CN1622816A - 增强肾功能的组合物及方法 - Google Patents
增强肾功能的组合物及方法 Download PDFInfo
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- CN1622816A CN1622816A CNA028285360A CN02828536A CN1622816A CN 1622816 A CN1622816 A CN 1622816A CN A028285360 A CNA028285360 A CN A028285360A CN 02828536 A CN02828536 A CN 02828536A CN 1622816 A CN1622816 A CN 1622816A
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- lactobacillus
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- bacillus
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Abstract
本发明提供了一种组合物，该组合物包括益生素和益生菌组分，用于降低高水平的含氮废物，并促使形成健康的肠内微环境。
Description
发明领域
本发明涉及降低含氮废物浓度的组合物及方法。组合物可以是食物、食物增补剂、医疗食物或者药品形式。
发明背景
正常健康的肾，除了具有调节性、内分泌和新陈代谢的作用外，一个主要作用就是处理废物。排泄功能的任何损伤会导致各种含氮废物的累积，所述含氮废物包括尿素、肌酸酐和尿酸。血流里的高浓度废物可以加剧肾衰竭和导致肾结石。另外，由于穿过肠壁的浓度梯度，在循环血液中的含氮溶质容易渗透扩散到内腔。这个扩散机制引出了口服吸着剂的概念，用来加大基于肠的含氮废物的清除。吸着剂或者微生物已经表现出移除大肠内各种化合物和含氮废物的能力。
针对尿素的吸着剂，如合成聚合物和改性的多糖，已经在其移除流经肠的尿素和其他含氮废物方面进行评估。其他吸着剂如氧化淀粉、活性炭和角豆粉也已在体内消除尿毒素方面进行了研究，并取得了一些成果。Prakash & Chang((1996)Nature Medicine 2：883-88)证明微胶囊化、遗传工程化的大肠杆菌(E.coli)DH5在体外系统中能有效移除尿素和氨。相同的研究者通过给患尿毒症的大鼠动物模型口服大肠杆菌DH5细胞，获得相似的结论。Bliss等人((1996)Am.J.Clin.Nutr.63：392-398)已经证明，补充的阿拉伯胶纤维提高了粪便的氮排泄，并且降低了食用低蛋白食物的慢性肾衰竭患者的尿素的氮浓度。Reinhart等人((1998)Rec.Adv.In Canine and Feline Nutr.Iams NutritionSymposium Proceedings.Vol.II：395-404)发现，食用含有可发酵纤维混合物的食物的犬肾患者改善了临床晚期肾疾病状况，说明了特定的营养变化通过结肠发酵或者附加的细菌生长，使氮排泄重新分配，离开肾而进入粪便。
益生素(prebiotic)组分是提高消化道中益生菌(probiotic)组分作用的食物成分。在这个协同或共生(synbiotic)的联系中，益生菌组分如双歧杆菌(Bifidobacteria)使未消化的碳水化合物如食物纤维、寡糖等产生代谢变化，以产生短链脂肪酸如醋酸、丙酸和丁酸。这些短链脂肪酸可以促进肠内的细胞生长，增加水和矿物的吸收，并抑制酵母、霉菌和病原菌的生长。另外，益生菌组分也可以通过产生抗微生物的和抗细菌的化合物如细胞因子和丁酸来直接抵抗病原体(De Vuyst andVandamme.Antimicrobial potential of lactic acid bacteria.In：De Vuyst L，Vandamme EL，eds.Bacteriocins of lactic acid bacteria.Glasgow，United Kingdom：Blackie Academic and Professional；1994：91-142；Doddand Gasson.Bacteriocins of lactic acid bacteria.In：Gasson MJ，de VosWM，eds.Genetics and biotechnology of lactic acid bacteria.Glasgow，United Kingdom：Blackie Academic and Professional；1994：211-51；Kailasapathy and Chin(2000)Immunol.Cell.Biol.78(1)：80-8)，通过刺激可产生乳酸的微生物区系来降低肠的pH(Langhendries，et al.