CN1188413A - 预防和治疗胃肠疾病的药物和饮食制品 - Google Patents
预防和治疗胃肠疾病的药物和饮食制品 Download PDFInfo
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- CN1188413A CN1188413A CN96194976A CN96194976A CN1188413A CN 1188413 A CN1188413 A CN 1188413A CN 96194976 A CN96194976 A CN 96194976A CN 96194976 A CN96194976 A CN 96194976A CN 1188413 A CN1188413 A CN 1188413A
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- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
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- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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Abstract
本发明涉及预防和治疗胃肠疾病的药物和饮食制品。
Description
本发明涉及预防和治疗胃肠疾病的药物和饮食制品。
胃肠疾病包括病毒性、细菌性及原虫性感染，以及慢性炎症或者辐射伤害，给胃肠细胞造成了压力。胃肠道粘膜细胞的主要营养素是谷氨酰胺。该氨基酸一般是非必需的，但当谷氨酰胺的需求超过了某个人生产足够量的该氨基酸的能力时，其在病理学上成为“有条件地必需的”物质。经肠或不经肠服用谷氨酰胺能改善患者的营养状况并促进其康复(Castel LM等人，(1994)氨基酸7，231-243；Lacey JM，Wilmore DW(1990)营养学评论48(8)，297-309)。谷氨酰胺对于一些具有快速增殖率的细胞如肠细胞和淋巴细胞来说，是优选的燃料，此外，它还是通过生成氨来调节酸碱平衡的调节器。肠细胞是用谷氨酰胺作为能源的小肠中最重要的细胞(Wu G等人，(1995)美国生理学杂志266，R334-R342；Nagy LE，Kretchmer N(1988)营养学杂志，118(2)，189-193)。事实上，小肠细胞吸收了大量由饮食提供的谷氨酰胺，每当这些氨基酸的供应减少时，便会从血液中得以调整。动物试验表明，当用服用谷氨酰胺酶的方式降低谷氨酰胺的浓度时，将会造成小肠疾病，例如慢性腹泻、绒毛萎缩，等等(Castel LM等人，(1994)氨基酸7，231-243)，由此确认了谷氨酰胺对小肠的重要性。总之，在某些胃肠道疾病中，谷氨酰胺可能是不足的。在谷氨酰胺缺乏的情形下，胃肠细胞变得更加脆弱，因此更容易受到诸如传染剂或离子辐射的伤害。相反，对胃肠细胞的伤害和压力可能提高它们的能量需求，以及它们为求生存或复位而对谷氨酰胺的需求。结果是服用谷氨酰胺能够增强胃肠细胞抵抗伤害的能力。另外，上述因服用谷氨酰胺而对胃肠细胞产生的积极作用可以通过添加能对免疫系统和伤口愈合率起作用的精氨酸而得到进一步的增强(Wu G等人，(1995)美国生理学杂志266，R334-R342)。碳水化合物被认为是和谷氨酰胺一起协同作用的，单独的碳水化合物不能代替谷氨酰胺(Wu G等人，(1995)美国生理学杂志266，R334-R342)。
在溶液中，谷氨酰胺不完全稳定，特别是在谷氨酰胺溶液的加热消毒过程中，可能形成焦谷氨酸和谷氨酸。含有多肽的谷氨酰胺稳定得多。一旦摄入这些多肽，谷氨酰胺可以通过蛋白酶而在胃肠中得以释放。因此，通过服用少量或大量含有谷氨酰胺的多肽如L-丙氨酰-L-谷氨酰胺、甘氨酰-L-谷氨酰胺或甘氨酰-甘氨酰-L-谷氨酰胺，也可获得足够量的谷氨酰胺。
乳酸菌，特别是乳杆菌，以及其他从健康人体或动物的胃肠道分离出来的细菌，很早就被发现对胃肠感染具有预防和治疗作用(Zoppi G.等人，(1982)Eur.J.Pediatrics 139，18-21)。这类细菌称作真生物细菌(eubiotic bacteria)。有些细菌种类可以与病原体竞争营养物和/或胃肠粘膜上的附着位点。另外，它们有利于使PH恢复到正常值。例如，在临床研究中已证明，最初是从猪肠中分离的菌株肠球菌SF 68(以前叫做链球菌SF 68)是有效的(Borgia M等人，(1982)Curr.Ther.Res.31(2)，265-271；Bellomo G等人，(1980)Curr.Ther.Res.28(6)，927-936；Camarri E等人，(1981)化学治疗27，466-470；Wunderlich PE等人，(1989)J.Int.Med.Res.17，333-338)。由于这些细菌对胃肠粘膜的亲和力较小，因此需要长期的规则给药。比较起来，用对粘膜有较好粘合力的细菌进行治疗的患者可以减少病愈所需的服药频率和时间。
