CN103327831A - 包含几丁质微粒的营养组合物 - Google Patents
包含几丁质微粒的营养组合物 Download PDFInfo
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- CN103327831A CN103327831A CN2011800501550A CN201180050155A CN103327831A CN 103327831 A CN103327831 A CN 103327831A CN 2011800501550 A CN2011800501550 A CN 2011800501550A CN 201180050155 A CN201180050155 A CN 201180050155A CN 103327831 A CN103327831 A CN 103327831A
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- chitin
- food
- particulate
- oral nutrition
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Abstract
本发明公开了营养口服组合物,其包含营养成分,如大量营养素或微量营养素。营养组合物还包括优选通过微流化获得的几丁质微粒制剂,其中几丁质微粒具有1至100μm之间的平均直径。
Description
技术领域
本发明涉及营养组合物,尤其是包含几丁质微粒(壳多糖微粒,chitinmicroparticle)的组合物,其可以用来促进细胞介导的免疫系统的上调以及用来预防或减轻将受益于Th1反应或调节免疫反应的上调的病症。
背景技术
存在以下持续需要:改善确保健康的免疫系统的方式,以便保护身体免受微生物和病原体的影响。巨噬细胞通过促进吞噬清除和分泌细胞因子在先天免疫系统中发挥关键作用,所述细胞因子促进对包括微生物和病原体的微粒的有效的细胞介导的免疫反应。在吞噬作用期间产生的主要细胞因子是IL-12、TNF-α、和IL-18。这些巨噬细胞细胞因子随后通过NK细胞和Th1淋巴细胞诱导IFN-γ产生。IFN-γ与这些细胞因子协同作用以促进Th1细胞介导的免疫反应并且还下调Th2细胞因子,尤其是作为过敏的强介质的IL-4、IL-5和IL-13的产生。
Shibata等人(1-4)的研究表明,通过超声处理、离心和筛分获得的1-10μm可吞噬微粒几丁质的口服递送导致在小鼠脾细胞培养物中Th1细胞因子的提高。这种效应是微粒特有的,这是因为可溶性几丁质并未产生提高。它还可以被再产生在涂布有作为几丁质的主要成分的N-乙酰基-D-葡糖胺的1μm聚苯乙烯微球中。还证明,在豚草过敏的鼠模型中,几丁质的口服给予会下调血清IgE和肺嗜伊红细胞增多(1)。
Shibata等人还已开发了变应性气道炎症的小鼠模型并将几丁质制剂口服给予小鼠(Shibata2000)。在免疫以前和期间,在将几丁质每日口服给予豚草致敏小鼠以后,豚草特异性IgE水平被显著降低。
当将几丁质预防性地给予随后被给予豚草的小鼠时,IL-4、IL-5和IL-10产生被显著降低并检测到低的但为显著水平的IFN-γ。
当给予C57BL6小鼠时,经声波处理的微粒几丁质还具有预防效果,与BALB/c小鼠相比,C57BL6小鼠是细胞介导免疫/Th1反应的较高应答者(responder),但对于变应反应则是较低应答者。当同时用豚草和几丁质来治疗豚草致敏小鼠时,与单独用豚草刺激的小鼠相比,产生的IL-4、IL-5和IL-10的水平被显著降低。
在我们较早的申请WO03/015744中,我们描述了小鼠实验,其表明,鼻内给予的CMP在盐水中的悬浮液具有有益的免疫调节性能,其可以通过上调先天免疫抵抗呼吸道的病毒和细菌感染的机制用于过敏性疾病的治疗并且可以增强保护作用。有益的免疫调节性能还可以用于治疗这样的病症,其将受益于自然杀伤(NK)细胞活性的上调和/或干扰素-γ(IFN-γ)的分泌,如癌症的治疗。
