CN1509144A - 益生素和益生菌组合物及其在肠道疾病治疗中的用法 - Google Patents
益生素和益生菌组合物及其在肠道疾病治疗中的用法 Download PDFInfo
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- CN1509144A CN1509144A CNA028100786A CN02810078A CN1509144A CN 1509144 A CN1509144 A CN 1509144A CN A028100786 A CNA028100786 A CN A028100786A CN 02810078 A CN02810078 A CN 02810078A CN 1509144 A CN1509144 A CN 1509144A
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Abstract
本发明提供了一种微囊化和/或肠衣包被的组合物，其包括益生菌、益生素和具有高尿素酶活性的亲氨细菌的混合物，所述混合物含有或不含有对诸如肌酸酐、尿酸、酚、吲哚、中等分子量的分子以及无机磷酸盐的尿毒性毒素有特异亲和力的吸附剂，以及包括水吸附剂。本发明还提供了缓解病人体内尿毒症症状的方法，所述方法包括给患有尿毒症的病人口服施用微胶囊化和/或肠衣包被的组合物。
Description
发明领域
本发明涉及药物组合物以及使用所述组合物通过排除毒素和其它代谢废物以及减少或抑制不需要的细菌过度生长来治疗肾、肝及肠胃疾病的方法。在一个实施方案中，所述药物组合物包括一种益生素，一种益生菌，一种亲氨细菌，以及吸附剂，上述所有物质均被微囊化和/或肠衣包被起来。或者，所述益生素，益生菌和亲氨细菌聚集在一个微胶囊中给药，而如果需要的话，所述吸附剂单独以一个微囊化的和/或肠衣包被的制剂给药。这些药物组合物对于治疗肾病和肝病以及胃肠道系统细菌的过度生长是有用的。
发明背景
在美国，肾脏疾病在主要疾病中位居第四，超过20,000,000的美国人为此痛苦。每年，超过90,000的病人死于肾脏疾病。近几年来，慢性肾衰竭的人数已经以每年11％的速率增长。每年大约80,000透析的美国人死于不同的并发症并且每年名单上有超过27,000人正在等待肾移植而他们当中只有约11,000病人接受肾移植。此外，将近250,000的美国人患有慢性肾衰竭的最后阶段-末期肾病(ESRD)。
通常，健康人的氮代谢废物主要通过肾脏以尿素形成从尿液中排出。然而，对于患有肾病以及许多其它疾病如尿循环酶先天缺乏的个体来说，废氮在体内积累从而出现中毒症状。铵过多会导致智力迟钝，严重的话，会导致昏迷。
目前，血液或腹膜透析和肾移植是唯一的治疗方式。然而，这些治疗方式的费用非常高。比如，1996年单单在美国，ESRD的年治疗费用超过140亿美元。在卫生保健预算较低的发展中国家和欠发达国家，由于高额的治疗费用，ESRD病人无法利用上述方式治病。因此，还需要治疗尿毒症的替代方式。
许多治疗试验一直建立在用肠代替肾起作用的基础上。在正常的消化过程中肠胃系统传递营养物和水到血液中并且通过肠道排除废物和未消化物。肠壁调节营养物、电解质、水和某些助消化物质如胆汁酸的吸收。肠壁也起到半透膜的作用，允许小分子从肠道进入血液并阻止大分子进入循环。
氮废物如尿素、肌酸酐和尿酸以及某些其它小的和中等分子量化合物流入到小肠中并且跨越小肠上皮平衡。肠道透析研究已经显示进入肠液的日流量为尿素71克，肌酸酐2.9克，尿酸2.5克和2.0克的磷酸盐(Sparks，R.E.Kidney Int.Suppl.1975 Suppl 3，7：373-376)。从而，人们已经做了各种介入性和非介入性的尝试从胃肠道中提取尿毒症废物，这些尝试包括外部肠瘘，肠道透析，导泄，口服吸附剂和/或胶囊尿素酶给药(Twiss，E.E.和Kolff，W.J.JAMA 1951 146：1019-1022；Clark等，Trans.Am.Soc.Artif.Intrn.Organs 1962 8：246-251；Pateras等，Trans.Am.Soc.Artif.Intrn.Organs 1965 11：292-295；Shimizu等，Chemical Abstracts 1955 103：129004；Kjellstrand等，Trans.Am.Soc.Artif.Intern.Organs 198127：24-29；以及Kolff，W.J.Kidney Int.1976 10：S211-S214)。
活性炭是第一个用来治疗尿毒症的口服吸附剂。活性炭是一种具有大的表面积的高度多孔材料，它是有机材料如木头、石油、煤、泥炭和椰子壳炭化后再经过蒸汽、二氧化碳或化学药品如氯化锌活化后获得的。活性炭的溶质吸附取决于许多因素，包括体相中溶质的浓度，溶质的化学性质，温度和pH值。而总体上说，相对于极性溶质，活性炭更易于吸收非极性溶质。在体内实验中，190克活性炭需要除去450毫克肌酸酐(Goldenhersh等，Kidney Int.1976 10：8251-8253)。这一减少的效力被认为是由于它还吸收了其它亲脂性的化合物如胆固醇和相关的胆汁酸(Kolff，W.J.Kidney Int.1976 10：8211-8214；Goldenhersh等，Kidney Int.1976 10：8251-8253)。微囊化的活性炭表明所需炭的数量可以减少到50克(Goldenhersh等，Kidney Int.1976 10：8251-8253)。
AST-120是一种专有的经特制的0.2-0.4毫米多孔炭的包被材料，已经证实它是一种更为有效的炭基吸附剂。已经公开，施用3.2至7.2克剂量到尿毒症病人身上可以延缓血液肌酸酐水平的上升，并且延迟了肾切除大鼠和27个尿毒症病人肾功能异常的发作(Owadu，A.和Shiigai，T.Am.J.Nephrol.1996 16(2)：124-7；及Okada，K.Takahashi，S.Nephrol.Dial.Transplant.1995 10(5)：671-6)。AST-120作为口服吸附剂也延迟了肾衰竭的发展(Miyazaki，T等，Nephrol Dial Transplant 2000Nov；15(11)：1773-81)。
一些研究已经表明，摄入二醛基淀粉，也指氧化淀粉，会导致非蛋白氮的排泄量增长(Giordano等，Bull.Soc.Ital.Biol.Sper.1968 44：2232-2234；Giordano等，Kidney Int.1976 10：S266-8268；Friedman等，Proc.Clin.Dia.Trans.Forum 1977 7：183-184).不象活性炭吸附尿毒性溶质是一种容易可逆的物理过程，二醛基淀粉是通过包括共价结合二醛基的化学吸附来结合尿素和氨的。然而，象活性炭一样，摄入大量的大约30-50克的含氧淀粉仅能除去1.5克的尿素。二醛基淀粉和活性炭都摄入的其他研究证实了一些尿毒症废物去除的改进(Friedman等，Proc.Clin.Dia.Trans.Forum 1977 7：183-184)。而且，与未包被的二醛基淀粉相比，用明胶和白蛋白包被的二醛基淀粉的吸附结果要好6倍(Shimizu等，Chemical Abstracts 1982 97：222903)。最近，慢性肾衰竭在给药包被有氧化纤维素(oxycel)或纤维素二醛的壳聚糖之后显示发展延迟(Nagano等，Medline Abstract UI 96058336 1995)。
