CN108368474A - 没有或几乎没有糖的稳定的干组合物 - Google Patents
没有或几乎没有糖的稳定的干组合物 Download PDFInfo
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- CN108368474A CN108368474A CN201680070453.9A CN201680070453A CN108368474A CN 108368474 A CN108368474 A CN 108368474A CN 201680070453 A CN201680070453 A CN 201680070453A CN 108368474 A CN108368474 A CN 108368474A
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Abstract
提供了干的稳定组合物。所述组合物包含一种或更多种活微生物、至少50重量%的一种或更多种水解蛋白质和少于10重量%的一种或更多种选自单糖、二糖及其组合的糖,各重量百分比基于该干组合物的总重量。优选地,所述组合物不包含单糖或二糖。所述组合物还可包含一种或更多种寡糖、一种或更多种多糖、一种或更多种羧酸盐或其组合。所述组合物的活力可以是至少1×1010CFU/g,并且在40℃的温度和33%的相对湿度下84天之后的活力损失小于1log单位/g。还提供了用于制备所述干的稳定组合物的方法。
Description
本申请涉及并要求2015年12月4日提交的标题为STABLE DRY COMPOSITIONSHAVING NO OR LITTLE SUGARS的美国临时申请No.62/263,061的权益,其内容通过引用并入本文。
技术领域
本发明涉及没有或几乎没有糖(即,单糖和/或二糖)的活微生物的稳定的干组合物及其制备方法。
背景技术
目前有多种用于补充动物(包括人)胃肠道的微生物。这些微生物可调节动物肠内的天然微生物区系以获得期望的生物效应。
向宿主提供有效量的活微生物的挑战之一是在高温和高湿度的典型工业制造过程和长期储存的苛刻条件下保持其活力。虽然关于向动物消化系统中递送生物材料的封装和配制技术已有发展,但在制造过程、分销和储存期间保护活微生物的活力的封装或稳定化技术方面几乎没有发展。需要能够使活微生物在暴露于多种苛刻环境(尤其是与高温和高湿相关的那些)后存活的组合物和稳定化技术。
此外,可食用产品本身的固有水分也带来其他挑战,因为活微生物通常对水活度敏感,尤其是在与高温组合时。迄今为止,没有发现在引入到产品(例如营养产品和动物饲料)中后在中等水分条件(即,水活度为约0.2或更高,或高至约0.4或更高)以及分销和储存期间的高温(例如,温度为至少约30℃,或高至约40℃或更高)下对活微生物提供显著保护的工艺或技术。因此,需要适合在多个地理位置(包括其中益生细菌的活力可受损的热带气候中的那些)中分销的稳定的活微生物组合物。
另外的挑战包括对适合于特定人群(如婴儿、幼儿、老年人和限于低糖饮食的糖尿病人)食用的常规食物成分的使用上的营养限制和法规限制。常规的合成封装和稳定化合物以及甚至一些天然化合物(例如乳蛋白质和某些糖(例如蔗糖、果糖、海藻糖和乳糖))不推荐用于这些特殊的饮食配方。允许用于特殊饮食用途的营养化合物推荐列表由联合FAO/WHO食品法典委员会(joint FAO/WHO Codex Alimentarius Commission)规定。
因此,期望包含活微生物(例如益生细菌和其他合适成分)的稳定的干组合物,以及用于制备此类组合物的稳定化技术。
发明概述
本发明涉及没有或几乎没有糖(即,单糖和/或二糖)的稳定的干组合物及其制备。除非另有说明,否则组合物中成分的所有重量百分比(wt%)均基于组合物的总重量。
提供了干组合物。所述组合物包含一种或更多种活微生物、至少50重量%的一种或更多种水解蛋白质和少于10重量%的一种或更多种选自单糖、二糖及其组合的糖,各百分比基于干组合物的总重量。所述组合物还可包含一种或更多种寡糖、一种或更多种多糖、一种或更多种羧酸盐或其组合。所述一种或更多种活微生物可选自活的细菌、真菌、酵母、单细胞藻类、病毒和噬菌体。
所述一种或更多种水解蛋白质可以是乳蛋白质、植物蛋白质或其组合。所述一种或更多种水解蛋白质可选自水解酪蛋白、水解乳清蛋白质、水解豌豆蛋白质、水解大豆蛋白质、及其组合。
基于干组合物的总重量,组合物还可包含5至30重量%的一种或更多种寡糖。所述一种或更多种寡糖可选自菊糖、短链寡糖、环糊精、麦芽糖糊精、右旋糖酐、果寡糖(fructo-oligosaccharide,FOS)、半乳寡糖(galacto-oligosaccharide,GOS)、寡甘露聚糖(mannan-oligosaccharide,MOS)、及其组合。所述一种或更多种寡糖可以是菊糖、短链寡糖或环糊精。
基于干组合物的总重量,组合物还可包含1至10重量%的一种或更多种多糖。所述一种或更多种多糖可选自藻酸类(alginate)、阿拉伯胶、槐豆胶、角叉聚糖、淀粉、改性淀粉、及其组合。
基于干组合物的总重量,组合物还可包含1至10重量%的一种或更多种羧酸盐。所述一种或更多种羧酸盐可以是选自以下的羧酸的一种或更多种盐:乳酸、抗坏血酸、马来酸、草酸、丙二酸、苹果酸、琥珀酸、柠檬酸、葡糖酸、谷氨酸、及其组合。所述一种或更多种羧酸盐可选自抗坏血酸盐、柠檬酸盐、及其组合。
基于干组合物的总重量,组合物还可包含1至5重量%的维生素E。组合物的活力可以是至少1×1010CFU/g,并且在40℃的温度和33%的相对湿度下84天之后,活力损失小于1log单位/g。所述一种或更多种水解蛋白质可以是水解豌豆蛋白质或水解酪蛋白。
提供了用于制备干组合物的方法,所述干组合物包含一种或更多种活微生物、基于干组合物总重量至少50重量%的一种或更多种水解蛋白质、一种或更多种寡糖、一种或更多种多糖和一种或更多种羧酸盐。该方法包括(a)将所述一种或更多种活微生物、所述一种或更多种水解蛋白质、所述一种或更多种寡糖、所述一种或更多种多糖和所述一种或更多种羧酸盐在碱性水性溶剂中混合以形成浆料;(b)将浆料在液氮中速冻以形成珠、微滴或串形式的固体冷冻颗粒;(c)在保持颗粒的温度高于其冻结温度的同时通过在真空下蒸发来对固体冷冻颗粒进行初级干燥,从而形成经初级干燥的制剂;以及(d)在全强度真空(full strength vaccum)和20℃或更高的热源温度下对经初级干燥的制剂进行次级干燥,进行足以将经初级干燥的制剂的水活度降低至0.3Aw或更低的时间,从而制备所述组合物。优选地,在制备方法中不添加单糖或二糖。
该方法还可包括:在步骤(a)中,向碱性水性溶剂中添加一种或更多种糖以形成浆料,其中所述一种或更多种糖选自单糖、二糖及其组合,并且所得干组合物包含基于干组合物总重量小于10重量%的所述一种或更多种糖。该方法还可包括:在步骤(a)之前,对所述一种或更多种水解蛋白质、所述一种或更多种寡糖、所述一种或更多种多糖、所述一种或更多种羧酸盐和所述一种或更多种糖进行灭菌。