在我们较早的申请WO07/148048中,我们描述了在疫苗组合物中CMP作为佐剂的应用。尤其是,已发现,当CMP组合物与另外的佐剂如霍乱毒素B亚单位(CTB)合并时,CMP组合物能够协同增强抵抗来自传染剂的抗原产生的保护。
WO09/142988披露了使用CMP作为佐剂来增强抵抗传染病如李斯特氏菌属的保护性免疫。尤其是,连同降胆固醇剂一起,几丁质微粒用作佐剂。
发明内容
将有利的是,在诊断过敏以前或者甚至在症状发展或变得严重以前,在主体中能够提高先天免疫反应。因此,本发明试图提供可以获得这一点的产品。
主要地,本发明提供了用于口服消费以及可选用于肠吸收(肠吸附,enteral adsorption)的口服营养组合物,其中营养组合物包含几丁质微粒制剂(chitin microparticle preparation)(CMP)。通常,几丁质微粒具有1至100μm之间并且更优选1至20μm之间的平均直径,并且可通过微流化(microfluidisation)获得。
因此,在第一方面,本发明提供了例如用于肠吸收的口服营养食物组合物,上述组合物具有一种或多种营养成分和几丁质微粒制剂(CMP),其中几丁质微粒具有1至100μm之间的平均直径并且可通过微流化获得。
在另一个方面,本发明提供了用于治疗过敏的方法的根据本发明的口服营养组合物,其中组合物包含几丁质微粒制剂(CMP),其中几丁质微粒具有1至100μm之间的平均直径并且可通过微流化获得。
在又一个方面,本发明提供了根据本发明的几丁质微粒制剂(CMP)在制备口服营养组合物中的应用,所述组合物具有一种或多种营养成分和几丁质微粒制剂(CMP),其中几丁质微粒具有1至100μm之间的平均直径并且可通过微流化获得。
在又一个方面,本发明提供了用于口服消费的食品,所述食品包括如本文中描述的具有一种或多种营养成分和几丁质微粒制剂(CMP)的营养组合物,其中几丁质微粒具有1至100μm之间的平均直径并且可通过微流化获得。
如上所述,可以口服给予本发明的组合物。在这方面,术语“给予”和/或“给药”优选指主体的口服摄入、摄取和/或消费。优选地,通过进食和/或饮用来消费组合物。在另一个实施方式中,通过管喂养来给予组合物。
如果将营养组合物配制成口服给予,则组合物可以是液体口服营养补充剂(例如,不完全补料(incomplete feeding))或完全补料(completefeeding)。以这种方式,可以以任何已知形式,包括例如片剂、胶囊剂、液体、咀嚼片、软凝胶剂、囊剂、散剂、糖浆剂、液体混悬剂、乳剂和溶液(方便剂型),来给予营养组合物。
“营养组合物”可以是用于人消费的食品,例如,饮品(饮料,beverage),饮料(drink),棒,点心(snack),冰淇淋,乳制品,例如冷藏或存贮稳定乳制品,发酵乳制品,饮料,例如基于乳的饮料,婴儿配方(乳)(infant formula),成长乳(growing-up milk),糖果品(confectioneryproduct),巧克力,谷类制品如早餐谷类食品(breakfast cereal),调味料,汤,速溶饮料,用于在微波或烤箱中加热以后消费的冷冻产品,方便食品,快餐或营养配方(产品)。
营养配方(产品)包括任何营养全面或补充配制品(配方产品,配方,formulation)(例如,营养补充剂)。如在本文中所使用的,“营养全面”优选为这样的营养产品,其包含足够类型和水平的大量营养素(macronutrient)(蛋白质、脂肪和碳水化合物)和微量营养素(micronutrient),从而足以作为待给予的主体的唯一的营养来源。患者可以从上述全面营养组合物接收100%的其营养需求。根据一个实施方式,营养配方是提供补充营养的补充配制品(补充配方产品,补充配方,supplementary formulation)。“补充配方”可以不是营养全面的,但优选包含特定营养素,其例如与体育锻炼一起进一步支持本发明的有益效果,和/或其解决主体的特殊的或另外的需要。
营养配方可以是一般适用的营养配方,例如适合于特定年龄的主体,例如儿童用配方,但它还可以是例如用于老年患者的配方,用于重症监护患者的配方,或用于患有特定疾病的患者的特别适合的配方。任何营养配方可以是可重构的(可复水的,reconstitutable),即,以基本上干燥的,例如粉末形式,或方便饮料,例如,以液体配方的形式存在。