刺槐豆胶是一种可天然获得的以碳水化合物为基础的聚合口服吸附剂，将其以25克/天的剂量于棉籽油中给药于尿毒症病人，也可证明去除了大量的尿素、肌酸酐和磷酸盐。而且，刺槐豆胶吸附了大约10倍自身重量的水(Yatzidis等，Clinical Nephrology 197911：105-106)。通过饮食补充阿拉伯纤维胶也被证明可使低蛋白饮食的慢性肾衰竭病人粪便中的氮排泄量增加以及血清氮浓度减少(Bliss等，Am.J.Clin.Nutr.1996 63：392-98)。
胶囊化的尿素酶也已被试验作为一种不可吸收的口服吸附剂来结合氨。在早期大量研究中，磷酸锆和胶囊化的尿素酶被用作一种不可吸收的口服吸附剂来结合氨(Kjellstrand等，Trans.Am.Soc.Artif.Intern.Organs 1981 27：24-29)。还研究了使用一种具有胶囊化尿素酶的液体膜胶囊装置将尿素水解为氨和柠檬酸以中和氨的方法(Asher等，KidneyInt.1976 10：8254-8258)。土壤细菌也被用来将尿素再生成为代谢有用的氨基酸(Setala，K.Kidney Intl Suppl.1978 8：8194-202)。
此外，遗传工程细胞E.herbicola也已被胶囊化并证明它可在氨经肠道排出之前将其转变成为对细胞有用的氨基酸。微囊化的遗传工程细胞大肠杆菌(E.coli)DH5在体外系统和尿毒症大鼠动物模型中也已显示出去除尿素和氨的有效性(Prakash，S.和Chang，T.M.S.Biotechnology and Bioengineering 1995 46：621-26；及Prakash，S.和Chang，T.M.S.Nature Med.19962：883-887)。然而，基因工程菌株的给药带来控制和安全担心以及增加的伦理问题可能导致病人不服从用药。
为了有效治疗肾衰竭，而且，已经估计出至少10至25.0克的尿素，1.0至2.5克的肌酸酐，0.7至1.5克的尿酸必须去除。因此，需要更为有效的治疗方法去除高浓度的多种尿毒素以缓解尿毒症病人的症状。
小肠细菌生长过度(SBO)也是肾衰竭发展的另外一个临床症状，其肾小球滤过率降到低于20ml/分钟。含氮废物流入小肠。结果，细菌更加过度生长，同时有益菌和致病菌的比例发生改变，这些致病菌可以产生次级毒素物质，这些次级毒素物质有致癌和诱变化合物如胺类，亚硝基胺类，酚类和吲哚衍生物。
人的胃肠道系统隐藏着复杂的微生物生态系统，包括大量的各种各样的细菌。这些在人的胃肠道中定居的细菌群主要影响着胃肠的功能，从而影响着人的健康和幸福。在此当中，一些细菌是条件性的或者被认为是有害的并能导致不利状况，如腹泻、感染、胃肠炎和内毒素血症，而一些菌种被认为是“益生菌”，它们对人类有机体起有益作用(Holzapfel WH等，Int J Food Microbiol 1998 May 26；41(2)：85-101)。
在这些益生菌中，双歧杆菌是最突出的。当双歧杆菌活着并有存活能力时，它可以刺激免疫系统并发挥竞争性作用排除致病和腐败细菌，减少血液中氨和胆固醇的数量，并可促进矿物质的吸收。此外，双歧杆菌已经被证明对结肠癌有预防作用，它能使一些酶的活性减少，这些酶将前致癌物转化为致癌物(von Wright等，Eur J GastroenterolHepatol 1999 Nov；11(11)：1195-1198)。
乳酸菌如保加利亚乳杆菌(Lactobacillus bulgaricus)，嗜酸乳杆菌(Lactobacillus acidophilus)，干酪乳杆菌(Lactobacillus casei)，植物乳杆菌(lactobacillus plantarum)和粪链球菌(streptococcus faecium)，嗜热链球菌(Streptococcus thermophilus)也是益生菌。这些细菌对于病原微生物产生拮抗作用，刺激免疫系统，改善乳糖消化，具有使脂肪更多消化的脂解活性，减少血浆的胆固醇值，保护肠粘膜以确保营养物质有均匀的消化吸收，产生在一些肿瘤中有活性的多糖，以及使一些产酶的微生物成活力降低，所述酶可催化前致癌物转变成为致癌物。
益生菌被认为能以协同的方式发挥作用从而减少并延迟肠道的致病菌/有害细菌的生长(Marteau，PR等，Am J Clin Nutr Feb；73(2 Suppl)：430S-436S；Cummings JH等，Am J Clin Nutr 2001 Feb；73(2 Suppl)：415S-420S)。
在接受抗生素治疗或其它疗法的病人体内，以及在患有肠炎，肾病和肝病的个体内，肠道细菌群能够减少，变得不平衡或者被除去。此外，已经表明，在正常衰老过程中，双歧杆菌种群在减少而致病菌和腐败细菌的浓度随之在增加(Orrhage K等，Drugs Exp Clin Res 2000；26(3)：95-111)。
已知象双歧杆菌这样的微生物的有益作用部分是由于它们具有发酵结肠中存在的不易消化的糖的能力，这种糖就是通常所说的益生素。益生素是一种不易消化的食品成分，它通过选择性地刺激结肠中一个或有限数量细菌的生长和/或活性来有益地影响着宿主。益生素通常被认为是具有相对短链的碳水化合物。与其它碳水化合物如非淀粉多糖，糖醇和抗性淀粉一样，益生素可以到达盲肠成为发酵的基质。然而，它们在选择性影响微生物区系上是有区别的。为了有效，它们必须到达盲肠(Bezkorovainy，A.Am J Clin Nutr 2001 Feb；73(2 Suppl)：399S-405S)。
能够发挥最佳益生素效果的不易消化的寡糖是菊粉型果聚糖，它能抵抗被体内的胃酸和胰酶消化。在纯培养基中，大多数双歧杆菌适合利用这些不易消化的寡糖。然而，许多其它细菌也能代谢它们。当菊粉和寡果糖或乳果糖(Lactulose)被加入到受控饮食中时，结肠中的双歧杆菌群出现显著增长，而这些变化通过调整肠道微生物区系促进了结肠和全身健康。菊粉和寡果糖由结肠的微生物区系迅速而完全地发酵，其发酵产物为醋酸盐和其它短链脂肪酸。菊粉、乳果糖和其它不可吸收的碳水化合物的有效性起源于它们都是二糖或寡糖并且人的胃肠道缺乏二糖酶来水解它们这一事实。这些可发酵的碳水化合物于是没有被消化就进入结肠。在结肠中，具有二糖酶的定居菌群能够水解这些寡糖或二糖并且把它们当作能量并用于生长。在这一过程中，它们产生了大量的酸化肠道的短链脂肪酸，并通过渗透机理，将水汲取到肠腔内，提供通便作用，阻止生长过度，并使得氨和其它废物氮易于清除。象乳果糖一样，它们也可以导致粪便生物量的增长，并在这种情况下，捕获氨用于合成细菌蛋白或者将其转变成铵离子。通过刺激细菌生长和发酵，益生素也影响了肠习惯并会发生轻度腹泻(Jenkins，DJ等，J Nutr 1999 Jul；129(7 Suppl)：143 1S-1433S)。
