WO2000006192A1 - Agents ameliorant la fonction hepatique - Google Patents
Agents ameliorant la fonction hepatique Download PDFInfo
- Publication number
- WO2000006192A1 WO2000006192A1 PCT/JP1999/004005 JP9904005W WO0006192A1 WO 2000006192 A1 WO2000006192 A1 WO 2000006192A1 JP 9904005 W JP9904005 W JP 9904005W WO 0006192 A1 WO0006192 A1 WO 0006192A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lactoferrin
- liver function
- hydrolyzate
- manufactured
- agent
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/40—Transferrins, e.g. lactoferrins, ovotransferrins
Definitions
- the present invention relates to a liver function improving agent containing lactoferrin as an active ingredient. More specifically, the present invention relates to metal-unsaturated lactofurin, metal-saturated lactofurin, or apolactoferrin (hereinafter, these may be collectively referred to as lactoferrins) and / or lactofurin. The present invention relates to a liver function improving agent containing a hydrolyzate of a kind as an active ingredient. Background art
- Liver function may be impaired for a variety of reasons and even lead to death. Liver function tests are usually performed using plasma glutamate ⁇ ogizaloacetate 'glutamate oxaloacetate transaminase (hereinafter abbreviated as GOT), glutamate ⁇ pirirebeto ⁇ It is measured by measuring the amount of glutamate pyruvate transaminase (hereinafter abbreviated as GPT), allyl phosphatase (hereinafter abbreviated as ALP), total pyrilvin, albumin, and total cholesterol. You.
- GOT plasma glutamate ⁇ ogizaloacetate 'glutamate oxaloacetate transaminase
- GPT glutamate ⁇ pirirebeto ⁇ It is measured by measuring the amount of glutamate pyruvate transaminase (hereinafter abbreviated as GPT), allyl phosphatase (hereinafter abbreviated as
- Lactofulin is a harmless, natural iron-binding protein (capable of binding two iron ions per molecule) contained in tears, saliva, peripheral blood, milk, etc., and has a molecular weight of Escherichia lactoferrin has 86,000 and human lactoferrin has 88,000 (Kazutomo Imabori, supervised by Tamio Yamakawa, "Biochemical Dictionary", 2nd ed., 1390, Tokyo Kagaku Dojin, 1990) .
- Lactoferrin is known to exhibit antibacterial activity against harmful microorganisms such as Escherichia coli, Candida and Clostridium (Journal of Pediatrics, Vol. 94, page 1, 1997).
- lactoferrin is effective for colonizing useful bacteria such as bifidobacteria and lactic acid bacteria in the intestine of humans and animals (Patent No. 25329111), and is a bifidobacterial growth factor (Patent No. 2529111). (Kaihei 2-225419) is also known.
- a wide variety of uses for lactoferrin are disclosed:
- antitumor agents JP-A-63-51337), gastrointestinal tract growth promoters (JP-A-1-93534), and bacterial toxin neutralizing agents (Kyokai Hei 2-207089 and JP-T-Hei 5-95) 501416), anti-aging agents (JP-A-4-58871 and JP-A-5-124980), antihypertensives (JP-A-4-316598), antirheumatic agents (JP-A-5-186368) , Nerve growth factor production promoter (JP-A-5-32557), gastrointestinal cell activator (JP-A-6-48955), brain protective agent (JP-A-6-172200), arteriosclerosis preventive agent (Japanese Patent Application Laid-Open No.
- JP-A-10-59864 oral cancer metastasis inhibitor
- endotoxin-induced disease therapeutic agent JP-A-10-1146675
- Gastrointestinal disorders prophylactic and or therapeutic agent JP-A 10-130164 JP
- An object of the present invention is to provide a liver function improving agent having almost no side effects.
- the present invention is a liver function improving agent containing lactoferrin and / or a hydrolyzate of lactoferrin as an active ingredient.
- the phosphorus is one or a mixture of two or more selected from the group consisting of metal-unsaturated lactoferrin, metal-saturated lactoferrin and apolactoferrin.
- the present inventors have intensively studied a novel use of lactoferrin, which has not been known before, and found that in the process, the hepatic function decreased by administration of lactoferrin can be improved.
- the inventors of the present invention have repeated animal tests on this fact and have scientifically proved that lactoferrin is effective in improving liver function, and have completed the present invention.
