CN110651824A - 益生菌和使用方法 - Google Patents
益生菌和使用方法 Download PDFInfo
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- CN110651824A CN110651824A CN201910988302.7A CN201910988302A CN110651824A CN 110651824 A CN110651824 A CN 110651824A CN 201910988302 A CN201910988302 A CN 201910988302A CN 110651824 A CN110651824 A CN 110651824A
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- lactobacillus paracasei
- food product
- paracasei cba
- fermented
- administered
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- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
本发明呈现治疗泌乳母亲的婴儿中微生物感染或减轻该感染严重性的方法。包含副干酪乳杆菌(Lactobacillus paracasei)CBA L74,国际保藏登录号LMG P‑24778的发酵食物产品的组合物被施给怀孕或泌乳母亲,以治疗其后代中的微生物感染或缓解该感染的严重性。
Description
本发明专利申请是国际申请号为PCT/US2014/037517,国际申请日为2014年5月9日,进入中国国家阶段的申请号为201480026882.7的发明专利申请的分案申请。
相关申请交叉参考
本申请要求2013年5月10日提交的的美国临时申请61/821,990的权益。为了任何美国申请可能要求美国临时申请号61/821,990的权益,该在先提交的申请在此通过引用完整引入。
技术领域
本发明涉及包含益生菌生物的组合物以及对怀孕和泌乳个体施用这些组合物的方法。这些方法用于治疗这些个体后代的感染。
背景技术
虽然现代临床医学有所进步,感染仍然导致新生儿,尤其是幼龄早产新生儿的显著患病和死亡。根据世界卫生组织,感染,包括脓毒血症、肺炎、破伤风和腹泻占到每年全世界范围内约3.3百万新生儿死亡的大约36%。新生儿的免疫系统在功能上不成熟。由于症状可能是细微和非特异性的,在新生儿中诊断感染具有挑战性。虽然许多感染对抗生素有良好的响应,但抗生素治疗延迟会导致感染急速进展,产生非常严重的病况例如新生儿脓毒血症。新生儿脓毒血症若不治疗,必然是致命的。在抗生素治疗的婴儿中因脓毒血症的死亡率在5%-60%之间,在最低收入国家中报道的死亡率最高。对于婴儿中感染的治疗和预防的新策略和药剂有持续的需求。
发明概述
本发明提供了一种治疗泌乳母亲的婴儿中微生物感染的方法,包括将有效量的包含食物产品的组合物施给泌乳母亲,其中所述食物产品经由益生菌,副干酪乳杆菌(Lactobacillus paracasei)CBA L74,国际保藏登录号LMG P-24778发酵。细菌可以不是复制性的。组合物的施用可在产前、产后或者产前和产后直到婴儿断奶。该方法还包括识别需要治疗的婴儿。微生物可以是鼠伤寒沙门氏菌(Salmonella typhimurium),阪崎克罗诺杆菌(Cronobacter sakazakii),大肠杆菌(Escherichia coli),单核细胞增生性李斯特菌(Listeria monocytogenes),
肺炎链球菌(Streptococcus pneumoniae),脑膜炎奈瑟氏菌(Neisseriameningitidis),或轮状病毒。发酵的食物产品可以是乳制品或谷物产品。还提供了预防泌乳母亲的婴儿中细菌感染或减轻其严重性的方法,包括将有效量的包含食物产品的组合物施给泌乳母亲,其中所述食物产品经由益生菌,副干酪乳杆菌(Lactobacillus paracasei)CBA L74,国际保藏登录号LMG P-24778发酵。细菌可以不是复制性的。
附图简要说明
下文更详细的对本发明优选实施方式的描述将使得本发明的这些和其他特征及优点得到更完全的公开或变得更明显。这些优选实施方式以及附图应一起考虑,其中同样的数字对应同样的部分,其中:
图1描述了母体施用副干酪乳杆菌CBA L74株发酵的稻米对感染阪崎克罗诺杆菌的后代存活率的效果的分析结果。
图2描述了母体施用副干酪乳杆菌CBA L74株发酵的稻米对感染阪崎克罗诺杆菌的后代存活率的效果的分析结果。
图3描述了母体施用副干酪乳杆菌CBA L74株发酵的牛奶对感染鼠伤寒沙门氏菌FB62的后代存活率的效果的分析结果。
优选实施方式的详细说明
本发明部分基于发明人的如下发现:对怀孕和泌乳动物施用益生菌生物副干酪乳杆菌菌株CBA L74发酵的食物能减少或减轻其后代中微生物感染的严重性。更具体的,发明人发现对怀孕或泌乳母体施用副干酪乳杆菌菌株发酵的稻米能提高阪崎克罗诺杆菌感染后子代的存活百分率。类似的,发明人还发现对怀孕和泌乳母体施用副干酪乳杆菌菌株CBAL74发酵的牛奶导致其后代在鼠伤寒沙门氏菌FB62感染后的存活百分率提高。因此,本发明涉及在新生生物体中减弱细菌感染的严重性或预防细菌感染的方法,通过对其母亲施用含副干酪乳杆菌菌株CBA L74发酵的食物产品的组合物来实现。可在母亲怀着婴儿时施用组合物,即产前。替代或补充地,可在婴儿出生后对母亲施用组合物,即产后。在一些实施方式中,副干酪乳杆菌菌株CBA L74不可复制。
