CN102231957A - 用于低出生体重婴儿的组合物 - Google Patents
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Abstract
本发明涉及用于低出生体重婴儿的组合物。具体地讲，所述组合物是用于实现低出生体重婴儿的完全肠道喂养的益生菌组合物。本发明还涉及特定益生菌在制备低出生体重婴儿配制品中的用途。
Description
发明领域
本发明涉及用于低出生体重婴儿的组合物。具体地讲，所述组合物是用于在低出生体重婴儿中实现完全肠道喂养的益生菌组合物。本发明还涉及特定益生菌在制备低出生体重婴儿配制品(infant formulations)中的用途。
发明背景
在新生儿加护病房中，肠道功能的不成熟、广谱抗生素的频繁使用、开始肠道喂养的延迟、感染控制措施和奶的巴氏灭菌限制了早产儿接触正常共生微生物。结果，低出生体重(≤1,500g)早产儿经历一个延迟的和异常的肠道菌落模式，特别是对于在正常健康的足月婴儿中占优势的双歧杆菌属(bifidobacteria)和乳杆菌属(lactobacilli)来讲。这种受损的肠道菌落可使早产儿易感染不期望的病患如坏死性小肠结肠炎，增加细菌移位的风险等。
在所述阶段，肠道功能的不成熟使完全肠道喂养几乎不可能。因此，所有低出生体重的婴儿要按常规接受几周静脉营养。然而，这是一伴随高的并发症风险的非常具损伤性的操作，所述并发症包括导管相关性脓毒症、血栓症和胆汁淤积。
根据从例如Deshpande，G.等人在Lancet，2007，369，1614-1620中；Alfaleh，K.等人在Cochrane Database Syst.Rev.，2008，(1)，CD005496中或者Kitajima，H.等人在Arch.Dis.Child，1997，76，F101-107中描述的临床试验中得到的结论，已发现肠内增补益生菌降低极早早产儿的坏死性小肠结肠炎的发病率。
Indrio，F.等人在Journal of Pediatrics，2008，801-806中还描述了益生菌的饮食增补对健康配方奶粉喂养的早产儿的喂养耐受和胃肠蠕动的作用。然而，所述研究未解决具有低于1500g出生体重的早产儿的需要。此外，益生菌的增补没有引起肠内喂养容量增加。
因此，虽然最近的报告表明增补益生菌可提高低出生体重早产儿的肠功能，但是肠内喂养比率没有得到提高。
因此，依然需要缩短实现低出生体重婴儿完全肠道喂养的时间，以便可降低或者甚至避免静脉营养。由此，胃肠外营养期的缩短将非常有利于绝大多数低出生体重婴儿。
发明目的
由此，本发明的目的是降低低出生体重婴儿的胃肠外营养的频次和/或持续时间。
发明概述
所述目的是借助独立权利要求来实现的。从属权利要求进一步发展了本发明的核心思想。
因此，一方面，本发明涉及用于实现出生体重不超过1500g的婴儿的完全肠道喂养的益生菌组合物。
另一方面，本发明还涉及鼠李糖乳杆菌(Lactobacillus rhamnosus)和长双歧杆菌(Bifidobacterium longum)在制备早产儿配制品中的用途。
附图
下文中，参照附图来进一步描述本发明，其中：
-图1描述了实验概况，且
-图2表明实现完全肠道喂养的时间。具体地讲，图2显示两个治疗组中(所有的婴儿组(top)和出生体重≤1500g的婴儿组)至完全肠道喂养的Kaplan-Meier曲线。
发明详述
在本发明中，认为益生菌微生物是通过改善宿主肠内微生物平衡而有利地影响宿主的微生物(Fuller，R；1989；J.Applied Bacteriology，66：365-378)。
根据本发明，已发现可将益生菌组合物用于实现出生体重不超过1500g的婴儿的完全肠道喂养。
通常来讲，具有不超过1500g出生体重的婴儿是早产儿和/或遭受宫内生长迟缓的婴儿。
早产儿是37周孕龄前出生的婴儿。在一具体实施方案中，本发明特别涉及早产儿，其中所述早产儿具有低于32周的孕龄。
“实现完全肠道喂养”意指婴儿能在对其健康没有任何不良影响的情况下摄取食物。当婴儿能吸收和消化食物时，优选没有不良反应如腹泻和/或反胃，完全肠道喂养得到实现。当食物能通过胃肠道提供婴儿需要的所有能量和营养时，完全肠道喂养也得以实现。
因此，所述组合物还可用于改善低出生体重婴儿的肠道喂养管理(management)。
可以通过改善所述婴儿的胃肠耐受来实现完全肠道喂养。这在具有不成熟的消化和能动功能且在出生时不具有完全建群的(colonised)肠道的低出生体重婴儿中是特别有挑战性的。
因此，本发明组合物可用于改善低出生体重婴儿对肠道喂养的耐受。
在一具体的实施方案中，可将本发明组合物用于改善低出生体重婴儿的胃肠耐受。
已令人惊奇地发现，本发明组合物不但有助于实现完全肠道喂养，而且具有提高肠道喂养比率和缩短至完全肠道喂养的时间的能力。
因此，可将本发明组合物用于缩短其中肠胃外喂养是必须的产后时间的长度。
低出生体重婴儿是指出生时重量不超过1500g的婴儿。
益生菌可改善极早早产儿的肠功能的机制有待解释。不期望受理论束缚，所述机制可能包括：降低细菌粘附至肠粘膜、提高肠屏障功能、保护免受局部缺血损伤或者NF-kB介导的炎症反应的降低。