该方法还可包括用组合物制备产品,并且产品选自药物产品、营养产品、食品产品、饲料产品和特殊饮食产品。特殊饮食产品可以是婴儿配方(infant formula)、后续配方(follow-on formula)、基于经加工谷类的食品、罐装婴儿食品或用于医疗目的的特殊食品。
附图简述
图1显示了在40℃和33%RH的加速储存条件下的分别根据实施例1和2制备的稳定化和未稳定化的干益生细菌产品的储存稳定性。
图2显示了在45℃和33%RH的加速储存条件下的根据实施例2制备的稳定化干益生细菌产品的储存稳定性。
发明详述
本发明提供了不含或几乎不含糖(即,单糖和/或二糖)的新的稳定的干组合物以及用于制备此类组合物的方法。这些组合物提供了出人意料地更好的稳定性和对活微生物的保护。在用于制备消费品的制造过程、通过分销渠道期间以及在极端的储存条件下,可保护活微生物。例如,大多数益生细菌微生物配方师(formulator)过度配制他们的产品以具有极高数量的细菌细胞,其有时可高达有效剂量的10倍甚至100倍,并且认识到显著数目的细胞在制造过程、运输和储存期间最终失去活力并死亡。
提供了稳定的干组合物。组合物包含一种或更多种活微生物和一种或更多种水解蛋白质,但不含或几乎不含单糖、二糖或其组合。干组合物还可包含一种或更多种寡糖、一种或更多种多糖、一种或更多种羧酸盐、或其组合。优选地,组合物包含至少约50重量%的所述一种或更多种水解蛋白质和少于约10重量%的一种或更多种选自单糖、二糖及其组合的糖,各百分比基于干组合物的总重量。更优选地,组合物包含少于约5重量%、1重量%或0.1重量%的一种或更多种选自单糖、二糖及其组合的糖。最优选地,组合物不包含单糖或二糖。
干组合物中的每种成分可以以基于组合物的总干重的重量百分比(w/w)来测量。
本文中使用的术语“碳水化合物”是指主要由碳、氢和氧构成的有机化合物。碳水化合物可以是单糖、二糖、寡糖或多糖。寡糖和多糖通常由以线性或非线性方式连接的重复结构单元的糖骨架构成,所述重复结构单元中的一些包含带正电荷或负电荷的化学基团。重复单元可以是三至数百万个。可用的碳水化合物包括还原糖和非还原糖以及糖醇、二糖、寡糖、水溶性多糖及其衍生物。
本文中使用的术语“糖”是指单糖或二糖。
本文中使用的术语“单糖”是指由单个糖单元组成的最简单形式的碳水化合物。合适单糖的实例包括葡萄糖、果糖和半乳糖。
本文中使用的术语“二糖”是指具有连接在一起的两个单糖的糖。二糖中的单糖可相同或不同。合适二糖的实例包括蔗糖、海藻糖、乳糖、麦芽糖、异麦芽糖。
本文中使用的术语“寡糖”是指具有连接在一起的单糖的少量糖单元(通常3至60个单元)的碳水化合物。含少于9个单糖单元的寡糖也称为短链寡糖。寡糖链中的单糖可相同或不同。寡糖是在营养应用中通常被认为是益生元的可溶性纤维。有利地,可溶性纤维未经消化地通过胃并且变得可用于被肠微生物菌区系消化。可溶性纤维的并入也有助于保护活微生物免受胃的消化酶和高酸度。商业寡糖产品可含有单糖和/或二糖。合适寡糖的实例包括菊糖、麦芽糖糊精、环糊精、右旋糖酐、果寡糖(FOS)、半乳寡糖(GOS)、寡甘露聚糖(MOS)及其组合。优选地,寡糖是菊糖、短链寡糖、环糊精或麦芽糖糊精。更优选地,寡糖是菊糖。
本文中使用的术语“多糖”是指具有连接在一起的大量(通常多于60个单元)单糖的碳水化合物。多糖中的单糖可相同或不同。合适多糖的实例包括甲基纤维素、羟丙基纤维素、羟乙基纤维素和羟丙甲纤维素;可溶性淀粉或淀粉级分、黄原胶、瓜尔胶、果胶、角叉聚糖、半乳甘露聚糖、结冷胶(gellan gum)(包括这些的任何衍生物)、邻苯二甲酸醋酸纤维素(CAP)、羧甲基纤维素、藻酸盐(例如,藻酸钠)、羟丙基甲基纤维素(HPMC)、阿拉伯胶、槐豆胶、壳聚糖和壳聚糖衍生物、胶原、聚乙醇酸、淀粉和改性淀粉以及环糊精。多糖可选自藻酸类、角叉聚糖、瓜尔胶、阿拉伯胶、槐豆胶、淀粉、改性淀粉、及其组合,优选藻酸类、阿拉伯胶、槐豆胶、角叉聚糖、淀粉、改性淀粉、及其组合,更优选藻酸类、槐豆胶和瓜尔胶。
干物质是脱水或无水(例如,基本上不含液体)的物质。干物质(例如,本发明的组合物)可通过一个或更多个干燥过程(例如,空气干燥、真空干燥、流化床干燥、喷雾干燥和冻干)进行干燥。
本文中使用的术语“水活度(water activity,Aw)”是指物质(例如,本发明的组合物)中水的可用性,其代表物质中水的能量状态。其可定义为物质上水的蒸气压除以相同温度下纯水的蒸气压。纯蒸馏水的水活度恰好为1,即Aw=1.0。干物质的Aw可以是约0.5或更低,优选约0.3或更低,更优选约0.2或更低,最优选约0.1或更低。
本文中使用的术语“活微生物”是指当以有效量向宿主施用时为宿主提供或赋予生物学益处(包括免疫原性应答)的活微生物。本文中使用的术语“有效量”是指当通过例如药物产品、营养补充产品、饮食产品或动物饲料产品向宿主施用时足以在宿主中实现期望的生物学益处的活微生物的量。活微生物可选自活的细菌、真菌、酵母、微型藻类(microalgae)、病毒和噬菌体。期望的生物学益处可以是任何有益的健康、预防或营养作用,例如维持健康的胃肠区系、增强生长、增强繁殖、增强免疫力,预防疾病、变态反应和感冒,或防止腹泻、特应性皮炎或泌尿系感染。
组合物可包含约1至30重量%、10至25重量%、10至20重量%或15至20重量%的一种或更多种活微生物。活微生物可以是活的细菌、真菌、酵母、单细胞藻类、病毒、噬菌体或其组合。细菌可以是益生细菌或非益生细菌。非益生细菌可以是减毒的致病菌。合适的微生物包括但不限于:微型藻类,包括任何海水或淡水物种;酵母,例如酵母属(Saccharomyces)、德巴利酵母属(Debaromyces)、假丝酵母属(Candida)、毕赤酵母属(Pichia)和球拟酵母属(Torulopsis);霉菌,例如曲霉属(Aspergillus)、根霉属(Rhizopus)、毛霉属(Mucor)、青霉属(Penicillium)和球拟酵母属(Torulopsis);以及细菌,例如双歧杆菌属(Bifidobacterium)、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)。