发明人分离了副干酪乳杆菌CBA L74株,并根据对专利程序目的的微生物保藏的国际认证布达佩斯条约将其于2008年9月9日保藏于比利时微生物协作保藏中心(BCCM)的微生物科学实验室(LMG),比利时根特。国际保藏机构给予的登录号为LMG P-24778。为了方便阅读,我们不会每次重复“登录号LMG P-24778”。应理解当我们提到副干酪乳杆菌菌株CBA L74时,我们指具有登录号LMG P-24778的保藏菌株。
虽然我们认为我们理解施用包含或从副干酪乳杆菌菌株CBA L74发酵制备的本发明的组合物后发生的一些事件,本发明的组合物并不限于通过作用于任何具体细胞机制来工作的组合物。
组合物
副干酪乳杆菌CBA L74
本发明的组合物可包含益生菌副干酪乳杆菌CBA L74。世界卫生组织将益生菌定义为:"当以足量施用时,对宿主赋予健康益处的活微生物。"在一些实施例中,可处理副干酪乳杆菌CBA L74使其无复制性,例如通过接触热、γ-辐射、或uv-辐射。非复制性副干酪乳杆菌CBA L74可以是死细胞,或不能细胞分裂的活细胞。非复制性副干酪乳杆菌CBA L74可以是完整细胞或完全或部分裂解的细胞。在一些实施方式中,无复制性细胞可包括完整和裂解细胞的混合物。
食物产品
本发明的组合物可包括生理学上可接受的运载体。生理学上可接受的载体可以是食物产品或药物学载体。我们用术语“生理学上可接受”(或“药学上可接受”)指分子实体和组合物在恰当地给予动物或人时不产生不利、过敏性或其它不良反应。因此,本发明的组合物可包含益生菌副干酪乳杆菌CBA L74发酵产生的食物产品。食物产品可包括副乳酪乳杆菌CBA L74细胞,不论活的或无复制性的。在一些实施方式中,可对食物产品进行处理,除去全部或基本全部副乳酪乳杆菌CBA L74细胞。可使用适合任何可经副乳酪乳杆菌CBA L74发酵的食物产品。食物产品可以是奶制品例如奶或基于奶的产品。示范性奶源包括但不限于奶牛、绵羊、山羊、牦牛、水牛、马、驴、麋鹿和骆驼。不论来源,奶或奶制品可以是任何适合副乳酪乳杆菌CBA L74发酵的形式。例如,奶可以是全奶或已处理除去部分或全部乳脂的奶,例如2%奶、1%奶和0脂奶。另选或额外的,奶可以是事先巴斯德消毒或匀化的,干燥或重建的,浓缩或蒸发的。还可以使用奶制品的组分包括酪蛋白、乳清蛋白或乳糖。在一些实施方式中,奶制品可以是约1%-30%的重建脱脂奶粉,例如约2%、约5%、约7%、约9%、约10%、约12%、约15%、约20%、约25%、约30%的重建脱脂奶粉。在发酵前,奶制品可以与一种或多种以下混合:a)碳水化合物(例如二糖如葡萄糖或淀粉);b)脂类;c)维生素和d)矿物质。例如,脱脂奶粉可以与约2%,例如,约0.25%、约0.50%、约0.75%、约1.0%、约1.5%或约2.0%的葡萄糖混合。
食物产品可以是谷物产品,例如稻米、燕麦、玉米、高粱或粟。在一些实施方式中,谷物产品可以是小麦、大麦、黑麦或黑小麦。谷物产品可以是全麦或磨成面粉。食物产品可以是一种谷物或两种或多种谷物的混合物,例如燕麦粉加稻米粉。谷物产品可以是适合人类消费的级别或类型,或适合驯养动物消耗的产品。通常谷物产品在发酵前经水润。谷物浓度可变,但有用的范围包括约5%到约50%重量/体积,例如约8%重量/体积、约10%重量/体积、约12%重量/体积、约15%重量/体积、约18%重量/体积、约20%重量/体积、约22%重量/体积、约25%重量/体积、约30%重量/体积、约35%重量/体积、约40%重量/体积、约45%重量/体积或约50%重量/体积。示范性浓度包括15%重量/体积的稻米或18.5%重量/体积燕麦粉加上5%重量/体积出芽大麦粉的混合物。水合谷物的pH可用任何适合消耗的酸来调节。酸可以是例如有机酸。有用的有机酸包括乙酸、柠檬酸、乳酸、己二酸、马来酸和酒石酸。可使用两种或多种酸的任意组合。在一些实施方式中,可用柠檬酸将pH调节到约4.0。
食物产品还可以是蔬菜或水果产品,例如汁、泥、浓缩物、膏、酱料、泡菜或番茄酱。示范性蔬菜和水果包括但不限于番瓜,例如节瓜、黄南瓜、笋瓜、南瓜;土豆;芦笋;西兰花;球芽甘蓝;豆类,例如青豆、菜豆、利马豆、蚕豆、黄豆;甘蓝;胡萝卜;花椰菜;黄瓜;大头菜;韭葱;青葱;洋葱;甜豌豆;英国豌豆;辣椒;芜青;芜青甘蓝;番茄;苹果;梨;桃;梅子;草莓;树莓;黑莓;蓝莓;越橘;博伊森莓(boysenberry);醋栗(gooseberries);葡萄;黑醋栗(currants);柠檬;柚子;香蕉;芒果;猕猴桃和杨桃。
食物产品还可以是用坚果或豆类制成的“奶”,例如豆奶或杏仁奶。
还考虑包含动物蛋白的食物产品,例如肉类,如香肠、干肉、鱼和鱼干产品。
无论使用哪种食物产品,产品与副乳酪乳杆菌CBA L74混合并在一定温度下培育足够的时间使其发酵。可使用任何本领域常规发酵法。具体发酵条件可因许多因素而异,例如食物产品的类型,食物产品的浓度,所用的器具,样品体积,副干酪乳杆菌CBA L74的接种初始浓度,如有存在的共接种物,发酵食物的感官性质,和发酵食品的目的用途。