本发明的营养组合物提供了可口服消费剂量的CMP,其可以被定期服用以经一段较长的时间来提高个体的免疫系统。以这种方式,个体的免疫系统可以更好地应对进入个体身体的微生物、病原体和变应原(过敏原)。因此,可以增加个体的一般健康,而没有特定痛苦的症状,或具有很少或较不严重的症状。
因此可以提高特异性和非特异性免疫系统。然而,本发明的组合物的特定优势在于,可以使用没有变应原的组合物,使得组合物可以增强个体的非特异性免疫系统。当然,可以连同营养组合物一起来使用变应原以便改善对该变应原的特异性免疫系统。作为进一步的优势,营养组合物可以形成个体的常规营养摄取的一部分,例如作为日常饮食补充剂。作为进一步的优势,可以更容易地与营养成分一起通过肠将CMP吸收进入系统中。
因此,除了个体的正常营养摄入以外,可以获取营养组合物,例如作为饮食补充剂。可替换地,营养组合物可以形成相当大比例的个体的营养摄取,例如,作为婴儿配方(用于婴幼儿人类个体)或作为动物食品(用于动物个体)。
营养成分可以是一种或多种大量营养素。大量营养素包括蛋白质、碳水化合物和脂质。营养组合物优选包含两种并且更优选蛋白质、碳水化合物和脂质大量营养素的组中的所有三种。
另外或可替换地,一种或多种营养成分可以是微量营养素。微量营养素包括维生素、矿物质和盐类。当一种或多种营养成分是微量营养素时,微量营养素优选以若干不同的维生素和/或矿物质存在,使得组合物可以提供广谱的微量营养素。
适宜的大量营养素和微量营养素是本领域中已知的并且营养组合物的选择将取决于营养组合物的特性。本领域技术人员将能够从那些已知适合任何特定营养组合物的需要的营养成分中选择营养成分。典型的蛋白质包括乳清蛋白、酪蛋白、乳源蛋白和大豆源蛋白。典型的碳水化合物包括乳糖、麦芽糊精(maxtodextrin)、果糖、葡萄糖、淀粉和蔗糖。典型的脂质包括棕榈油酸甘油酯(palm olein)、亚油酸、α-亚麻酸、高油酸葵花籽油、高油酸红花油以及包含花生四烯酸和/或二十二碳六烯酸的油。
在食品组合物中可以包括一定范围的维生素和/或矿物质,如维生素A、维生素B1、维生素B2、维生素B6、维生素B12、维生素C、维生素D、维生素K、叶酸、肌醇、烟酸、生物素、泛酸、胆碱、钙、磷、碘、铁、镁、铜、锌、锰、氯化物、钾、钠、硒、铬、钼、牛磺酸和L-肉碱。通常以盐形式来添加矿物质。
营养组合物可以具有任何形式,如液体混悬剂、半液体、固体、散剂、胶或片剂形式。该组合物可以以粉末形式存储并在消费以前与另一种物质混合。通常,将粉状营养组合物与水混合以产生营养饮料。在营养饮料中的CMP将是悬浮液,但一种或多种营养成分可以被溶解或在悬浮液中。在与营养组合物混合以前,用来制作营养饮料的水还可以包含营养(或以其他方式的)颗粒或溶质。
营养组合物可以是人乳强化剂、婴儿配方、随后配方(follow onformula)、成长乳、蛋白配方、运动恢复配方、运动能量配方或运动电解液配方(sport electrolyte formula)。营养组合物可以是婴儿谷类食品、婴儿食品、酸乳、压缩干粮(谷物棒,cereal bar)、早餐谷类食品、点心(dessert)、饮品、糖果物品、冷冻食品、汤或动物食品的成分。优选地,组合物是婴儿配方或被包括在婴儿配方中。
在每种营养组合物中CMP的量将取决于个体消费组合物的量和频率。通常,营养组合物包括可达到100mg的CMP/营养组合物的每日供给量。这可以以单次摄入或作为一个系列的摄入来消费,例如,一天的每餐中营养组合物的摄入。优选地,营养组合物包括1至100mg之间,更优选20至80mg之间,以及更优选40至60mg之间/营养组合物的每日供给量。在营养组合物中CMP的量可以取决于消费营养组合物的个体的体重。组合物优选提供约0.01至100mg之间的活性化合物/kg个体体重,并且更优选约0.5至10mg之间/kg体重。
可以通过许多方式,包括通过激光衍射或不透光度,来测量微粒的平均直径。如本领域技术人员所理解的,不同技术的使用可以导致所记录的微粒的平均直径大小的差异。例如,一种技术可以给出作为颗粒的最小长度的球体的颗粒尺寸,而另一种技术则可以给出作为颗粒的最大长度的颗粒尺寸,因此,对于形状不规则的颗粒,两种测量值会有所不同。