能粘着在人胃肠粘膜，并由此与具有类似粘着性能的病原体竞争的乳杆菌属细菌已从健康人体中分离出来，它们的特性公开于美国专利No.4839281，美国专利No.5032399，和WO专利申请95/33046中。例如，美国专利No.4839281和5032399公开了从成人体上分离出的嗜酸乳杆菌菌株ATCC53103，它们具有良好的粘着性能。最近对菌株的分类法进行了修改，该菌株被纳入乳杆菌(Lactobacillus casei sbsp.rhamnosus)。在有些国家，基于这一菌株生产的饮食制品，一般称作乳杆菌GG，已经进入市场(例如芬兰的Gefiles(R)发酵奶和Gefiles(R)乳清饮料)。具有明显改善的粘着性能的其他乳杆菌属菌株为：菌株CNCM I-1390，CNCM I-1391，CNCM I-1392和CNCM I-1447。它们公开在WO专利申请95/33046中。除了优良的粘着性能外，它们还具有良好的生产和保存方面的技术性能。
抗生素被广泛用于治疗急性感染。胃肠菌丛变得枯竭。服用乳杆菌可以用来恢复功能完好的菌丛。在这种情况下，选择能耐受抗生素的细菌是有用的。事实上，许多细菌对抗生素具有本能的耐受性。否则，抗生素耐受性可以由诱变引起，例如，通过使用能加速正常突变率的试剂引起。于是可以利用已知方法来选择突变菌株。另一方面，广为熟知的遗传工程技术能够生产对抗生素具有特异耐受性的细菌。
有一些真生物细菌显示出针对病原体的制菌或甚至是杀菌行为。这些行为部分是由于代谢产物如乳酸、乙酸和过氧化氢的生成，使得环境不适于病原体的生长。另外，已知有几个乳酸菌能产生其他物质如抗生素和细菌素。很显然(人们)对这些细菌具有特别的兴趣。
为了验证谷氨酰胺的同时出现是否可能影响真生物细菌的生长而进行了体外试验。在37℃，5％CO2气氛下，在不含和含有4％谷氨酰胺两种条件下，在MRS液体培养基(乳杆菌菌株)或BHI液体培养基(肠球菌)中孵育真生物菌株。12、24和48小时后分别进行细菌计数。结果归纳在表I中。
表I.在不同时间有与无谷氨酰胺的条件下细菌的生长
菌株 12h 24h 48h
-Gln +Gln -Gln +Gln -Gln +Gln
ATCC 53103 9.1 9.0 9.4 9.3 9.0 9.2
CNCM I-1447 9.0 8.8 9.0 8.6 9.1 8.9
CNCM I-1391 9,0 8.9 9.2 9.1 9.5 9.5
肠球菌 8.4 8. 5 9.5 9.3 9.0 9.4
a数值的单位是log CFU/mL。CFU＝菌落形成单位
该数据表明在培养基中谷氨酰胺的同时出现没有抑制细菌的生长。在胆汁参与下，以及在不同的PH值进行类似试验。即使在这些试验中谷氨酰胺的存在也没有干扰被测细菌的生长。
作为本发明的一部分，我们发现由于治疗细菌和谷氨酰胺或含有谷氨酰胺的多肽的结合，能够生产十分先进的药品，其治疗效果远远优于各结合成分单独使用的效果。特别是用真生物细菌治疗可加快康复。
正如美国专利No.3897307和欧洲专利申请EP-A-259739所公开的那样，在药物制品中，真生物细菌通常被冻干以保持其稳定性。在某些情况下，细菌冷冻干燥需要在水相中使用稳定剂，以减少长冰晶体的形成。所述试剂包括，例如碳水化合物、氨基酸、多肽、蛋白质、合成聚合物和二甲基亚砚。美国专利No.3897307公开了稳定的干菌菌株的制备，是通过在干燥前，向生长培养基中加入“增效剂”，特别是L-抗坏血酸和水溶性可食用盐来实现的。可用于该方法的另一化合物是海藻糖。
现在，我们已经惊奇地发现，谷氨酰胺或含有谷氨酰胺的多肽，特别是在加入了碳水化合物和/或其他动物或植物提取物的复合混合物例如酵母、肉提取物或干奶的情形下，也可在冷冻干燥中用于稳定细菌。另外，在冷冻干燥过程中，也可用本领域技术人员熟知的方法来稳定细菌，并以含有药品的其他成分，也就是谷氨酰胺或其衍生物并优选带有添加剂如精氨酸、碳水化合物或干奶等的颗粒混合物的形式进行储存。在对单独使用真生物细菌和有4％谷氨酰胺或谷氨酰胺与干奶的混合物存在的条件下所进行的冷冻干燥试验确认了上面的陈述。另外，储存于分离的香袋(sachets)的冷冻干燥细菌及其添加剂以及谷氨酰胺或含有谷氨酰胺的多肽及其添加剂，将在药品的两个成分的每一个溶解或悬浮于水中后同时予以摄取。
目前有些细菌产品是在药物胶囊中的冻干粉末。显然本发明的一个特别之处即是实现了所述含有细菌的胶囊的制备，该胶囊将用通过将其他成分、谷氨酰胺或含有谷氨酰胺的多肽以及或有的添加剂如精氨酸溶解/悬浮于水中而制得的饮料来摄取。在这种情况下，该胶囊和含有氨基酸的香袋可以包装在同一糖膏中，以确保两种不同成分的单个剂量的正确给药。实施例1