合适的益生菌微生物的示例包括酵母如酵母菌属(Saccharomyces)、德巴利酵母菌属(Debaromyces)、念珠菌属(Candida)、毕赤酵母属(Pichia)和球拟酵母菌属(Torulopsis)；霉菌如曲霉菌属(Aspergillus)、根霉菌属(Rhizopus)、毛霉菌属(Mucor)和青霉菌属(Penicillium)和球拟酵母菌属(Torulopsis)；以及细菌如双岐杆菌属(Bifidobacterium)、拟杆菌属(Bacteroides)、梭菌属(Clostridium)、梭杆菌属(Fusobacterium)、蜜蜂球菌属(Melissococcus)、丙酸杆菌属(Propionibacterium)、链球菌属(Streptococcus)、肠球菌属(Enterococcus)、乳球菌属(Lactococcus)、葡萄球菌属(Staphylococcus)、消化链球菌属(Peptostrepococcus)、芽孢杆菌属(Bacillus)、片球菌属(Pediococcus)、微球菌属(Micrococcus)、明串珠菌属(Leuconostoc)、魏斯氏菌属(Weissella)、气球菌属(Aerococcus)、酒球菌属(Oenococcus)和乳杆菌属(Lactobacillus)。
可用于本发明的合适的益生菌微生物的具体示例包括：酿酒酵母(Saccharomyces cereviseae)、凝结芽孢杆菌(Bacillus coagulans)、地衣芽孢杆菌(Bacillus licheniformis)、枯草芽孢杆菌(Bacillus subtilis)、两歧双歧杆菌(Bifidobacterium bifidum)、婴儿双歧杆菌(Bifidobacterium infantis)、长双歧杆菌(Bifidobacterium longum)、乳双歧杆菌(Bifidobacterium lactis)、短双歧杆菌(Bifidobacterium breve)、屎肠球菌(Enterococcus faecium)、粪肠球菌(Enterococcus faecalis)、嗜酸乳细菌(Lactobacillus acidophilus)、消化乳杆菌(Lactobacillus alimentarius)、干酪乳杆菌干酪亚种(Lactobacilluscasei subsp.casei)、干酪乳杆菌代田菌(Lactobacillus casei Shirota)、弯曲乳杆菌(Lactobacillus curvatus)、德氏乳杆菌乳酸亚种(Lactobacillus delbruckiisubsp.lactis)、香肠乳杆菌(Lactobacillus farciminus)、加氏乳杆菌(Lactobacillus gasseri)、瑞士乳杆菌(Lactobacillus helveticus)、类干酪乳杆菌(Lactobacillus paracasei)、约汉逊氏乳杆菌(Lactobacillus johnsonii)、罗伊氏乳杆菌(Lactobacillus reuteri)、鼠李糖乳杆菌(Lactobacillus rhamnosus)(Lactobacillus GG)、清酒乳杆菌(Lactobacillus sake)、乳酸乳球菌(Lactococcus lactis)、变异微球菌(Micrococcus varians)、乳酸片球菌(Pediococcus acidilactici)、戊糖片球菌(Pediococcus pentosaceus)、乳酸片球菌(Pediococcus acidilactici)、嗜盐片球菌(Pediococcus halophilus)、粪链球菌(Streptococcus faecalis)、嗜热链球菌(Streptococcus thermophilus)、唾液链球菌(Streptococcus salivarius)、肉葡萄球菌(Staphylococcus carnosus)和木糖葡萄球菌(Staphylococcus xylosus)。
不希望被理论束缚，认为鼠李糖乳杆菌尤其可通过诱导热休克伴侣蛋白的表达和活化肠细胞的信号传导通路来保护肠上皮细胞免于氧化应激。
如同Rousseaux，C.等人，在Nat.Med.，2007，13，35-37中所提出的，嗜酸乳杆菌可通过诱导肠细胞中的阿片受体和大麻素受体来调节腹部疼痛。
在本发明中，已发现益生菌优选选自鼠李糖乳杆菌、长双歧杆菌或其混合物。更优选地，益生菌是鼠李糖乳杆菌GG ATCC 53103或鼠李糖乳杆菌CGMCC 1.3724和以ATCC BAA-999登记的长双歧杆菌BB536。这些微生物菌株是可商购的。
在一实施方案中，本发明包括可购自Biogaia AB(Kungsbroplan 3A，斯德哥尔摩，瑞典)的菌株罗伊氏乳杆菌ATCC55730、罗伊氏乳杆菌DSM-17938。
益生菌可以是粉末状的干燥形式。另外，如果需要，可将益生菌微生物包入胶囊，以进一步提高存活几率；例如包入糖基质、脂肪基质或多糖基质中。
已发现本发明的益生菌组合物可用于实现出生体重不超过1500g的婴儿的完全肠道喂养。