(1995)J.Pediatr.Gastroenterol.Nutr.21：177-81)，竞争被病原体占据的结合部位和受体部位(Kailasapathy and Chin(2000)Immunol.Cell.Biol.78(1)：80-8；Fujiwara et al.，(1997)Appl.Environ.Microbiol.63：506-12)，提高免疫功能和刺激免疫调节细胞(Isolauri et al.(1991)Pediatrics 88：90-97；Isolauri et al.(1995)Vaccine 13：310-312；Rolfe(2000)J.Nufr.130(2S)：396S-402S)，与病原体竞争可利用的营养素和其他生长因子(Rolfe(2000)J.Nufr.130(2S)：396S-402S)，或产生有助于乳糖消化的乳糖酶。
本发明将益生素和益生菌组分的有益效果结合到可有效降低含氮废物的共生素产品中。
发明概述
本发明的目的是提供一种包括益生素和益生菌组分的组合物。该组合物可以添加到食品、食物增补剂、医疗食物或者药品中，一旦被摄取，这些产品将促使形成一个健康的肠内微环境，并有助于消除能在血液循环中积聚浓度的含氮废物。已知这些废物的浓度增加会对个体的生理机能产生负面影响，导致健康感的降低和全身不适。本发明还提供了使用这些产品减少含氮废物的方法。
优选实施方案详述
在血流内累积的含氮废物对健康有害。通过将含氮废物转移到结肠而将它们去除是一种降低废物累积对个体生理机能产生的负面影响的可行方法。本发明将益生菌和益生素组分的特性结合到一种共生素产品中，有效地降低了含氮废物的血液浓度，并具有促进所希望的肠内微生物区系生长的额外有益效果。
本发明的益生菌组分是指活的或者冷冻干燥的微生物单一培养物或微生物混合培养物，当其应用于人或动物时，可以通过提高土著微生物区系如双歧杆菌有机体的性质来影响宿主，所述土著微生物区系能使未消化碳水化合物产生代谢变化，从而对个体产生有益影响。本发明的益生菌组分根据如下因素来选择：它们对宿主产生有益影响的能力、通过肠道时的生存能力、粘附到肠内上皮细胞内层的可能性、产生针对病原体的抗微生物物质的能力、和/或稳定肠内微生物区系的能力。另外，益生菌组分必须有一个长的贮藏寿命。本发明的共生素产品应包含在消耗的同时能繁殖的大量活细胞，并且它们是不致病的和无毒的。益生菌组分的例子包括但不局限于：双歧杆菌(Bifidobacterium spp.)(例如，双歧双歧杆菌(Bifidobacteriumbifidum)、长双歧杆菌(Bifidobacterium longum)、婴儿双岐杆菌(Bifidobacterium infantis)，乳杆菌(Lactobacillus spp.)(例如，保加利亚乳杆菌(Lactobacillus bulgaricus)、嗜酸乳杆菌(Lactobacillusacidophilus)、乳乳杆菌(Lactobacillus lactis)、瑞士乳杆菌(Lactobacillushelveticus)、干酪乳杆菌(Lactobacillus casei)、路氏乳杆菌(Lactobacillusreuteri)、德氏乳杆菌(Lactobacillus delbruecki))，链球菌(Streptococcusspp.)(例如，嗜热链球菌(Streptococcus thermophilus)、双乙酰乳链球菌(Streptococcus diacetilactis)、乳脂链球菌(Streptococcuscremoris)、耐久链球菌(Streptococcus durans)、粪链球菌(Streptococcusfaecalis))，糖酵母菌(Saccharomyces spp.)(例如粟酒糖酵母菌(Saccharomyces pombe)、Saccharomyces Boulardii)、明串珠菌(Leuconostoc spp.)(例如噬柠檬酸明串珠菌(Leuconostoccitrovorum)、葡聚糖明串珠菌(Leuconostoc dextranicum))和芽孢杆菌(Bacillus sp.)(例如，巴氏芽孢杆菌(Bacillus pasteurii))。在优选实施方案中，益生菌组分包括一种或多种来自双歧杆菌属或者乳杆菌属的微生物。