美国专利5,733,568教导使用微囊化的乳杆菌治疗与抗生素相关的或其它急性或慢性腹泻以及皮肤和阴道真菌感染的方法。所述微囊化据说能抑制杆菌的失活并且将其传送至肠道中也避免了腹泻中见到的乳糖不耐性。
美国专利5,032,399教导使用嗜酸乳杆菌附着在肠粘膜上，从而减少了抗生素疗法对于胃肠道的副作用，抗生素疗法能削弱有益菌群。
美国专利5,531,988除了有益细菌外还教导在组合物中使用免疫球蛋白作为补充饮食。
美国专利5,840,318也教导一种能够调节动物免疫系统的有益细菌组合物。
使用诸如嗜酸乳杆菌的益生菌已提示能够减少细菌的过度生长和尿毒素与致癌物的积累。尿毒症病人饮食中不可吸收的碳水化合物也表明益生菌可以增加氮排泄量。使用乳果糖和食用纤维也显示可减少血浆尿素11-27％并使粪便中氮的排泄量增至39-62％(Wrong，O.，Nature Medicine 2-3，1997)。
然而，上述这些现有技术方法的主要问题之一是，它们倾向于针对个别的尿毒性溶质或毒素。然而临床上，肾、肝和胃肠疾病或紊乱事实上需要减轻多种症状。
发明概述
本发明的目的是为肾机能不全、肝机能不全、尿素代谢先天性障碍以及胃肠紊乱和疾病提供一种完整的、以肠为基础的、低成本的替代治疗方法。本发明不同于现有技术的是，可以同时减缓一个以上的症状。而且，肠内菌群在恢复正常健康状况的有益效果可以加以控制。
因此，本发明提供了一种包含益生菌的药物组合物，可使有益菌和有害菌恢复正常的平衡，除去正常蛋白代谢的过量尿素废物，从而减轻病态肾的负担，还可除去氨以避免智力迟钝和相关症状。本发明的药物组合物还包含一种益生素，可刺激有益菌群，也可确保益生菌的活力，以便使尿素和氨等氮源可以被有效利用。此外，该药物组合物可以包含一种具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物。在一些实施方式中，益生菌可以恢复有益菌和有害菌之间正常平衡，除去正常蛋白代谢的过量尿素废物从而减轻病态肾的负担，还可除去氨以避免智力迟钝和相关症状，以及可用作亲氨尿素降解微生物。
在一个实施方式中，本发明的药物组合物可以进一步包含一种水吸附剂，以在腹泻和肾机能不全时除去水，还包含吸附剂混合物，它能除去其它氮代谢废物和细胞过度生长产物如尿酸、肌酸酐和胍，以及酚和吲哚，和/或无机磷酸盐吸附剂以保持磷酸盐平衡。在优选的实施方式中，活性炭和无机磷酸盐吸附剂在组合物中组合在一起以产生协同效应并可减少这两种成分相对于益生菌和益生素的相对比例。而且，由于益生菌和益生素除去了大部分的尿素并削弱了细菌的过度生长，所以其它正常氮废物和细菌终产物的量被降到最小，因而比起现有技术的组合物，本申请的组合物需要较少的活性炭和无机吸附剂。
此外，药物组合物包含一种益生菌和益生素，和亲氨微生物，它可以预防性地用于由于疾病发展而患有尿毒症的急性或慢性症状的病人，仅当必须控制腹泻或其它胃肠紊乱时，水吸附剂、吸附剂混合物和/或无机磷酸盐吸附剂可以单独给药。
本发明的药物组合物最好用肠衣包被或微囊化，用于传送至需要它的病人肠内的回肠或结肠区域。
该药物组合物尤其用于阻止或延迟肾病患者的透析需要，使透析的频率和持续时间减少。
发明详述
肾衰竭时，肾小球滤过率减少且肾脏不能维持血液的体内平衡。水、钠、钾、钙和其它盐的稳态平衡不再是可能的，且氮废物不能被排出。水滞留导致浮肿，且随着氢离子浓度的增加，产生酸中毒。氮废物积累，一种被称为尿毒症的病状产生于血液和组织中。尿毒素可以被定义为具有下列性质的溶质：(i)它们通常由健康的肾排出，(ii)在肾衰竭发展过程中日益积累以致浓度增加，以及(iii)抑制各种生理和生化机能，总之，尿毒素导致了一系列复杂的包含尿毒症综合症的临床症状。尿毒素的实例包括但不限于氨、尿素、肌酸酐、酚类、吲哚和中等分子量分子。更具体而言，在尿毒症中，血清肌酸酐浓度，血液尿素氮(BUN)，尿酸和胍基化合物如N-甲胍(NMG)和胍基琥珀酸(GSA)都随着酸基平衡、电解质和水分保持的异常而产生了显著的改变。另外，还有一些已知的或未知的小的和中等分子量的物质被鉴定为尿毒素，它们也可积累。如果不经治疗，酸中毒和尿毒症将导致昏迷并最终导致死亡。
进一步，由于缺乏对代谢废物的清除，出现了一些补偿性和适应性的过程，这使得病状变得更加复杂。例如，当肾功能减少至小于20％并且血清内肌酸酐水平增至8mg/dl时，肠内正常菌群的细菌就会出现过度生长。正常基质代谢基本上增长和大量各种毒性胺如甲胺、二甲胺、三甲胺、酚类和吲哚代谢也在该菌的过度生长物中出现。当小肠细菌生长增长时，氨释放也增加，然而其进入到肠肝循环并转化为尿素。
肾透析的引入为肾衰竭的临床治疗和尿毒症解释的快速进步作出了贡献。一个具有轻度肾衰竭病人的血清肌酸酐水平少于400μmol/L，该病人不需要肾脏置换治疗如透析或肾移植。然而，通常当血清肌酸酐水平上升到900μmol/L时，病人需要常规透析或肾移植以维持生命。
对于ESRD病人，透析可以作为一种终身疗法。磷酸盐粘合剂，如乙酸钙、碳酸钙或氢氧化铝，通常也要给接受透析的尿毒症病人使用，以减少升高的磷酸水平。而一般来说，透析非常昂贵、不方便、耗费时间并且偶尔产生一种或多种副作用。如果肾移植成功，病人可以过上更正常的生活而不用支出长期的费用。然而，移植手术、恢复期以及需要连续的抗排斥药物治疗仍需高额费用。况且，经常缺少合适的捐赠体。因此需要可替代的方法。
本发明涉及的药物组合物包括益生菌和益生素的混合物，和具有高尿素酶活性的亲氨细菌，和/或对尿毒素具有特定吸附亲和力的吸附剂，所述尿毒素如肌酸酐、尿酸、酚类、吲哚、中等分子量分子和无机磷酸盐，以及水吸附剂，用来减轻尿毒症。在一个优选实施方案中，该组合物包括益生菌细菌，益生素如菊粉、果聚糖寡糖、乳果糖以及其它植物纤维，还包括具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物，吸附剂如刺槐豆胶，其对肌酸酐和尿素具有特定的吸附亲和力，对肌酸酐、胍、酚、尿蓝母和中等分子量的不确定成分具有特定亲和力的活性炭，以及水吸附剂如车前子纤维(Psilliumfiber)、瓜尔胶和刺槐豆胶。
优选益生菌的细菌源能够将尿素和氨代谢成尤其可被细菌或病人利用的氨基酸。具有上述特性的典型菌是双歧杆菌和乳杆菌。
巴氏芽孢杆菌(Baeillus pasteurii)和脲芽孢八叠球菌(Sporosarcinaureae)与土壤细菌密切相关，二者均对尿素具有高度的亲和力。这些细菌是非致病且无害的。而且，它们在高浓度的铵离子和碱性pH下生长得很好，这种条件存在于肠内，尤其是尿毒症情形中。在巴氏芽孢杆菌和脲芽孢八叠球菌中，不会发生铵积累并且这些有机物依赖于氨跨越细胞膜的被动扩散。巴氏芽孢杆菌和脲芽孢八叠球菌都显示出对铵的低亲和力，Km值分别为55.2mM和36.7mM。相比于只能在中性pH和2mM的低铵浓度下生长的病原体普通变形杆菌(P.vulgaris)，巴氏芽孢杆菌和脲芽孢八叠球需要高氨浓度(40mM)和高碱性pH(Kaltwasser，Morsdorf G.H.Arch Microbiol 1989；152(2)：125-31)。此外，已知在pH 7.5下，脲芽孢八叠球菌的尿素酶比活性为每分钟降解高于9300μmol尿素。