具体地讲，已发现本发明的益生菌组合物对于体重不超过1500g的婴儿是有益的。优选地，婴儿具有1000-1500g的出生体重。实际上，已发现在所述的重量组中，本发明的益处较快和/或较大程度地得到实现。
优选地，在本发明中，实现完全肠道喂养的时间低于50天，更优选低于40天，最优选低于30天。
因此，本发明组合物可较快地减轻与肠胃外喂养相关的并发症。
因此，本发明组合物可用于改善低出生体重婴儿的肠道喂养管理。
本发明的益生菌组合物可以是婴儿口服配制品的部分。所述配制品可包含在婴儿配制品、特别是低出生体重婴儿配制品中通常使用的组分。例如所述配制品通常包含脂肪、蛋白质、碳水化合物、矿物质和微量营养素。
脂肪可选自必需脂肪酸类、油类如MCT油类等。蛋白质优选选自乳蛋白质(dairy protein)。碳水化合物可选自麦芽糊精、乳糖等。微量营养素可包括微生素类等。
所述配制品可以是溶液或者可以是用于重构的粉末形式。所述配制品可以是包含所述益生菌的奶粉。一旦重构后，就可将所述配制品喂给早产儿并由此改善其肠道喂养管理。
益生菌的量优选是至少107～109cfu/克组合物，优选是2x108～8x108cfu/克。在一优选的实施方案中，如果作为母乳添加物提供，其可含有4x108cfu/克组合物。在另一实施方案中，如果掺入到早产儿配方食品(preterm infantformula)中，其可含有2x108cfu/克。
它优选被每天使用。因此，它可作为日常肠内补充物应用于低出生体重婴儿的肠胃外喂养。例如，根据早产儿的需要，可将其每天一次至多每天5次使用。
优选的是，婴儿应该接受大约106～1010cfu/天，更优选大约109cfu/天。所述量保证足够的微生物细胞到达婴儿的胃肠道以实现有益作用。
考虑到Manzoni，P.等人在Clin.Infect.Dis.，2006，42，1735-1742中所确定的益生菌菌株寄居肠道的概率随出生体重的降低而减小的事实，本发明的发现，即益生菌可用于实现体重低于1500g的婴儿的完全肠道喂养，是令人惊奇的。
其更是完全出乎意料的，因为口服益生菌的效力通常受到所述低出生体重婴儿出生后抗生素治疗的频繁使用和频繁抵制肠道喂养需求的限制。
因此，本发明的一主要益处在于加速从肠胃外喂养到肠道喂养的转化。通过避免损伤性的肠胃外技术或者至少减少必须进行肠胃外喂养的时间，所述益处很大在缓解了所讨论的婴儿。图2解释说明喂食安慰剂组合物的婴儿和喂食本发明组合物的婴儿至实现完全肠道喂养的时间的差异。图2还表明效果在体重不超过1500g的婴儿中是显著的。
在另一方面，本发明还涉及鼠李糖乳杆菌和长双歧杆菌在制备低出生体重婴儿配制品中的用途。优选地，婴儿配制品用于出生体重不超过1500g的婴儿。
优选地，将选自鼠李糖乳杆菌GG ATCC 53103、鼠李糖乳杆菌CGMCC 1.3724、以ATCC BAA-999保藏的长双歧杆菌BB536或其混合物的益生菌菌株用于制备所述配制品。
所述配制品可以是溶液或者可以是用于重构的粉末形式。所述配制品可以是包含所述益生菌的奶粉。一旦重构后，就可将所述配制品喂给低出生体重婴儿，因此通过实现完全肠道喂养来改善其肠道喂养管理。
用于实现低出生体重婴儿的完全肠道喂养的方法，其包括喂食益生菌组合物(优选以109cfu/天的量)的步骤，也构成本发明的组成部分。
利用下面的实施例进一步解释说明本发明。
实施例1
研究人群
两个中心(Mère-Enfant Hospital，南特，法国和Institut dePuériculture，巴黎，法国)参加了本试验。方法得到了南特医学伦理委员会的许可并登记为编号NCT00290576。对于每个婴儿来讲，加入实验之前，得到了书面的、正式的父母同意书。对于适合加入本项研究来讲，婴儿必须满足下面的加入标准：孕龄＜32周、出生体重≤1,500g、出生后年龄不超过2周、除了与早产相关的疾病外没有任何疾病，并且肠道喂养必须在加入前已开始。
方法
图1概述了试验概况。在内部软件(Nantes University Hospital，法国)的帮助下将婴儿随机分至安慰剂组或益生菌组，并且随机取样是根据NICU(南特或巴黎)和出生体重类别(1,500g或更低，和＞1500g)分级的。将婴儿喂食母乳(自己母亲挤出的奶或母乳库的奶)和/或早产配方奶，并将婴儿随机分配以从开始接受肠道喂养至脱离NICU每天接受四个添加物的胶囊，所述胶囊包含(a)单独的麦芽糊精(作为安慰剂组)或者(b)每单位108个鼠李糖乳杆菌GG(ATCC 53103)和长双歧杆菌BB536(Morinaga MilkIndustry Co.，Ltd.，日本)的冻干细胞及麦芽糊精(作为益生菌组)。将由NestléResearch Center(Lausanne，Switzerland)制备的安慰剂和益生菌提供在封闭的胶囊中并在4℃贮存至使用。在施用至在增补当天接受肠道喂养的婴儿之前，即刻将胶囊打开并与1mL无菌水混合。
对每个NICU登记的前24个婴儿完成粪便收集用于肠内微生物丛和粪便钙卫蛋白的追踪。从出生至出院每周收集粪便样品。通过使得能够分离早产儿粪便微生物丛中发现的主要属的培养，每周分析肠内微生物丛。并行地，利用PCR-TTGE分析肠内微生物丛的优势细菌的多样性。利用适当的软件如
