WO2005072718A1 - 乳清発酵物を含有する医薬組成物 - Google Patents
乳清発酵物を含有する医薬組成物 Download PDFInfo
- Publication number
- WO2005072718A1 WO2005072718A1 PCT/JP2005/001218 JP2005001218W WO2005072718A1 WO 2005072718 A1 WO2005072718 A1 WO 2005072718A1 JP 2005001218 W JP2005001218 W JP 2005001218W WO 2005072718 A1 WO2005072718 A1 WO 2005072718A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- propionic acid
- whey
- bacteria
- disease
- dihydroxy
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/20—Milk; Whey; Colostrum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- composition containing fermented whey
- the present invention relates to a pharmaceutical composition containing a whey fermentation product by propionic acid bacteria, and more particularly to a pharmaceutical composition for treating or preventing inflammatory bowel disease or chronic liver disease.
- IBD Inflammatory bowel disease
- UC ulcerative colitis
- CD Crohn's disease
- UC ulcerative colitis
- CD Crohn's disease
- the cause of inflammatory bowel disease is still unknown, and various causes have been considered, such as those caused by infection with bacteria, parasites, viruses or fungi, those caused by drugs or chemicals, and those caused by radiation.
- chronic liver diseases include chronic viral hepatitis, viral cirrhosis, alcoholic hepatitis, alcoholic cirrhosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, non-alcoholic steatohepatitis, Hemochromatosis and Wilson's disease are included.
- the number of patients with chronic hepatitis and cirrhosis due to hepatitis C virus is large and progresses from these conditions to liver cancer at a high rate.
- Non-alcoholic steatohepatitis is rapidly increasing with the westernization of dietary habits, and it has been clarified that some of them progress to cirrhosis and liver cancer (Non-Patent Document 2). Regardless of gender, treatment of chronic liver disease is considered important in preventing carcinogenesis.
- Non-Patent Document 3 reports suggesting the involvement of intestinal bacteria in the onset and progression of IBD have been around for a long time, it is important to know what substances and how much artificial manipulation of intestinal flora can improve the pathology of IBD. Has many unclear points. On the other hand, there are no reports clearly demonstrating the direct involvement of intestinal bacteria in the pathogenesis of chronic liver disease.
- antibiotics antibiotics
- probiotics probiotics
- prebiotics treatments with antibiotics has many problems, such as side effects such as diarrhea and the emergence of resistant bacteria after long-term administration.
- Probiotakes are live bacteria that benefit the host by improving the balance of intestinal bacteria, while prebiotakes promote the growth or enhance the activity of useful bacteria that live in the colon. It is an indigestible food ingredient that has an advantageous effect on the health of the host.
- These probiotakes and prebiotakes have the potential to be positioned as important treatment strategies in the future because they can avoid the problems of treatment with antibiotics and can be administered for a long time.
- Non-patent Document 4 As control effects of probiotics and prebiotics on these intestinal microflora, it is assumed that growth of harmful bacteria is suppressed through the production of antibacterial substances and intestinal immunity and systemic immunity are activated (Non-patent Document 4).
- Non-patent document 5 many of which are the results of studies in animal models or small-scale pilot studies in humans, and reports that immunostimulatory effects cannot be expected (Non-patent document 6). The mechanism of action remains to be considered.
- Nonspecific reduction of gut microbiota by antibiotics or bowel washing may improve hepatic encephalopathy associated with advanced chronic liver disease (advanced cirrhosis) It is only known empirically since ancient times (Non-Patent Document 7). This mechanism is based on the fact that ammonia produced by intestinal bacteria was initially not metabolized due to liver function deterioration, but excessively flowed into the blood, affecting the brain. In some cases, hepatic encephalopathy occurs independently of blood ammonia, and the detailed mechanism is still unknown.
- hepatic encephalopathy can be improved by reducing intestinal bacterial flora, but liver function that has already decreased (hepatic reserve) No improvement in Noh) is observed.
- Non-Patent Document 8 lactic acid-producing bacteria
- bifidobacterium-fermented milk have been used as probiotics.
- Non-patent Document 9 non-pathogenic Escherichia coli (Non-patent Document 10), VSLJ3 (Non-patent Document 11), etc. have been subjected to clinical trials for IBD, and have achieved certain results. It has not been reached.
- many of the supplemented bacteria are killed by stomach acid, etc., and a large amount of probiotics must be ingested to obtain an effect that does not reach the colon efficiently.
- prebiotics such as germinated barley foodstuff (GBF) (Non-patent Document 12) and lactulose are basically capable of inducing physiological effects based on changes in individual-specific bacterial flora ingested.
- GBF germinated barley foodstuff
- lactulose is basically capable of inducing physiological effects based on changes in individual-specific bacterial flora ingested.