优选地,基于最小长度的球体,几丁质微粒具有小于50μm,更优选小于40μm,还更优选小于20μm,更优选小于10μm并且最优选小于5μm的平均直径。
优选地,基于最大长度的球体,几丁质微粒具有小于100μm的平均直径。更优选地,基于最大长度的球体,几丁质微粒具有小于80μm,更优选小于70μm以及更优选小于60μm的平均直径。
如果通过不透光度,例如利用Accusizer?加以测量,则平均颗粒尺寸优选为小于10μm。如果通过激光衍射加以测量,则平均颗粒尺寸优选为40至60μm之间。可以使用用于测量颗粒尺寸的其它技术。
因为我们已经发现由几丁质微粒引起的效应是尺寸依赖性的,所以优选的是,基于最小长度的球体,几丁质微粒具有10μm或小于10μm的平均直径。可以通过并不识别颗粒的巨噬细胞来功能上定义几丁质颗粒尺寸的上限。尺寸下限是不太重要的,但优选地,颗粒的直径为至少1μm。通过变成可溶的并且因此还未被巨噬细胞识别的几丁质颗粒,来功能上定义尺寸下限。本领域技术人员可以容易地确定颗粒尺寸和尺寸分布,例如利用流式细胞计或显微镜。可替换地或另外,可以通过用N-乙酰基-D-葡糖胺、几丁质或其片段(fragment)涂布载体颗粒,例如,形成自生物相容性材料如聚苯乙烯或乳胶,来制备几丁质微粒,以形成具有如上文所定义的尺寸的颗粒,并且,如在本文中所使用的,这些组合物被包括在术语几丁质微粒组合物的范围内。
应当认识到,在组合物中,几丁质微粒将具有尺寸分布,通常为正态分布,并且并不是群体中的所有颗粒一定会满足这些尺寸限制。然而,在形成CMP制剂的几丁质微粒的群体内,优选至少60%,更优选至少75%,更优选至少90%,更优选95%以及最优选至少99%的几丁质颗粒具有在上文所陈述的限制内的尺寸分布。
优选地,通过物理上减小几丁质,例如通过超声处理或研磨,来产生几丁质。在一个优选的实施方式中,颗粒由微射流仪,如在我们较早的专利申请WO 2008/053192中所描述的方法而产生。并不限制颗粒形状。超声处理将通常产生“圆石形”颗粒,其基本上本质为球体,但具有与球体的不同程度的偏离。换句话说,颗粒是具有角边的球体。
然而,本发明已发现,可由微流化器方法(微流化剂方法,microfluidiser method)获得的几丁质微粒的形状不同于由超声处理产生的那些几丁质微粒的形状。当由微流化器方法产生时,颗粒是“蓬松的(fluffy)”。因此,颗粒具有高表面积。与通过技术如超声处理或研磨产生的角球体(有角的球体,angular spheroid)几丁质微粒相比,上述“蓬松的”几丁质微粒在悬浮液中是更加稳定的,因而产生更加稳定的几丁质微粒制剂。本领域技术人员能够测量可通过微流化获得的几丁质微粒组合物的稳定性,例如通过确定组合物是否能够在5mg/ml的浓度和25°C的温度下形成稳定的含水悬浮液至少一个小时。这可以与通过筛分、超声处理或研磨所产生的组合物对比,所述通过筛分、超声处理或研磨所产生的组合物倾向于在短时间内,例如,在小于10分钟内,从悬浮液中掉下来并沉降在它们的容器的底部。一种示例性的几丁质微粒制剂利用由微流化器方法获得的几丁质微粒制备。这种组合物在溶液中稳定数周。以这种方式,由微流化器方法获得的几丁质微粒特别适用于本发明的营养组合物,如酸乳饮料。可替换地或另外,本领域技术人员将能够认识到,可通过微流化获得的几丁质微粒不同于通过技术如研磨所产生的颗粒,这是因为微流化制造过程产生这样的组合物,其具有在含水组合物中的微凝胶或凝胶样稠度,然后可以干燥凝胶组合物以产生粉末。
除了具有不同的物理性能以外,本文中报道的实验证明了,与通过技术如超声处理或研磨产生的相应组合物相比,可通过微流化获得的几丁质微粒组合物具有增强的生物效应,尤其是增强由来自过敏性个体的白细胞产生的IFN-γ的分泌水平。优选地,与通过研磨或超声处理获得的几丁质制剂相比,在人白细胞中,可通过微流化获得的几丁质微粒组合物能够产生至少2倍,更优选至少3倍,以及更优选至少4倍的IFN-γ反应。