合适益生细菌微生物的具体实例可由以下物种代表,并包括这些物种内的所有培养生物型:黑曲霉(Aspergillus niger)、米曲霉(A.oryzae)、凝结芽孢杆菌(Bacillus coagulans)、迟缓芽孢杆菌(B.lentus)、地衣芽孢杆菌(B.licheniformis)、马铃薯杆菌(B.mesentericus)、短小芽孢杆菌(B.pumilus)、枯草芽孢杆菌(B.subtilis)、纳豆芽孢杆菌(B.natto)、嗜淀粉拟杆菌(Bacteroidesamylophilus)、多毛拟杆菌(Bac.capillosus)、栖瘤胃拟杆菌(Bac.ruminocola)、猪拟杆菌(Bac.suis)、青春双歧杆菌(Bifidobacteriumadolescentis)、动物双歧杆菌(B.animalis)、短双歧杆菌(B.breve)、双歧双歧杆菌(B.bifidum)、婴儿双歧杆菌(B.infantis)、乳酸双歧杆菌(B.lactis)、长双歧杆菌(B.longum)、假长双歧杆菌(B.pseudolongum)、嗜热双歧杆菌(B.thermophilum)、Candida pintolepesii、丁酸梭菌(Clostridium butyricum)、Enterococcus cremoris、二乙酰乳酸肠球菌(E.diacetylactis)、屎肠球菌(E.faecium)、中间肠球菌(E.intermedius)、乳酸肠球菌(E.lactis)、E.muntdii、嗜热肠球菌(E.thermophilus)、大肠杆菌(Escherichia coli)、脆壁克鲁维酵母(Kluyveromycesfragilis)、嗜酸乳杆菌(Lactobacillus acidophilus)、消化乳杆菌(L.alimentarius)、淀粉乳杆菌(L.amylovorus)、卷曲乳杆菌(L.crispatus)、短乳杆菌(L.brevis)、干酪乳杆菌(L.case)、弯曲乳杆菌(L.curvatus)、纤维二糖乳杆菌(L.cellobiosus)、德氏乳杆菌保加利亚亚种(L.delbrueckii ss.bulgaricus)、香肠乳杆菌(L farciminis)、发酵乳杆菌(L.fermentum)、加氏乳杆菌(L.gasseri)、瑞士乳杆菌(L.helveticus)、乳酸乳杆菌(L.lactis)、植物乳杆菌(L.plantarum)、约氏乳杆菌(L.johnsonii)、罗伊乳杆菌(L.reuteri)、鼠李糖乳杆菌(L.rhamnosus)、清酒乳杆菌(L.sakei)、唾液乳杆菌(L.salivarius)、肠系膜明串珠菌(Leuconostocmesenteroides)、啤酒片球菌(P.cereviseae(damnosus))、乳酸片球菌(Pediococcusacidilactici)、戊糖片球菌(P.pentosaceus)、费氏丙酸杆菌(Propionibacteriumfreudenreichii)、谢氏丙酸杆菌(Prop.shermanii)、酿酒酵母(Saccharomyces cereviseae)、肉葡萄球菌(Staphylococcuscarnosus)、木糖葡萄球菌(Staph.xylosus)、婴儿链球菌(Streptococcus infantarius)、唾液链球菌嗜热亚种(Strep.salivarius.thermophilus)、嗜热链球菌(Strep.Thermophilus)和乳酸链球菌(Strep.Lactis),以及病毒或噬菌体。优选地,益生细菌是乳酸菌和双歧杆菌。
组合物可包含有效量的一种或更多种活微生物,用于在药物产品、营养补充产品、饮食产品或动物饲料产品(例如,特殊饮食产品,例如婴儿配方、后续配方、基于经加工谷类的食品、罐装婴儿食品或用于医疗目的的特殊食品)中向宿主提供生物学益处或益生细菌益处。
本文中使用的术语“特殊饮食用途”是指制备或向宿主施用特殊饮食产品。优选地,特殊饮食产品由联合FAO/WHO食品法典委员会在标题为“Standard For InfantFormula and Formulas For Special Medical Purposes Intended for Infants,CODEXSTAN 72-1981”(“US Standard Codex 72”)的文件中推荐。特殊饮食产品的实例包括婴儿配方、后续配方、基于经加工谷类的食品、罐装婴儿食品和用于医疗目的的特殊食品。优选地,特殊饮食产品是婴儿配方。
宿主可以是任何动物,包括哺乳动物、人或动物。宿主可以是婴儿、儿童或老年人。本文中使用的术语“婴儿”是指从出生至约12月龄的人。本文中使用的术语“儿童”是指约12月龄至约12岁的人。本文中使用的术语“老年人”是指至少约55、60、65或70岁(优选至少约65岁)的人。
组合物可包含至少约40重量%、45重量%、50重量%、55重量%、60重量%、65重量%、75重量%或80重量%,优选至少约50重量%,更优选至少约60重量%或的一种或更多种水解蛋白质。例如,组合物可包含约40至80重量%、40至70重量%、50至60重量%、50至70重量%、50至75重量%或50至80重量%,优选40至80重量%的水解蛋白质。
术语“水解蛋白质”和“蛋白质水解产物”在本文中可互换使用,并且是指通过水解或消化成更短的肽片段和/或氨基酸分解的蛋白质。水解或消化可通过强酸、强碱、酶或其组合进行。水解蛋白质可来自动物或植物。水解蛋白质可以是乳蛋白质、植物蛋白质或其混合物。
水解蛋白质可部分地或广泛地水解,优选广泛地水解。水解蛋白质可以是多肽和氨基酸的混合物。在一些实施方案中,至少约60重量%、70重量%、80重量%、90重量%、95重量%或99重量%,优选至少约75重量%的水解蛋白质的分子量小于约100,000、75,000、50,000、25,000、10,000、5,000、1,000或500道尔顿,优选约50,000道尔顿,更优选约10,000道尔顿,更优选约2,000道尔顿。例如,至少约50重量%、60重量%、70重量%、80重量%或90重量%,优选至少约70重量%的水解蛋白质的分子量小于约2,000道尔顿。
适合于制备本发明组合物的水解蛋白质的蛋白质包括乳蛋白质、植物蛋白质、及其组合。例如,合适的蛋白质包括卵蛋白质、明胶、乳蛋白质、酪蛋白、乳清蛋白质、卵白(albumen)、大豆蛋白质、豌豆蛋白质、稻米蛋白质、小麦蛋白质和其他植物蛋白质。优选地,蛋白质是推荐用于非变应原性饮食用途的那些。
水解蛋白质的实例包括水解酪蛋白、水解乳清蛋白质、水解豌豆蛋白质、水解大豆蛋白质、及其组合。在一个实施方案中,水解蛋白质包含水解酪蛋白或豌豆蛋白质,其至少约80%的分子量小于约2,000道尔顿。
组合物可包含寡糖和多糖的碳水化合物混合物,其中包埋活微生物。基质可通过将碳水化合物混合物与广泛水解蛋白质组合来形成,以允许更快速干燥并有助于所得干组合物的期望的无定形和刚性结构。
组合物可包含约1至30重量%、1至20重量%、1至10重量%、5至30重量%、5至20重量%、5至10重量%、10至15重量%、10至20重量%或10至25重量%的一种或更多种寡糖。优选地,组合物包含约5至30重量%的一种或更多种寡糖。
组合物可包含约0.1至40重量%、0.5至30重量%、1至30重量%、1至20重量%、1至10重量%、1至5重量%或5至10重量%的一种或更多种多糖。优选地,组合物包含约1至10重量%的一种或更多种多糖。