和软件，在测序后通过将细菌16S rRNA基因序列与数据库中的条目进行比较鉴定最普遍的分子种类。通过培养-PCR方法在粪便样品中特异性检测本研究中所用的两种益生菌菌株。利用商品化的酶联免疫测定(
Eurospital，Trieste，意大利)以2周间隔一式两份地测定粪便钙卫蛋白浓度。
统计分析
原始结果是在出生后14天时通过肠道途径接受超过其全部营养需求的一半的婴儿的百分率。用于分析原始结果的样本容量估测基于安慰剂组的50％的预期比率，而益生菌组的为70％。据估计对于检测具有80％功效和5％α风险的差异，每组104名患者是必需的。为了避免使过多数量的非常早产婴儿暴露于益生菌的推定风险下(万一有可能的有害作用)，利用Whitehead三角检验完成序贯实验(参见Whitehead J.，Statistics inpractice，第二版，rev.Chichester，英国：John Wiley 1997)。每20个患者进行数据检验和间断分析并利用
软件完成。利用
15.0软件完成最终统计分析。在适当时，将Student’s t检验或Mann-Whitney用于比较连续变量和Khi-2检验，或者在适当时，将Fisher’s精确检验用于比较分类变量(categorical variable)。根据Kaplan-Meier方法计算“实现完全肠道喂养的时间”曲线，并利用时序(log rank)检验法进行统计学比较。完成Cox回归模型以调控潜在的混杂因素(potential confounders)：孕龄、中心点、肠道喂养类型。进行logistic回归，以分析因素是否与益生菌建群相关。所有检验是双尾检验。认为小于0.05的P-值是显著的。
结果
该研究的结果显示在图2中。
可以看出，实现完全肠道喂养的时间在出生体重不超过1500g的早产儿中显著缩短。
实施例2
上表中显示了根据本发明的典型组合物。
Claims (16)
1.用于实现出生体重不超过1500g的婴儿的完全肠道喂养的益生菌组合物。
2.根据权利要求1所述的益生菌组合物，其中完全肠道喂养是通过改善所述婴儿的胃肠耐受来实现的。
3.根据权利要求1或2所述的组合物，其中必须肠胃外喂养的产后时间被缩短。
4.根据前面任何一项权利要求所述的组合物，其中实现完全肠道喂养的时间低于出生后50天、优选低于出生后40天、更优选低于出生后30天。
5.根据前面任何一项权利要求所述的组合物，其中婴儿具有1000-1500g的出生体重。
6.根据前面任何一项权利要求所述的组合物，其中早产儿具有低于32周的孕龄。
7.根据前面任何一项权利要求所述的组合物，其中益生菌选自酵母如酵母菌属、德巴利酵母菌属、念珠菌属、毕赤酵母属和球拟酵母菌属，霉菌如曲霉菌属、根霉菌属、毛霉菌属、青霉菌属和球拟酵母菌属，细菌如双岐杆菌属、拟杆菌属、梭菌属、梭杆菌属、蜜蜂球菌属、丙酸杆菌属、链球菌属、肠球菌属、乳球菌属、葡萄球菌属、消化链球菌属、芽孢杆菌属、片球菌属、微球菌属、明串珠菌属、魏斯氏菌属、气球菌属、酒球菌属和乳杆菌属或其任何混合物。
8.根据前面任何一项权利要求所述的组合物，其中益生菌选自鼠李糖乳杆菌、罗伊氏乳杆菌、长双歧杆菌或其混合物。
9.根据前面任何一项权利要求所述的组合物，其中益生菌选自鼠李糖乳杆菌GG ATCC 53103、鼠李糖乳杆菌CGMCC 1.3724、以ATCCBAA-999保藏的长双歧杆菌BB536、罗伊氏乳杆菌ATCC55730、罗伊氏乳杆菌DSM-17938或其混合物。
10.根据前面任何一项权利要求所述的组合物，所述组合物是婴儿口服配制品的部分。
11.根据权利要求10所述的组合物，其中所述配制品还包含选自以下的组分：碳水化合物如麦芽糊精、乳糖；脂肪如必需脂肪酸类、油类；蛋白质如乳蛋白质；矿物质；微量营养素；或其任何混合物。
12.根据前面任何一项权利要求所述的组合物，其中益生菌的量是至少107～109cfu/克组合物，优选2×108～8×108。
13.根据前面任何一项权利要求所述的组合物，其中组合物被每天喂给婴儿。
14.根据权利要求13所述的组合物，其中组合物被每天一次、至多每天五次喂给婴儿。
15.根据权利要求13或14所述的组合物，其中益生菌的日剂量是106～1010cfu/天，优选109cfu/天。
16.鼠李糖乳杆菌优选鼠李糖乳杆菌GG ATCC 53103和/或鼠李糖乳杆菌CGMCC 1.3724、长双歧杆菌优选以ATCC BAA-999保藏的长双歧杆菌BB536或其混合物在制备婴儿配制品中的用途。
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| CA (1) | CA2745234A1 (zh) |
| CL (1) | CL2011001320A1 (zh) |
| MX (1) | MX2011005490A (zh) |
| RU (1) | RU2509478C2 (zh) |
| TW (1) | TW201026240A (zh) |
| WO (1) | WO2010063601A1 (zh) |