几丁质是N-乙酰基-D-葡糖胺的聚合物并具有与纤维素类似的结构。在自然界中,它是丰富的多糖,包括在蟹、虾、龙虾、墨鱼、和昆虫的外骨骼中以及真菌中的角质。几丁质的任何这些或其它来源适用于制备用于根据本发明的应用的CMP制剂。在几丁质的处理期间,可以发生几丁质的小程度的脱乙酰作用。然而,可以容许不大于50%的脱乙酰作用,优选不大于40%,更优选不大于30%,更优选不大于20%以及最优选不大于10%的脱乙酰作用。在大于50%脱乙酰作用的水平,形成脱乙酰几丁质(葡糖胺的脱乙酰化聚合物)。
通常,根据本发明,连同食品或饮料的营养成分一起来使用几丁质微粒组合物,使得消费食品或饮料的个体的免疫系统得到提高,从而有助于预防或治疗过敏。然而,在一些替代的实施方式中,组合物可以包括变应原。这些组合物可以用于治疗过敏和变应性症状,如过敏性休克,其与常规脱敏疗法有关。已表明,IL-12的口服应用会抑制过敏反应,因此连同营养组合物中的CMP组合物一起给予变应原将有助于缓和在用来建立对变应原的耐受性的脱敏疗法期间产生的过敏反应。变应原可以容易地从食品中提取并且可市场上获得,因为它们用于过敏的诊断和治疗。不论变应原是否包括在组合物中,本发明特别适用于治疗食物过敏,例如那些涉及常见的食物变应原,如牛奶、小麦、麸质、鸡蛋、坚果或贝类的食物过敏。本领域技术人员将能够配制这些食物变应原与CMP组合物,以供个体消费。
本发明可以用来上调细胞介导的免疫系统,所以在另一个方面,本发明提供了在本文中描述的营养组合物的应用,用来帮助预防、治疗或缓解与细胞介导的免疫系统的上调有关的若干病症的症状。受益于细胞介导的免疫系统的上调的病症包括微生物感染,包括细菌感染、真菌感染和病毒感染的治疗或预防,尤其是在易受伤害的患者组,如老年者、早产儿、婴幼儿、移植患者、免疫抑制患者如化疗患者、具有机会性感染的风险的医院患者、使用呼吸器的患者、囊性纤维化患者和患有AIDS的患者中。本发明特别适用于耳、鼻、喉和肺部感染的治疗。
细菌感染的具体实例包括治疗由微生物如铜绿假单胞菌(Pseudomonas aeruginosa),链球菌属物种如肺炎链球菌(Streptococcuspneumoniae),化脓性链球菌(Streptococcus pyrogenes),无乳链球菌(Streptococcus agalactiae),流感嗜血杆菌(Haemophilus influenza),肺炎克雷伯菌(Klebsiella pneumoniae),小肠结肠炎耶尔森菌(Yersiniaenteocolitica),沙门氏菌属(Salmonella),李斯特氏菌属(Listeria)引起的感染,分枝杆菌感染,包括结核分枝杆菌(Mycobacterium tuberculosis),麻风分枝杆菌(Mycobacterium leprae),寄生虫感染,包括利什曼原虫物种(Leishmania species)和血吸虫物种(Schistosoma species)。
由微生物感染,通常由肺炎链球菌引起的一种病症是复发性耳部感染如中耳炎。这些病症发生在儿童和成人中并且目前利用抗生素来治疗。将是有利的是,使用本发明的几丁质微粒组合物来预防或治疗这些病症,并且减少对抗生素的需要。
本发明的制剂可以用于结核病的治疗以治疗现有的感染或保护易受伤害的患者组免受感染。
微生物感染的其它实例包括细菌性肺炎,如呼吸器相关性肺炎、和囊性纤维化相关的感染。
真菌感染的实例包括例如在免疫抑制患者中的真菌感染如侵袭性肺曲霉病和侵袭性肺念珠菌病、肺孢子虫性肺炎、球孢子菌属和隐球菌属感染。
根据本发明可治疗的病毒性病症的实例包括肺病毒感染如呼吸道合胞体病毒细支气管炎,尤其是在婴幼儿和老年者中,或流感病毒、或鼻病毒。许多研究表明,在AIDS的进展期间,单核细胞失去它们分泌IL-2、IL-12和IFN-γ的能力并产生增加水平的IL-4,其允许HIV病毒增殖。因此,用以营养组合物给出CMP进行的治疗通过恢复IL-12和IFN-γ水平将在减少HIV感染的进展中是有用的。