- conventional biobiotakes have the disadvantage that, for example, GBF requires 30 g / day of ingestion, is inferior in texture and taste, and is difficult to use continuously for a long time (Non-patent Document 12).
- lactulose causes diarrhea and promotes the growth of gas-producing bacteria, there is a need for a new substance that specifically grows only useful bacteria.
- Patented B ⁇ l Omata-M et al .. Progression from chronic hepatitis to hepatocellular carcinoma: natural course and treatments. J Gastroenterol Hepatol 2002; 17 Suppl
- Non-Patent Document 2 Bugianesi-E et al .. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma.
- Non-Patent Document 3 Bengmark-S. Use of some pre-, pro and synbiotics in critically ill patients. Best Pract Res Clin Gastroenterol 2003; 17: 833-848.
- Non-Patent Document 4 Saavedra JM et al..Human studies with probiotics and preoiotics: clinical implications.Br J Nutr 2002; 87 Suppl 2: S241—S246.
- Non Patent Literature 5 Kei Mitsuyama et al. Treatment of Inflammatory Bowel Disease Targeting Intestinal Bacteria: Probiotics and Prebiotics. Clinical Gastroenterology 2003; 18: 101-109
- Patent Document 7 Weber FL.Therapy of portal-systemic encephalopathy: the practical and the promising.Gastroenterology 1981; 81: 174-177.
- Non-Patent Document 8 Gupta P, et al. Is Lactobacillus GG helpful in children with Crohn's disease? Results of a preliminary, open-label study.J Pediatr Gastroenterol Nutr 2000; 31: 453-457.
- Non-Patent Document 9 Ishikawa_H, et al..Randomized controlled trial of the effect of bifidobacteria-fermented milk on ulcerative collitis.J Am Coll Nutr 2003; 22:
- Non-Patent Document i3 ⁇ 4 0 Rembacken BJ, et al. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial.Lancet 1999; 354: 635-639.
- Patent Document 11 Gionchetti—P, et al. Prophylaxis of pouchitis onset with probiotic therapy: a douole-blind, placebo-controlled trial.Gastroenterology 2003; 124: 1202-1209.
- Patent Document 12 Kanauchi-O, et al. Germinated barley foodstuff feeding.A novel neutraceutical therapeutic strategy for ulcerative collitis.Digestion 2001; 63 (Suppl 1): 60-67.
- This ingestion enables specific useful bacteria in the intestinal flora unique to the ingested individual to be proliferated and activated specifically, and is expected to improve intestinal lesions. Furthermore, it may act on the liver anatomically connected to the intestinal tract via the portal vein through some humoral factors, which can improve the reduced liver function (liver reserve). .
- Fermented whey produced by propionic acid bacteria has been shown to have an intestinal action in healthy individuals and is marketed as a specially functional food B.G.S. Until now, no medical effect has been verified on human diseases.
- the present invention provides a pharmaceutical composition containing a processed product of a whey fermented product by a propionic acid bacterium, preferably 1,4-dihydroxy-2-naphthoic acid or a salt thereof, and a treatment using the same.
- a preventive method specifically, a pharmaceutical composition of the present invention for treating or preventing inflammatory bowel disease or chronic liver disease, and a method for treating or preventing inflammatory bowel disease or chronic liver disease using the same About.
- a whey fermented product by propionic acid bacteria (Bifidogenic growth stimulator: BGS) is obtained by fermenting whey with propionic acid bacteria isolated from Emmental cheese.
- Propionic acid bacteria include propionibatteridium spp. 'Aknes, Propionibaterimu', Lymphophilum, Propionibatarimu ', Dalanurosum.
- Bacillus bacteria include Bacillus subtilis, Bacillus coagulans, and the like.
- Propionibacterium used in the present invention Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium used in the present invention, Propionibacterium
- a whey fermented product produced by propionic acid bacteria has the function of specifically increasing the amount of bifidobacteria in a small amount and improving the intestinal environment.
- oligosaccharides that fall under the same category of prebiotics, they have a 1: Bifidobacterium-specific growth promoting effect (oligosaccharides also act on intestinal bacteria other than Bifidobacteria), 2: 1 day Low intake (1-5 g / day for oligosaccharides, 0.2 g / day for fermented whey produced by propionic acid bacteria), 3: No side effects (oligosaccharides are Increased abdominal discomfort) Force S characteristic (Hojo—K, et al. Effect of ingested culture of Propioni or acterium freudenreichn ⁇ - ⁇ on fecal microflora and stool frequency in healthy females.Bioscience Microflora 2002; 21: 115 —120.).
- the "processed product of whey fermented product by propionic acid bacteria” in the present invention is a supernatant of a culture obtained by culturing propionic acid bacteria with whey, a disinfecting solution obtained by removing the bacteria from the culture, Or these concentrates and dried products are meant.