在用副乳酪乳杆菌CBA L74接种之前,对器具和基质(即要发酵的食物产品)进行灭菌,以降低或消除活细菌和/或真菌和/或感染性病毒的水平。可用标准方法或根据厂商说明书对器具灭菌。对基质灭菌的具体方法的选择部分依赖于基质对灭菌法的稳定程度。例如,可用蒸汽和压力,例如高压灭菌,重复加热和冷却循环(例如丁达尔灭菌法),接触高压(例如超高压灭菌法),超滤,或辐射(例如接触γ-,x-,e-射线和/或紫外(10nm-320nm波长,例如50nm-320nm,100nm-320nm,150nm-320nm,180nm-320nm,或200nm-320nm)对基质灭菌。处理后,可取出基质等份,铺在合适的培养基上以确认不存在细菌和/或真菌污染物。如果通过接触高温对基质灭菌,应在接种副乳酪乳杆菌CBA L74之前冷却到至少37℃。
可根据标准方法用副乳酪乳杆菌CBA L74对基质接种,例如从新鲜液体培养物或在接种前短时重悬浮于水性培养液中的冻干培养物的那些。一般以约0.5x 106到约1x106cfu/ml基质的浓度,例如约1x 106cfu/ml,约2x106cfu/ml,约5x 106cfu/ml,7x 106cfu/ml,8x 106cfu/ml加入副乳酪乳杆菌CBA L74。应充分搅动培养物以产生相对均匀的细菌和基质分布,但不宜过度搅动,因为副乳酪乳杆菌CBA L74是一种厌氧菌。例如,可以约150rpm搅动5升的培养物。发酵温度一般为37℃。可在发酵过程中监控和相应调节各种参数,例如pH、氧分压、搅拌器速度、温度、气体混合、泡沫水平和基质浓度。可用标准微生物学方法监测副乳酪乳杆菌CBA L74的生长。进行发酵直到副乳酪乳杆菌CBA L74浓度在约108/ml-109/ml之间。根据基质和其他条件,该浓度可在接种后约10-30小时,例如约12小时、约15小时、约18小时、约24小时、约30小时达到。
可用标准微生物学方法在发酵前、中和后测试基质样品以确保质量。示范性方法包括但不限于在Rogoso琼脂上副乳酪乳杆菌CBA L74的生长,平板计数琼脂(PCA)上的生长以测定总需氧菌,McConkay琼脂上的生长以测定大肠菌群,增强梭菌琼脂(RCM)上的生长以测定梭菌。除了集落计数,还可观察集落形态并与参比样品比较。
在一些实施方式中,除了副乳酪乳杆菌CBA L74还可加入共接种物,以帮助引发发酵。对于奶产品发酵的有用共接种物包括但不限于嗜热链球菌(Streptococcusthermophiles),副乳酪乳杆菌(Lactobacillus paracasei),唾液乳杆菌(Lactobacillussalivarious),鼠李糖乳杆菌(Lactobacillus rhamnosus),乳酪乳杆菌(Lactobacilluscasei),乳酸乳杆菌(Lactobacillus lactis),德氏乳杆菌保加利亚亚种(Lactobacillusdelbrueckii,subsp.Bulgaricus),嗜酸乳杆菌(Lactobacillus acidophilus),短乳杆菌(Lactobacillus brevis),或肠系膜明串珠菌(Leuconostocmesenteroides)。一般共接种物的浓度将比副干酪乳杆菌低,例如约1x 104/ml x105/ml。嗜热链球菌的最终浓度范围可以是约0.5x 108/ml到约2.5x 108/ml。
一旦达到合适的副干酪乳杆菌CBA L74浓度,可进一步处理发酵食物以供使用。在一些实施方式中,发酵的食物可组分化,以除去所有或几乎所有副干酪乳杆菌CBA L74细胞。在一些实施方式中,可加入NaOH或KOH调节发酵食物的pH,例如从约3.0到近乎中性,例如6.5。在一些实施方式中,可干燥发酵食物。可用任何本领域已知能使发酵食物的免疫调节性质得以保留的方法来干燥发酵的食物产品。示范性干燥方法包括喷雾干燥,冷冻干燥如冻干,或转鼓式干燥。发酵食物产品的最终水含量可变,但可以是约1%到约10%或以上。在一些实施方式中,干燥过程可让副干酪乳杆菌CBA L74不复制。
可在使用前水化干燥的发酵食物。根据水化中使用的液体量,发酵食物产品可含有相当于约102到1012cfu/ml的副干酪乳杆菌CBA L74。干燥的副干酪乳杆菌CBA L74不能形成集落,因此可理解该量是根据干燥步骤前发酵食物中存在的活细菌数计算的。在一些实施方式中,发酵食物产品可包括相当于约107到约1012cfu/g,例如约5x107 cfu/g,约1x108cfu/g,约5x108 cfu/g,约1x109cfu/g,约5x109 cfu/g,约1x1010 cfu/g,约5x1010 cfu/g,约1x1011 cfu/g,约5x1011 cfu/g干重。
可在施用前混合用本发明方法制备的两种或多种发酵食物产品。例如,可将发酵的奶制品与谷物产品混合。另外,可将发酵的食物产品与其他食物产品混合,例如与非发酵食物产品或用其他细菌菌株发酵的食物产品混合。可使用任何组合,条件是保留发酵食物对醇溶蛋白肽的效果。示范性食物产品包括但不限于奶制品,例如奶、酸奶、凝乳干酪、乳酪和基于乳酪的产品、发酵奶、奶基发酵产品、基于奶的粉末、婴儿配方、奶基去渣婴儿食品、冰淇淋、意大利冰糕、布丁、汤、酱、泥、或顶料、老年人的营养配方;谷物产品,例如儿童食品、基于谷物的去渣婴儿食品、燕麦片、谷粉、粗粒小麦粉、玉米糊、通心粉、饼干、苏打饼干、能量棒;蔬菜产品,例如菜泥、基于蔬菜的去渣婴儿食品、腌菜,包括黄瓜、卷心菜、胡萝卜、豆、辣椒或开胃菜;水果产品,例如基于水果的去渣婴儿食品、番茄产品、泥、酱、糊、番茄酱、果泥;或基于蛋白质的产品,例如豆类、香肠、午餐肉、热狗或肉糊。在一些实施方式中,发酵食品可以与宠物食品或动物饲料混合。