在本发明中同样有用的微生物是那些通过自然选择或遗传操作具有可以使不同的含氮化合物发生分解代谢的能力的微生物，所述含氮化合物包括但不局限于：尿素、肌酸酐、尿酸和氨。一个例子就是具有高水平的脲酶分泌的微生物。通过把基因编码脲酶插入到原核微生物如乳杆菌、芽孢杆菌、或双歧杆菌内，或插入到真核微生物如糖酵母菌内，可以获得高水平的分泌。脲酶基因可以由可诱导的启动子或组成型启动子来调节控制。在重组的原核表达载体中，最常用的启动子包括β-内酰胺酶(青霉素酶)和乳糖启动子系统(Chang et al.(1978)Nature 275：615 and Goeddel et al.(1979)，Nature 281：544，a tryptophan(trp)promoter system(Goeddel et al.(1980)Nucleic Acids Res.8：4057and EPO App.Publ.No.36,776)and the tac promoter(H.De Boer et al.(1983)Proc.Natl.Acad.Sci.USA 80：21)。尽管这些启动子是常用的，但是其他的微生物启动子也是合适的。关于很多启动子的核苷酸序列的详细资料已经公开，这使熟练的技术工人能把它们操作连接到可编码在质粒或病毒载体中的蛋白质的DNA(Siebenlist et al.(1980)Cell 20：269)。启动子和SD序列(用于原核宿主表达)被操作连接到编码所需蛋白质的DNA上，即它们被定位以促进从DNA到蛋白质信使RNA的转录。
真核微生物如酵母培养物可以用合适的编码蛋白质的载体转化。参见例如美国专利4,745,057。尽管许多其他菌株也是常用的，但酿酒糖酵母菌(Saccharomyces cerevisiae)在低等真核宿主微生物中是最常用的。酵母载体可包含来自2微米酵母质粒复制或者自主复制序列(ARS)的起始点、启动子、编码所需蛋白质的DNA、用于聚腺苷酸化和转录终止的序列、以及选择基因。示例性质粒为YRp7(Stinchcomb et al.(1979)Nature 282：39；Kingsman et al.(1979)Gene 7：141；Tschemper et al.(1980)Gene 10：157)。这个质粒包含trpl基因，该基因可为在色氨酸中缺乏生长能力的酵母突变菌株提供选择标记，所述菌株为例如ATCC No.44076或PEP4-1(Jones(1977)Genetics85：12)。然后，酵母宿主细胞基因组中trpl损伤的存在为在没有色氨酸的情况下探测生长转化提供了有效环境。
酵母载体中的合适启动序列包括金属硫蛋白的启动子、3-磷酸-甘油酸激酶的启动子(Hitzeman et al.(1980)J.Biol.Chem.255：2073)或其他糖酵解酶的启动子(Hess et al.(1968)J.Adv.Enzyme Reg.7：149Holland et al.(1978)Biochemistry 17：4900)，所述糖酵解酶为例如烯醇化酶、甘油醛-3-磷酸脱氢酶、己糖激酶、丙酮酸脱羧酶、果糖磷酸激酶、葡萄糖-6-磷酸异构酶、3-磷酸甘油酸变位酶、丙酮酸激酶、丙糖磷酸异构酶、磷酸葡糖异构酶和葡糖激酶。用于酵母表达的合适载体和启动子在R.Hitzeman et al.，EPO Publn.No.73,657中有进一步描述。
本领域技术人员将理解，含有可编码脲酶的多核苷酸的表达载体可以设计为包含信号序列，这些序列指导脲酶通过原核细胞膜或真核细胞膜的分泌。
这里定义的转化微生物描述了一个过程，通过这个过程外源DNA进入并改变了受体细胞。它可以在自然或人工条件下使用本领域中熟知的各种方法进行。转化可以依赖任何已知的方法，将外源核酸序列插入到原核或者真核的宿主细胞中。这种方法的选择以被转化的宿主细胞类型为基础，可以包括但是不局限于：病毒感染、电穿孔、热激、脂质转染法、和粒子轰击。这些“转化”细胞包括稳定转化的细胞，其中被插入的DNA能作为自主复制的质粒或者宿主染色体的一部分进行复制。它们也包括在有限时间段内瞬时表达被插入的DNA或者RNA的细胞。