- Whey is a type of fermented lactic acid bacterium such as the supernatant of yogurt.
- DHNA 1,4-dihydroxy-2-naphthoic acid
- DHNA is described in JP-A-8-98677, and can be easily produced by a chemical synthesis method or a culture method well known to those skilled in the art.
- Examples of the salt of DHNA include sodium salt, potassium salt, calcium salt, magnesium salt and the like.
- the pharmaceutical composition of the present invention can be made into oral dosage forms such as tablets, capsules, granules, powders, syrups and the like. These various dosage forms can be usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspending agents, coating agents and the like in accordance with a conventional method. It can be formulated using additives.
- the administration method is preferably oral administration.
- Therapeutically effective amount of DHNA is age of the patient to be administered, the daily dose per body weight of the human lkg force generally varies depending on the condition of about 0.01-100 / ig, preferably ( ⁇ -10 ⁇ ⁇ , specifically-inflammatory In the case of intestinal disease, the daily dose is about 0.4 / ig / kg of human body weight, and in the case of chronic liver disease, the daily dose is about 0.26-0.4 / ig / kg of human body weight. If so, determine the amount taking into account the therapeutically effective amount of DHNA and the DHNA content in the treated product.
- the pharmaceutical composition of the present invention is a composition for treating or preventing inflammatory bowel disease or chronic liver disease.
- Intestinal inflammatory diseases include infectious enteritis caused by bacterial, parasite, viral or fungal infections, drug-induced enteritis caused by drugs and chemicals, radiation-induced enteritis due to radiation, ischemic colitis, obstructive enteritis, There are various types such as solitary ulcers.
- IBD inflammatory bowel disease
- IBD ulcerative colitis
- CD Crohn's disease
- the chronic liver disease in the present invention includes chronic hepatitis, cirrhosis, hepatocellular carcinoma and liver failure.
- the present invention is particularly useful for chronic liver disease accompanied by hepatic encephalopathy and hypocoagulability. Further, the present invention can improve the decrease in hepatic reserve capacity associated with chronic liver disease.
- Liver reserve refers to the ability to synthesize liver-specific proteins, such as albumin and coagulation factors.
- the tablet (trade name: B.G.S., Meiji Dairies) used in the following examples is currently commercially available and has the following composition:
- Per 3 grains (1.5 g): Calorie 5.7 kcal, protein 0.03 g, fat 0.04 g, carbohydrate 1.3 g, sodium 3.0 mg, whey fermented product by propionic acid bacteria (as DHNA) 6.6 or more / 3 .
- the dosage of the processed product of the whey fermented product by the propionic acid bacterium is 9 tablets (product name: BGS, Meiji Dairies) containing the processed product of the whey fermented product by the propionic acid bacterium in the morning, afternoon, and evening. , Three tablets each. Comparison of clinical activity index scores (Clinical Activity Index (CAI) Score, N Engl J Med 1994; 330: 1839-1845), colonoscopy findings, and fecal microbiological findings before and after BGS administration. I did it.
- CAI Clinical Activity Index
- Hepatic encephalopathy associated with cirrhosis is often accompanied by hyperammonemia, but administering 3 tablets of BGS a day reduces blood ammonia levels by about 40% one week after administration, and clarifies consciousness. Some neurological improvements, such as becoming, were also observed.
- BGS administration showed an improvement in the heparaplastin test (% value), which reflects vitamin K-dependent coagulation factor activity (increase rate: about 12%), and amelioration of coagulation factor hypoplasia associated with cirrhosis. I understood.
- DHNA a processed product of whey fermented product by propionic acid bacteria or its main component, controls inflammation in inflammatory bowel disease and improves hepatic encephalopathy and liver reserve capacity associated with cirrhosis.
- the pharmaceutical composition of the present invention containing a processed product of a whey fermented product by a propionic acid bacterium or DHNA which is a main component thereof is useful for treating or preventing inflammatory bowel disease or chronic liver disease.