因此，本发明用作亲氨细菌的细菌源的实例包括，但不限于，脲芽孢八叠球菌，巴氏芽孢杆菌，驯化的乳杆菌和芽孢杆菌菌种，以及乳酸菌新种KB-I或其它适合的芽孢杆菌菌种。
在一些实施方式中，益生菌可以用作恢复有益菌和有害菌之间的正常平衡，除去正常蛋白代谢的过剩尿素废物从而减轻病态肾的负担，除去氨来避免智力迟钝和相关症状，还可以作为亲氨尿素降解微生物。因此，在本实施方式中，不需要单独的亲氨尿素降解有机体。取而代之，在本实施方式中，益生菌和亲氨尿素降解有机体包含同菌种的细菌。
含有这些混合物的组合物被肠衣包被和/或被微囊化。组合物的肠衣特定地设计为传送吸附剂和细菌源至肠的回肠和结肠区域，尿素溶质和其他分子可以在此处以最大的吸收出现。这更适宜通过在pH为7.5或更高时崩解和溶解的肠衣物质实现。具有这些特征的肠衣的实例包括，但不限于，玉米蛋白，聚glycolactic acid，聚乳酸，聚乳酸/聚甘醇酸共聚物和类似的包被物质。肠衣也能将吸附剂在到达靶区域之前以相对天然的形式传送至其作用区域，而不会将消化物质结合到吸附剂上。
此外，本发明的组合物被微囊化，因此如Chang，T.M.S.所述，允许组合物象显微的透析单元一样起作用(人工单元(Artificial Cells)，第5章，在“Biomedical Applications of Microencapsulation”，Lim，F.主编CRC Press Florida，第86-100页)。在本实施方式中，组合物包被有一层不宜吸收的聚合物，该聚合物仅能使小的和中等尺寸的分子进入到溶剂混合物和细菌源所在的核心部位。用于微囊化的不易吸收的聚合物包被的实例包括，但不限于，藻酸盐/藻酸，壳聚糖，醋酸邻苯二甲酸盐纤维素，羟乙基纤维素，以及类似的包被物质。微囊化阻止了大分子和其它消化物质的结合，这些物质基本上削弱吸附剂特异性地将尿毒性溶质吸附到混合物的吸附剂中的效力。随着吸附剂混合物吸附多种尿毒性溶质、细菌源代谢尿素、氨和尿素，微囊化囊通过了肠，然后从肠内完整地排出。因而，在本实施方式中，由于细菌源保持在微胶囊中，病人避免了由细菌源引起的微生物感染的可能性。
在本发明的优选方案中，药物组合物既被微囊化，又被肠衣包被。
本发明的药物组合物可进一步包含一种磷酸盐结合剂如氢氧化铝凝胶、碳酸钙或醋酸钙、氢氧化镁凝胶和/或水结合剂如车前子纤维，天然胶，如刺槐豆胶，瓜尔豆胶或改性淀粉。
本申请的药物组合物是口服给药至需要的受试者，从而减缓毒素和代谢废物的集聚和/或抑制或降低受试者中非需要细菌的过度生长。在一个实施方式中，将该药物组合物施于患有尿毒症的受试者以减轻尿毒症症状。尿毒症的“症状减轻”意味着组合物除去了足够水平的尿毒素，以至于患有尿毒症的病人不需要透析，或透析频率减少，或透析的持续时间缩短，或不需要马上透析。本发明的组合物也可以施于需要其的受试者，从而不仅治疗肾机能不全和先天性肾代谢障碍，还可治疗肝机能不全和胃肠功能紊乱和疾病。
在优选实施方案中，用2-4盎司的乳液或糊状物混合易于食用的食品如奶昔或酸奶等来口服组合物。微囊化的细菌益生菌和益生素可以与乳状或糊状吸附剂混合物一起给药或单独以可吞咽的明胶胶囊给药。
口服吸附剂溶质传输的数学模型基于溶质受控扩散流入肠腔然后物理结合或化学诱捕已经发展起来(Gotch等，Journal of Dialysis 1976-1977 1(2)：105-144)。这一模型为从肠中除去溶质提供了理论依据。
例如，在正常的肾功能中，尿素的肠清除率是10-12ml/分钟，而对肾功能严重削弱的病人，该值减少到3-4ml/分钟。这种清除率的减少与血液尿素浓度无关，并直接关系到受损的肾功能。正常的肌酸酐清除率是2-5ml/分钟。
进一步，在稳定状态时，由于质量产生率与质量消除率是相同的，第一级吸附剂促进任何溶质的肠内清除，由质量平衡方程式给出：
Gs＝(Kr+Kg)Cs
其中Gs＝溶质产生率，Kr＝肾清除率，Kg＝肠清除率，以及Cs＝溶质浓度
对于给定数量的吸附剂，吸附结合过程是可饱和的。当低于饱和水平时，由于溶质的肠清除率是第一级的，因而上述平衡可以描述如下：
Cs＝Gs/(Kr+Kg)。
当高于饱和水平时，由于肠清除率为零，该等式可写为：
Cs＝(Gs-吸附能力)/Kr。
这些等式根据体外研究预测从肠中除去溶质的有效性是有用的。
事实上，通过对尿毒症病人的肠道使用氧化淀粉口服吸附剂，该模型被应用到Friedman氏去除尿素数据(Friedman等，Trans.Am.Soc.Artif.Intern.Organs 1974 20：161-167)。通过这些数据，该模型显示天然氧化淀粉口服吸附剂的最大吸附能力是1.5克/天，这不足以取代透析或减少透析频率。这一模型也预测，对于蛋白质分解代谢率为0.95克/千克/24小时和尿素产率为5毫克/分钟的同样的病人资料，氧化淀粉的最大吸附能力应为7.2尿素氮/天以及肠清除率应为5.6毫升/分钟。吸附力低于该值，如5.4克尿素/天，最多会延迟每月透析，只要蛋白分解代谢率保持在0.6克/千克/24小时。这样，该模型对于本发明组合物的不同组成确定最优结是有用的，以减缓病人尿毒症症状。
以下不受限制的实施例将对本发明提供进一步的说明。
实施例
实施例1：吸附剂来源
氧化淀粉(二醛基淀粉)购自MPD Labs，Feasterville，PA。这是一种药物级物质(纯度98％)，含水量为13％，根据供应商分析证明，具有最小90％的氧化物质。
刺槐豆胶(最小纯度99％)购自Sigma-Aldrich，St.Louis，MO。
活性炭，超A，药物级(纯度99.9％)，购自Norit Corporation ofAmerica，GA。每种吸附剂都由玉米蛋白肠衣包被，乙基纤维素(ethocel)微囊化，以及先用乙基纤维素微囊化然后用玉米蛋白肠衣包被作为外壳材料。胶囊化利用圆盘工艺进行运转。三种壳溶液分别加以制备：仅乙基纤维素，仅玉米蛋白，玉米蛋白结合乙基纤维素。壳物质制备完后，各种吸附剂加入到壳溶液中(为了提供60％的理论有效负荷)并混合形成分散液。然后分散液经声波处理并以接近50克/分钟的速度泵送到以接近20,000rpm旋转的圆盘中从而形成微球。这些微球在内部温度将近50℃的热锥体内形成以蒸发掉乙醇和水。胶囊通过旋风分离器收集。天然的粒度和经过各种吸附剂胶囊化后的粒度在表1中描述。
表1
| 氧化淀粉 | ||
| 氧化淀粉％ | 尿素/肌酸酐/尿酸 | 细菌％ |
| 0.1 | 150/30/30 | 10 |
| 0.2 | 150/30/30 | 10 |
| 0.3 | 150/30/30 | 10 |
| 0.4 | 150/30/30 | 10 |
| 0.5 | 150/30/30 | 10 |
| 刺槐豆胶 | ||
| 刺槐豆胶％ | 尿素/肌酸酐/尿酸 | 细菌％ |
| 0.1 | 150/30/30 | 10 |
| 0.2 | 150/30/30 | 10 |