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| CN107960656A (zh) * | 2018-01-19 | 2018-04-27 | 云南省第三人民医院 | 一种孕妇产前营养组合物 |
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| EP2452575A1 (en) * | 2010-11-15 | 2012-05-16 | Nestec S.A. | Array of age-tailored nutritional formula with probiotics |
| EP2452571A1 (en) * | 2010-11-15 | 2012-05-16 | Nestec S.A. | Array of complementary infant/young child nutritional compositions |
| GB201112091D0 (en) | 2011-07-14 | 2011-08-31 | Gt Biolog Ltd | Bacterial strains isolated from pigs |
| GB201117313D0 (en) | 2011-10-07 | 2011-11-16 | Gt Biolog Ltd | Bacterium for use in medicine |
| ITMI20112238A1 (it) * | 2011-12-09 | 2013-06-10 | Probiotical Spa | Ceppi di batteri probiotici produttori di vitamina b12 |
| US11179427B2 (en) | 2013-01-21 | 2021-11-23 | Eth Zurich | Baby food composition comprising viable propionic acid-producing bacteria |
| GB201306536D0 (en) | 2013-04-10 | 2013-05-22 | Gt Biolog Ltd | Polypeptide and immune modulation |
| SG11201704814SA (en) | 2014-12-23 | 2017-07-28 | 4D Pharma Res Ltd | Pirin polypeptide and immune modulation |
| DK3065748T3 (da) | 2014-12-23 | 2018-01-29 | 4D Pharma Res Ltd | En bacteroides thetaiotaomicron stamme og dens anvendelse til reduktion af inflammation |
| WO2016183535A1 (en) | 2015-05-14 | 2016-11-17 | University Of Puerto Rico | Methods for restoring microbiota of newborns |
| AU2016278067B2 (en) | 2015-06-15 | 2022-09-22 | Cj Bioscience, Inc. | Compositions comprising bacterial strains |
| MA41060B1 (fr) | 2015-06-15 | 2019-11-29 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
| PT3360559T (pt) | 2015-06-15 | 2020-01-06 | 4D Pharma Res Ltd | Composições compreendendo estirpes bacterianas |
| SG10201912326QA (en) | 2015-06-15 | 2020-02-27 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
| MA41010B1 (fr) | 2015-06-15 | 2020-01-31 | 4D Pharma Res Ltd | Compositions comprenant des souches bactériennes |
| GB201520497D0 (en) | 2015-11-20 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
| GB2561748B (en) | 2015-11-20 | 2019-05-08 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
| GB201520631D0 (en) | 2015-11-23 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