组合物可包含0.1至20重量%、0.5至20重量%、1至20重量%、0.1至10重量%、0.5至10重量%、1至10重量%或1至5重量%的一种或更多种羧酸盐、酯或其衍生物。术语“羧酸”、“羧酸盐”、“羧酸酯”和“羧酸衍生物”在本文中可互换使用,并且是指含有羧基(-COO-)的任何有机化合物。该组分可为组合物提供增强的基质稳定性,并且为活微生物、宿主或这两者提供额外的益处。例如,该组分可为接受组合物的宿主提供治疗或免疫原性作用。合适的羧酸可选自:乳酸、抗坏血酸、马来酸、草酸、丙二酸、苹果酸、琥珀酸、柠檬酸、葡糖酸、谷氨酸及其组合。合适的盐可包含阳离子,例如钠、钾、钙、镁及其组合。合适的羧酸盐的实例包括柠檬酸钠、乳酸钠、马来酸钠、葡糖酸镁和抗坏血酸钠,优选柠檬酸或抗坏血酸的盐(例如,柠檬酸钠或柠檬酸钾、柠檬酸三钠脱水物)。
组合物还可包含一种或更多种另外的试剂。例如,基于组合物的总重量,组合物还可包含1至5重量%的维生素E。
在一个实施方案中,组合物包含约50至80重量%的水解蛋白质、约5至30重量%的寡糖、约1至10重量%的多糖、约1至10重量%的羧酸盐、以及少于约10重量%的一种或更多种选自单糖、二糖及其组合的糖,优选不含单糖或二糖。
在另一个实施方案中,组合物包含约50至75重量%的水解豌豆蛋白质、约10至25重量%的菊糖、约1至5重量%的槐豆胶、约1至10重量%的一种或更多种选自柠檬酸钠、抗坏血酸钠或抗坏血酸钾及其组合的羧酸盐、以及少于约10重量%的一种或更多种选自单糖、二糖和及其组合的糖,优选不含单糖或二糖。
本文中使用的术语“活力”是指组合物中的微生物在适于微生物生长的营养介质上形成菌落或病毒噬斑的能力,并且可表达为基于组合物重量的菌落形成单位(colonyforming unit,CFU)或噬斑形成单位(plaque forming unit,PFU),例如CFU/g。
组合物的初始活力可以是约1×109、1×1010、1×1011或1×1012CFU/g,优选至少约1×1010CFU/g。在预定储存条件下预定时间段之后,组合物可具有预定的活力损失。
预定储存条件可包括预定温度和预定相对湿度(relative humidity,RH)。本文中使用的术语“相对湿度(RH)”是指通常在给定的温度下空气中水蒸气的量。相对湿度通常小于饱和空气所需的湿度,并且通常以饱和湿度的百分比表示。预定温度可以是至少约25、37、40、45、50或55℃。预定相对湿度(RH)可以是至少约10%、20%、30%、33%、35%、40%、50%、60%、70%或80%。预定条件可以是加速储存条件。例如,预定条件可以包括约40℃和约33%RH,或约45℃和约33%RH。
预定时间段可以是至少约1、2、3或4周,或者1、2、3、4、5、6、12、18、24或36个月,优选至少约1、2或3个月,更优选至少约1或3个月。指定的时间段可包括在指定时间段的10%以内的更短或更长的时间段。本文中使用的术语“3个月”是指约84至90天的时间段。本文中使用的术语“2个月”是指约56至60天的时间段。本文中使用的术语“1个月”是指约28至30天的时间段。
在一个实施方案中,组合物在预定条件下预定时间段之后的活力损失小于约1log单位/g。例如,组合物在约40℃和33%RH或在约45℃和33%RH下约1、2或3个月之后的活力损失小于约1log单位/g。
在一个实施方案中,组合物的初始活力为至少1×1010CFU/g,并且在40℃和33%RH下3个月(例如,84天)之后的损失小于1log单位/g。优选地,水解蛋白质是水解豌豆蛋白质或水解酪蛋白。
本发明的组合物可通过本领域中已知的技术制备。制备方法可包括例如混合、冷冻、冷冻干燥、环境空气干燥、真空干燥、喷雾干燥、真空喷雾干燥或其组合的方法。优选地,在制备组合物期间不添加单糖或二糖。所得组合物中的活微生物,无论是单独的还是整合到例如饮食产品的产品中,当暴露于宽范围的温度和湿度条件时具有增强的活力。
用于制备本发明组合物的微生物优选为发酵收获物,其浓缩成固体细菌含量为约5至30%w/v的湿糊样稠度。在与其他成分组合之前,浓缩物可以是湿的、冷冻的或解冻的糊状物的形式。从干燥形式的微生物开始是替代方案。
组合物的制备可包括浓缩选择的微生物,将成分与浓缩的微生物混合以形成浆料,将浆料在液氮中速冻以形成微滴、串或珠形式的颗粒,在向颗粒提供热的同时通过在减压方案下蒸发颗粒中的水分来干燥颗粒。所得稳定的干组合物可被包装或与其他成分组合以形成产品,例如药物产品、营养补品产品、饮食产品或动物饲料产品。特别地,所得组合物可用于制备特殊饮食产品,例如婴儿配方、后续配方、基于经加工谷类的食品、罐装婴儿食品或用于医疗目的的特殊食品。
一种合适的混合方法可包括将组合物中除微生物以外的所有成分的干混合物直接添加到包含微生物的浓缩培养物或培养基溶液中以形成浆料。干混合物可在20至80℃预溶解在用浓碱溶液(例如,1M或5M氢氧化钠(NaOH)溶液)调节至pH 8至9的水溶液中。在浆料中,微生物的干重质量可占约5至30%w/v,而干混合物可占约20至60%或30至50%w/v。浆料中的总固体含量可以是约25至90%或30至60%。可调节干混合物中多糖的量以实现浆料的期望黏度,允许高效干燥同时避免在干燥期间可发生的橡胶形成或过度发泡。通过本领域中已知的任何方式,例如通过在真空下脱气或注射气体(例如空气、氮气、二氧化碳或氩气),可实现期望的浆料密度。
浆料可冷冻至约-30℃或约-80℃,或者通过雾化、滴入或注入到液氮浴中来在液氮中速冻。所得到的珠、串或微滴形式的颗粒可被收集并在冷冻干燥器或真空干燥器中干燥,或者作为替代地储存在深冷冻器(例如-30℃至-80℃)中以用于随后以冷冻形式使用或者用于随后(例如通过冷冻干燥或真空干燥)干燥。
通常来说,有用的干燥技术包括冷冻干燥,或在解冻的冷冻浆料或干燥产品的温度保持在高于其冻结温度(例如-20至-5℃)的同时在真空烘箱或离心蒸发器中将解冻的浆料蒸发干燥,然后研磨至期望粒度。优选地,颗粒中的微生物被非结晶无定形材料涂覆。用无定形状态的材料涂覆微生物的优点是提高颗粒的物理稳定性并降低颗粒内的有害结晶形成。实现非结晶的无定形结构不是长期稳定性的先决条件,因为一些微生物在更结晶的状态下可更好。
速冻浆料可以以约0.1kg/平方英尺至约1.5kg/平方英尺的装载容量装载到托盘上,并随后立即转移至真空干燥室,其中干燥过程可在三个主要步骤中进行,包括:(a)在低于<1000mTORR的真空压力下冷冻颗粒的任选的短的温度适应和结构稳定化步骤,(b)在真空和高于其冻结点的颗粒温度下的初级干燥或初级蒸发干燥,以及(c)在全强度真空压力和升高的热源温度下进行次级干燥,进行足以将所得干组合物的水活度降低至例如约0.3Aw或更低的时间。所得的干组合物可以是玻璃状无定形的。
术语“冻干”和“冷冻干燥”在本文中可互换使用,并且是指通过速冻并在冷冻状态下脱水(也称为升华)制备干燥形式的组合物。冻干在可导致组合物中成分结晶的温度下发生。