将含有106-1012个冻干的肠球菌SF 68细胞的胶囊包装于泡罩(blisters)中。数量与胶囊相等、含有3g谷氨酰胺和6g蔗糖颗粒的香袋与该泡罩包装在一起。为了制备单一剂量，香袋的内含物必须溶解/悬浮于100-150mL水中，然后必须用制备好的溶液/悬液来吞服一个胶囊，如果需要，还可借助另外的水。实施例2
将菌株Lactobacillus casei sbsp casei CNCM I-1391种植于MRS液体培养基中并通过离心收获细胞。以大约1010细胞/mL的浓度将这些细胞再次悬浮于由75g/L的L-谷氨酰胺和150g/L的蔗糖组成的无菌滤液中，然后冷冻干燥。将所得冻干的产品以9g剂量分配于密封的香袋中。每个剂量由溶解/悬浮于100-150ml水中的一香袋的内容物组成。实施例3
通过使用各自浓度为约109细胞/mL的乳杆菌菌株CNCM I-1390和CNCM I-1447的混合物制得与实施例2类似的制品。实施例4
制备含有由3g谷氨酰胺、6g蔗糖和至少107嗜酸乳杆菌CNCM I-1447的混合物组成的颗粒的香袋。将香袋内容物稀释于100-150mL水中后服用该制品。实施例5
用同样浓度的菌株ATCC 53103制备实施例4的制品。实施例6
以葡聚糖稳定的冻干型式，制备含有由4g甘氨酰-甘氨酰-L-谷氨酰胺、3g L-精氨酸和5g蔗糖组成的颗粒的香袋和含有至少106Lactobacillus casei sbsp casei菌株CNCM I-1391的香袋。各种香袋的内容物应溶解/悬浮于100-150mL水中以得到预期的治疗、预防或饮食剂量。实施例7
让两名已显示出旅行者腹泻典型症状两天的志愿患者在第三天和第四天的早上、中午和晚上服用含有链球菌SF 68(Bioflorin(R)，Bracco S.p.A.，Milan)的胶囊以及3g谷氨酰胺和6g蔗糖。观察到迅速的缓解感觉并且在治疗停止两天后未再出现症状。
Claims (20)
1.一种药物或饮食组合物，包含：-至少一种肠道真生物细菌菌株，其量为106-1012细胞/剂量，优选108-1011细胞/剂量，-0.5-10g/剂量，优选2-5g/剂量的谷氨酰胺。
2.按照权利要求1的组合物，其中谷氨酰胺被含有谷氨酰胺的多肽取代。
3.按照权利要求1或2的组合物，其中该组合物进一步含有L-精氨酸，其量为0.5-10g，优选2-5g。
4.按照权利要求1-3的组合物，其中该组合物进一步含有单一或复合的0-10g的碳水化合物如蔗糖、葡萄糖或淀粉，或任何常用于制药工艺中的其他稳定剂。
5.按照权利要求1或2的组合物，其中该组合物进一步包含0.5-10g动物或植物提取物的混合物。
6.按照权利要求1-5的组合物，其中至少有一种成分是冻干的。
7.按照权利要求6的组合物，其中在冷冻干燥之前或之后加入稳定剂。
8.按照权利要求7的组合物，其中所述稳定剂选自：谷氨酰胺，含有谷氨酰胺的多肽，氨基酸，碳水化合物，包括抗坏血酸、海藻糖和淀粉。
9.按照权利要求1-5的组合物，其中所述细菌是冻干的。
10.按照权利要求9的组合物，其中所述冻干的细菌，不论稳定与否，都与含有其他成分的颗粒混合。
11.按照权利要求9的组合物，其中冻干的细菌与其他化合物分开包装，这两个包装构成药品的剂量。
12.按照权利要求1的组合物，其中所述细菌是乳酸菌。
13.按照权利要求12的组合物，其中所述细菌是乳杆菌。
14.按照权利要求12的组合物，其中所述细菌是能粘着于肠粘膜的乳杆菌。
15.按照权利要求13的组合物，其中所述乳杆菌是从健康人体的胃肠道分离出的。
16.按照权利要求13的组合物，其中所述乳杆菌是下列菌株中的一种：CNCM I-1390，CNCM I-1391，CNCM I-1392，CNCM I-1477，ATCC53103。
17.按照权利要求1的组合物，其中所述细菌发挥对病原体的杀菌或制菌作用。
18.按照权利要求1的组合物，其中所述细菌为肠球菌SF 68。
19.按照权利要求1的组合物，其中所述细菌是因其自发的耐受性而被选择的，或是已突变或通过基因工程使其可抵抗一种或多种抗生素。
20.肠道真生物细菌并结合谷氨酰胺或含有谷氨酰胺的多肽在制备预防和/或治疗胃肠疾病的药物或饮食组合物中的应用。
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| BRPI0611492B1 (pt) * | 2005-05-31 | 2021-10-13 | Mars, Incorporated | Bifidobactéria probiótica felina |
| CA2609617C (en) * | 2005-05-31 | 2014-07-08 | The Iams Company | Feline probiotic lactobacilli |
| JPWO2007119502A1 (ja) * | 2006-03-23 | 2009-08-27 | 協和発酵バイオ株式会社 | 便通改善剤 |