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biomedical Technology (AREA)
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- Developmental Biology & Embryology (AREA)
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Abstract
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2004020070 | 2004-01-28 | ||
JP2004-020070 | 2004-01-28 |
Publications (1)
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WO2005072718A1 true WO2005072718A1 (ja) | 2005-08-11 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/JP2005/001218 WO2005072718A1 (ja) | 2004-01-28 | 2005-01-28 | 乳清発酵物を含有する医薬組成物 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2253323A1 (en) * | 2008-02-29 | 2010-11-24 | Meiji Dairies Corporation | Anti-allergic agent |
WO2022124324A1 (ja) * | 2020-12-09 | 2022-06-16 | 株式会社明治 | アシディプロピオニバクテリウム属菌またはその処理物を含んでなる組成物 |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03151854A (ja) * | 1989-11-10 | 1991-06-28 | Calpis Food Ind Co Ltd:The | 腸内有害腐敗産物低減剤 |
JPH07126177A (ja) * | 1993-10-29 | 1995-05-16 | Meiji Milk Prod Co Ltd | 潰瘍性大腸炎治療剤 |
JPH0898677A (ja) * | 1994-04-26 | 1996-04-16 | Meiji Milk Prod Co Ltd | ビフィズス菌増殖促進組成物 |
JPH10179087A (ja) * | 1996-12-26 | 1998-07-07 | Morinaga Milk Ind Co Ltd | 肝疾患患者用食品組成物 |
JP2002534113A (ja) * | 1999-01-15 | 2002-10-15 | エンタープライズ・アイルランド(トレイディング・アズ・バイオリサーチ・アイルランド) | 炎症性疾患治療におけるビフィドバクテリウム(Bifidobacterium) |
JP2002332242A (ja) * | 2001-03-09 | 2002-11-22 | Morinaga Milk Ind Co Ltd | C型慢性肝炎治療剤 |
WO2003010297A1 (en) * | 2001-07-26 | 2003-02-06 | Alimentary Health Limited | Probiotic bifidobacterium strains |
WO2003016544A1 (fr) * | 2001-08-10 | 2003-02-27 | Meiji Dairies Corporation | Procede d'elaboration d'acide 1,4-dihydroxy-2-naphtoique |
JP2005034135A (ja) * | 2003-06-30 | 2005-02-10 | Meiji Seika Kaisha Ltd | 一般食品、保健機能食品または健康補助食品の機能増強組成物及びその方法 |
-
2005
- 2005-01-28 WO PCT/JP2005/001218 patent/WO2005072718A1/ja active Application Filing
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03151854A (ja) * | 1989-11-10 | 1991-06-28 | Calpis Food Ind Co Ltd:The | 腸内有害腐敗産物低減剤 |
JPH07126177A (ja) * | 1993-10-29 | 1995-05-16 | Meiji Milk Prod Co Ltd | 潰瘍性大腸炎治療剤 |
JPH0898677A (ja) * | 1994-04-26 | 1996-04-16 | Meiji Milk Prod Co Ltd | ビフィズス菌増殖促進組成物 |
JPH10179087A (ja) * | 1996-12-26 | 1998-07-07 | Morinaga Milk Ind Co Ltd | 肝疾患患者用食品組成物 |
JP2002534113A (ja) * | 1999-01-15 | 2002-10-15 | エンタープライズ・アイルランド(トレイディング・アズ・バイオリサーチ・アイルランド) | 炎症性疾患治療におけるビフィドバクテリウム(Bifidobacterium) |
JP2002332242A (ja) * | 2001-03-09 | 2002-11-22 | Morinaga Milk Ind Co Ltd | C型慢性肝炎治療剤 |
WO2003010297A1 (en) * | 2001-07-26 | 2003-02-06 | Alimentary Health Limited | Probiotic bifidobacterium strains |
WO2003016544A1 (fr) * | 2001-08-10 | 2003-02-27 | Meiji Dairies Corporation | Procede d'elaboration d'acide 1,4-dihydroxy-2-naphtoique |
JP2005034135A (ja) * | 2003-06-30 | 2005-02-10 | Meiji Seika Kaisha Ltd | 一般食品、保健機能食品または健康補助食品の機能増強組成物及びその方法 |
Non-Patent Citations (2)
Title |
---|
HOJO K. ET AL: "Effect of Ingested Culture of Propionibacterium freudenreichii ET-3 on Fecal Microflora and Stool Freqeuncy in Healthy Females.", BIOSCHIENCE MICROFLORA, vol. 21, no. 2, 2002, pages 115 - 120, XP002989411 * |
ISAWA K. ET AL: "Isolation and Indentification of a new Bifidogenic Growth Stimulator Produced by Propionibacterium freudenreichii ET-3.", BIOSCI.BIOTECHNOL. BIOCHEM., vol. 66, no. 3, 2002, pages 679 - 681, XP008041283 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2253323A1 (en) * | 2008-02-29 | 2010-11-24 | Meiji Dairies Corporation | Anti-allergic agent |
CN102488716A (zh) * | 2008-02-29 | 2012-06-13 | 株式会社明治 | 抗过敏剂 |
EP2253323A4 (en) * | 2008-02-29 | 2012-08-22 | Meiji Co Ltd | ANTIALLERGENIC ACTIVE SUBSTANCE |
WO2022124324A1 (ja) * | 2020-12-09 | 2022-06-16 | 株式会社明治 | アシディプロピオニバクテリウム属菌またはその処理物を含んでなる組成物 |
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