本文中使用的术语“初级干燥”是指这样的干燥步骤,其中产品的温度保持在显著低于热源的温度(即,热源温度或搁板温度(shelf temperature))以制备初级干燥产品。通常来说,在初级干燥步骤期间,大量的水分通过广泛蒸发从产品中除去,同时产品温度保持在高于其冻结温度但显著低于热源温度。
本文中使用的术语“次级干燥”是指这样的干燥步骤,其中将初级干燥产品的温度保持在热源的温度(即,热源温度或搁板温度)附近以制备干产品。该过程可在足以降低所得干产品的水活度的真空下进行。在典型的干燥过程中,次级干燥步骤将制剂的水活度降低至例如约0.3Aw或更低。
在一个实施方案中,通过包括以下的方法制备包含一种或更多种活微生物、至少约50重量%的一种或更多种水解蛋白质、一种或更多种多糖和一种或更多种羧酸盐的干组合物:(a)将活微生物、水解蛋白质、寡糖、多糖和羧酸盐在碱性水性溶剂中组合以形成浆料;(b)将浆料在液氮中速冻以形成珠、微滴或串形式的固体冷冻颗粒;(c)在保持颗粒的温度高于其冻结温度的同时通过在真空下蒸发对固体冷冻颗粒进行初级干燥,从而形成经初级干燥的制剂;以及(d)在全强度真空和20℃或更高的热源温度下对经初级干燥的制剂进行次级干燥,进行足以将经初级干燥的制剂的水活度降低至0.3Aw或更低的时间。优选地,在该方法中不添加单糖或二糖。
本发明的制备方法还可包括:在步骤(a)中,向碱性水性溶剂添加一种或更多种糖以形成浆料。所述一种或更多种糖选自单糖、二糖及其组合。所得干组合物包含小于10重量%的所述一种或更多种糖。
该方法还可包括:在步骤(a)之前,对水解蛋白质、寡糖、多糖和羧酸盐进行灭菌。当在步骤(a)中添加单糖和/或二糖时,可在步骤(a)之前对单糖和/或二糖进行灭菌。灭菌可通过本领域中已知的任何方法来实现。例如,在步骤(a)之前在压力下加热水解蛋白质、寡糖、多糖和羧酸盐的水性混合物,并随后冷却。
该方法还可包括:在步骤(a)之前,溶解水解蛋白质、寡糖、多糖和羧酸盐。当在步骤(a)中添加单糖和/或二糖时,可在步骤(a)之前溶解单糖和/或二糖。
该方法还可包括将组合物切割、破碎、研磨或粉碎成自由流动的粉末。粉末的粒度可小于约10,000、1,000、500、250或100μm,优选小于约1,000μm,更优选小于约250μm。
本发明的组合物可作为薄片(flake)直接使用,或者粉碎成粉末并筛分成平均粒度为约1至10,000μm,优选10至1,000μm。
本发明的组合物可作为浓缩粉末或重构液体(例如,饮料)施用。其也可以以薄片或粉末形式并入到现有的食品产品中。
该方法还可包括用本发明的组合物制备药物产品、营养补品产品、饮食产品或动物饲料产品,其包含有效量的一种或更多种益生细菌微生物,用于在产品中向宿主提供益生细菌益处。特殊饮食产品的实例可包括婴儿配方、后续配方、基于经加工谷类的食品、罐装婴儿食品或用于医疗目的的特殊食品。优选地,特殊饮食产品是婴儿配方。
包含活微生物的所得干燥的稳定粉末可与熔融脂肪团聚。可将干燥粉末置于40至50℃的行星式混合器(planetary mixer)中,并将熔融脂肪如可可脂、天然蜡或棕榈油、硬脂酸、甾烷(stereane)或其混合物缓慢添加至温热的粉末。可将混合物冷却至低于脂肪的熔化温度,同时继续混合直至实现团聚粉末的视觉上均匀的大小。所得组合物中熔融脂肪的重量质量可以是约20至70%,优选30至50%。
实施例1.含有唯一作为冷冻保护剂的海藻糖的干益生细菌产品的稳定性。
向双歧杆菌属物种的浓缩收获物中添加10%w/w海藻糖并在液氮中速冻。将所得冷冻珠在不加热的情况下在全真空下48小时冷冻干燥成干燥产品。干燥产品的初始活力为11.63log CFU/g。将该干燥产品的样品置于40℃和33%RH下的加速的稳定性挑战下,并且显示14天之后活力损失为1.46log单位/g,28天之后活力损失为3.17log单位/g。这些结果表明含有活微生物和作为唯一冷冻保护剂的海藻糖干样品的固有不稳定性。
实施例2.干益生细菌组合物的制备
制备根据本发明的干益生细菌组合物。在75℃下将水解豌豆蛋白质(75g,Friesland Capina Doma,Paramus,NJ)溶解在100ml温热的蒸馏水中。使用20%浓NaOH溶液将所得豌豆溶液的pH调节至8.5。将槐豆胶(3g,Tic gum,Belcamp,MD)、菊糖(含7%糖的17g速溶菊糖,Cargill Minneapolis,MN)和抗坏血酸钠(5g,Sigma)干燥共混,并在叶轮搅拌器中以700rpm持续混合下添加至豌豆溶液。将所得混合物在持续混合下冷却并保持在35℃至40℃的温度。
所得混合物为半透明,具有糖浆稠度和琥珀色。将液体混合物转移至配备有控温夹套的双行星式混合器(DPM,1qt,Ross Engineering,Inc.Savannah,GA)。混合器夹套温度为环境温度或更低。添加冷冻的益生细菌双歧杆菌属物种浓缩物(120g,含有10%w/w细菌固体),以20rpm混合2至3分钟,或者直至所有细菌均充分融化并均匀分布。将益生细菌浆料冷却至4℃并在该温度下保持30至60分钟。然后将浆料滴入并在液氮浴中速冻以形成冷冻珠,将其从液氮中收集并储存在-80℃以待后续干燥。
为了干燥,将冷冻珠以800g/平方英尺的装载容量在预冷的托盘(-20℃)上铺开,并随后立即放置在冷冻干燥机(Model 25SRC,Virtis,Gardiner,NY)的搁板上。通过调节900至1500mTORR的真空和升高至20℃的搁板温度开始初级干燥步骤。这些初级干燥温度和真空压力设置保持16小时。在初级干燥之前,通过在不加热的情况下施加约1000mTORR的真空压力以使冷冻珠的温度稳定在约-20℃约10分钟,来任选地使冷冻珠的温度适应约-20℃。任选的适应步骤之后是通过将真空压力调节至900至1500mTORR并将搁板温度调节至+20℃的初级干燥步骤。这些温度和真空压力设置保持约16小时。在初级干燥步骤之后,接着是在全强度真空(即,150至200mTORR)下的次级干燥步骤,并且将搁板温度升高至40℃持续另外8小时。结果,组合物完全干燥,且其通过Hygropalm Aw1仪器(Rotonic InstrumentCorp.,Huntington,NY)测量的水活度低于Aw 0.3。然后将干燥材料研磨并筛分成≤250μm的粒度并在4℃下储存。
实施例3.储存稳定性的比较
将实施例1的干益生细菌产品和实施例2的干益生细菌组合物各自与等量的麦芽糖糊精(1∶1比例)混合并置于加速储存条件下的干燥器中。定期取样,用于使用标准微生物稀释和LMRS琼脂平板接种程序进行微生物CFU评估。
图1显示了实施例1的干益生细菌产品(未稳定化的双歧杆菌属物种)和实施例2的干益生细菌组合物(稳定化的双歧杆菌属物种)在40℃和33%RH的加速储存条件下的储存稳定性结果。实施例1的干益生细菌产品在前几周内完全丧失活力,而根据本发明的实施例2的干益生细菌组合物在84天之后仅损失0.49log单位/g。