药物组合物
本文所述的组合物可与药学上可接受的运载体混合。本文所述的术语“药学上可接受的运载体”包括任何和全部可为药学上可接受物质用作介质的溶剂、分散介质、包衣、抗菌剂、等渗和吸收延迟剂、缓冲剂、赋形剂、粘合剂、润滑剂、凝胶、表面活性剂等。
因此,本发明还包括药物组合物,其包含作为活性成分的副干酪乳杆菌CBA L74或本文所述的副干酪乳杆菌CBA L74产生的一种或多种代谢物,以及一种或多种药学上可接受的运载体。在一些实施方式中,可在与药学上可接受的运载体混合前或后用常规消毒技术对副干酪乳杆菌CBA L74进行消毒。为了制备本发明的组合物,副干酪乳杆菌CBA L74或其产生的一种或多种代谢物一般与赋形剂混合,用赋形剂稀释或包裹在载体内,其形式可以是胶囊、片剂、囊袋、纸或其他容器。如果辅料用作稀释剂,它可以是固体、半固体或液体材料(例如生理盐水),用作活性成分的运载体、载体或介质。因此,组合物可以是片剂、丸剂、粉末剂、锭剂、药袋、扁胶囊、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体形式或在液体介质中)、软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液以及无菌包装的粉末剂。如本领域所知,稀释剂类型可根据所需的给药途径改变。得到的组合物可包含额外试剂,例如防腐剂。赋形剂或运载体根据给药模式和途径选择。合适的药物运载体以及药学配方中使用的一些药学必要物如本领域熟知的教科书《雷明顿药物科学》(Remington'sPharmaceutical Sciences(E.W.Martin)),,以及USP/NF(美国药典和国家配方)所述。合适的赋形剂的一些例子包括:乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、西黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。制剂还可包含:润滑剂,例如滑石、硬脂酸镁和矿物油;湿润剂;乳化剂和悬浮剂;防腐剂,例如甲-和丙羟基苯甲酸酯;甜味剂;和调味剂。药物组合物可配制成在使用本领域已知的方法施给病人后,提供活性成分的快速、持续或延迟释放。
可用标准技术制备用于本方法的药物学上可接受的组合物,包括其中副干酪乳杆菌CBA L74及其产生的一种或多种代谢物被包裹在胶体中用于口腔传递的那些。副干酪乳杆菌CBA L74或其产生的一种或多种代谢物可经干燥或通过碾磨或粉碎压缩,置入用于口服给药的胶囊中。在一些实施方式中,副干酪乳杆菌CBA L74或其产生的一种或多种代谢物可与一种或多种辅料混合,例如与崩解剂、填充剂、助流剂或防腐剂混合。合适的胶囊包括硬壳胶囊或软壳胶囊。可用任何基于脂质或基于聚合物的胶体形成胶囊。用于胶体制备的示范性聚合物包括明胶、植物多糖或其衍生物,例如角叉菜胶和淀粉的改性形式和纤维素,如羟丙甲纤维素。可任选的,可在成胶剂溶液中加入其他成分,例如增塑剂,如甘油和/或山梨糖醇来降低胶囊的硬度,着色剂,防腐剂,崩解剂,润滑剂和表面处理剂。在一些实施方式中,胶囊不包含明胶。在其他实施方式中,胶囊不包含植物多糖或其衍生物。
不论其最初来源或其获得的方式,副干酪乳杆菌CBA L74及其产生的一种或多种代谢物可根据其用途来配制。这些组合物可根据药学领域熟知的方法制备,可以各种途径施用,视需要局部或系统性治疗和要治疗的区域而定。给药可以是口服或外用(包括眼科和粘膜,包括鼻内、阴道内和直肠内给药)。在一些实施方式中,给药可以是经肺(例如通过粉末或气溶胶的吸入或吹气,包括通过喷雾器);经气管;经鼻;表皮和透皮)或眼。眼部给药的方法包括外用(滴眼剂)、结膜下、眼周、或通过球导管来玻璃体内注射或引入,或手术置于结膜囊内的眼科插入物。胃肠外给药包括静脉内、动脉内、皮下、腹膜内或肌肉内注射或输液;或颅内如鞘内或心室内给药。胃肠外给药可以单次推注剂量形式,或可以是通过连续灌注泵。外用给药的药物组合物和配方可包括透皮贴片、油膏剂、乳液、软膏剂、凝胶、滴剂、栓剂、喷剂、液体、粉末等。常规药学载体、水、粉末或油状基底、增稠剂等可能是必须或需要的。
组合物可配制成单位剂型,每种剂型包括每日剂量例如约0.005mg到2000mg的副干酪乳杆菌CBA L74或其产生的一种或多种代谢物。术语“单位剂量形式”指适合作为单一剂量用于人体对象或其他哺乳动物的物理上离散的单位,每个单位包含预定量的活性成分和合适的药用赋形剂,所述预定量经计算能够产生所需的治疗效果。为制备固体组合物如片剂,将主要的活性成分与药用辅料混合,形成包含本发明化合物均质混合物的固体预制组合物。当这些预制混合物为均匀时,活性成分通常均匀地分散在组合物中,使得组分能容易地进一步分成等同的有效单位剂型,例如片剂、药丸和胶囊。然后将固态预制混合物分成上述类型的单位剂型,包含例如从0.005mg到约1000mg的本发明所述的副干酪乳杆菌CBAL74或其产生的一种或多种代谢物。