- the liver function-improving agent of the present invention has a remarkable effect on improving liver function.Lactoferrin, which is an active ingredient of the agent, is contained in milk and the like, and the protein or its protein that is taken in daily. Since it is a hydrolyzate, it has almost no side effects even if taken continuously for a long period.
- the agent for improving liver function of the present invention is used in combination with other therapeutic agents for liver disease (eg, interferon, SNMC, etc.), the dose of these therapeutic agents can be reduced.
- the lactoferrins used as the active ingredient of the present invention may be commercially available products, and may be derived from the colostrum and the migraine of mammals (for example, humans, sea lions, sea lions, sea lions, goats, higgies, etc.).
- Raw milk, normal milk, end-of-life milk, etc., these processed products skim milk, lactoferrin, which has been separated from whey, etc. by conventional methods such as ion exchange chromatography, and iron from lactoferrin by conventional methods.
- Metal-unsaturated lactoferrin obtained by partially or completely chelating metals such as iron, copper, zinc, and manganese to It may be phosphorus or metal-saturated lactoferrin.
- human ⁇ lactoferrin cannot be produced in large quantities
- human ⁇ lactoferrin produced by recombinant fungi and dairy cows (transgenic cows) obtained by recombinant DNA technology, etc. Phosphorus can also be used in the present invention.
- the hydrolyzate of lactoferrin used as the active ingredient of the present invention is produced by hydrolyzing the lactoferrin with an acid or an enzyme.
- the details are as follows.
- Hydrolysis with acid is obtained by dissolving lactoferrins in water, purified water, etc. at a concentration of 0.1 to 20% (weight; hereinafter, unless otherwise specified, the same), preferably 5 to 15%.
- An acid eg, an inorganic acid such as hydrochloric acid or phosphoric acid, or an organic acid such as citric acid
- the pH of the solution is adjusted to 1 to 4
- the solution is maintained at a predetermined temperature and hydrolyzed for a predetermined time. More specifically, when the pH was adjusted to 1 or more and less than 2, the temperature was kept at 80 to 130 ° C, preferably 90 to 120 ° C, for 1 to 120 minutes, and the pH was adjusted to 2 or more and less than 4. If 80 ⁇ "! 30 ° C, preferably 100 ⁇ 120 ° C, keep it! Hydrolyze for ⁇ 120 minutes. Then, the reaction solution can be cooled, and if necessary, neutralized, desalted, and decolorized.
- Enzymatic hydrolysis involves dissolving lactoferrin at a concentration of 0.5 to 20%, preferably 5 to 15% in water, sterile water, purified water, etc., and adjusting to the optimal pH of the enzyme used for hydrolysis. The enzyme is added, and hydrolysis is carried out while maintaining the enzyme at the optimum temperature.
- the enzymatic hydrolysis is carried out at a temperature of 15 to 55 ° C, preferably 30 to 50 ° C, for 30 to 600 minutes, preferably 60 to 300 minutes.
- the reaction solution is directly or neutralized, the enzyme is heated and inactivated by a conventional method, and if necessary, decolored to obtain a hydrolyzate.
- the hepatic function-improving agent of the present invention containing the lactoferrin and / or a hydrolyzate thereof as an active ingredient is formulated into various forms by a known method and orally administered.
- Specific dosage forms include tablets (including sugar-coated tablets, coated tablets, and buccal tablets), powders, capsules, (including soft capsules), and granules (including those coated). Pills, troches, liquids, or pharmaceutically acceptable sustained-release preparations thereof.
- the above-mentioned preparation is formulated as a pharmaceutical composition together with a pharmacologically acceptable carrier, excipient, disintegrant, lubricant, coloring agent, etc. according to a known pharmaceutical manufacturing method It is made.
- Carriers and excipients used in these preparations include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, kanzo powder, gentian powder.
- the binder include starch, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropylcellulose, ethylcellulose, methylcellulose, carboxymethylcellulose and the like. Can be.
- disintegrant examples include starch, agar, gelatin powder, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, sodium alginate and the like.
