CN107073021A - 合成组合物以及用于治疗肠易激综合症的方法 - Google Patents
合成组合物以及用于治疗肠易激综合症的方法 Download PDFInfo
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Abstract
本申请涉及包含一种或多种人乳单糖或寡糖的合成组合物,其用于治疗肠易激综合症以及与肠易激综合症相关的症状。HMS优选选自唾液酸和岩藻糖,HMO优选选自2’‑岩藻糖基乳糖(2’‑FL)、3’‑岩藻糖基乳糖(3’‑FL)、二岩藻糖基乳糖(DFL)、3’‑唾液酸基乳糖(3’‑SL)、6’‑唾液酸基乳糖(6’‑SL)、乳‑N‑四糖(LNT)、乳‑N‑新四糖(LNnT)、乳‑N‑岩藻糖基五糖(LNP‑I)和3’,6‑二唾液酸基乳糖基‑N‑四糖(DSLNT)。
Description
技术领域
本发明总体上涉及组合物以及用于治疗肠易激综合症(IBS)的方法。
背景技术
肠易激综合症是人类,特别是成人的一种临床异质性疾病,患者具有慢性症状,如腹痛、腹部不适、腹胀、疲劳和肠运动模式改变比如稀少或更频繁的肠运动模式、腹泻和便秘。对患者的常规临床检查通常不显示异常,尽管他们的肠可能对某些刺激,例如气球吹入测试(balloon insufflation testing)更敏感。全球范围的IBS患病率约为10-20%(Longstreth等,Gastroenterology 130,1480(2006)),但在某些国家可能会更高。IBS病因不明,但脑-肠轴紊乱、急性胃肠道感染、小肠细菌过度生长、抗生素的使用和菌群失调被认为是重要的危险因素(Kim等,Digest.Dis.Sci.57,3213(2012))。其他危险因素是年轻、长期发烧、焦虑和抑郁。IBS患者中通常会出现慢性低度炎症,但临床表现却很少或根本没有观察到。
IBS的诊断是困难的。无法进行基于生物标志物的检测来诊断IBS。诊断通常包括排除产生IBS样症状的病症,然后遵循对患者症状进行归类的程序。在诊断IBS之前,推荐对所有患者排除寄生虫感染、乳糖不耐症和乳糜泻。一旦诊断,通常根据罗马III标准基于大便硬度(stool consistency)将患者分为四种症状亚型:腹泻为主(IBS-D)、便秘为主(IBS-C)、腹泻和便秘交替发作的混合亚型(IBS-M)、以及未定亚型IBS(IBS-U)。
IBS无法治愈,目前的治疗方法致力于试图缓解症状。治疗采取多种形式,如饮食调整、药物治疗和心理干预。患者教育和良好的医患关系也很重要。然而,大多数治疗不能令人满意,大多数患者仍继续经历慢性疼痛、疲劳和其他症状。虽然IBS对预期寿命没有直接影响,但其高发病率和对生活质量的显著影响使其成为社会成本高的病症。对患者及对其进行治疗的医护人员而言,与IBS相关的总体上的无助感是令他们沮丧的源头。
在IBS的病理生理学中,目前的研究涉及胃肠道微生物群、脑-肠轴和肥大细胞。人类胃肠道微生物群包括至少1,000种细菌,约1014个来自约160个不同种属的个体细菌细胞栖居在每个个体的肠中(Qin等,Nature 464,59(2010))。据信,个体的遗传构成和获得性免疫以及环境因素影响他们的胃肠道微生物群。微生物群又进而塑造了个体的胃肠系统内的免疫力和生理机能。还据信,一个健康的个体与其肠道定植的微生物群保持共生关系,而患有IBS的个体在这种微生物群-免疫相互作用中具有不平衡性。
研究表明,IBS患者的胃肠道微生物与健康对照组不同。还有证据表明胃肠道微生物群引起感染后IBS(PI-IBS)。鞭毛蛋白是细菌鞭毛的主要结构成分,已被证明可激活个体的先天免疫和适应性免疫系统。例如,在IBS患者中,比在健康对照组中更频繁地检测到抗细菌鞭毛蛋白的抗体(A4-F3a2和Fla-X)(分别为p=0.004和p=0.009;Schoepfer等,Neurogastroenterol.Motil.20,1110(2008))。此外,患有与IBS相关的感染后小肠细菌过度生长(SIBO)的个体可能具有抗感染细菌的鞭毛蛋白的抗体(Spiller等,Gastroenterology 136,1979(2009))。这些细菌通常是空肠弯曲杆菌(Campylobacterjejuni)、大肠杆菌(Escherichia coli)、肠炎沙门氏菌(Salmonella enterilidis)和弗氏志贺氏菌(Shigella flexneri)。
针对胃肠道微生物群的治疗,如抗生素、益生菌和益生元,似乎可以缓解IBS的症状(至少是暂时地)。例如,抗生素利福昔明(rifaximin)似乎减少了对IBS患者有负面影响的细菌产物。
与IBS相关的腹痛和不适与脑-肠轴和对应激激素的反应相关。IBS患者通常会经历由脑-肠轴或中枢应激反应系统介导的肠道活动异常和内脏超敏反应。脑-肠轴的一个臂(arm)是中枢传出通路,由交感神经系统和下丘脑-垂体-肾上腺轴(HPA)形成。在包括IBS在内的应激敏感性疾病中,释放出HPA轴的应激激素,如促肾上腺皮质激素(ACTH)、皮质醇和儿茶酚胺。一些研究表明,IBS患者中的HPA轴反应是由粘膜免疫活化增加引起的,这进而增加了血浆细胞因子水平以刺激HPA轴。
除了肠道微生物群和肠-脑轴之外,肥大细胞也可能在IBS的发病机理中起重要作用。远端肠段肥大细胞浸润和活化的增加与IBS的症状的发作和严重程度相关。这些细胞也涉及在IBS患者中内脏传入神经对粘膜刺激的反应性升高。在感染后IBS和非感染后IBS中,通常在被上述细菌感染之后观察到肥大细胞增生。