组合物可配制成单位剂型,每剂包含例如从约0.1mg到约50mg、从约0.1mg到约40mg、从约0.1mg到约20mg、从约0.1mg到约10mg、从约0.2mg到约20mg、从约0.3mg到约15mg、从约0.4mg到约10mg、从约0.5mg到约1mg;从约0.5mg到约100mg、从约0.5mg到约50mg、从约0.5mg到约30mg,、从约0.5mg到约20mg、从约0.5mg到约10mg、从约0.5mg到约5mg;从约1mg到约50mg、从约1mg到约30mg、从约1mg到约20mg、从约1mg到约10mg、从约1mg到约5mg;从约5mg到约50mg、从约5mg到约20mg、从约5mg到约10mg;从约10mg到约100mg、从约20mg到约200mg、从约30mg到约150mg、从约40mg到约100mg、从约50mg到约100mg活性成分。
在一些实施方式中,可对本发明的片剂或丸剂进行包衣或另行复合,提供能够实现延长作用优点的剂型。例如,片剂或丸剂可包含内部剂量和外部剂量组分,后者包封前者。两种组分可由肠衣层分离,该层阻止胃内崩解并允许内部组分完整地通过十二指肠或延迟释放。多种材料可用于此类肠衣层或包衣,这些材料包括各种聚合酸以及聚合酸与诸如虫胶、十六醇和醋酸纤维素等材料的混合物。
可掺有本发明组合物用于口服给予或通过注射给予的液体剂型包括:水性溶液剂,适当调味的糖浆;水性或油性混悬剂;和含食用油的经调味乳剂,所述食用油例如棉籽油、芝麻油、椰子油或花生油,以及酏剂和类似的药用运载体。
在药物组合物中本发明组合物的比例或浓度可根据许多因素变化,包括剂量、化学性质(例如疏水性)、以及给药途径。例如本发明的副干酪乳杆菌CBA L74或其产生的一种或多种代谢物可以包含约0.005mg-1000mg的胶囊提供,用于口服给药。
在一些实施方式中,组合物可包含副干酪乳杆菌CBA L74发酵物,其中可已除去全部或几乎全部副干酪乳杆菌CBA L74。从生长培养基分离细胞的方法是本领域公知的,可依靠物理方法,例如离心来产生细胞沉淀和培养上清液,过滤、超滤、切向流过滤、正常流动过滤或反渗透。另选或额外的,分离方法可基于配体,包括例如与副干酪乳杆菌CBA L74特异性结合的抗体。抗体可偶联于固相载体,例如磁珠。
组合物可包含一种或多种副干酪乳杆菌CBA L74代谢物,即副干酪乳杆菌CBA L74产生的任何物质。代谢物可以由一种或多种基因编码,或可通过一种或多种基因产物的酶活性产生。代谢物包括例如小分子,如氨基酸、核苷、核苷酸以及较大的聚合物结构,例如多肽、碳水化合物、核酸、蛋白聚糖和脂类。代谢物可以是初级代谢物,例如直接参与正常细胞功能的代谢物,或次级代谢物,例如通常基础细胞功能不需要的代谢物。代谢物还可包括任何在初级或次级代谢物合成过程中产生的代谢中间物。中间物可包括但不限于EMP、磷酸戊糖(戊糖-P)途径、ED途径、柠檬酸循环和氨基酸生物合成的中间物。
示范性的初级代谢物包括但不限于醇,例如乙醇、甲醇、丁醇;氨基酸,例如赖氨酸、精氨酸、鸟氨酸、组氨酸、瓜氨酸、异亮氨酸、丙氨酸、缬氨酸、亮氨酸、甘氨酸、苏氨酸、丝氨酸、脯氨酸、苯丙氨酸、酪氨酸、色氨酸、半胱氨酸、甲硫氨酸、谷氨酸、天冬氨酸、谷氨酰胺和天冬酰胺;核酸,例如5’鸟氨酸;抗氧化物,例如抗坏血酸;有机酸,例如乙酸、乳酸、柠檬酸;维生素,例如维生素B12;糖;脂肪酸。
代谢物也可以是次级代谢物。次级代谢物通常是基础细胞功能不必须的那些。次级代谢物变化广泛,示范性次级代谢物包括抗生素、激素、类黄酮、类萜、生物碱、苯丙素、苯衍生物、己醇衍生物、香豆素、茋类、氰醇、硫代葡糖酸盐、类固醇和皂素。
乳杆菌通常在发酵奶制品时产生如下代谢物:乳酸/乳酸酯、乙酸酯、乙醇、甲酸酯、乙醛、α-乙酰乳酸、乙偶姻、二乙酰和2,3-丁烯二醇(丁二醇)。发酵可以是任何微生物导致或参与复杂有机物分解成简单物质的过程。
副干酪乳杆菌CBA L74代谢物可包含在培养基、发酵物或培养上清液内。在一些实施方式中,代谢物可从培养物、发酵物或培养上清液中部分或基本分离出来。分离代谢物的方法根据具体代谢物的结构和化学性质而变。部分或基本分离的代谢物将保留功能活性,即当施给子代的泌乳母亲时,能赋予子代疗效的能力。可用领域已知的标准方法分离和确定副干酪乳杆菌CBA L74代谢物的性质。示范性方法包括例如稳定性分析,例如对热、pH、和/或酶活性的稳定性;层析分析,例如尺寸排阻层析、高效液相层析(HPLC)、气相层析、薄层层析、离子交换层析、亲和力层析、反相层析;质谱。
使用方法
本文所述的方法和组合物当施给婴儿的泌乳母亲时,一般用于治疗或减轻婴儿中的微生物感染严重性。可在产前即婴儿出生前,或产后即婴儿出生后,或产前和产后即在婴儿出生前和出生后将组合物施给母亲。受益于该治疗的个体包括正常的足月婴儿和不足月或出生体重过轻的婴儿。