另外,本发明的营养组合物可以用来帮助预防、治疗或缓解胃肠道病症,如炎性肠病、克罗恩病、溃疡性结肠炎、炎症性肠病、肠易激综合征、腹泻型肠易激综合征、便秘型肠易激综合征、交替式肠易激综合征(irritablebowel syndrome-alternating)、混合型肠易激综合征(irritable bowelsyndrome-mixed)、消化不良、胃食管反流、憩室炎、憩室病、胃轻瘫、微观结肠炎、淋巴细胞性结肠炎、胶原性结肠炎、不确定结肠炎(indeterminantcolitis)、嗜酸性粒细胞性食管炎、HIV相关性腹泻、伪膜性结肠炎、与免疫缺陷症有关的腹泻、小肠过度生长综合征、乳糜泻、惠普尔氏病、CMV相关性结肠炎、白塞综合征和它们的组合的症状。尤其是,营养组合物可以用来预防、治疗或缓解克罗恩氏病的症状。
除了几丁质微粒以外,CMP制剂还可以包含一种或多种可接受的赋形剂、载体、推进剂、缓冲剂、稳定剂、等渗剂、防腐剂或抗氧化剂、增香剂、或本领域技术人员众所周知的其它材料。上述材料应是无毒的并且不应干扰几丁质微粒的功效。
在营养组合物中可以包括防腐剂以延长组合物的保质期,例如,通过延缓微生物的生长,以便允许多次使用的包装。防腐剂的实例包括丙酸钙、硝酸钠、亚硝酸钠、亚硫酸盐(二氧化硫、亚硫酸氢钠、亚硫酸氢钾等)、EDTA二钠、丁基化羟基苯甲醚(丁羟茴醚)(BHA)和丁基化羟基甲苯(丁羟甲苯)(BHT)。防腐剂通常在约0.1%至1.0%(w/v)的范围内使用。
优选地,以用于个体的“预防有效量”或“治疗有效量”(视情况而定,虽然预防可以认为是治疗)来提供营养组合物,这足以显示对个体的益处,例如,缓解过敏或另一种病症,或预防持续可以接受的时间。通常,这将引起治疗有用的活性,从而对个体提供益处。组合物优选提供在约0.01至100mg之间的活性化合物/kg个体体重,以及更优选在约0.5至10mg之间/kg体重。通过示例的方式,这可以利用婴儿配方来实现,以提供大约1.25mg CMP颗粒/25g粉状配方部分(以制作大约150ml再造配方)。
在另一个方面,本发明提供了包含如本文中描述的营养组合物的食品。食品包含一种或多种食物营养素,其来自加工或未经加工的食品材料,如水果、蔬菜、种子、豆类、干豆(pulses)、乳制品、肉类和其它动物源性产品。因此,本发明可以源于将营养成分和CMP加入常规食品,如糖果或酸乳饮料中。通过将CMP加入食品中,可以作为消费者平常每日膳食或点心的一部分来消费几丁质微粒。
可以一起或分开地将营养组合物的CMP和营养成分加入食物营养素中。如果分开地添加,则应在相同食品加工过程中添加CMP和营养成分。换句话说,应在相同的生产线或位置,添加CMP和营养成分。
本发明的一个方面的可选和优选特点可应用于本发明的其它方面,反之亦然。现将通过示例而非限制的方式来描述本发明的实施方式。
本发明包括所描述的方面和优选特点的组合,除非这样的组合是明确地不允许的或被说明是要明确避免的。现将通过示例而非限制的方式参照附图来描述本发明的实施方式。
附图说明
图1示出了实验结果,其中测试口服给予的CMP组合物在预防和控制过敏症状方面的功效。
图2示出了在体外研究中CMP组合物对来自过敏性个体的白细胞分泌细胞因子的作用。
具体实施方式
材料和方法
几丁质微粒悬浮液制备(CMP)
几丁质微粒通过在不含内毒素的PBS中超声处理10mg/ml的悬浮液由纯化的几丁质(Sigma-Aldrich,Poole,UK)而制备,最大输出20分钟,每隔5分钟在冰上冷却。在1000xg下离心淤浆10分钟以除去较大颗粒并通过在4000xg下离心来收集微粒,然后用PBS洗涤3次以除去任何溶解的几丁质。上清液包含小颗粒的均匀悬浮液,如通过光学显微镜术并利用50μm2的血球计所判断的,并且尺寸可与1μm乳胶球体比较(Polysciences,Inc.,Warrington,Pennsylvania,USA)。用Celltac血液分析仪(CelltacHematology Analyser)(Nihon Kohden,Inc.)来量化直径小于5μm的颗粒。已发现,制剂包含99.9%的直径小于5μm以及浓度为约1011/ml的微粒。通过鲎变形细胞溶解物试验(鲎阿米巴样细胞溶解物试验,LimulusAmebocyte Lysate Assay)(BioWhittaker Co)来测量内毒素并且显示为<1EU/ml。在其它实施方式中,利用如在WO2008/053192中描述的微流化器来制备CMP悬浮液。
婴儿配方制剂