IBS治疗的最新进展是FODMAP饮食。这种饮食要求患者限制摄入FODMAP碳水化合物。这些碳水化合物是可发酵的寡糖、二糖、单糖和多元醇,其在近端小肠中吸收不良,具有渗透活性,并且由肠道细菌发酵而伴随有氢的产生。坚持这种饮食已经导致一些患者的症状改善(Staudacher等,J.Hum.Nutr.Diet 24,487(2011))。然而,一些FODMAP碳水化合物是有益的纤维,含有它们的食物是常见的、高营养的水果、蔬菜和豆类。然而,仍然需要通常安全和有效的方法来进一步改善IBS患者的症状。
发明内容
在一方面,本发明提供了一种用于以下用途的合成组合物:
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者;
-减轻患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损的患者的IBS症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的腹痛、腹部不适和/或腹胀中的一种或多种慢性症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的肠运动模式改变如稀少或更频繁的肠运动模式、腹泻和便秘的一种或多种慢性症状,;
-预防曾患有IBS的患者,特别是之前曾患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者IBS的复发;
-增加IBS患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者结肠中的双歧杆菌(Bifidobacteria)、优选青春双歧杆菌(Bifidobacteriumadolescentis),以减轻患者的IBS症状;和/或
-在正在接受或已接受抗生素治疗的患者中预防IBS或IBS症状,
其特征在于,所述组合物包含有效量的一种或多种人乳单糖(“HMS”)或一种或多种人乳寡糖(“HMO”),或者二者均有。合成组合物优选为营养组合物。
在一些实施方式中,患者中的IBS表现为细菌过度生长和/或菌群失调。
在另一方面,本发明提供了一种方法,其用于:
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者;
-减轻患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的IBS症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的一种或多种IBS症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的肠运动模式改变如稀少或更频繁的肠运动模式、腹泻和便秘的一种或多种慢性症状,;
-预防曾患有IBS的患者,特别是之前曾患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者IBS的复发;
-增加IBS患者,特别是患有细菌过度生长和/或菌群失调和粘膜屏障受损中的一种或多种的患者结肠中的双歧杆菌(Bifidobacteria)、优选青春双歧杆菌(Bifidobacterium adolescentis),以减轻患者的IBS症状;和/或
-在正在接受或已接受抗生素治疗的患者中预防IBS或IBS症状,
该方法包括优选以合成组合物的形式口服给予患者有效量的一种或多种HMS或一种或多种HMO,或者二者都有。
在一些实施方式中,患者中IBS的表现为细菌过度生长和/或菌群失调。
优选地,内脏敏感性和排便异常得到改善。例如,在IBS便秘患者中,内脏敏感性和完全自发性肠运动得到改善。此外,在IBS腹泻患者中,内脏敏感性和粪便硬度得到改善。对初始治疗期,可以优选以较高量给予患者一种或多种中性HMO,优选每天5g至10g,随后,对维持期,以较低量给予,优选每天1g至5g。初始治疗期可为1至8周,维持期为至少1个月。
在另一方面,本发明提供优选为合成组合物形式的一种或多种HMS或一种或多种HMO或二者的用途,其用于治疗/减轻患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或更多种的患者的IBS症状。在这方面,本发明提供一种或多种HMS或一种或多种HMO或两者的以下用途:
-减轻患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的IBS症状;
-治疗患有IBS的患者的腹痛、腹部不适或腹胀中的一种或多种慢性症状;
-治疗患有IBS的患者的肠运动模式改变、特别是稀少或更频繁的肠运动模式、腹泻或便秘的一种或多种慢性症状,;
-增加IBS患者,特别是患有细菌过度生长和/或菌群失调和粘膜屏障受损中的一种或多种的患者结肠中双歧杆菌(Bifidobacteria)、优选青春双歧杆菌(Bifidobacteriumadolescentis),以减轻患者的IBS症状;
-预防曾患有IBS的患者IBS的复发;
-在正在接受或已接受抗生素治疗的患者中预防IBS或IBS症状。
在一些实施方式中,患者中的IBS表现为细菌过度生长和/或菌群失调。
优选地,在本发明的所有方面,HMS选自唾液酸和岩藻糖,HMO选自2'-FL、3-FL、DFL、3'-SL、6'-SL、LNT、LNnT、LNFP-I和DSLNT。更优选HMO是一种或多种骨架HMO和一种或多种岩藻糖基HMO的组合;例如2'-FL和LNnT。2'-FL和LNnT可以以约4:1至1:1的质量比存在;更优选约3:1至1:1。