通过在高水平尿素上培养转化菌株而为高水平脲酶分泌选择所得的转化菌株。脲酶分泌水平也可用标准酶促化验进行检测。从而，转化菌株可以在不断增长的尿素水平上进行次培养，以增大脲酶分泌。在优选实施方案中，可分泌脲酶的微生物为巴氏芽孢杆菌。在另一个优选实施方案中，可分泌脲酶的微生物为粟酒糖酵母菌。
益生菌组分或可分泌脲酶的微生物包括食品添加剂，如健康棒(health bar)、健康饮料、酸乳酪、或达希酸奶(dahi)、或肠溶衣片剂、胶囊、粉末、软凝胶、软胶囊(gencap)或液体。因此，在本发明的优选实施方案中，当益生菌组分或可分泌脲酶的微生物作为液体加入时，其浓度为108cfu/ml、109cfu/ml、1010cfu/ml、1011cfu/ml、或1012cfu/ml；当作为固体加入时，其浓度为108cfu/g、109cfu/g、1010cfu/g、1011cfu/g、或1012cfu/g。
本发明的益生素组分是指不消化的食物，它通过选择性地刺激结肠内一种或多种非致病性细菌的生长和/或活性对宿主产生有益影响。本发明的益生素组分被认为具有抗癌、抗微生物、降血脂和葡萄糖调节活性。它们也可以改善矿物吸收和平衡。另外，属于双歧杆菌科和乳杆菌科的细菌在益生素组分和增殖物的存在下被刺激。在药物动力学上，益生素组分基本完整地达到结肠。在优选实施方案中，益生素组分是寡糖(例如，果寡糖或菊粉、异麦芽寡糖、反式乳寡糖、木寡糖、或大豆寡糖或焦糊精(pyrodextrin)(例如，阿拉伯半乳聚糖、拉克替醇(lactilol)、乳蔗糖(lactosucrose)、或乳果糖(lactulose))。加到益生菌组分中的益生素的量为100毫克/份、500毫克/份、1克/份、5克/份、或10克/份。在优选实施方案中，益生素组分不小于100毫克/份，并且不大于10克/份。
结合了益生菌和益生素组分的有益特性的共生素产品可以包括食品、食物增补剂、可食用的医疗食物、或者药品。在本发明的上下文下，“共生素”是指益生菌和益生素组分的混合物，以提高健康增强效果(Gibson and Roberfroid(1995)J.Nutr.125：1401-1412)。摄取所述共生素产品可降低在循环血流中累积的含氮废物的血液浓度。本发明中的这些废物可以是内生源，如正常或非正常新陈代谢途径或细菌的腐败物。另外，废物是可以作为饮食中蛋白质和氨基酸的摄取的外生源。还有，共生素产品的重复摄取，通过在大肠内已知微生物的定位和建群，对肠内微生物区系产生非常有益的影响，从而促使形成健康的肠内微环境。
本发明的食品包括但不局限于：健康棒、健康饮料、酸乳酪、或达希酸奶。例如，一个酸乳酪食品可以用如下方法制备：将一加仑市售的完整匀质的、用巴氏法灭菌的牛奶加热到沸腾，再快速冷却至约45℃。向其中加入约一盎司酸乳酪起子培养物，其包含乳杆菌属、芽孢杆菌属或双歧杆菌属的乳酸细菌。将混合物充分混合，在37℃发酵10至12小时。可以将所有的水果添加剂、调味剂、甜味剂、粘合剂、或其他添加剂混合，然后添加到酸乳酪中，以得到具有理想稠度的产品，或者适合潜在消费者的喜好。在本发明的优选实施方案中，食品中包括满足患有肾机能不全的个体的特殊饮食需要的组分。
健康棒可通过如下方法制得：混合各种赋形剂如粘合剂、添加剂、调味剂、着色剂等、以及益生素和益生菌组分，再混合成一个可塑的整块(mass consistency)。然后将这个整块挤压或塑造，以形成“糖果棒”形状，接着使其干燥或固化，形成最终产品。
各种添加剂可以加入到本组合物中。本组合物中可选择的添加剂包括但不限于：淀粉、糖、脂肪、抗氧化剂、氨基酸、蛋白质、核酸、电解质、维生素、及其衍生物、或其组合。在优选实施方案中，共生素产品添加剂是角豆粉如刺槐豆胶。在另一个优选实施方案中，添加剂是来自双孢蘑菇(Agaricus bisporus)的蘑菇提取物。
可任选地添加到本组合物中的香料是制药领域中熟知的香料。其例子包括但不局限于：合成香料油、和/或来自植物叶子、花、水果等中的油，其混合油是有用的。香料油的例子包括但不局限于：荷兰薄荷(spearming)油、胡椒薄荷(peppermint)油、肉桂油、冬青油(水杨酸甲酯)。还可使用人造的、天然的或合成的水果香料，如柠檬油，其包括柠檬、橙、葡萄、梨莓和葡萄柚，和果香香精，其包括苹果、草莓、樱桃、菠萝等。