然而,本发明不限于此,该方法可用于治疗和预防任何年龄例如1、2、3、4、5、6、7、8、9、10,11、12、13、14、15、20、30天大;或1、2、3、4、5、6、7、8、9、10、11或12个月大;或1、2、3或约4岁大,或直到婴儿断奶的哺乳期婴儿中的感染。方法可用于先天性感染,即在子宫内获得的感染和新生儿感染,即出生时或短期后获得的感染。微生物感染可以是细菌、病毒、原生动物或真菌导致的感染。先天性感染然通常是透胎盘传播的结果,存在于出生前、出生时或出生后立即。常见先天性感染因素包括草绿色链球菌(Viridans streptococci)和无乳链球菌(S.agalactiae)。新生儿感染通常是由于生殖道的上行感染或通过外部环境,或通过母乳。这些感染存在于产后期,例如在出生后约一个月内。常见的新生儿感染因子包括例如草绿色链球菌(Viridans streptococci),无乳链球菌(S.agalactiae)和其他B族链球菌,阪崎克罗诺杆菌(Cronobacter sakazakii),鼠伤寒沙门氏菌(Salmonellatyphimurium),大肠杆菌(Escherichia coli),克雷伯氏菌(Klebsiella spp.),单核细胞增生性李斯特菌(Listeria monocytogenes),肺炎链球菌(Streptococcus pneumoniae),脑膜炎奈瑟氏菌(Neisseria meningitidis),金黄色葡萄球菌(Staphylococcus aureus),酿脓链球菌(Streptococcus pyogenes),耶尔森氏菌属,志贺氏杆菌,梭菌素和幽门螺杆菌(Helicobacter pylori)。在一些实施方式中,感染性因子可以是病毒,例如轮状病毒、风疹病毒、巨细胞病毒或疱疹病毒。在一些实施方式中,感染性因子可以是原生动物,例如痢疾内变形虫(Entamoeba histolytica),隐孢子虫属(Cryptosporidium spp),弯曲杆菌属(Campylobacter spp.)或弓形虫(Toxoplasma spp).在一些实施方式中,感染性因子可以是真菌,例如念珠菌(Candida spp.),如白色念珠菌(C.albicans)或近平滑念珠菌(parapsilosis),或马拉色氏霉菌(Malassezia),接合菌类(Zygomycetes)或曲霉菌(Aspergillus)。
无论何时当发生临床有益结果时,都认为个体,例如接受本文所述的包含副干酪乳杆菌CBA L74的食物产品或药物组合物的泌乳母亲的子代被有效治疗。这可能意味着例如完全解决了与感染有关的症状,与感染有关的症状的严重性下降,或延缓了与感染有关的症状的进程。这些方法还可包括步骤a)鉴定有感染的个体(例如患者和更具体的,人类患者);和b)对患者的泌乳母亲提供包含本文所述的副干酪乳杆菌CBA L74的组合物,例如在生理学可接受的载体中包含副干酪乳杆菌CBA L74的任何发酵食物产品或组合物。当这类组合物被提供给泌乳母亲的量能导致完全解决婴儿与感染有关的症状,与感染有关的症状的严重性下降,或延缓与感染有关的症状的进程,认为这样的量是治疗有效量。本发明的方法还可包括监测步骤,来帮助优化施药和定制计划,以及预测结果。
本文公开的方法可用于广泛物种,例如人类、非人灵长类(例如猴)、马、猪、牛或其他牲畜、狗、猫、或其他作为宠物的哺乳动物、大鼠、小鼠或其他实验室动物。本文所述的组合物可用于治疗组合物或治疗方案,或用于制造药物,以治疗本文所述的病症(例如新生儿或先天性感染)。
本文所述的营养组合物可作为怀孕或泌乳母亲的一般膳食的部分来口服给予。当配制成药物时,组合物可施给宿主身体的任何部分,随后传递给靶细胞。组合物可传递给(不限于)哺乳动物的脑、脑脊髓液、关节、鼻粘膜、血液、肺、肠、肌肉组织、皮肤或腹腔。对于递送途径,组合物可通过静脉内、颅内、腹膜内、肌肉内、皮下、肌肉内、直肠内、阴道内、鞘内、气管内、皮内、或透皮注射,通过口腔或鼻给药,或通过随时间逐渐灌注给药。在另一个例子中,可对宿主通过吸入给予组合物的气溶胶制剂。
不论组合物是否配制成食物产品或药物,需要的剂量都依赖于给药途径,配方性质,母亲的体积、重量、表面积、年龄和性别,其他同时给予的药物和临床医师的判断。合适的剂量是0.01-1,000mg/kg。一些典型剂量范围是约1μg/kg到约1g/kg体重/天。在一些实施方式中,剂量范围是从约0.01mg/kg到约100mg/kg体重/天。在一些实施方式中,剂量可以是例如1mg/kg,2mg/kg,5mg/kg,10mg/kg,20mg/kg,50mg/kg或100mg/kg。剂量似乎依赖于这样一些变量,例如疾病或紊乱的种类和进展程度,具体病人的总体健康状况,所选化合物的相对生物学效力,辅料配制以及给药途径。有效剂量可从体外或动物模型测试系统所得剂量反应曲线外推。例如,免疫系统效应的体外分析,如外周血单核细胞(PBMC)的细胞因子产生可以是促-和抗-炎症反应的有用测试,例如IL-1β,IL-12,IL-4,TNF-a,或IL-10的分泌。还可分析组合物在动物模型中的效果,例如在模型感染系统(如阪崎克罗诺杆菌或鼠伤寒沙门氏菌)中的存活率,或其他免疫系统效应的指标,例如IgA生产,派氏结(Peyer’s patch)外植体的细胞因子产生,和树突细胞及T细胞应答。
根据细胞靶标的不同和不同给药途径的效率不同,可预期所需剂量将会变化很大。可使用标准经验程序调节这些剂量水平的变化以进行优化,这是本领域所熟知的。给药可以是单次或多次,例如2-或3-,4-,6-,8-,10-,20-,50-,100-,150-或更多倍。将化合物包裹在合适的递送载体(例如聚合物微粒或可植入装置)中可提高递送效率。
还可改变本文提供的任何组合物的治疗持续时间。组合物的给药可以在怀孕期开始并持续到分娩后,直到子代断奶。或者,给药可在分娩后中断,或给药可从子代出生后任何时间开始,持续直到子代断奶。还注意治疗频率也可变化。例如,本组合物可每日、每周或每月施用一次(或两次、三次等)。当组合物配制成食物产品时,组合物可每日在每餐时施用。