具体实施方式
根据本发明,已经令人惊讶地发现,人乳单糖(HMS)(有利的是唾液酸和/或岩藻糖)以及人乳寡糖(HMO)(有利地是2'-FL、3-FL、LNT、LNnT、3'-SL、6'-SL、DFL、DSLNT和/或LNFP-1)能够减轻IBS患者,特别是那些受到细菌过度生长、菌群失调或粘膜屏障受损困扰的患者的肠易激综合症的慢性症状。此外,已经发现,HMS/HMO降低了患者,特别是那些受到细菌过度生长、菌群失调或粘膜屏障受损困扰的患者IBS复发的风险。据信,HMS/HMO可以:(1)作为益生元促进有益细菌生长并减少细菌过度生长和菌群失调;(2)通过与病原体相结合作为病原体的诱饵(decoy),从而减少/防止病原体与胃肠道上皮细胞的结合;(3)减轻慢性粘膜炎症;和/或(4)修复粘膜屏障的损伤。HMS/HMO也可以神经元依赖性地对肠道迁移运动综合征起作用,以解决肠道运动紊乱,并可能对患者的中枢神经系统产生有益作用。
术语“口服给药”优选是指任何将组合物经口递送给患者的常规方式,其导致组合物沉积在患者的胃肠道(包括胃)中。因此,口服给药包括患者吞咽组合物、通过鼻胃管进行肠内喂养等。
术语“有效量”优选是指提供足量的人乳单糖或人乳寡糖以使患者实现期望的治疗结果的组合物的量。有效量可以以一种或多种剂量施用于患者以达到预期的治疗结果。
术语“人乳单糖”或“HMS”优选是指人母乳中发现的单糖。实例包括唾液酸和L-岩藻糖。在人乳中,唾液酸为N-乙酰神经氨酸。
术语“人乳寡糖”或“HMO”优选是指人母乳中发现的复合碳水化合物,其可以是酸性或中性形式的。已知超过约200种不同的HMO结构存在于人类母乳中(Urashima等:MilkOligosaccharides,Nova Biomedical Books,New York,2011)。HMO可以是主链、岩藻糖基化和唾液酸化的寡糖。主链HMO由Glu,Gal和GlcNAc组成,不含Fuc和唾液酸。主链HMO的实例包括乳-N-四糖(LNT)、乳-N-新四糖(LNnT)、乳-N-新六糖(LNnH)和乳-N-十糖(LNH)。岩藻糖基HMO是岩藻糖基乳糖或岩藻糖基主链HMO,如2'-岩藻糖基乳糖(2'-FL)、乳-N-岩藻五糖I(LNFP-I)、乳-N-二岩藻糖基六糖I(LNDFH-I)、3-岩藻糖基乳糖(3-FL)、二岩藻糖基乳糖(DFL)、乳-N-岩藻五糖III(LNFP-III)、岩藻糖基-对-乳-N-新六糖(F-pLNnH)、乳-N-二岩藻糖基六糖I(LNDFH-I)、岩藻糖基-乳-N-六糖II(FLNH-II)、乳-N-岩藻五糖V(LNFP-V)、乳-N-二岩藻糖基六糖II(LNDFH-II)、岩藻糖基-乳-N-六糖I(FLNH-I)、岩藻糖基-乳-N-六糖III(FLNH-III)和岩藻糖基-对-乳-N-新六糖(F-pLNnH)。唾液酸HMO是唾液酸化乳糖或唾液酸化主链HMO,例如3',6-二唾液酸基乳糖-N-四糖(DSLNT)、6'-唾液酸基乳糖(6'-SL)、3'-唾液酸基乳糖(3'-SL)、6'-唾液酸基乳糖-N-新四糖(LSTc)、3'-唾液酸基乳糖-N-四糖(LSTa)和6-唾液酸基乳糖-N-四糖(LSTb)。含有唾液酸基和岩藻糖基二者的HMO可被认为属于后两组中的一个。唾液酸基和岩藻糖基HMO的实例包括二唾液酸基-岩藻糖基-乳-N-六糖II(DSFLNH-II)、岩藻糖基-唾液酸基-乳-N-新六糖I(FSLNnH-I)、岩藻糖基-唾液酸基-乳-N-六糖I(FSLNH-I)和3-岩藻糖基-3'-唾液酸基乳糖(FSL)。
术语“微生物群”、“微生物群落”和“微生物群系”优选是指通常栖居于身体器官或部位的活的微生物群体。胃肠道微生物群的最主要的成员包括以下微生物门: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)、和古生菌(Euryarchaeota);属于属水平的微生物:拟杆菌属(Bacteroides)、粪便杆菌(Faecalibacterium)、双歧杆菌属(Bifidobacterium)、罗斯氏菌(Roseburia)、Alistipes、柯林斯氏菌(Collinsella)、Blautia、粪球菌属(Coprococcus)、瘤胃球菌属(Ruminococcus)、真杆菌属(Eubacterium)和Dorea;以及属于种水平的微生物:单形拟杆菌(Bacteroides uniformis)、Alistipes putredinis、Parabacteroidesmerdae、布氏瘤胃球菌(Ruminococcus bromii)、Dorea longicatena、粪便拟杆菌(Bacteroides caccae)、多形拟杆菌(Bacteroides thetaiotaomicron)、霍氏真杆菌(Eubacterium hallii)、扭链瘤胃球菌(Ruminococcustorques)、柔嫩梭菌(Faecalibacterium prausnitzii)、乳酸乳球菌(Ruminococcus lactaris)、产气克柯林斯菌(Collinsellaaerofaciens)、Dorea formicigenerans、普通拟杆菌(Bacteroidesvulgatus)和罗斯拜瑞氏菌(Roseburia intestinali)。在某些情况下,胃肠道微生物群包括粘膜相关的微生物群,其位于或附着于覆盖胃肠道上皮的粘液层,以及在胃肠道的内腔中发现的腔内相关的微生物群。