| GB201520638D0 (en) | 2015-11-23 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
| WO2017117142A1 (en) | 2015-12-28 | 2017-07-06 | New York University | Device and method of restoring microbiota of newborns |
| GB201612191D0 (en) | 2016-07-13 | 2016-08-24 | 4D Pharma Plc | Compositions comprising bacterial strains |
| KR102010207B1 (ko) | 2016-03-04 | 2019-08-12 | 4디 파마 피엘씨 | 세균 균주를 포함하는 조성물 |
| TW201821093A (zh) | 2016-07-13 | 2018-06-16 | 英商４Ｄ製藥有限公司 | 包含細菌菌株之組合物 |
| GB201621123D0 (en) | 2016-12-12 | 2017-01-25 | 4D Pharma Plc | Compositions comprising bacterial strains |
| JP6766253B2 (ja) * | 2017-03-28 | 2020-10-07 | 森永乳業株式会社 | 新規ビフィドバクテリウム属細菌 |
| WO2018215758A1 (en) | 2017-05-22 | 2018-11-29 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
| WO2018215782A1 (en) | 2017-05-24 | 2018-11-29 | 4D Pharma Research Limited | Compositions comprising bacterial strain |
| PL3804737T3 (pl) | 2017-06-14 | 2022-09-12 | 4D Pharma Research Limited | Kompozycje zawierające szczepy bakteryjne |
| JP6884889B2 (ja) | 2017-06-14 | 2021-06-09 | フォーディー ファーマ リサーチ リミテッド４Ｄ Ｐｈａｒｍａ Ｒｅｓｅａｒｃｈ Ｌｉｍｉｔｅｄ | 細菌株を含む組成物 |
| KR20200095472A (ko) * | 2017-11-10 | 2020-08-10 | 디펜신 테라퓨틱스 에이피에스 | 조산아에서의 점막 방어 및 장/폐 기능의 성숙화 |
| BE1025428B1 (nl) * | 2018-01-23 | 2019-02-14 | Omega Pharma Innovation & Development Nv | Voedingssupplement en gebruiken daarvan |
| RU2705379C1 (ru) * | 2019-06-03 | 2019-11-07 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Астраханский государственный медицинский университет" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Астраханский ГМУ Минздрава России) | Способ ранней диагностики язвенно-некротического энтероколита у новорожденных |
| AU2021391603A1 (en) | 2020-12-04 | 2023-05-18 | Société des Produits Nestlé S.A. | Composition for preterm infants to reduce time to full enteral feeding |
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| EP1034788A1 (en) * | 1999-03-11 | 2000-09-13 | Société des Produits Nestlé S.A. | Lactic acid bacteria strains capable of preventing diarrhea |
| US6613549B2 (en) * | 2000-02-10 | 2003-09-02 | Urex Biotech, Inc. | Probiotic therapy for newborns |