任何本领域已知的方法可用于确定是否诱导了特定应答。可评估特定疾病状态程度的临床方案可用于确定是否引起了应答。例如,可监测个体是否有症状缓解,例如发热、腹痛、腹泻、恶心、呕吐、痉挛、黄疸、低血糖的缓解,并用临床实验监测,例如培养微生物,血液计数,脑脊髓液筛查,血清标记物,显像技术如超声、x光和内窥镜检。
还可将组合物于其他治疗形式联合施用。在一些实施方式中,可用标准药剂,例如抗生素、消炎药、抗组胺药和其他膳食治疗如低敏婴儿配方来治疗子代。并行施用两种或多种治疗剂不需要同时或用同一途径施用药剂,只要这些药剂发挥其疗效的时间期有所重叠。考虑同时或依次给药,也考虑在不同日或不同周给药。
优选例的这种描述需要联合作为本说明书一部分的附图一起阅读。附图并不一定按比例,出于清楚和简要考虑,本发明的一些特征可能在比例上有所放大,或是呈示意性形式。在说明书中,一些术语例如“水平的”、“垂直的”、“上”、“下”、“顶部”和“底部”及其变化形式(“水平地”、“向下地”、“向上地”等)应当被认为是指朝向,如所讨论的附图中所述或所示。这些相关术语是为了方便描述,一般并不指需要特别的朝向。包括“向内”对“向外”,“径向”对“侧向”的术语等只是相对或相对于延伸的轴,或旋转轴或中心适当解释。有关结合,偶联等的术语,例如“连接的”和“互连的”指结构间直接或间接通过介入结构彼此固定或附着的关系,以及可活动或刚性的结合或关系,除非另外说明。术语“可操纵性连接”是这样的结合、偶联或连接,其使得相关结构能由于该关系而按需操作。当仅显示一台机器时,术语“机器”还应包括任何机器集合,其单独或共同执行一组(或多组)指令,来进行任何本文所述的一种或多种方法学。在权利要求中,如使用方法加功能的条款,意味着覆盖由书面说明或附图所述、所提示、或显见用于进行所述功能的结构,不仅仅包括结构等价物,还包括等效结构。
实施例
实施例1:材料和方法
副干酪乳杆菌CBA L74发酵奶的制备:
基质:9%重建脱脂奶粉,加入0.25%葡萄糖
·基质热处理:UHT-135℃,3秒钟或相等的F0
·共接种:副干酪乳杆菌CBA L74 5x 106
嗜热链球菌5x 104(作为发酵起始菌种)
·发酵温度37℃
·发酵时间:15小时
·发酵中的pH:不调节
·在发酵终点,用NaOH溶液将发酵pH调节到6.5
·用输入温度190℃和输出温度90℃喷雾干燥。
分析:对发酵物进行细胞计数,确定嗜热链球菌和副干酪乳杆菌CBA L74
铺板:用乳杆菌选择性琼脂(LBS)检测副干酪乳杆菌CBA L74。L-M17琼脂用于嗜热链球菌计数。两者都在37℃厌氧培养。用平板计数琼脂(PCA)检测污染物,在30℃好氧培养。
发酵:加入副干酪乳杆菌CBA L74和嗜热链球菌1773共接种物作为新鲜培养物。发酵进行15小时,直到副干酪乳杆菌CBA L74浓度为108cfu/mL。初始pH为6.6。发酵终点,pH为5.1。加入2.5N NaOH调节pH至6.5。副干酪乳杆菌CBA L74的最初浓度为5x 106CFU/ml;最终浓度高于108CFU/ml。嗜热链球菌的最初浓度为5x 104CFU/ml;最终浓度为1x 108CFU/ml。在接种前的奶中,PCA上最初全细菌计数为0,在T0时集落太少无法计数(TFTC);在15小时发酵期后,为5x 104CFU/ml;最终浓度为1x 108CFU/ml。
干燥:以输入温度190℃和输出温度90℃干燥发酵物。喷雾干燥后粉末的含水量为4.87%。
副干酪乳杆菌CBA L74发酵大米的制备:我们通过混合150g大米和900ml水,制备了1升15%重量/体积的大米溶液。室温制备混合物,以1000-1300rpm振荡数分钟。将大米混合物进行分段灭菌法处理,将混合物在仪器内加热到70℃,在70℃饥饿20-30分钟,冷却到30-37℃,在30-37℃饥饿20-30分钟,加热到70℃,在70℃饥饿20-30分钟,150-600rpm振荡的同时冷却到发酵温度(37℃)。
从冻干样品加入副干酪乳杆菌CBA L74,至终浓度1x106 CFU/ml。冻干样品重悬浮于水中,在37℃稍作培养,以激活细菌。接种后,混合物在300-600rpm稍作振荡以匀化;发酵过程中以150rpm振摇溶液。发酵在37℃进行24小时,氧分压<15%。在接种时(T0),16小时(T16),18小时(T18),21小时(T21)和24小时(T24)收集等份。发酵后,谷物加热到50℃,持续混合。然后在输入气体温度80℃,输出气体温度210℃喷雾干燥已加热的谷物。最终含水量为6%。
在Rogosa琼脂(+万古霉素12μg/ml)上分析样品(37℃下48小时),以定量副干酪乳杆菌CBA L74,在PCA上进行总好氧菌计数(37℃下24小时),在McKonkay琼脂上定量大肠菌群,在RCM琼脂上定量梭菌。
该发酵结果如下:
接种物(副干酪乳杆菌CBA L74):1x106(+/-1/2log)CFU/ml(在仪器上)
发酵24小时后副干酪乳杆菌CBA L74浓度:1x 108(+/-1/2log)CFU/ml
接种前PCA上的污染物:<104CFU/ml
接种前McConKay上的污染物:<104CFU/ml
接种前RCM上的污染物:<10CFU/ml
接种后PCA上的污染物:<104CFU/ml
24小时发酵后PCA上的污染物:<104CFU/ml
加入接种物前的pH:6(+/-0.20)
16-18小时的pH:3.70(+/-0.20)
24小时的pH:3.60(+/-0.20).