术语“肠易激综合征”和“IBS”优选是指人类,特别是成年人的一类功能性肠紊乱,其特征在于一种或多种慢性症状,包括腹痛、腹部不适、腹胀、疲劳和肠运动模式改变如稀少或更频繁的肠运动模式、腹泻和便秘,通常没有任何明显的结构性异常。至少有三种形式的IBS,取决于哪个症状是主要的:(1)腹泻为主(IBS-D);(2)便秘为主(IBS-C);和(3)具有交替排便模式的IBS(IBS-A或IBS-M)。IBS也有各种临床亚型,如感染后IBS(IBS-PI)。
HMO可以通过众所周知的方法从哺乳动物,包括但不限于人、牛、羊、猪或者山羊,分泌的乳汁进行分离或富集。HMO也可以通过众所周知的方法使用微生物发酵、酶法、化学合成或这些技术的组合进行生产。作为实例,使用的化学品LNnT可以如WO 2011/100980和WO 2013/044928中所述制备,LNT可以如WO 2012/155916和WO 2013/044928中所述合成,LNT和LNnT的混合物可以如WO 2013/091660中所述制备,2'-FL可以如WO 2010/115934和WO2010/115935中所述制备,3-FL可以如WO 2013/139344中所述制备,6'-SL及其盐可以如WO2010/100979中所述制备,唾液酸基化寡糖可以如WO 2012/113404中所述制备,人乳寡糖的混合物可以如WO 2012/113405中所述制备。作为酶促生产的实例,唾液酸基化寡糖可以如WO2012/007588中所述制备,岩藻糖基化寡糖可以如WO 2012/127410中所述制备,有利的是可以如WO 2012/156897和WO 2012/156898所述制备人乳寡糖的多样化混合物。关于生物技术方法,WO 01/04341和WO 2007/101862描述了如何使用转基因大肠杆菌制备任选被岩藻糖或唾液酸取代的核心人乳寡糖。
本发明的合成组合物包含一种或多种人乳单糖或者一种或多种人乳寡糖,或者可以采取任何合适形式的二者。例如,组合物可以是营养组合物的形式,其含有其他常量营养素如蛋白质、脂质或其他碳水化合物。合成组合物也可以是药物组合物。在一个实施方式中,合成组合物含有一种或多种主链HMO和一种或多种岩藻糖基HMO和任选的岩藻糖。在另一个实施方式中,合成组合物含有一种或多种主链HMO和一种或多种唾液酸基HMO和任选的唾液酸。在进一步的实施方式中,合成组合物包含一种或多种岩藻糖基HMO和一种或多种唾液酸基HMO,以及任选的岩藻糖和/或唾液酸,优选两者都有。在优选的实施方式中,合成组合物含有一种或多种主链HMO,一种或多种唾液酸基HMO和一种或多种岩藻糖基HMO,以及任选的岩藻糖和/或唾液酸,优选两者都有。
营养组合物
本发明的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。该组合物可以被设计成唯一的营养来源或营养补充剂。对于IBS患者,优选营养补充剂;特别是可以形成膳食或加餐替代物的补充剂。优选地,营养组合物是少乳糖的或更好地不含乳糖的。优选地,营养组合物也不含FODMAP碳水化合物或含少量的FODMAP碳水化合物。
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、或它们的混合物。牛奶蛋白质可以是乳蛋白浓缩物、乳清蛋白或酪蛋白或两者的混合物。大豆、大米、豌豆和燕麦蛋白可以是分离蛋白的形式。蛋白质可以是全蛋白或水解蛋白(部分水解或大量水解)。蛋白质可以提供营养组合物约5%至约50%、优选约10%至30%的能量。蛋白质源优选不是不可发酵的碳水化合物、如乳糖的来源。因此,如果使用乳蛋白作为蛋白质来源,则乳蛋白质优选为少乳糖的或不含乳糖的。
合适的可消化碳水化合物包括麦芽糖糊精,、水解或改性淀粉或玉米淀粉,、葡萄糖聚合物,、玉米糖浆,、玉米糖浆固体,、木薯淀粉,、蔗糖和葡萄糖,、或其它们的混合物。通常,可消化型碳水化合物提供营养组合物约35%至约75%、优选约45%至70%的营养组合物的能量。优选地,可消化的碳水化合物不含乳糖。
合适的脂质包括菜籽油、葵花籽油、棕榈油、大豆油、乳脂、玉米油和大豆卵磷脂。长链多不饱和脂肪酸(LC-PUFA),尤其是ω-3脂肪酸如二十二碳六烯酸(DHA)可以包含在脂质来源中,因为它们具有抗炎特性。合适的LC-PUFA来源是植物油、海洋浮游生物油、真菌油(fungal oil)和鱼油。脂质来源还可以包括中链甘油三酯(MCT)。分馏椰子油是中链甘油三酯的合适来源。脂质来源优选提供营养组合物约5%至约25%的能量;例如约10%至20%。脂质含量优选降低,因为高脂肪饮食可引起IBS症状。
营养组合物优选还包括维生素和矿物质。如果营养组合物旨在成为唯一的营养来源,其优选包括完整的维生素和矿物质。维生素的实例包括维生素A、B-复合物(例如B1、B2、B6和B12)、C、D、E和K,烟酸和泛酸、叶酸和生物素等酸性维生素。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,如叶黄素、番茄红素、玉米黄质和β-胡萝卜素。包含的类胡萝卜素的总量可以在约0.001μg/ml至约10μg/ml之间变化。叶黄素可以以约0.001μg/ml至约10μg/ml被包含,优选约0.044μg/ml至约5g/ml的量的叶黄素。番茄红素的含量可以为约0.001μg/ml至约10μg/ml、优选约0.0185mg/ml至约5g/ml的番茄红素。β-胡萝卜素可以包含约0.001μg/ml至约10mg/ml,例如约0.034μg/ml至约5μg/ml的β-胡萝卜素。