甜味剂可以选自很多材料，如水溶性甜味剂、水溶性人造甜味剂、二肽基甜味剂，包括它们的盐和它们的混合物，且还不限于这些。
粘合剂可以选自很多材料，如羟丙基甲基纤维素、乙基纤维素或其他合适的纤维素衍生物、聚烯吡酮、丙烯酸和甲基丙烯酸的共聚物、药用釉料、树胶、牛奶衍生物如乳清、淀粉、及它们的其衍生物，以及本领域技术人员熟知的其他常规粘合剂。溶剂的例子包括但不局限于：水、乙醇、异丙醇、二氯甲烷、或其混合物、和它们的组合。填充剂的例子包括但不局限于：糖、乳糖、明胶、淀粉、和二氧化硅。
本发明的食物增补剂可以由乳杆菌属、芽孢杆菌属或双歧杆菌属的乳酸菌和可分泌脲酶的微生物制得。微生物被无菌冷冻干燥，然后根据Kim等人((1988)J.Indust.Microbiol.3：253-257)的方法将处理过的散装细菌制成肠溶衣胶囊。每个胶囊中包含80至250毫克的冷冻干燥微生物，胶囊通过在胶囊流化床上喷射羟丙基甲基纤维素邻苯二甲酸酯进行肠衣包覆。最终的食物增补剂具有小的表面积，相对无孔，可以保护内部物质在几小时内免受胃环境低pH值的影响，并将内部物质释放到其中pH值为相对中性或弱碱性的肠内。
除了上述的控释剂型，还有许多被研制优选用于口服的控释剂型。这些剂型包括但不局限于：渗透压控制的胃肠递药系统；流体压力控制的胃肠递药系统；膜渗透控制的胃肠递药系统，其包括微孔膜渗透控制的胃肠递药装置；抗胃液的肠靶向控释胃肠递药装置；凝胶扩散控制的胃肠递药系统；离子交换控制的胃肠递药系统，其包括阳离子和阴离子药物。关于控释药物递送系统的其他信息可以参见Yie W.Chien，Novel Drug Delivery Systems，1992(Marcel Dekker，Inc.)。其中的一些剂型将在这里较详细讨论。将肠溶衣涂敷到片剂上，以免药物在胃部释放，从而降低产生不希望的副作用的危险或者保持药物的稳定性，否则这些药物由于暴露在胃环境中而可能发生降解。用于这个目的的大多数聚合物是多酸，它们根据或由于以下事实发挥作用：它们在水介质中的溶解度取决于pH值，且它们需要具有比胃内通常遇到的pH要高的pH的条件。口服控释结构的一个优选类型是固体或液体剂型的肠溶衣。当剂型暴露于胃液中时，肠溶衣使化合物仍然在指定的时间内在物理上保持在剂型中。然而，肠溶衣被设计在肠液中分解以便于快速吸收。吸收延迟取决于通过胃肠道的移动速度，所以胃排空的速度是一个重要因素。一些研究者已经报道说，多单位类型剂型如颗粒可能优于单个单位剂型。
典型的肠溶衣试剂包括但不局限于：羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸-甲基丙烯酸酯共聚物、聚乙酸乙烯酯-邻苯二甲酸酯和醋酸纤维素邻苯二甲酸酯(Hasegawa，(1985)Chem.Pharm.Bull.33：1615-1619)。各种肠溶衣材料可以在测试基础上选择，以获得肠溶衣剂型，肠溶衣剂型被设计为首先具有溶解时间、包衣厚度和径向抗碎强度的优选组合(Porter et al.(1970)J.Pharm.Pharmacol.22：42p)。
通过混合燕麦片、脱水苹果、蜂蜜、菊粉、角豆粉、肉桂、糖、香草精、和生孢乳杆菌(Lactobacillus sporogenes)、嗜酸乳杆菌与发酵乳杆菌(Lactobacillus fermentum)的冻干培养物(每个108至1010cfu)来制备医疗食物。这些成分以适当比例混合，形成一个约12.5至15厘米长、3至4厘米宽、1厘米高的矩形条，在无菌真空炉中放置12至24小时，以得到具有所需稠度的可食用食品。用于患有肾机能不全的患者的药品可以通过无菌冷冻干燥可分泌脲酶的微生物而制得。然后根据Kim等人((1988)J.Indust.Microbiol.3：253-257)的方法将处理过的散装微生物制成肠溶衣胶囊，例如，每个胶囊中包含80毫克至1克的冷冻干燥微生物，胶囊通过在胶囊流化床上喷射羟丙基甲基纤维素邻苯二甲酸酯进行肠溶衣包覆。最终的药品具有小的表面积，相对无孔，可以保护内部物质在几个小时内免受胃环境的低pH的影响，并将内部物质释放到其中pH为相对中性或弱碱性的肠内。
Claims (6)
1.一种组合物，该组合物包括至少一种益生菌组分和至少一种益生素组分。
2.如权利要求1所述的组合物，其中益生菌组分包括乳杆菌属(Lactobacillus)、芽孢杆菌属(Bacillus)或双歧杆菌属(Bifidobacteria)的微生物。
3.如权利要求1所述的组合物，其中益生素组分包括寡糖或焦糊精。