| AU2003242763B2 (en) * | 2002-06-28 | 2008-02-21 | Biosearch, S.A. | Probiotic strains, a process for the selection of them, compositions thereof, and their use |
| NZ546664A (en) * | 2003-10-24 | 2009-04-30 | Nutricia Nv | Synbiotic composition for infants |
| EP1974743A1 (en) * | 2007-03-28 | 2008-10-01 | Nestec S.A. | Probiotics to Improve Gut Microbiota |
| US8137718B2 (en) * | 2008-09-19 | 2012-03-20 | Mead Johnson Nutrition Company | Probiotic infant products |
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- 2009-11-23 BR BRPI0922296-0A patent/BRPI0922296A2/pt not_active IP Right Cessation
- 2009-11-23 EP EP09756496A patent/EP2373182A1/en not_active Withdrawn
- 2009-11-23 AU AU2009321592A patent/AU2009321592B2/en not_active Ceased
- 2009-11-23 WO PCT/EP2009/065634 patent/WO2010063601A1/en active Application Filing
- 2009-11-23 JP JP2011538942A patent/JP2012510800A/ja active Pending
- 2009-11-23 MX MX2011005490A patent/MX2011005490A/es not_active Application Discontinuation
- 2009-11-23 US US13/129,547 patent/US20110223137A1/en not_active Abandoned
- 2009-11-23 CN CN200980148209XA patent/CN102231957A/zh active Pending
- 2009-11-23 CA CA2745234A patent/CA2745234A1/en not_active Abandoned
- 2009-11-23 RU RU2011127463/13A patent/RU2509478C2/ru not_active IP Right Cessation
- 2009-12-04 TW TW098141583A patent/TW201026240A/zh unknown
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2011
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| WO2008116708A1 (en) * | 2007-03-28 | 2008-10-02 | Nestec S.A. | Reduction of risk of diarrhoea |
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| CN107960656A (zh) * | 2018-01-19 | 2018-04-27 | 云南省第三人民医院 | 一种孕妇产前营养组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010063601A1 (en) | 2010-06-10 |
| RU2509478C2 (ru) | 2014-03-20 |
| CA2745234A1 (en) | 2010-06-10 |
| RU2011127463A (ru) | 2013-01-10 |
| BRPI0922296A2 (pt) | 2015-08-11 |
| JP2012510800A (ja) | 2012-05-17 |
| CL2011001320A1 (es) | 2012-03-30 |
| AU2009321592B2 (en) | 2014-12-04 |
| TW201026240A (en) | 2010-07-16 |
| EP2373182A1 (en) | 2011-10-12 |
| US20110223137A1 (en) | 2011-09-15 |
| MX2011005490A (es) | 2011-06-20 |
| AU2009321592A1 (en) | 2010-06-10 |
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