实施例2:母体施用副干酪乳杆菌CBA L74发酵大米对感染阪崎克罗诺杆菌的子代存活的效果
如实施例1所述制备副干酪乳杆菌CBA L74发酵的大米。将标准小鼠食物粒(Mucedola,SLR,4RF21 GLP认证)与副干酪乳杆菌CBA L74发酵的大米或未发酵的大米混合,使大米占到小鼠每日总饮食的10%。该量设计成模拟如果发酵大米是直接施给婴儿,婴儿应接受的副干酪乳杆菌CBA L74的每日量。怀孕CD1小鼠从怀孕第14日开始,至怀孕第21日分娩以及在泌乳期间接受含有副干酪乳杆菌CBA L74发酵的大米或未发酵大米的食物粒。
如下用阪崎克罗诺杆菌感染幼鼠。阪崎克罗诺杆菌N13菌株在M17肉汤中生长,直到OD600≈0.6,重悬浮于碳酸盐缓冲液中(5%水中),浓度为1010CFU/100μΙ。系列稀释液铺在在LB琼脂上,验证接种浓度。
在出生后第3日,通过口管对幼鼠施以100μl细菌溶液(即,1010CFU)。每日评估幼鼠存活率,结果表示成卡普兰-迈耶存活曲线。该实验的结果如图1和图2所示。如图2所示,母鼠在怀孕和泌乳期间接受副干酪乳杆菌CBA L74发酵的大米的幼鼠(“E(RF)”)(实心柱)与母鼠接受未发酵大米的幼鼠(“D(RNF)”)(白色柱)相比,对阪崎克罗诺杆菌感染的存活百分率较高。
实施例3:母体施用副干酪乳杆菌CBA L74发酵奶对感染鼠伤寒沙门氏菌FB62的子代的效果
如实施例1所述制备副干酪乳杆菌CBA L74发酵的奶。将标准小鼠食物粒(Mucedola,SLR,4RF21 GLP认证)与副干酪乳杆菌CBA L74发酵奶或未发酵的奶混合,使奶占到小鼠每日总饮食的5%。该量设计成模拟如果发酵奶是直接施给婴儿,婴儿应接受的副干酪乳杆菌CBA L74的每日量。怀孕CD1小鼠从怀孕第14日开始,至怀孕第21日分娩以及在泌乳期间接受含有副干酪乳杆菌CBA L74发酵的奶或未发酵奶的食物粒。
如下用鼠伤寒沙门氏菌FB62来细菌感染幼鼠。鼠伤寒沙门氏菌FB62菌株在LB中生长,直到OD600≈0.6,重悬浮于碳酸盐缓冲液中(5%水中),浓度为108CFU/100μΙ。系列稀释液铺在在LB琼脂上,验证接种浓度。
在出生后第15日,通过口管对幼鼠施以100μl细菌溶液。每日评估幼鼠存活率,结果表示成卡普兰-迈耶存活曲线。该实验的结果如图3所示。如图3所示,母鼠在怀孕和泌乳期间接受副干酪乳杆菌CBA L74发酵奶的幼鼠(“C(LF)”)与母鼠接受未发酵奶的幼鼠(“B(LNF)”)相比,接受鼠伤寒沙门氏菌FB62感染后的存活百分率较高。
Claims (14)
1.国际保藏登录号为LMG P-24778的益生菌副干酪乳杆菌Lactobacillus paracaseiCBA L74在制备用于治疗泌乳母亲的婴儿中微生物感染或减轻其感染严重性的食物产品中的用途,其中将有效量的所述食物产品给予所述母亲,所述引起待治疗的感染的所述微生物是鼠伤寒沙门氏菌和阪崎克罗诺杆菌中的至少一种。
2.如权利要求1所述的用途,其特征在于,所述食物产品在产前和产后给予。
3.如权利要求1所述的用途,其特征在于,还包括识别需要治疗的婴儿。
4.如权利要求1所述的用途,其特征在于,所述微生物是鼠伤寒沙门氏菌。
5.如权利要求1所述的用途,其特征在于,所述微生物是阪崎克罗诺杆菌。
6.如权利要求1所述的用途,其特征在于,所述食物产品是乳制品或谷物产品。
7.如权利要求1所述的用途,其特征在于,施用所述组合物直到感染症状改善。
8.国际保藏登录号为LMG P-24778的益生菌副干酪乳杆菌Lactobacillus paracaseiCBA L74在制备用于治疗泌乳母亲的婴儿中微生物感染或减轻其感染严重性的发酵食物产品中的用途,其中所述食物产品由国际保藏登录号为LMG P-24778的益生菌副干酪乳杆菌Lactobacillus paracasei CBA L74发酵,其中将有效量的所述发酵食物产品给予所述母亲,引起待治疗的所述感染的所述微生物是鼠伤寒沙门氏菌和阪崎克罗诺杆菌中的至少一种。
9.如权利要求8所述的用途,其特征在于,所述发酵食物产品在产前和产后给予。
10.如权利要求8所述的用途,其特征在于,还包括识别需要治疗的婴儿。
11.如权利要求8所述的用途,其特征在于,所述微生物是鼠伤寒沙门氏菌FB62。
12.如权利要求8所述的用途,其特征在于,所述微生物是阪崎克罗诺杆菌。
13.如权利要求8所述的用途,其特征在于,所述发酵食物产品是乳制品或谷物产品。
14.如权利要求8所述的用途,其特征在于,施用所述发酵食物产品直到感染症状改善。
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