4.如权利要求1所述的组合物，该组合物还包括至少一种可分泌脲酶的微生物。
5.一种移除含氮废物的方法，该方法包括施用有效量的权利要求1的组合物。
6.一种治疗肾衰竭的方法，该方法包括施用有效量的权利要求4的组合物。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2002/007554 WO2003088984A1 (en) | 2002-03-13 | 2002-03-13 | Compositions and methods for augmenting kidney function |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1622816A true CN1622816A (zh) | 2005-06-01 |
| CN100402042C CN100402042C (zh) | 2008-07-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB028285360A Expired - Lifetime CN100402042C (zh) | 2002-03-13 | 2002-03-13 | 增强肾功能的组合物及方法 |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1492549B1 (zh) |
| JP (1) | JP2005532294A (zh) |
| KR (1) | KR20050004805A (zh) |
| CN (1) | CN100402042C (zh) |
| AU (1) | AU2002255717B2 (zh) |
| CA (1) | CA2478991C (zh) |
| WO (1) | WO2003088984A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100464781C (zh) * | 2006-01-19 | 2009-03-04 | 苏州大学 | 慢性肾病营养液及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5349744B2 (ja) * | 2005-12-19 | 2013-11-20 | 松谷化学工業株式会社 | ミネラル吸収促進剤、食品及び飼料 |
| EP2057992B1 (en) * | 2006-08-21 | 2013-02-27 | Calpis Co., Ltd. | Renal-function-ameliorating agent |
| CN101686716B (zh) * | 2007-06-25 | 2013-12-18 | 帝斯曼知识产权资产管理有限公司 | 益生元 |
| JP5487379B2 (ja) | 2008-03-19 | 2014-05-07 | 森下仁丹株式会社 | 血中リン濃度上昇抑制剤 |
| JP5932662B2 (ja) * | 2009-12-22 | 2016-06-08 | プロビ アクティエボラーグ | 穀物ベースフラクション及びプロバイオティックを含む非発酵組成物、並びにそれらの使用 |
| EP3609351B1 (en) * | 2017-04-10 | 2024-03-06 | Kibow Biotech, Inc. | Multifiber prebiotic composition for digestive health, weight control, boosting immunity and improving health |
| CN109662259B (zh) * | 2017-10-16 | 2022-07-29 | 江苏省农业科学院 | 一种富益生菌冻干毛豆粒产品及其制备方法 |
| CN109864270B (zh) * | 2017-12-01 | 2022-07-29 | 江苏省农业科学院 | 一种富益生菌冻干胡萝卜丁产品及其制备方法 |
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| JPH0482827A (ja) * | 1990-07-23 | 1992-03-16 | Snow Brand Milk Prod Co Ltd | 腸溶性カプセル |