营养组合物还可以含有各种其它常规成分,例如防腐剂,乳化剂,增稠剂,缓冲剂,纤维和益生菌,特别是有助于减轻IBS患者症状的益生菌(例如VSL#3、B.infantis 35624、B.animalis亚种链球菌BB-12、乳双歧杆菌Bi-07、鼠李糖乳杆菌GG、鼠李糖乳杆菌Lc705、胚芽乳杆菌DSM9843、胚芽乳杆菌CECT7484、胚芽乳杆菌CECT7485、嗜酸乳杆菌NCFM、发酵乳杆菌CECT5716、短双歧杆菌Bb99、Propionibacterium freundenreichii ssp.、ShermaniiJS、乳酸片球菌CECET7483、粪链球菌),包括生育酚、类胡萝卜素B、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(瓜)等在内的抗氧化/抗炎化合物,其他生物活性因子(例如生长激素、细胞因子、TFG-β),着色剂,调味剂和稳定剂,润滑剂等。
营养组合物可以是可溶性粉末、液体浓缩物或即用型制剂的形式。还可以存在各种调味剂、纤维和其它添加剂。
营养组合物可以通过任何用于制备固体或液体形式的营养组合物的通用制备技术来制备。例如,组合物可以由各种料液制备。蛋白质脂肪料液可以通过加热和混合脂质源,然后在加热和搅拌下加入乳化剂(例如卵磷脂)、脂溶性维生素和蛋白质源的至少一部分来制备。还可以通过在加热和搅拌下将矿物质、痕量和超微量矿物质、增稠剂或悬浮剂加入到水中来制备碳水化合物料液。在加入碳水化合物(例如,HMO和可消化碳水化合物源)之前,将所得溶液持续加热和搅拌保持10分钟。然后将所得的料液在加热搅拌下混合,并将pH调节至6.6-7.0,然后对组合物进行高温短时处理,在此期间组合物被热处理、乳化和均化,然后使其冷却。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,加入调味剂,加入水以达到所需的总固体含量。
对于液体产品,所得溶液可以随后被无菌包装以形成无菌包装的营养组合物。在这种形式中,营养组合物可以是即食或浓缩的液体形式。或者,组合物可以经喷雾干燥和处理,作为可重新配制的粉末包装。
当营养产品是即食营养液时,液体中HMS/HMO的总浓度(以液体重量计)为约0.0001%至约2.0%,包括约0.001%至约1.5%和约0.01%至约1.0%;或约0.002%至约3.0%,包括约0.005%至约2%和约0.05%至约1.0%。当营养产品为浓缩营养液时,液体中HMS/HMO的总浓度(以液体重量计)为约0.0002%至约4.0%,包括约0.002%至约3.0%和约0.02%至约2.0%;或约0.004%至约6.0%,包括约0.01%至约4.0%和约0.1%至约2.0%。
单位剂型
本发明的合成组合物也可以是单位剂型,例如胶囊、片剂或袋装剂。例如,组合物可以是包含人乳单糖和/或寡糖、以及一种或多种帮助成型和给药的辅助成分的片剂,辅助成分例如是稀释剂、赋形剂、抗氧化剂、润滑剂、着色剂、粘合剂、崩解剂等。
合适的稀释剂、赋形剂、润滑剂、着色剂、粘合剂和崩解剂包括聚乙烯、聚氯乙烯、乙基纤维素、丙烯酸酯聚合物及其共聚物、羟乙基纤维素、羟丙甲基纤维素(HPMC)、羧甲基纤维素钠、聚甲基丙烯酸羟乙酯(PHEMA)、聚乙烯醇(PVA)、聚乙烯吡咯烷酮(PVP)、聚环氧乙烷(PEO)或聚丙烯酰胺(PA)、卡拉胶、藻酸钠、聚卡波非、聚丙烯酸、黄蓍胶、甲基纤维素、果胶、天然树胶、黄原胶、瓜尔胶、卡拉亚胶、羟丙甲纤维素、硬脂酸镁、微晶纤维素和胶体二氧化硅。合适的抗氧化剂是维生素A、类胡萝卜素、维生素C、维生素E、硒、类黄酮、多酚、番茄红素、叶黄素、木酚素、辅酶Q10(“CoQ10”)和谷胱甘肽。
单位剂型,特别是袋装剂(sachet)形式的剂型,还可以包括各种营养素,包括常量营养素。
施用剂量
为了减少患有细菌过度生长、菌群失调和/或粘膜屏障受损的患者的IBS症状,需要施用于患者的HMS和/或HMO的量将取决于诸如疾病的风险和严重程度、患者的年龄、组合物的形式和患者服用的其它药物的因素。然而,所需量可以由医生容易地确定,通常在每天约20mg至约20g的范围内,在某些实施方式中,优选每天约50mg至约10g,更优选每天约100mg至约7.5g,甚至更优选每天约500mg至约5g,特别是每天约1g至约2.5g;在其它实施方式中,优选每天约50mg至约20g,更优选每天约100mg至约15g,甚至更优选每天约500mg至约10g,特别是每天约1g至约7.5g。在初期治疗阶段,剂量可以更高;例如每天100mg至20g或100mg至30g,优选每天500mg至15g,更优选每天1g至10g,在某些实施方案中为每天2.5g至7.5g。在继发的预防阶段,可以减少剂量;例如,在某些实施方式中,减少至每天20mg至10g,优选每天100mg至7.5g,更优选每天500mg至2.5g,甚至更优选每天至750mg至1.5g,或者在其它实施方案中,减少至每天20mg至20g,优选每天100mg至10g,更优选每天500mg至7.5g,甚至更优选每天750mg至5g。
实施例
现在将描述实施例以进一步阐明发明:
实施例1-人体试验
招募了总计60名男女IBS患者参与研究。经过筛查访问和1-2周的导入(run-inperiod)期,选择患者。将患者随机分为3组,每组20例,两组使用治疗产品,一组使用安慰剂产品8周。治疗产品含有5或10克2'-FL、LNnT、LNT、3-FL、6'-SL和3'-SL的组合,而对照产物含有2克葡萄糖。这两种产品都是单位剂量容器中的粉末形式。