| 0.3 | 150/30/30 | 10 |
| 0.4 | 150/30/30 | 10 |
| 0.5 | 150/30/30 | 10 |
| WATERLOCK TM(A-220) | ||
| WL％ | 尿素/肌酸酐/尿酸 | 细菌％ |
| 0.1 | 150/30/30 | 10 |
| 0.2 | 150/30/30 | 10 |
| 0.3 | 150/30/30 | 10 |
| 0.4 | 150/30/30 | 10 |
| 0.5 | 150/30/30 | 10 |
| 活性炭 | ||
| 炭％ | 尿素/肌酸酐/尿酸 | 细菌％ |
| 0.1 | 150/30/30 | 10 |
| 0.2 | 150/30/30 | 10 |
| 0.3 | 150/30/30 | 10 |
| 0.4 | 150/30/30 | 10 |
| 0.5 | 150/30/30 | 10 |
| 单个微生物 | |
| 尿素/肌酸酐/尿酸 | 接种％ |
| 100/15/15 | 3 |
| 100/15/15 | 5 |
| 100/15/15 | 10 |
| 150/30/30 | 5 |
| 150/30/30 | 10 |
原材料的扫描电子显微照片(SEM)包括二醛基淀粉，刺槐豆胶，活性炭和氢氧化铝，并且预备了十二种微胶囊配方。第11批产生了棒状胶囊，因其没有直接加料到盘的中间或因其固体含量太高。第13批重复了第11批只是玉米蛋白含量从15％降到12％，结果成功了。
除了每一批的扫描电子显微照片之外，还拍摄了数字光显微照片。
实施例2：大肠杆菌(E.coli)DHS和其它细菌源
依照Chang和Prakash(Biotechnology and Bioengineering 1995 46：621-26)所述的程序，基因工程大肠杆菌DH5经接种后培养，生长，收集并进行微囊化。本发明的益生菌和亲氨细菌也以同样的方式处理。
实施例3：制剂
各种益生菌，益生素和吸附剂与不同的食品添加剂混合形成本发明的不同制剂。它们的一般组分描述于下表2中。
表2：60克剂量中的成分和数量(以B.I.D.摄入量为基础)
| 成分 | 范围(克) | 最优选量(克) |
| 益生菌 | 5-20 | 12.5 |
| 刺槐豆胶 | 10-20 | 15 |
| WATERLOCKTM | 1-5 | 3 |
| 活性炭 | 0.5-2 | 1 |
| 菊粉 | 1-10 | 5 |
| 食品添加剂 | ～3-～42 | ～23 |
| 总计 | 60克 | 60克 |
实施例4：体外效力评价
制备模拟胃液，其含有NaCl，HCl和胃蛋白酶的蒸馏水，pH调节至1.2。根据美国药典规程在酸性pH和胃环境下对制剂的稳定性进行试验。每种改性吸附材料和二元的和三元的制剂都在37℃通过将近5克量的材料搅拌进入模仿胃液的测试溶液中测试1-2小时，以确保改性吸附剂的完整性。
模拟合成的小肠液含有磷酸二氢钾，氢氧化钠，胰酶制剂混合物及蒸馏水，它也是根据美国药典的试液制剂来制备并调节pH至7.5。小肠液用尿毒性溶质强化以得到每100毫升的合成小肠液中含有150毫克尿素，30毫克肌酸酐和30毫克尿酸的溶液。
为改变浓度，原液用非强化的肠原液稀释得到75％和50％浓度的可变的尿毒性肠液。首先，100％、75％和50％浓度的尿毒性肠液由15克吸附制剂来评价，所述吸附制剂分别含有5克的氧化淀粉，刺槐豆胶和活性炭。从这些数据可知，各种实验参数可以被优化，它们包括但不限于，体积、尿毒性肠液浓度和预处理和后处理的时间。优化参数于是用于所有其他吸附剂的评价，配制和实验确定。所有实验的观测重复三次。
然而，最初，含有5，10或15克吸附剂或制剂的吸附剂/制剂试验批次是在量筒中用500毫升不同浓度的强化肠液处理并轻晃8小时进行的。样品以一小时的间隔从上清液中吸出，必要时离心，通过商业上可获得的试剂盒(Sigma Diagnostics Company，St.Louis，MO)分析尿素，肌酸酐和尿酸。一旦吸收能力和平衡时间得以确定，至少估算2小时，这一周期就可使用。
用生孢乳杆菌(Lactobacillus sporogenes)，嗜酸乳杆菌，巴氏芽孢杆菌(B.p.)和大肠杆菌(Escherichia coli)DH5(E.c.)通过尿素酶活性来评价它们从强化的人工肠液(FAIF：100/150mg/dL尿素，15/30mg/dL肌酸酐和15/30mg/dL尿酸的水性胰酶制剂，KH2PO4和NaOH)中去除尿素的能力。
在无菌条件下，不同的混合物中，各天然细菌，活性炭和刺槐豆胶分别加入到50毫升FAIF中并在37℃和100rpm下培养。在单独研究中，含有B.p.或E.c.、直径接近1毫米的藻酸盐-聚-L-赖氨酸-藻酸盐的微胶囊以一定量加入，以使得对于50毫升FAIF的细胞蛋白含量正常化。在1，2，3，4，6和24小时取等分试样并评价尿素氮、氨组成及尿酸和肌酸酐稳定性的减少。所有的试验都重复三次，结果取平均值。
细菌浓度被优化之后，将不同浓度的Water Lock(WL)A-220加入到50mg/dL氨的溶液中并评价氨的摄入值。氨浓度的分析测定由过滤悬浮液的上清液确定。然后向系统中加入不同浓度的刺槐豆胶(LBG)至高浓缩的FAIF，而不需要加入细菌。在37℃和100rpm下培养2小时后，该系统通过剩余肌酸酐和尿酸来分析。一旦确定了合适浓度的LBG，以变量加入活性炭至高浓缩FAIF，而不需加入细菌。该系统在37℃和100rpm下培养，并且经过2小时培养后确定剩余肌酸酐和尿酸。
尿素，氨，肌酸酐和尿酸的定量分析方法可利用市售的诊断试剂盒(分别为Sigma，St.Louis，MO.目录号535和171，以及分别为Advanced Diagnostics，Inc.Division of Inamco Group，South Plainfield，NJ.目录号131 500和CASO-50)。
实施例6：TNO胃肠模型(TIM)
TNO胃肠模型(TIM)非常近似地模仿了胃肠道腔内成功的动力学条件(van der Werf等，J.Agric.Food Chem.49，378-383，2001)。模仿的动力学参数包括：食品和饮料摄入量，pH曲线，包括唾液的胃和包括胰液的小肠中的酶和酶原浓度；肠不同部位的胆汁浓度；经过胃和小肠的食糜的动力学通道；以及水溶性消化产物和水的吸收。大肠模型中，在天然的结肠环境(模拟pH值、水分吸收和微生物代谢物如短链脂肪酸和气体的吸收)，人源复杂的高密度微生物区系发酵未消化的食品化合物。因此，这一模型用来评价大小肠中本发明组合物不同配方的结果。
实施例7：体内研究
重约150±15克的大鼠，其慢性肾衰竭(CRF)程度类似于人的末期肾病，接近10次透析初期(10 initiation of dialysis)，用该大鼠测试口服微囊化的吸附剂和大肠杆菌DH5细胞对于去除积累在CRF中的尿毒素和缓解尿毒症症状的效果。总体上，包括对照组在内共有4组，1组患有慢性肾衰竭(n＝15)而2组患有急性肾衰竭。具体而言，雄大鼠重250-300克，将近8周龄大，它们购自Charles River或Harlan，并饲养在笼子中，所述笼子禁止与其粪便接近。对于所有的动物，标准临床化学的基线测定和20种被认为是尿毒素的化合物的测定加以确定。然后，使用外科方法使大鼠患有急性或慢性尿毒症。