| PL2004201T3 (pl) * | 2006-03-29 | 2019-02-28 | Nestec S.A. | Suplementy diety zawierające probiotyki |
| PL2124966T3 (pl) | 2007-02-01 | 2016-01-29 | Iams Europe B V | Sposób zmniejszania reakcji zapalnej i stresu u ssaków za pomocą antymetabolitów glukozy, awokado lub ekstraktów awokado |
| CN101273738B (zh) * | 2007-03-28 | 2011-06-01 | 哈尔滨正方科技有限公司 | 在常温下保持高活菌数的调配型酸性乳饮料的制备方法 |
| US9771199B2 (en) | 2008-07-07 | 2017-09-26 | Mars, Incorporated | Probiotic supplement, process for making, and packaging |
| EP2206506A1 (en) * | 2008-12-18 | 2010-07-14 | Bracco Imaging S.p.A | Probiotic formulations |
| WO2011009848A2 (en) | 2009-07-20 | 2011-01-27 | Bracco Spa | Therapeutic use of probiotics |
| US10104903B2 (en) | 2009-07-31 | 2018-10-23 | Mars, Incorporated | Animal food and its appearance |
| JP5468183B2 (ja) | 2011-12-28 | 2014-04-09 | 株式会社山田養蜂場本社 | ＩｇＡ産生促進作用を有する新規乳酸菌及びその用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4839281A (en) * | 1985-04-17 | 1989-06-13 | New England Medical Center Hospitals, Inc. | Lactobacillus strains and methods of selection |
| US5397803A (en) * | 1985-09-12 | 1995-03-14 | Brigham And Women's Hospital | Use of glutamine to reduce rate of pathogenic microorganism infection |
| JPH0367046A (ja) * | 1989-08-05 | 1991-03-22 | Mitsubishi Motors Corp | エンジンの吸入空気量制御装置 |
| CN1105544A (zh) * | 1994-09-09 | 1995-07-26 | 扬州大学农学院 | 一种制取活性乳酸菌口服液的方法 |
| US5531681A (en) * | 1995-01-13 | 1996-07-02 | Abbott Laboratories | Apparatus for altering composition of nutritional product during enteral tube feeding |
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1995
- 1995-06-23 IT IT95MI001359A patent/IT1276783B1/it active IP Right Grant
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1996
- 1996-06-19 NZ NZ312121A patent/NZ312121A/xx unknown
- 1996-06-19 DE DE0833644T patent/DE833644T1/de active Pending
- 1996-06-19 CA CA002219739A patent/CA2219739A1/en not_active Abandoned
- 1996-06-19 AU AU63575/96A patent/AU707399B2/en not_active Ceased
- 1996-06-19 BR BR9609413A patent/BR9609413A/pt not_active Application Discontinuation