图2显示了实施例2的干益生细菌组合物(稳定的双歧杆菌属物种)在45℃和33%RH的加速储存条件下的储存稳定性。根据本发明的实施例2的干益生细菌组合物在30天之后仅损失0.59log单位/g。
实施例4.二糖对稳定性的影响
评价了二糖乳糖对本发明干益生细菌组合物稳定性的影响。通过使用实施例2中所述的方法将包含提高量的乳糖和成比例降低量的水解豌豆蛋白质以及冷冻益生细菌双歧杆菌属物种(120g,含有10%w/w细菌固体)的干燥成分混合制备五种干组合物,并随后使用实施例3中所述的方法测试稳定性。表1显示了每种成分的重量百分比(w/w)以及初始活力(CFU/g的log单位)以及在40℃和33%RH下一个月之后(组合物No.1至3)或3个月之后(组合物No.4至5)的活力损失(CFU/g的log单位损失)。组合物No.4(具有8.9%w/w乳糖和58%w/w水解豌豆蛋白质)和组合物No.5(具有66.9%w/w水解豌豆蛋白质并且不含乳糖)在40℃和33%RH下84天之后显示小于1log单位的CFU/g损失。组合物No.1至3(具有17%w/w或更多的乳糖和49.1%w/w或更少的水解豌豆蛋白质)在40℃和33%RH下1个月之后各自显示大于1log单位的CFU/g的活力损失。
表1.乳糖对稳定性的影响(%w/w)
实施例5.羧酸盐对稳定性的影响
评价了羧酸盐抗坏血酸钠和柠檬酸钠对本发明干益生细菌组合物的稳定性的影响。通过使用实施例2中所述的方法将包含抗坏血酸钠(组合物No.3至5)、柠檬酸钠(组合物No.6)和维生素E(组合物No.2至4)以及冷冻益生细菌双歧杆菌属物种(120g,含有10%w/w细菌固体)的干燥成分混合制备六种干组合物,并随后使用实施例3中所述的方法测试稳定性。表2显示了每种所得干组合物的每种成分的重量百分比(w/w)以及初始活力(CFU/g的log单位)和在40℃和33%RH下84天之后的活力损失(CFU/g的log单位损失)。组合物No.3至6(具有0.9至4.5%w/w抗坏血酸钠或4.5%w/w柠檬酸钠)在40℃和33%RH下84天之后显示小于1log单位的CFU/g损失。
表2.羧酸盐对稳定性的影响(%w/w)
实施例6.寡糖对稳定性的影响
评价了寡糖菊糖、短链寡糖和γ环糊精对本发明干益生细菌组合物的稳定性的影响。使用实施例2中所述的方法制备含有75g酪蛋白水解产物(DMV internationalAmersfoort,the Netherlands)、17g环糊精(Wacker,München,Germany)或l7g菊糖(含7%糖的速溶菊糖,Cargill Minneapolis,MN)或17g短链寡糖(含5%糖的Orafti P-95,Beneo,Tienen,Belgium)、3g阿拉伯胶(Tic gum,Belcamp,MD)和5g柠檬酸钠与抗坏血酸钠之混合物(1∶1w/w,Sigma)的组合物,并且使用实施例3中所述的方法测试稳定性。用短链寡糖制备的所得干组合物包含小于1%w/w的单糖和/或二糖。所有这些组合物导致初始活力(CFU/g的log单位)为11.2至11.3logCFU/g,并且在40℃和33%RH下三个月之后活力损失为0.43至0.66log CFU/g。
实施例7.多糖的影响
评价了多糖槐豆胶、阿拉伯胶、角叉聚糖和藻酸类对本发明的干益生细菌组合物稳定性的影响。使用实施例2中所述的方法制备含有75g酪蛋白水解产物(DMVinternational Amersfoort,the Netherlands)、17g环糊精(Wacker,München,Germany)、3g阿拉伯胶(Tic gum,Belcamp,MD)、或3g槐豆胶(Tic gum,Belcamp,MD)、或3g海藻酸类(FMC BioPolymer,Philadelphia,PA)、或3g角叉聚糖(Tic gum,Belcamp,MD)和5g柠檬酸钠与抗坏血酸钠之混合物(1∶1w/w,Sigma)的组合物,并随后使用实施例3中所述的方法测试稳定性。所有这些组合物导致初始活力(CFU/g的log单位)为11.2至11.3log CFU/g,并且在40℃和33%RH下三个月之后活力损失为0.46至0.81log CFU/g。
实施例8.蛋白质来源的影响
评价蛋白质来源豌豆蛋白质水解产物、酪蛋白水解产物和小麦蛋白质水解产物对本发明干益生细菌组合物之稳定性的影响。使用实施例2中所述的方法制备含有65g酪蛋白水解产物(DMV international Amersfoort,the Netherlands)或小麦水解产物(MarcorDevelopment Corp.,Carlstadt,NJ)或豌豆蛋白质水解产物(Friedsland Campina Domo,Paramus,NJ)、27g环糊精(Wacker,München,Germany)、3g阿拉伯胶(Tic gum,Belcamp,MD)和5g维生素E与抗坏血酸钠之混合物(4∶1w/w,Sigma)的组合物,以及含有75g大豆水解产物(Sigma)、17g菊糖(含7%糖的速溶菊糖,Cargill Minneapolis,MN)、3g槐豆胶(Tic gum,Belcamp,MD)或3g藻酸类(FMC BioPolymer,Philadelphia,PA)或3g角叉聚糖(Tic gum,Belcamp,MD)和5g柠檬酸钠与抗坏血酸钠之混合物(1∶1w/w,Sigma)的组合物,并随后使用实施例3中所述的方法测试稳定性。六种所得干组合物显示初始活力为11.01至11.34log单位CFU/g。同时,含有豌豆水解产物或大豆水解产物或酪蛋白水解产物的所得组合物在40℃和33%RH下84天之后显示0.51至0.81log单位CFU/g损失,含有小麦蛋白质水解产物的组合物损失2.01log单位/g。
实施例9.多种益生细菌物种的稳定性
评价了本发明的干益生细菌组合物中多种益生细菌嗜酸乳杆菌和双歧杆菌属物种的稳定性。使用实施例2中所述的方法制备含有75g豌豆蛋白质水解物(FriedslandCampina Domo,Paramus,NJ)、17g菊糖(Cargill Minneapolis,MN)、3g槐豆胶(Tic gum,Belcamp,MD)和5g柠檬酸钠与抗坏血酸钠之混合物(1∶1w/w,Sigma)的组合物,并随后使用实施例3中所述的方法测试稳定性。嗜酸乳杆菌组合物的初始活力(CFU/g的log单位)为10.57log CFU/g,并且在40℃和33%RH下三个月之后的活力损失为0.64log单位/g损失。双歧杆菌属物种组合物的初始活力(CFU/g的log单位)为11.11log CFU/g,并且在40℃和33%RH下三个月之后活力损失为0.41log单位/g。
实施例10.婴儿配方