符合参与条件的患者为:至少18周岁,符合IBS的罗马III标准,并被诊断患有细菌过度生长/菌群失调。所有招募的患者都能够并愿意了解并遵守研究程序。如果患者存在以下情况,则将其排除:患者在筛选访问前一个月参与了临床研究;他们在与本研究临床相关的筛选检查中结果异常;他们正在遭受严重的疾病,如恶性肿瘤、糖尿病、严重冠心病、肾脏疾病、神经系统疾病或严重的精神疾病或任何能混淆研究结果的病症;在研究前3个月使用高剂量的益生菌补充剂(酸奶是允许的);在研究前3个月使用抗生素药物;在研究前2周内定期使用任何可能干扰症状评估的药物;以及怀孕或哺乳。
在筛选访问中,登记了用药史和合并药物,收集用于安全性分析的血液样本。分发粪便样本试剂盒。指示患者将样品保存在冷冻室直到下次访问。
在第二次访问时,检查资格标准,符合条件的受试者在试验中被随机分配入三组。收集粪便样品并分发新样品设备。患者熟悉交互互联的系统,其每天记录数据并向患者提供治疗或对照产品。提醒受试者在研究过程中不要改变他们平时的饮食习惯。收集血样用于生物标志物研究。
将来自血液样品中的血清转移到低温条件下,储存于-80℃。测定以下生物标志物:醛固酮、血管紧张素II、ApoA1、ApoB、血尿素氮、铁、BNP(脑利钠肽)、皮质醇、ECP(嗜酸性粒细胞阳离子蛋白)、雌二醇,FFA(脂肪族羧酸酯)、胰高血糖素、HbA1c、IgA、IgM、IgG、IL-10、IL-6、胰岛素、溶菌酶、孕激素、睾丸激素、TNF-α、转铁蛋白、维生素A、维生素B1、维生素B12、维生素B6、维生素D、维生素K1、A-1-抗胰蛋白酶。
将粪便样品储存在-80℃直到分析。对粪便样品进行16S RNA测序分析。
该研究进行8周,患者每天服用安慰剂或治疗产品。指示患者在早晨随餐使用产品。通过交互互联的系统监测顺应性。患者还使用系统记录以下信息:
-Bristol大便分类表(BSF)信息,
-症状信息如腹痛、腹部不适、腹部绞痛、腹胀和腹部饱胀,
-另外的胃肠症状等级评定量表(GSRS)信息。
该调查问卷包括15项,覆盖五个方面(腹痛、消化不良、反流、腹泻、便秘),并使用七级李克特(Likert)量表。
在研究结束时,每个病人都有医疗团队的退出访问。粪便样本和血液样本如前所述进行收集和分析。
与安慰剂组相比,治疗的患者报告了疼痛的减轻和排便的改善。血液生物标志物分析表明,治疗的患者炎症标志物水平降低。粪便分析表明,治疗的患者的细菌过度生长/菌群失调水平降低。
实施例2-人体试验
总计招募300名男、女IBS患者参与研究。经过筛选访问和1-2周的导入期,选择患者。将患者随机分为两组,每组150例,一组使用治疗产品,一组使用安慰剂产品8周。治疗产品含有5克2'-FL和LNnT的组合,而对照产品含有2克葡萄糖。这两种产品都是单位剂量容器中的粉末形式。
符合参与条件的患者为:在18至60岁之间;符合IBS的罗马III标准;报告每周平均最大的每日腹痛强度评分≥3(以0-10分的量表计);在筛选评估期间报告每周至少2天的疼痛/不适频率;对IBS-C亚组患者而言,报告每周不超过3次完全自发排便(CSBM);对IBS-D亚型患者而言,报告每周至少2天具有Bristol大便分类法(BSS)6型或7型硬度的粪便。所有招募的患者都能够并愿意了解并遵守研究程序。如果患者存在以下情况,则将其排除:患者在筛选前一个月参与了临床研究;他们在与本研究临床相关的筛选检查中结果异常;他们正在遭受严重的疾病,如恶性肿瘤、糖尿病、严重冠心病、肾脏疾病、神经系统疾病或严重的精神疾病或任何能混淆研究结果的病症;在研究前3个月使用高剂量的益生菌补充剂(酸奶是允许的);在研究前3个月使用抗生素药物;在研究前2周内定期使用任何可能干扰症状评估的药物;以及怀孕或哺乳。
在首次访问(筛选)时,给予每位患者关于研究的书面和口头信息,并要求患者签署知情同意书。
通过对临床病史的全面浏览,并根据临床症状来评价患者,临床症状的特征在于以下三组之一:腹泻为主(IBS-D)、便秘为主(IBS-C)或交替/混合(IBS-A/M)。这能够在后续分析将患者分配到亚组。
收集用于资格分析的血液样本。进行有关电子问卷调查(GSRS,IBS-SSS,QoL和BSFS)的详细谈话,以使患者熟悉电子系统,并向每位患者分配粪便取样设备。指示患者将样品保存在冷冻室直到下次访问。
在第二次访问(开始干预)时,检查资格标准,符合条件的受试者在试验中被随机分入两组。对症状(由GSRS、IBS-SSS、BSFS和QoL量表测量)进行评估。将试验补充品与电子顺应性日志的使用说明一起发放。收集粪便样品并分发收集新样品的设备。提醒患者在研究期间不要改变他们平时的饮食习惯。
收集血样用于生物标志物研究和生物样本库。将来自血液样品的血清转移到低温管中,储存于-80℃。测定以下生物标志物TNF-α、IL-1β、IL-8、IL-6、IL-12、IL-10、MIP-1β、hs-CRP、脂多糖结合蛋白、类胰蛋白酶、抗鞭毛蛋白(antiflagellin)、连蛋白(zonulin)、组胺、前列腺素2和皮质醇。
将粪便样品储存在-80℃直到分析。使用16S rRNA基因序列对粪便样品进行微生物分析。
该研究进行8周,患者每天服用安慰剂或治疗产品。指示患者在早晨随餐使用产品。通过交互互联的系统监测顺应性。患者还使用系统记录以下信息:
-Bristol大便分类表(BSF)信息,
-症状信息如腹痛、腹部不适、腹部绞痛、腹胀和腹部饱胀,
-生活品质(QoL)信息,