- 1996-06-19 US US08/973,676 patent/US6007808A/en not_active Expired - Lifetime
- 1996-06-19 EP EP96922842A patent/EP0833644B1/en not_active Expired - Lifetime
- 1996-06-19 ES ES96922842T patent/ES2194107T3/es not_active Expired - Lifetime
- 1996-06-19 JP JP9503576A patent/JPH11507934A/ja active Pending
- 1996-06-19 AT AT96922842T patent/ATE234623T1/de not_active IP Right Cessation
- 1996-06-19 WO PCT/EP1996/002650 patent/WO1997000688A1/en active IP Right Grant
- 1996-06-19 DE DE69626818T patent/DE69626818T2/de not_active Expired - Lifetime
- 1996-06-19 CN CN96194976A patent/CN1082373C/zh not_active Expired - Fee Related
- 1996-06-19 HU HU9901707A patent/HUP9901707A3/hu unknown
- 1996-06-19 MX MX9709238A patent/MX9709238A/es not_active IP Right Cessation
- 1996-06-19 DK DK96922842T patent/DK0833644T3/da active
- 1996-06-20 ZA ZA965235A patent/ZA965235B/xx unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101259140B (zh) * | 2007-03-08 | 2012-08-22 | 重庆北碚现代应用药物研究所 | 一种治疗胃炎、胃溃疡及十二指肠溃疡的复方药物及其制备方法 |
Also Published As
| Publication number | Publication date |
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| ES2194107T3 (es) | 2003-11-16 |
| US6007808A (en) | 1999-12-28 |
| HUP9901707A2 (hu) | 1999-09-28 |
| AU6357596A (en) | 1997-01-22 |
| EP0833644A1 (en) | 1998-04-08 |
| DE69626818D1 (de) | 2003-04-24 |
| NO976048L (no) | 1998-02-23 |
| DE833644T1 (de) | 1998-09-03 |
| ITMI951359A0 (it) | 1995-06-23 |
| DK0833644T3 (da) | 2003-07-21 |
| MX9709238A (es) | 1998-03-31 |
| ITMI951359A1 (it) | 1996-12-23 |
| BR9609413A (pt) | 1999-05-18 |
| IT1276783B1 (it) | 1997-11-03 |
| ATE234623T1 (de) | 2003-04-15 |
| JPH11507934A (ja) | 1999-07-13 |
| CA2219739A1 (en) | 1997-01-09 |
| HUP9901707A3 (en) | 2001-04-28 |
| WO1997000688A1 (en) | 1997-01-09 |
| EP0833644B1 (en) | 2003-03-19 |
| CN1082373C (zh) | 2002-04-10 |
| NZ312121A (en) | 1999-03-29 |
| AU707399B2 (en) | 1999-07-08 |
| DE69626818T2 (de) | 2003-11-20 |
| ZA965235B (en) | 1997-01-09 |
| NO976048D0 (no) | 1997-12-22 |
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