根据实施例2制备含有活双歧杆菌属物种的稳定的干组合物,并筛分成粒度为50至250μm。通过将19.9g Gerber Good Start(Nestle Infant Nutrition,Florham Park,NJ.)与0.1g大小为50μm至250μm的干组合物颗粒混合制备包含益生细菌的婴儿配方。最终产品含有8.03log CFU/g双歧杆菌属物种。将益生细菌婴儿配方包装在封闭的180cc HDPE瓶中并暴露于25℃和40℃的受控温度。瓶内的水活度为Aw-0.2)。每月对产品进行微生物稳定性测试,持续9个月的时间,或直至观察到测定计数降低为低于1log CFU/g。在25℃和40℃下储存的婴儿配方产品中双歧杆菌属物种的活力损失分别为0.09和0.82log CFU/g。
实施例11.益生细菌补充剂
根据实施例2制备包含嗜酸乳杆菌的稳定的干组合物,并配制成口服剂型,例如片剂、囊片或胶囊剂。通过使用1/2″圆形标准凹面工具在旋转压片机上直接压片制备包含19.9g压制剂(compression agent)(右旋糖)和0.1g大小为50μm至250μm的干组合物颗粒的橙味片剂。最终产品含有约5E+8CFU/单位剂量。片剂的硬度为8至10kp,且崩解时间为约20秒。将压制片剂以每瓶100片包装在180cc HDPE瓶中,并暴露于40℃/33%RH的受控温度/湿度。每月对产品进行微生物稳定性测试,持续12个月的时间,或直至观察到测定计数降低为低于1E+6CFU/单位剂量。
实施例12.功能饮料饮品
根据实施例2制备包含嗜酸乳杆菌的稳定的干组合物,并配制成含有(重量%)71%蔗糖、14%麦芽糖糊精、10%菊糖、2%右旋糖、1%无水柠檬酸、0.3%阿拉伯胶、0.3%香料、0.3%磷酸三钙和0.1%大小为50μm至250μm的干益生细菌组合物颗粒(嗜酸乳杆菌)的干混合物。最终产品含有约1E+9CFU/单位剂量(30g干混合物)。将产品包装在小铝箔袋(1单位剂量/袋)中,用于通过在340ml水中搅拌而饮用。每月对含有益生细菌的饮料干混合物进行微生物稳定性测试,持续12个月的时间,或直至观察到测定计数降低为低于1E+7/单位剂量。
实施例13.多维生素/益生细菌片剂
如实施例2中所述制备10g含有益生细菌干酪乳杆菌的干粉末组合物。为了制片,将干的且稳定的益生细菌组合物(100mg)与含有2%w/w硬脂酸镁和2%w/w亲水性煅制二氧化硅(fumed silica)(200,Evonik Industries)的400mg市售多维生素粉(Pfizer)混合,并在手持式压片设备(使用1/2″片剂直径外壳)中压制。每个片剂包含约1E+7CFU/片剂)。将片剂以每瓶100片包装在180cc HDPE瓶中,并暴露于40℃/33%RH的受控温度/湿度。每月对瓶进行微生物稳定性测试,持续12个月的时间,或直至观察到测定计数降低为低于1E+6CFU/片剂。
实施例14.种子接种微生物
根据实施例2在干组合物中制备生物控制剂(biological control agent),例如根际菌(Rhizobacteria)。在用以1E+6CFU/种子的干组合物粉末涂覆的大豆上评价根瘤菌的效力。将经涂覆的种子包装在纸袋中并保持在室温(23至25℃)。每月对袋进行微生物稳定性测试,持续12个月的时间,或直至观察到测定计数降低为低于1E+5CFU/种子。
实施例15.益生细菌宠物食品
将市售的狗用丸粒状宠物食品在对流烘箱中干燥至0.1的水活度,并随后用如实施例2中所述制备的稳定的嗜酸乳杆菌干组合物涂覆。将干丸粒用约5%的基于脂肪的水分屏障物(40%鸡脂肪、40%可可脂和20%蜂蜡的混合物)喷涂,在转鼓(drum tumbler)中与干粉末制剂(通常为总宠物食品的0.1至0.5%,其提供1E+8CFU/g的剂量)混合,并且最后用额外的基于脂肪的水分屏障物的涂料喷涂。涂层总量为(宠物食品的)约15%。涂覆时间为约30分钟。
实施例16.鱼饲料
用数种益生细菌的混合物制备根据本发明的鱼用丸粒状益生细菌饲料。如实施例2中所述制备含有鼠李糖乳杆菌、嗜酸乳杆菌和乳酸双歧杆菌之混合物的稳定的干益生细菌组合物。首先将市售的鲑鱼初始饲料(Zeigler Bros.,Gardners,PA)在对流烘箱中干燥至0.1的水活度,并随后在转鼓中用益生细菌组合物涂覆。将饲料丸粒(1000g)用约5重量%的基于脂肪的水分屏障物(40%鱼油、40%可可脂和20%蜂蜡的混合物)喷涂,随后与1g的稳定剂干益生细菌组合物混合(以达到1E+7CFU/g饲料的剂量),并且最后用额外的基于脂肪的水分屏障物的涂料喷涂。涂层总量为(鱼饲料的)约10%。
实施例17.动物饲料
将约500g阉牛(steer)用或鸡用市售动物饲料在转鼓中用3%油混合物在顶部涂覆,所述油混合物含有一份如实施例2中所述制备的干稳定嗜酸乳杆菌组合物和2份植物油(例如玉米油)。益生细菌的CFU计数为约1E+9/g饲料。将经涂覆饲料置于40℃的43%相对湿度室中,并且在这些极端条件下贮存14天之后,预期益生细菌的活力损失小于1log单位的初始CFU计数。另一种益生细菌涂覆的饲料放置在30℃的33%相对湿度室中,并且在这些条件下贮存6个月之后,预期益生细菌的活力损失小于1log单位的初始CFU。
实施例18.含有针对鳗弧菌(Vibrio anguillarum)的活噬菌体的干组合物
如实施例2中所述制备10g稳定组合物。将干活噬菌体组合物与20g鱼油混合,并将悬浮液涂覆在1kg罗非鱼饲料丸粒上。经涂覆饲料在典型的仓库储存条件下储存。当使用本发明的组合物和方法时,在暴露于高湿度和非冷藏储存条件14天之后,预期鱼饲料中噬菌体的活力被保留。
这些实施例表明,用于治疗包括人、鱼、鸡、Swaine和伴侣动物在内的多种动物的不同微生物(例如益生细菌、真菌和病毒)可在本发明的组合物和干燥方法中保留,并随后涂覆食品或饲料或混合在其中,用于在货架上长期储存,或在储存未涂覆饲料的典型湿度和温度条件下的喂料斗(feeding hopper)中储存至少2周。
本文中使用的术语“约”在涉及可测量值(例如量、百分比等)时意指涵盖距离指定值±20%或±10%,更优选±5%,甚至更优选±1%,且还更优选±0.1%的变化,因为这样的变化是适当的。
本文中引用的所有文献、书籍、手册、论文、专利、公开的专利申请、指南、摘要和其他参考文献通过引用整体并入本文。考虑到本文中公开的本发明的说明书和实践,本发明的其他实施方案对于本领域技术人员将是明显的。说明书和实施例旨在仅被认为是示例性的,本发明的真实范围和精神由所附权利要求书指明。
Claims (24)
1.干组合物,其包含一种或更多种活微生物、至少50重量%的一种或更多种水解蛋白质和少于10重量%的一种或更多种选自单糖、二糖及其组合的糖,各百分比基于所述干组合物的总重量。
2.权利要求1所述的组合物,其中所述一种或更多种活微生物选自活的细菌、真菌、酵母、单细胞藻类、病毒和噬菌体。
3.权利要求2所述的组合物,其中所述细菌是益生细菌。
4.权利要求1所述的组合物,其中所述一种或更多种水解蛋白质选自乳蛋白质、植物蛋白质、及其组合。