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| JPH09110707A (ja) * | 1995-10-12 | 1997-04-28 | Wakamoto Pharmaceut Co Ltd | 慢性腎不全改善剤および透析患者のクオリティー オブ ライフ改善剤 |
| EP0856259B1 (en) * | 1996-12-23 | 1998-08-12 | SITIA-YOMO S.p.A. | Composition for feed use comprising lyophilized live lactic bacteria |
| EP0904784A1 (en) * | 1997-09-22 | 1999-03-31 | N.V. Nutricia | Probiotic nutritional preparation |
| KR100387245B1 (ko) * | 1997-10-17 | 2003-08-19 | 일양약품주식회사 | 유산균의안정화를위한미세장용성코팅과립 |
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| DE20202562U1 (de) * | 2002-02-19 | 2002-05-23 | Orthomol Pharmazeutische Vertr | Mikronährstoffkombinationsprodukt mit Pro- und Prebiotika |
-
2002
- 2002-03-13 CA CA2478991A patent/CA2478991C/en not_active Expired - Lifetime
- 2002-03-13 KR KR10-2004-7014358A patent/KR20050004805A/ko not_active Application Discontinuation
- 2002-03-13 EP EP02725132.1A patent/EP1492549B1/en not_active Expired - Lifetime
- 2002-03-13 AU AU2002255717A patent/AU2002255717B2/en not_active Expired
- 2002-03-13 CN CNB028285360A patent/CN100402042C/zh not_active Expired - Lifetime
- 2002-03-13 JP JP2003585736A patent/JP2005532294A/ja active Pending
- 2002-03-13 WO PCT/US2002/007554 patent/WO2003088984A1/en active IP Right Grant
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100464781C (zh) * | 2006-01-19 | 2009-03-04 | 苏州大学 | 慢性肾病营养液及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1492549B1 (en) | 2016-05-11 |
| CA2478991C (en) | 2015-06-30 |
| AU2002255717B2 (en) | 2007-07-26 |
| WO2003088984A1 (en) | 2003-10-30 |
| KR20050004805A (ko) | 2005-01-12 |
| EP1492549A4 (en) | 2005-10-26 |
| EP1492549A1 (en) | 2005-01-05 |
| JP2005532294A (ja) | 2005-10-27 |
| CN100402042C (zh) | 2008-07-16 |
| CA2478991A1 (en) | 2003-10-30 |
| AU2002255717A1 (en) | 2003-11-03 |
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