急性肾衰竭按照Waynforth，H.B.和Flecknell，P.A.Nephrectomy.在“大鼠的实验和外科技术”(1992年第2版，学术出版社(Harcourt，Brace，Jovanovich)，伦敦，第29，274-275页)中所描述的程序通过双侧肾切除术的方法制备。术后，将大鼠随机配对成年龄或大小匹配的组，并成对饲养。大鼠利用一个弯曲的服药针通过胃内给药饲养。一组用口服吸附剂连同Kayexylate处理以控制钾(处理组)。另外一组仅接受Kayexylate用于控制钾(对照组)。对这两组进行密切监测至少7至10天。相对于非处理组，有效的吸附剂可使生命延长。
慢性肾衰竭(CRF)通过一个两阶段外科步骤产生，类似于Niwa等(Miner.Electr.Metab.1997 23：179-184)及Einbacher和Carter(J.Exp.Med.1966 123：239-250)所公开的5/6肾切除术模型，但是有一些修改发现可以引起深度肾衰竭，类似于人接近需要血液透析的程度。在这一修改过程中，在残肾周围缝合一个软的塑料盒子以防止对侧肾切除术后肾的过度增大。这也有助于控制器官出血。
具体而言，使用一种两步途径。在建议的外科手术当天，禁食一个小时。然后让动物吸入异氟烷(FORANE)麻醉。被麻醉的大鼠腹面向上对着外科医生从左向右放置。两个侧面用剃刀最小限度的清除毛皮，并用聚维酮碘预处理。在大鼠的左侧准备一块无菌区域。在大鼠左侧胸廓接近肋骨边缘的下方，做一个背腹侧的切口进入到腹腔。把左肾与其相连的组织游离开来并小心取出，优选地，同时抓取肾周脂肪。肾上腺被结缔组织和脂肪松弛地连接到肾的前极，撕开附着物，小心的取下肾上腺。肾脏被安置到两个极都紧紧的连接到肾动脉进入器官的位点上。把一个4.0单丝的套索环绕到上面的极上，系紧，小心不破坏结节。打一个双结。检查器官是否过多的失血。有必要的话，使用热透疗法阻止出血并在皮层上使用氧化纤维素(oxycel)。对下方的极重复同样的操作。剩下的肾装入事先准备好的塑料盒，优选是SARAN包中，并保护好。然后把器官放回进腹腔，将切口缝合两层。用聚维酮碘擦拭这个区域，让动物痊愈。施用一种止痛药叔丁啡(buprenor phine)(0.25mg/kg)来止痛。大约3-4周后，移去右肾。在这个手术中，使用了一种腹部的途径，从而能对残余的肾进行检查。用同样的方法麻醉，但沿着脑白质做一个中线的切口，以减少流血。轻轻的移开肠，观察残余的左肾，确保其功能。如果有必要，对盒子做一些调整。假定左肾完全正常，暴露出右肾，使其从包膜上游离出来(留下肾上腺)，然后给肾血管四周绑上绷带，取下右肾。在输尿管上的尽量远离肾的位置绑上另一个绷带，朝着中线，但是不要破坏或阻塞周围可能碰到的任何一条侧血管。绷带安全地打上双结，把靠近肾脏的血管阻断，之后把肾移出。缝合切口，给动物施用止痛剂，让其在温暖的环境中痊愈。
通过这一修改步骤，在大鼠身上取得了一致的结果：血清肌酸酐值为2.6±0.2(范围是2.3-2.5)和血液尿素值98±5，发病率低，(术后4星期，少于20％)。
在第二次手术后大约5天，抽出对侧的血液，尽可能接近地匹配大鼠的体重、血清肌酸酐和血液尿素的数值。把它们随机分为4组。A组和B组成对饲养。A组由没有接受任何吸附剂的CRF大鼠组成，B组的大鼠接受了吸附剂。第三组C组，施用吸附剂，让其自由摄取食物和水。比较B组和C组，发现了尿毒症对食欲和营养的影响。第四组为假性操作组D组，用作对照。对大鼠进行4-7个月的观察，在这期间，每两周收集血和尿，用Dunn等在《分析化学》1976 48：41-44中所描述的方法，对二甲基和/或三甲基胺进行气相色谱分析。同时，每周测量一次体重，每月测量一次血压和尿渗透性(osmalities)。每天通过食物和水的摄取量来衡量他们的食欲。每月还定时收集尿样一次，每两周收集斑点尿样一次。同时测量皮肤褶厚度作为评价营养状况的辅助性指标。大鼠在7个月时被杀死，最后的血液被抽出来用作临床化学和其他特殊的检验。血、尿和脑组织也进行了二甲胺的化验。在上述研究中，无菌盐水中以悬浮形式存在的吸附剂是用12-号的洗胃管给大鼠口服给药的。
Claims (16)
1.一种药物组合物，包括一种益生菌和一种益生素，以及一种具有碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物，所述组合物被微囊化或肠衣包被。
2.权利要求1所述的药物组合物，进一步包括一种水吸附剂。
3.权利要求2所述的药物组合物，其中所述水吸附剂选自刺槐豆胶，车前子纤维，瓜尔豆胶和沸石。
4.权利要求1所述的药物组合物，进一步包括一种无机磷酸盐吸附剂和一种除尿素以外的特异尿毒性溶质吸附剂。
5.权利要求4所述的药物组合物，所述无机磷酸盐吸附剂选自氢氧化铝凝胶，氢氧化钙凝胶和氢氧化镁凝胶，且特异尿毒性溶质吸附剂是活性炭。
6.权利要求1所述的药物组合物，其中所述益生菌选自双歧杆菌或乳酸杆菌。
7.权利要求1所述的药物组合物，其中所述益生素选自果聚糖寡糖和阿拉伯聚糖寡糖。
8.权利要求1所述的药物组合物，其中所述亲氨细菌选自巴氏芽孢杆菌(Bacillus pasteurii)、脲芽孢八叠球菌(Sporosarcina ureae)、芽孢杆菌和乳酸杆菌KB-1。
9.权利要求1所述的药物组合物，其中所述益生菌和具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物包含同一种细菌。
10.一种药物组合物，包括一种益生菌和一种益生素，一种具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物，一种水吸附剂，一种无机磷酸盐吸附剂和一种除尿素以外特异尿毒性溶质吸附剂，所述组合物经微囊化或肠衣包被。
11.一种抑制受试者体内毒素和代谢废物积累以及不需要的细菌过度生长的方法，包括将权利要求1所述的药物组合物给受试者施用。
12.权利要求11所述的方法，进一步包括给受试者施用一种水吸附剂，一种无机磷酸盐吸附剂以及一种除尿素以外特异尿毒性溶质吸附剂。
13.权利要求11所述的方法，其中所述药物组合物进一步包括一种水吸附剂，一种无机磷酸盐吸附剂以及一种除尿素以外特异尿毒性溶质吸附剂。
14.权利要求11所述的方法，其中所述药物组合物给药于受试者以减轻尿毒症症状。
15.权利要求14所述的方法，其中所述尿毒症症状是由肾病或一种先天性尿素代谢缺陷引起的。
16.权利要求11所述的方法，其中所述的药物组合物被给药以治疗肾机能不全，肝机能不全，先天性尿素代谢缺陷或肠胃紊乱和疾病。