-IBS严重性评分系统(IBS-SSS)信息,
另外的胃肠症状等级评定量表(GSRS)信息。该调查问卷包括15项,覆盖五个方面(腹痛、消化不良、反流、腹泻、便秘),并使用七级李克特量表。
开始4周后,有中间检查。进行身体检查,重新评估症状(由GSRS,IBS-SSS,BSFS和QoL量表等测量)。粪便样本和血液样品如前所述进行收集和分析,并分发收集新粪便样品的设备。
在干预结束时(8周),医疗团队对每位病人进行访问。进行身体检查,重新评估症状(由GSRS,IBS-SSS,BSFS和QoL量表等测量)。收集试验补充产品以检查顺应性。
粪便样本和血液样本如前所述进行收集和分析。
在这次访问中,参与者被问及是否希望继续进行开放标记(open label)的随访研究。对50%的继续参与者给予活性产品的一半剂量,其余的不服用该产品。对同意继续的患者给予粪便样本采集设备,对于继续活性产品的患者,分发试验补充品。
在研究结束时,对患者进行最终访问,收集粪便样本,并从开放标记随访研究的患者重新评估症状(由GSRS,IBS-SSS,BSFS和QoL量表测量)。另外还询问有关不良事件。
对于不参加开放标记随访研究的患者,此次访问将仅与患者是否有不良事件有关。此次访问可以通过电话完成。与安慰剂组相比,治疗的患者报告疼痛/内脏敏感性降低,排便改善。血液生物标志物分析表明,治疗的患者的炎症标志物水平降低,肠道渗透性降低(表明粘膜屏障改善),有证据表明肥大细胞脱粒减少。粪便分析表明,治疗的患者细菌过度生长/菌群失调水平降低,双歧杆菌水平较高;特别是青春双歧杆菌。
实施例3-营养组合物
即食营养组合物由水、麦芽糖糊精、玉米糖浆、糖、乳蛋白浓缩物、植物油(油菜、高油酸向日葵和玉米)、大豆蛋白分离物、阿拉伯树胶、调味剂、HMO、柠檬酸钾、磷酸镁、纤维素凝胶和胶、碳酸钙、抗坏血酸钠、大豆卵磷脂、酒石酸胆碱、磷酸钙、α-生育酚乙酸酯、抗坏血酸、角叉菜胶、焦磷酸铁、调味剂、甜味剂(甜叶菊)、维生素A棕榈酸酯、烟酰胺、维生素D3、泛酸钙、硫酸锰、硫酸铜、盐酸吡哆醇、盐酸硫胺素、β-胡萝卜素、核黄素、氯化铬、叶酸、生物素、碘化钾、植醇激素、亚硒酸钠(sodiumselinite)、钼酸钠、维生素B12制备。
该组合物提供营养补充剂,其是蛋白质、低脂肪、维生素、矿物质和抗氧化剂的良好来源,并且符合FODMAP标准。此外,组合物含有能够促进有益肠细菌生长并调节慢性炎症的HMO。
实施例4-胶囊组合物
通过使用灌装机将约1g的HMS/HMO填充到000明胶胶囊中来制备胶囊。然后将胶囊封闭。HMS/HMO是自由流动的粉末形式。
实施例5-粘膜屏障功能
针对2'-FL和LNnT诱导MUC2,TFF3,EIMβ,CHST5和GAL3ST2在杯状细胞的人LS174T细胞培养模型中表达的能力对其进行了测试。人LS174T细胞获取自美国模式培养物保藏所(ATCC)。将LS174T细胞根据说明书保持在以37℃、5%的CO2补充的最低必需培养基(MEM)中。将2'-FL和LNnT在细胞培养级水溶解至所需浓度。用含有0或5mg HMO/ml的HMO溶液处理LS174T细胞。
收集LS174T细胞并将其悬浮在Trizol试剂中,并使用RNA分析试剂盒(Qiagen)根据制造商的说明书分离总的RNA,并使用Nanodrop分析仪(Thermo Fisher Scientific)对RNA分离物定量。使用高容量cDNA逆转录试剂盒(Applied Biosystems)将RNA分离物逆转录以产生cDNA,然后通过定量RT-PCR用于评估基因表达。
对于定量RT-PCR,从Applied Biosystems获得特异性TaqMAN基因表达测定法,其包括用于MUC2、TFF3、CHST5和GAL3ST2的表达分析。使用TaqMAN PCR Master Mix(AppliedBiosystems)进行定量实时PCR。使用Applied Biosystems 7900HT快速实时PCR系统,在384孔板中以重复的方式进行反应。使用SDS 2.3软件分析结果,并用δCt法计算。所有样品均被归一化为Gus-β表达,并且在未处理的对照组上计算双重诱导。与无HMO的对照细胞相比,基因表达表现为成倍的增加。实验重复三次。
结果表明,与对照培养物相比,用2'-FL和LNnT处理增加了MUC2和TFF3基因的表达。杯状细胞基因的表达增加是特异性的并且不是普遍的,如分别被CHST5和GAL3ST2的最小诱导或诱导缺失所证明的。MUC2和TFF3是粘膜屏障的关键组成部分,并改善粘膜屏障功能。
Claims (16)
1.用于以下用途的合成组合物:
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者;
-减轻患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的IBS症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的腹痛、腹部不适和/或腹胀中的一种或多种慢性症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的肠运动模式改变如稀少或更频繁的肠运动模式、腹泻和便秘中的一种或多种慢性症状;
-预防曾患有IBS的患者,特别是之前曾患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者IBS的复发;