5.权利要求1所述的组合物,其中所述一种或更多种水解蛋白质选自水解酪蛋白、水解乳清蛋白质、水解豌豆蛋白质、水解大豆蛋白质、及其组合。
6.权利要求1所述的组合物,其还包含一种或更多种寡糖。
7.权利要求6所述的组合物,其中基于所述干组合物的总重量,所述组合物包含5至30重量%的所述一种或更多种寡糖。
8.权利要求6所述的组合物,其中所述一种或更多种寡糖选自菊糖、短链寡糖、环糊精、麦芽糖糊精、右旋糖酐、果寡糖(FOS)、半乳寡糖(GOS)、寡甘露聚糖(MOS)、及其组合。
9.权利要求6所述的组合物,其中所述一种或更多种寡糖是菊糖、短链寡糖或环糊精。
10.权利要求1所述的组合物,其还包含一种或更多种多糖。
11.权利要求10所述的组合物,其中基于所述干组合物的总重量,所述组合物包含1至10重量%的所述一种或更多种多糖。
12.权利要求10所述的组合物,其中所述一种或更多种多糖选自藻酸类、阿拉伯胶、槐豆胶、角叉聚糖、淀粉、改性淀粉、及其组合。
13.权利要求1所述的组合物,其还包含一种或更多种羧酸盐。
14.权利要求13所述的组合物,其中基于所述干组合物的总重量,所述组合物包含1至10重量%的所述一种或更多种羧酸盐。
15.权利要求13所述的组合物,其中所述一种或更多种羧酸盐是选自以下的羧酸的一种或更多种盐:乳酸、抗坏血酸、马来酸、草酸、丙二酸、苹果酸、琥珀酸、柠檬酸、葡糖酸、谷氨酸、及其组合。
16.权利要求13所述的组合物,其中所述一种或更多种羧酸盐选自抗坏血酸盐、柠檬酸盐、及其组合。
17.权利要求1所述的组合物,其中所述组合物的活力为至少1×1010CFU/g,并且其中在40℃的温度和33%的相对湿度下84天之后所述组合物的活力损失小于1log单位/g。
18.权利要求17所述的组合物,其中所述一种或更多种水解蛋白质是水解豌豆蛋白质或水解酪蛋白。
19.权利要求1所述的组合物,基于所述干组合物的总重量,其还包含1至5%w/w的维生素E。
20.权利要求1所述的组合物,其还包含一种或更多种寡糖、一种或更多种多糖和一种或更多种羧酸盐。
21.用于制备干组合物的方法,所述干组合物包含一种或更多种活微生物、基于所述干组合物的总重量至少50重量%的一种或更多种水解蛋白质、一种或更多种寡糖、一种或更多种多糖和一种或更多种羧酸盐,所述方法包括:
(a)将所述一种或更多种活微生物、所述一种或更多种水解蛋白质、所述一种或更多种寡糖、所述一种或更多种多糖和所述一种或更多种羧酸盐在碱性水性溶剂中组合以形成浆料;
(b)将所述浆料在液氮中速冻以形成珠、微滴或串形式的固体冷冻颗粒;
(c)在保持所述颗粒的温度高于其冻结温度的同时通过在真空下蒸发来对所述固体冷冻颗粒进行初级干燥,从而形成经初级干燥的制剂;以及
(d)在全强度真空和20℃或更高的热源温度下对所述经初级干燥的制剂进行次级干燥,进行足以将所述经初级干燥的制剂的水活度降低至0.3Aw或更低的时间,从而制备所述组合物。
22.权利要求21所述的方法,其还包括:在步骤(a)中,向所述碱性水性溶剂添加一种或更多种糖以形成所述浆料,其中所述一种或更多种糖选自单糖、二糖及其组合,并且其中所得干组合物包含基于所述干组合物的总重量小于10重量%的所述一种或更多种糖。
23.权利要求22所述的方法,其还包括:在步骤(a)之前,对所述一种或更多种水解蛋白质、所述一种或更多种寡糖、所述一种或更多种多糖、一种或更多种羧酸盐和所述一种或更多种糖进行灭菌。
24.权利要求21所述的方法,其还包括用所述组合物制备产品,其中所述产品选自药物产品、营养产品、食品产品、饲料产品和特殊饮食产品。
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JP2019165690A (ja) * | 2018-03-23 | 2019-10-03 | 株式会社ダイセル | 魚類飼育用飼料、魚類の養殖方法及び魚類飼育用飼料の添加剤 |
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KR102174589B1 (ko) * | 2018-08-03 | 2020-11-05 | 부경대학교 산학협력단 | 뱀장어 사료내 항생제 대체를 위한 신바이오틱스 개발 |
JP7178203B2 (ja) * | 2018-08-07 | 2022-11-25 | 株式会社ヤクルト本社 | 乳酸菌凍結乾燥菌体の製造方法 |
KR102189273B1 (ko) * | 2019-02-13 | 2020-12-09 | 의령왕메추리 영농조합법인 | 메추리 급이사료 조성물 |
JP7377478B2 (ja) * | 2019-09-27 | 2023-11-10 | 学校法人東海大学 | 魚介類養殖方法、プロバイオティクス細菌液、およびプロバイオティクス細菌含有飼料 |
KR102453960B1 (ko) * | 2020-01-20 | 2022-10-11 | 조선대학교산학협력단 | 프로바이오틱스 및 돈혈장 가수분해물을 유효성분으로 포함하는 뱀장어용 사료첨가제 조성물 |
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US20180325967A1 (en) | 2018-11-15 |
EP3383999A4 (en) | 2019-07-03 |
CA3005048C (en) | 2023-03-28 |
RU2018117943A (ru) | 2020-01-09 |
MX2018006567A (es) | 2018-08-01 |
US10792313B2 (en) | 2020-10-06 |
RU2731158C2 (ru) | 2020-08-31 |
EP3383999A1 (en) | 2018-10-10 |
NZ742496A (en) | 2021-10-29 |
AU2016365214B2 (en) | 2021-02-25 |
CA3005048A1 (en) | 2017-06-08 |
KR20180081170A (ko) | 2018-07-13 |
CN108368474B (zh) | 2021-11-16 |
BR112018010789A2 (pt) | 2018-11-21 |
AU2016365214A1 (en) | 2018-05-31 |
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RU2018117943A3 (zh) | 2020-03-26 |
JP2019503707A (ja) | 2019-02-14 |
CL2018001492A1 (es) | 2018-07-13 |
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