- Lubricants include magnesium stearate, hydrogenated vegetable oils, macrogol, etc.Red No. 2, Yellow No. 4, which are permitted to be added to pharmaceuticals as coloring agents 0/1 2
- Tablets and granules are sucrose, hydroxypropylcellulose, purified shellac, gelatin, sorbitol, glycerin, ethylcellulose, hydroxypropylcellulose, hydroxydipropylmethylcellulose, polyvinylpyrrolidone, and cellulose phthalate. It can also be coated with acetate, hydroxypropyl methylcellulose phthalate, methyl methacrylate, methacrylic acid polymer and the like.
- the liver function improving agent of the present invention desirably contains at least 1 mg of lactoferrin or a degradation product thereof as an active ingredient per 1 g of the drug, and the dosage varies depending on age, symptoms, etc. It is administered orally at a rate of at least 1 mg / kg body weight, preferably 20 to 15 g / day.
- the liver function improving agent of the present invention is a milk-derived component and has high safety, the dosage of these drugs can be reduced by using it in combination with other therapeutic agents for liver diseases, such as interferon and SNMC. In addition, a synergistic effect of improving liver function can be expected.
- Wis-ne male rats of about 200 g in weight purchased from Nippon Chars River 30 animals were randomly divided into 5 groups of 6 animals per group, and solid feed (Funabashi Farm) and water were freely available They were pre-bred for one week.
- Lactoferrin used was a commercially available product (manufactured by Morinaga Milk Products Co., Ltd.), and lactoferrin hydrolyzate was prepared by the same method as in the Reference Example.
- a rat model of chronic liver injury was developed according to the method of Tamada et al. (Kitaken, Vol. 28, No. 7, page 39, 1987).
- the remaining four rats were treated in the same manner as the control group, but from the 6th week after the start of carbon tetrachloride administration, the doses shown in Table 1 (500 mg / kg / day or 250 mg / kg / day) were used. Lactofurin or lactofol dissolved in purified water;!: Phosphorus hydrolyzate was orally administered daily for 3 weeks.
- lactoferrin The effects of lactoferrin on carbon tetrachloride-induced chronic liver injury models are shown in Table 1. Compared with the control group, the lactoferrin administration group showed lower GOT, GPT, and ALP values, indicating a higher liver function improvement effect. Lactofurin hydrolyzate was also slightly less effective than lactoferrin, but a clear improvement in liver function was observed.
- Lactof:! The effects of phosphorus and lactofulin hydrolyzate on carbon tetrachloride-induced acute liver injury models are shown in Table 2. Compared with the control group, the lactofurin-administered group showed lower values for GO, GP, and ALP, indicating a higher liver function-improving effect. The effect of lactoferrin hydrolyzate was almost the same as that of lactoferrin.
- Human lactoferrin was produced from human milk by the following method described in the official gazette of Japanese Patent No. 2130919 (Japanese Patent Publication No. 6-13560).
- the obtained recovered solution was dialyzed to remove sodium chloride and freeze-dried to obtain about 12 g of human lactoferrin powder.
- the composition of the obtained human ⁇ lactoferrin was 2.8% in water, 96.3% in lactoferrin, and 0.5% in ash.
- Reference example 2
- Example 1 Preparation of a tablet containing ⁇ 'lactofulin I
- a liver function improving agent for tablets having the following composition was produced by the following method.
- Carboxymethylcellulose calcium (Gotoku Yakuhin) 9.4
- Lactoferrin (Mirai) 8.0 (%) Fructose dextrose liquid sugar (Sanmatsu Kogyo) 1 2.4
- Lactose manufactured by Wako Pure Chemical Industries 600 g, corn starch (manufactured by Seisei Flour Mills) 400 g, crystalline cellulose (manufactured by Wako Pure Chemical Industries) 400 g, and lactoferrin (manufactured by Mirai) 600 g was sieved through a 50 mesh sieve (manufactured by Yamato Scientific Co., Ltd.), placed in a 0.5 mm-thick polyethylene bag, and mixed by inversion.
- a fully automatic capsule filling machine manufactured by Cesere Pedini). Pressing the powder into capsules (Nippon Elanco Co., Ltd., No. 1 gelatin capsule, ⁇ p. Yellow No.6 Body, empty weight: 75 mg), and filling the contents with 275 mg of lactoferrin. 7,000 capsules containing mg were obtained.
- Magnesium stearate (manufactured by NOF Corporation) 1.4
- Carboxymethylcellulose calcium (Gotoku Yakuhin) 9.4 Pesticide ⁇
- a mixture of lactophosphorin, lactose, potato starch and carboxymethylcellulose is kneaded uniformly while adding sterile purified water as appropriate and dried at 55 ° C for 2 hours. Magnesium was added and mixed, and the mixture was compressed in a conventional manner to give tablets.
