基乳糖和任选的乳糖组成的人乳寡糖的合成混合物在制备用于以下的组合物中的用途:预防和/或治疗非婴儿人类中的万古霉素抗性屎肠球菌(Enterococcus faecium)胃肠道感染。
2.由乳-N-新四糖、乳-N-四糖、2’-O-岩藻糖基乳糖、3’-O-唾液酸基乳糖、6’-O-唾液酸基乳糖、3-岩藻糖基乳糖和任选的乳糖组成的人乳寡糖的合成混合物在制备用于以下的组合物中的用途:预防和/或治疗非婴儿人类中的万古霉素抗性屎肠球菌(Enterococcus faecium)胃肠道感染。
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BR112018010505B1 (pt) | 2021-11-16 |
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