连同温水(50-80°C)一起混合7.0g蛋白源(70%乳清蛋白,30%酪蛋白)、36g碳水化合物源(乳糖)和17g脂质源(高油酸葵花籽油)的混合物以形成液体混合物。在压热器中均化和热处理混合物以减小混合物的细菌含量。使混合物冷却,并将维生素A、D、E、K1、C、B1、B2、B6、B12、烟酸和叶酸(μg至mg标准量),包含Na、K、Cl、Ca、P、Mg、Mn、Se、Fe、Cu、Zn和I的矿物盐(μg至mg标准量),以及0.75mlCMP颗粒的5mg/ml悬浮液(以在大约70g配方中产生3.75mg的CMP微粒)加入到冷却的混合物中。
将液体混合物转移到冷冻干燥器中以便将混合物干燥成粉末。粉末具有按重量计小于约5%的水分含量。然后将粉末真空密封在塑料容器中,供以后重建和消费。
益生素酸乳饮料制剂
将脱脂乳、在水中的CMP悬浮液(5ml的5mg/ml悬浮液)、葡萄糖、果胶、阿斯巴特(天冬酰苯丙氨酸甲酯,aspartame)、乙酰舒泛K、益生素和维生素K加入到120ml酸乳中。搅拌混合物10分钟以产生益生素酸乳饮料。冷藏产生的饮料,准备好用于消费。
能量棒
将麦芽糊精(100g)、燕麦麸(200g)、爆米花(60g)、乳蛋白分离物(100g)、结晶果糖(80g)、矿物质预混料(30g)、米粉(60g)的干燥成分混合在一起。向此干燥混合物中缓慢加入金黄糖浆(golden syrup)(340g)、黄油(40g)、增香剂(10g)和CMP悬浮液(20ml的25mg/ml水悬浮液)的温热混合物,同时混合。卷起得到的混合物并压制成厚片,然后切成50g棒,用于包装。
狗食
混合以下宠物食品级成分以制备犬食物混合物:玉米淀粉(650g);大豆蛋白(250g);碳酸钙(20g);纤维素(22g);椰子油(17g);磷酸二钙(12g);含水CMP悬浮液(5ml的5mg/ml悬浮液);氯化胆碱(2.5g);氧化镁(2g);氯化钠(1g);维生素D3、E和B12;核黄素和叶酸。
体内研究
在OVA食物过敏动物模型中,测试了用CMP组合物进行的口服治疗的作用,以确定CMP组合物在降低发展过敏症状的风险方面是否具有预防效果以及确定当在已发生致敏作用以后给予时CMP组合物是否可用于治疗过敏症状。通过口服途径来致敏六周龄成年常规BALB/c小鼠:在第一周施加3次,然后在7周期间以每周的间隔施加20mg卵清蛋白(OVA)加上10μg/小鼠的霍乱毒素(用作佐剂)。在最后致敏作用以后一周,经由灌胃法并用100mg的OVA进行口服激发(oral challenge)。在激发当日,在激发以前,饥饿小鼠2小时。在激发以后30分钟,在30分钟期间单独观察小鼠。记录和量化临床症状如下(过敏性评分):0)没有症状,少于4个搔抓事件;1)4-10个在鼻子和头部周围的搔抓事件,没有腹泻;2)多于10个搔抓或软便事件;3)腹泻或吃力的呼吸或发绀或存在两种或更多种症状(搔抓和软便);4)腹泻连同在催促以后的不动性、竖起皮毛、吃力的呼吸或发绀;5)过敏反应。在激发以后4小时,处死小鼠。结果示于图1中,其表明,CMP组合物在致敏小鼠的过敏症状的控制中具有有益作用。
体外人细胞研究
进行体外研究以表征几丁质微粒对获自特应性个体的全血细胞的作用。将来自10次微流化循环的微流化几丁质与适当对照比较。
在补充有1%L-谷氨酰胺(Sigma)、1%青霉素/链霉素(Sigma)、0.1%庆大霉素(Sigma)的RPMI中培养来自过敏性供体(临床史+对花粉的SPT)的全血细胞。单独用抗CD2和抗CD28来刺激细胞,或连同抗CD2和抗CD28一起添加浓度为50μg或100μg的CMP。还添加未刺激的对照。在5天以后,获取培养物上清液并冻结,直到进一步的分析。利用人Th1/Th2复用试剂盒(multiplex kit)测量了人IL-5、IL-10、IL-13、和IFN-γ。研究结果示于图2中。其表示,在过敏性个体中CMP会提高IFN-γ水平,并且降低Th-2细胞因子(IL-5、IL-13)。该作用是剂量依赖性的。
参考文献
本文披露的文献的全部内容以引用方式明确地结合于本文。
1.Shibata et al,J.Immunol.,164:1314-1321,2000.