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Families Citing this family (63)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7029702B2 (en) * | 1998-07-07 | 2006-04-18 | Ritter Natural Sciences Llc | Method for increasing lactose tolerance in mammals exhibiting lactose intolerance |
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| MXPA06001821A (es) * | 2003-08-18 | 2006-05-31 | Bio Balance Corp | Una composicion probiotica, liquida, estable, preparacion y aplicaciones de la misma. |
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| US6936598B2 (en) * | 2003-11-21 | 2005-08-30 | Hill's Pet Nutrition, Inc. | Composition and method |
| US7754677B2 (en) * | 2003-12-05 | 2010-07-13 | Hill's Pet Nutrition, Inc. | Composition and method for reducing diarrhea in a mammal |
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| WO2005105068A1 (en) * | 2004-04-15 | 2005-11-10 | Dow Global Technologies Inc. | In vivo stimulation of intestinal transporters for excretion of nitrogenous wastes |
| EP1600062A1 (en) * | 2004-05-25 | 2005-11-30 | Cognis IP Management GmbH | Oral and/or topical compositions comprising prebiotics and sterols |
| EP1600060A1 (en) * | 2004-05-25 | 2005-11-30 | Cognis IP Management GmbH | Oral and/or topical compositions comprising prebiotics and fatty acid |
| ITMI20041232A1 (it) * | 2004-06-18 | 2004-09-18 | Dietetics Pharma S R L | Composizione nutraceutica contenente un numero elevato di fermenti lattici utile come sinbiotico |
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| JP6999175B2 (ja) * | 2018-07-31 | 2022-02-04 | 株式会社東洋新薬 | 経口組成物 |
| FR3097742B1 (fr) * | 2019-06-25 | 2021-06-25 | Lnc Therapeutics | Bactérie de la famille desChristensenellacéeset composition en contenant pour la prévention et/ou le traitement de l’insuffisance rénale. |
| EP4034253A4 (en) * | 2019-09-23 | 2024-02-07 | Univ Michigan Regents | COMPOSITIONS AND METHODS FOR INCREASING THE EFFECTIVENESS OF IMMUNOTHERAPIES AND VACCINES |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1466702A (en) * | 1973-02-09 | 1977-03-09 | Sandoz Ltd | Polymer encapsulated-activated carbon |
| DE2414156A1 (de) * | 1974-03-23 | 1975-09-25 | Kleist Johann Georg Dr | Arzneimittel zur beseitigung uraemischer symptome und verfahren zu seiner herstellung |
| US4581141A (en) * | 1978-02-27 | 1986-04-08 | Purdue Research Foundation | Dialysis material and method for removing uremic substances |
| JPS5731864A (en) * | 1980-08-04 | 1982-02-20 | Teijin Ltd | Oral activated carbon microcapsule |
| JPS59110621A (ja) * | 1982-12-17 | 1984-06-26 | Meiji Seika Kaisha Ltd | 利尿剤 |
| DE3406772A1 (de) * | 1984-02-24 | 1986-03-13 | Angelo 8137 Berg Schuler | Diaetetisches mittel zur herabsetzung der harnstoffkonzentration in koerperfluessigkeiten und seine herstellung |
| US4839281A (en) | 1985-04-17 | 1989-06-13 | New England Medical Center Hospitals, Inc. | Lactobacillus strains and methods of selection |
| DE3936319C3 (de) * | 1989-11-01 | 1997-05-07 | Bartz Volker | Phosphatbinder zur oralen Verabreichung |
| EP0684958B1 (en) * | 1993-02-17 | 1998-06-10 | Btg International Limited | Polymers containing guanidino groups for use in therapy |