- Purified water (made by Fuso Pharmaceutical Co., Ltd.) 78.9
- the respective components were mixed to produce a syrup preparation according to a conventional method.
- the agent for improving liver function of the present invention is useful as a drug for improving liver function in patients suffering from liver dysfunction.
- the hepatic function-improving agent of the present invention is also useful for reducing the dose of such a therapeutic agent when used in combination with an agent for treating liver diseases such as interferon and SNMC.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99931550A EP1116490A4 (en) | 1998-07-30 | 1999-07-27 | LIVER FUNCTION IMPROVING AGENTS |
CA002338884A CA2338884A1 (en) | 1998-07-30 | 1999-07-27 | Liver function ameliorating agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22943498 | 1998-07-30 | ||
JP10/229434 | 1998-07-30 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09744648 A-371-Of-International | 2001-03-16 | ||
US10/189,623 Continuation US20030008811A1 (en) | 1998-07-30 | 2002-07-08 | Agent for improving hepatic functions in chronic hepatitis and methods of using thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000006192A1 true WO2000006192A1 (fr) | 2000-02-10 |
Family
ID=16892176
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/004005 WO2000006192A1 (fr) | 1998-07-30 | 1999-07-27 | Agents ameliorant la fonction hepatique |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1116490A4 (ja) |
CN (1) | CN1195544C (ja) |
CA (1) | CA2338884A1 (ja) |
WO (1) | WO2000006192A1 (ja) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001226289A (ja) * | 2000-02-16 | 2001-08-21 | Snow Brand Milk Prod Co Ltd | 肝機能改善剤 |
JP2001247474A (ja) * | 2000-03-07 | 2001-09-11 | Snow Brand Milk Prod Co Ltd | 肝疾患予防及び/又は治療剤 |
WO2002041912A1 (fr) * | 2000-11-24 | 2002-05-30 | Nuclear Receptor Ligand Co., Ltd. | Medicaments et aliments destines a ameliorer la qualite de vie et leur procede de preparation |
WO2002043752A1 (fr) * | 2000-11-29 | 2002-06-06 | Morinaga Milk Industry Co., Ltd. | Agents therapeutiques de potentialisation d'effet a base d'interferon |
WO2002043753A1 (fr) * | 2000-11-30 | 2002-06-06 | Morinaga Milk Industry Co., Ltd. | Substances therapeutiques destinees a l'hepatite b chronique |
JP2010053141A (ja) * | 2009-12-02 | 2010-03-11 | Meiji Milk Prod Co Ltd | 栄養組成物 |
JP2012250990A (ja) * | 2012-09-07 | 2012-12-20 | Meiji Co Ltd | 栄養組成物 |
CN105521485A (zh) * | 2007-09-05 | 2016-04-27 | 尼古拉·叶夫根尼耶维奇·沙图诺夫斯基 | 脱铁乳铁蛋白组合物及其用于治疗病毒性丙型肝炎的方法 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2471766C (en) * | 2001-12-28 | 2011-01-11 | Nrl Pharma, Inc. | Compositions for improving lipid metabolism |
US20030191193A1 (en) | 2002-04-03 | 2003-10-09 | Jillian Cornish | Lactoferrin |
NZ589988A (en) | 2008-06-16 | 2012-08-31 | Campina Nederland Holding Bv | Heat-stable, aqueous lactoferrin composition and its preparation and use |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01233226A (ja) * | 1988-02-02 | 1989-09-19 | Roussel Uclaf | 抗ウイルス薬剤の製造への乳蛋白の利用 |
JPH05276896A (ja) * | 1992-04-02 | 1993-10-26 | Meiji Milk Prod Co Ltd | 高フィッシャー比ペプチド混合物、その製造法、 および肝疾患患者用栄養補給組成物 |