-增加IBS患者,特别是患有细菌过度生长和/或菌群失调和粘膜屏障受损中的一种或多种的患者结肠中的双歧杆菌(Bifidobacteria)、优选青春双歧杆菌(Bifidobacteriumadolescentis),以减轻患者的IBS症状;和/或
-在正在接受或已接受抗生素治疗的患者中预防IBS或IBS症状,
其特征在于,所述组合物包含有效量的人乳单糖(HMS)或人乳寡糖(HMO)或者二者均有。
2.根据权利要求1所述的组合物,其是营养组合物。
3.根据权利要求1或2所述的组合物,其中所述HMS选自唾液酸和岩藻糖,所述HMO选自2’-FL、3-FL、DFL、3’-SL、6’-SL、LNT、LNnT、LNFP-I和DSLNT。
4.根据权利要求1-3任一项所述的组合物,其包括一种或多种主链HMO、一种或多种唾液酸基HMO和一种或多种岩藻糖基HMO,以及任选的岩藻糖和/或唾液酸,优选二者都有。
5.根据权利要求4所述的组合物,其包括2’-FL和LNnT。
6.一种方法,其用于:
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者;
-减轻IBS患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的IBS症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的一种或多种IBS症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的肠运动模式改变如稀少或更频繁的肠运动模式、腹泻和便秘中的一种或多种慢性症状;
-预防曾患有IBS的患者,特别是之前曾患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者IBS的复发;
-增加IBS患者,特别是患有细菌过度生长和/或菌群失调和粘膜屏障受损中的一种或多种的患者结肠中的双歧杆菌(Bifidobacteria)、优选青春双歧杆菌(Bifidobacteriumadolescentis),以减轻患者的IBS症状;和/或
-在正在接受或已接受抗生素治疗的患者中预防IBS或IBS症状,
所述方法包括以合成组合物的形式口服给予患者有效量的一种或多种HMS或者一种或多种HMO,或者二者都有。
7.根据权利要求6所述的方法,其中所述合成组合物为营养组合物。
8.根据权利要求6或7所述的方法,其中所述HMS选自唾液酸和岩藻糖,所述HMO选自2’-FL、3-FL、DFL、3’-SL、6’-SL、LNT、LNnT、LNFP-I和DSLNT。
9.根据权利要求6-8任一项所述的方法,其中所述合成组合物包括一种或多种主链HMO、一种或多种唾液酸基HMO和一种或多种岩藻糖基HMO,以及任选的岩藻糖和/或唾液酸,优选二者都有。
10.根据权利要求9所述的方法,其中所述合成组合物包括2’-FL和LNnT。
11.根据权利要求6-10任一项所述的方法,其用于改善内脏敏感性和排便异常。
12.包括一种或多种HMS、一种或多种HMO或二者均有的合成组合物的用途,其用于:
-减轻患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的IBS症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的腹痛、腹部不适或腹胀的慢性症状;
-治疗患有IBS的患者,特别是患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者的肠运动模式改变、特别是稀少或更频繁的肠运动模式、腹泻或便秘的慢性症状;
-预防曾患有IBS的患者,特别是之前曾患有细菌过度生长、菌群失调和粘膜屏障受损中的一种或多种的患者IBS的复发;
-增加IBS患者,特别是患有细菌过度生长和/或菌群失调和粘膜屏障受损中的一种或多种的患者结肠中双歧杆菌(Bifidobacteria)、优选青春双歧杆菌(Bifidobacteriumadolescentis),以减轻患者的IBS症状;和/或
-在正在接受或已接受抗生素治疗的患者中预防IBS或IBS症状。
13.根据权利要求12所述的用途,其中所述合成组合物为营养组合物。
14.根据权利要求12或13所述的用途,其中所述HMS选自唾液酸和岩藻糖,所述HMO选自2’-FL、3-FL、DFL、3’-SL、6’-SL、LNT、LNnT、LNFP-I和DSLNT。
15.根据权利要求12-14任一项所述的用途,其中所述合成组合物包括一种或多种主链HMO、一种或多种唾液酸基HMO和一种或多种岩藻糖基HMO,以及任选的岩藻糖和/或唾液酸,优选二者都有。
16.根据权利要求15所述的用途,其中所述合成组合物包括2’-FL和LNnT。
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US11833165B2 (en) | 2023-12-05 |
WO2016066175A1 (en) | 2016-05-06 |
US20210308158A1 (en) | 2021-10-07 |
CN115364113A (zh) | 2022-11-22 |
US20180169122A1 (en) | 2018-06-21 |
EP3212197A1 (en) | 2017-09-06 |
US11026959B2 (en) | 2021-06-08 |
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