| US5840318A (en) | 1993-05-11 | 1998-11-24 | Immunom Technologies, Inc. | Methods and compositions for modulating immune systems of animals |
| US5733568A (en) | 1993-12-03 | 1998-03-31 | Lafor Laboratories Limited | Micro-encapsulated lactobacilli for medical applications |
| US5531989A (en) * | 1994-10-28 | 1996-07-02 | Metagenics, Inc. | Immunoglobulin and fiber-containing composition for human gastrointestinal health |
| US5531988A (en) | 1994-10-28 | 1996-07-02 | Metagenics, Inc. | Bacteria and immunoglobulin-containing composition for human gastrointestinal health |
| 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 |
| GB9601333D0 (en) * | 1996-01-23 | 1996-03-27 | Univ Mcgill | Microencapsulated genetically engineered microorganisms for clinical application |
| ATE206873T1 (de) * | 1997-01-09 | 2001-11-15 | Nestle Sa | Probiotik enthaltendes getreideprodukt |
| JPH11199495A (ja) * | 1998-01-10 | 1999-07-27 | Nichinichi Seiyaku Kk | 腸溶性カプセルを用いた抗アレルギー剤 |
| JPH11302158A (ja) * | 1998-04-16 | 1999-11-02 | Oruto Corporation:Kk | 腸溶性シームカプセルを用いた整腸作用を有する健康食品 |
| IT1304170B1 (it) * | 1998-12-15 | 2001-03-08 | Novartis Nutrition Ag | Composti organici |
-
2001
- 2001-05-15 US US09/855,346 patent/US6706287B2/en not_active Expired - Lifetime
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2002
- 2002-05-10 JP JP2002588760A patent/JP4693085B2/ja not_active Expired - Lifetime
- 2002-05-10 WO PCT/US2002/015073 patent/WO2002091833A1/en active IP Right Grant
- 2002-05-10 CN CNB028100786A patent/CN100337549C/zh not_active Expired - Lifetime
- 2002-05-10 EP EP02769723A patent/EP1397044A4/en not_active Withdrawn
- 2002-05-10 KR KR1020037014919A patent/KR100896669B1/ko active IP Right Grant
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100357444C (zh) * | 2005-10-10 | 2007-12-26 | 东南大学 | 利用微生物沉积制备碳酸钙的方法 |
| CN100535119C (zh) * | 2006-11-07 | 2009-09-02 | 上海交通大学医学院附属第九人民医院 | 一种制备唾液链球菌尿素酶基因的方法 |
| CN102864088A (zh) * | 2011-07-05 | 2013-01-09 | 中南大学湘雅二医院 | 一种基因工程乳酸杆菌及其应用 |
| CN102864088B (zh) * | 2011-07-05 | 2014-08-27 | 中南大学湘雅二医院 | 一种基因工程乳酸杆菌及其应用 |
| CN103536909A (zh) * | 2013-10-18 | 2014-01-29 | 天津太平洋制药有限公司 | 一种新型的尿素氮固体吸附制剂及其制备方法 |
| CN106173751A (zh) * | 2016-08-05 | 2016-12-07 | 北京致成生物医学科技有限公司 | 一种治疗尿毒症的保健饮品及其制备方法 |
| CN106234896A (zh) * | 2016-08-05 | 2016-12-21 | 北京致成生物医学科技有限公司 | 一种治疗肾病的保健饮品及其制备方法 |
| CN113038958A (zh) * | 2018-10-12 | 2021-06-25 | 华盛顿大学 | 用于从患者身体移除尿毒症毒素的系统和方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1397044A1 (en) | 2004-03-17 |
| JP2004533442A (ja) | 2004-11-04 |
| US20020187134A1 (en) | 2002-12-12 |
| JP4693085B2 (ja) | 2011-06-01 |
| EP1397044A4 (en) | 2008-10-29 |
| US6706287B2 (en) | 2004-03-16 |
| CA2447376A1 (en) | 2002-11-21 |
| WO2002091833A1 (en) | 2002-11-21 |
| CN100337549C (zh) | 2007-09-19 |
| CA2447376C (en) | 2012-04-24 |
| KR100896669B1 (ko) | 2009-05-14 |
| KR20040029995A (ko) | 2004-04-08 |
| AU2002342641B2 (en) | 2007-04-26 |
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