JPH0625006A (ja) * | 1992-04-08 | 1994-02-01 | Clintec Nutrition Co | 免疫障害、炎症および慢性感染症を治療するための方法および組成物 |
DE4426165A1 (de) * | 1994-07-23 | 1996-01-25 | Nitsche Gmbh H | Verwendung von Laktoferrin zur Prophylaxe und Therapie von Funktionsstörungen der Leber |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000325046A (ja) * | 1999-05-19 | 2000-11-28 | Meiji Milk Prod Co Ltd | 肝炎を予防および治療する食品もしくは医薬品 |
-
1999
- 1999-07-27 EP EP99931550A patent/EP1116490A4/en not_active Withdrawn
- 1999-07-27 CA CA002338884A patent/CA2338884A1/en not_active Abandoned
- 1999-07-27 CN CNB998106399A patent/CN1195544C/zh not_active Expired - Fee Related
- 1999-07-27 WO PCT/JP1999/004005 patent/WO2000006192A1/ja not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01233226A (ja) * | 1988-02-02 | 1989-09-19 | Roussel Uclaf | 抗ウイルス薬剤の製造への乳蛋白の利用 |
JPH05276896A (ja) * | 1992-04-02 | 1993-10-26 | Meiji Milk Prod Co Ltd | 高フィッシャー比ペプチド混合物、その製造法、 および肝疾患患者用栄養補給組成物 |
JPH0625006A (ja) * | 1992-04-08 | 1994-02-01 | Clintec Nutrition Co | 免疫障害、炎症および慢性感染症を治療するための方法および組成物 |
DE4426165A1 (de) * | 1994-07-23 | 1996-01-25 | Nitsche Gmbh H | Verwendung von Laktoferrin zur Prophylaxe und Therapie von Funktionsstörungen der Leber |
Non-Patent Citations (4)
Title |
---|
CHEMICAL ABSTRACTS, vol. 124, no. 15, 1996, Columbus, Ohio, US; abstract no. 194352P, H. NITSCHE GMBH: "Lactoferrin for the prophylaxis and therapy of liver function disorders" page 161; column 1; XP002923167 * |
IKEDA MASANORI: "Lactoferrin markedly inhibits Hepatitis C Virus Infection in Cultured Human Hepatocytes", BIOCHEM. BIOPHYS. RES. COMM., vol. 245, no. 2, 17 April 1998 (1998-04-17), pages 549 - 553, XP002923168 * |
KEIJI MITAMURA: "HVB ryuushi no kouzou to fukusei, zoushoku, bunshi virus byougaku (Structure and Replication of HBV)", NIHON RINSHOSHA, vol. 53, 1995, pages 3 - 12, XP002923169 * |
See also references of EP1116490A4 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001226289A (ja) * | 2000-02-16 | 2001-08-21 | Snow Brand Milk Prod Co Ltd | 肝機能改善剤 |
JP4679687B2 (ja) * | 2000-02-16 | 2011-04-27 | 雪印乳業株式会社 | 肝機能改善剤 |
JP2001247474A (ja) * | 2000-03-07 | 2001-09-11 | Snow Brand Milk Prod Co Ltd | 肝疾患予防及び/又は治療剤 |
WO2002041912A1 (fr) * | 2000-11-24 | 2002-05-30 | Nuclear Receptor Ligand Co., Ltd. | Medicaments et aliments destines a ameliorer la qualite de vie et leur procede de preparation |
WO2002043752A1 (fr) * | 2000-11-29 | 2002-06-06 | Morinaga Milk Industry Co., Ltd. | Agents therapeutiques de potentialisation d'effet a base d'interferon |
WO2002043753A1 (fr) * | 2000-11-30 | 2002-06-06 | Morinaga Milk Industry Co., Ltd. | Substances therapeutiques destinees a l'hepatite b chronique |
CN105521485A (zh) * | 2007-09-05 | 2016-04-27 | 尼古拉·叶夫根尼耶维奇·沙图诺夫斯基 | 脱铁乳铁蛋白组合物及其用于治疗病毒性丙型肝炎的方法 |
JP2010053141A (ja) * | 2009-12-02 | 2010-03-11 | Meiji Milk Prod Co Ltd | 栄養組成物 |
JP2012250990A (ja) * | 2012-09-07 | 2012-12-20 | Meiji Co Ltd | 栄養組成物 |
Also Published As
Publication number | Publication date |
---|---|
CN1195544C (zh) | 2005-04-06 |
EP1116490A1 (en) | 2001-07-18 |
CN1316909A (zh) | 2001-10-10 |
EP1116490A4 (en) | 2004-08-04 |
CA2338884A1 (en) | 2000-02-10 |
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