2.Shibata et al,J.Immunol.,161:4283-8,1998.
3.Shibata et al,Infection and Immunity,65(5):1734-1741,1997.
4.Shibata et al,J.Immunol.,159:2462-2467,1997.
5.WO03/015744
6.WO07/148048
7.WO09/142988。
Claims (20)
1.一种口服营养组合物,所述组合物包含一种或多种营养成分和几丁质微粒制剂(CMP),其中所述几丁质微粒具有1至100μm之间的平均直径并且可通过微流化获得。
2.根据权利要求1所述的口服营养组合物,其中,可通过微流化获得的所述几丁质微粒具有以下特性中的一种或多种:
(a)所述几丁质微粒在5mg/ml的浓度和25°C的温度下形成稳定的含水悬浮液持续至少一个小时;和/或
(b)所述几丁质微粒在含水组合物中具有凝胶样稠度;和/或
(c)与通过超声处理产生的角球体几丁质微粒对比,所述几丁质微粒具有蓬松形状。
3.根据权利要求1或权利要求2所述的口服营养组合物,其中,所述组合物是营养全面的配制品或补充配制品。
4.根据权利要求1至3中任一项所述的口服营养组合物,其中,所述组合物是用于肠吸收的营养组合物。
5.根据权利要求4所述的口服营养组合物,其中,至少一种营养成分是大量营养素。
6.根据权利要求4所述的口服营养组合物,其中,所述组合物包含选自蛋白质、碳水化合物和脂质的大量营养素的组中的两种或更多种营养成分。
7.根据权利要求2至6中任一项所述的口服营养组合物,其中,至少一种营养成分是微量营养素。
8.根据权利要求7所述的口服营养组合物,其中,所述组合物包含选自矿物质、维生素和盐类的微量营养素的组中的两种或更多种营养成分。
9.根据前述权利要求中任一项所述的口服营养组合物,其中,所述组合物是饮料。
10.根据权利要求1至8中任一项所述的口服营养组合物,其中,所述组合物是食品。
11.根据前述权利要求中任一项所述的口服营养组合物,其中,所述组合物是婴儿谷类食品、婴儿食品、酸乳、压缩干粮、早餐谷类食品、点心、饮品、糖果品、冷冻食品、汤或动物食品。
12.根据前述权利要求中任一项所述的口服营养组合物,其中,所述组合物是饮品,饮料,棒,点心,冰淇淋,乳制品,例如冷藏或存贮稳定乳制品,发酵乳制品,饮料,例如基于乳的饮料,婴儿配方,成长乳,糖果品,巧克力,谷类制品如早餐谷类食品,调味料,汤,速溶饮料,用于在微波或烤箱中加热以后消费的冷冻产品,方便食品,快餐或营养配方。
13.根据前述权利要求中任一项所述的口服营养组合物,其中,所述几丁质微粒具有20μm或更小的平均直径。
14.根据前述权利要求中任一项所述的口服营养组合物,其中,所述几丁质微粒通过利用微流化器减小在几丁质微粒组合物中的颗粒的尺寸而制备。
15.根据权利要求1至13中任一项所述的口服营养组合物,用于在治疗过敏的方法中使用。
16.根据权利要求1至13中任一项所述的几丁质微粒制剂(CMP)在制备口服营养组合物中的应用,所述组合物具有一种或多种营养成分和所述几丁质微粒制剂(CMP),其中所述几丁质微粒具有1至100μm之间的平均直径并且可通过微流化获得。
17.根据权利要求15所述的应用,其中,所述营养组合物用于治疗或预防过敏。
18.根据权利要求15所述的应用,其中,所述营养组合物用于受益于细胞介导的免疫系统的上调的病症的治疗或预防。
19.一种用于口服消费的食品,所述食品包含具有一种或多种营养成分和几丁质微粒制剂(CMP)的营养组合物,其中所述几丁质微粒具有1至100μm之间的平均直径并且可通过微流化获得。
20.根据权利要求18所述的食品,其中,所述食品是婴儿谷类食品、婴儿食品、酸乳、压缩干粮、早餐谷类食品、点心、饮品、糖果品、冷冻食品、汤或动物食品。
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