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WO2018194149A1 - Régulateur de production de cytokines - Google Patents

Régulateur de production de cytokines Download PDF

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Publication number
WO2018194149A1
WO2018194149A1 PCT/JP2018/016228 JP2018016228W WO2018194149A1 WO 2018194149 A1 WO2018194149 A1 WO 2018194149A1 JP 2018016228 W JP2018016228 W JP 2018016228W WO 2018194149 A1 WO2018194149 A1 WO 2018194149A1
Authority
WO
WIPO (PCT)
Prior art keywords
cytokine production
eps
cytokine
control agent
production control
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2018/016228
Other languages
English (en)
Japanese (ja)
Inventor
北澤　春樹
聖也 牧野
宏 狩野
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Meiji Co Ltd
Original Assignee
Meiji Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Meiji Co Ltd filed Critical Meiji Co Ltd
Publication of WO2018194149A1 publication Critical patent/WO2018194149A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • 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
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a cytokine production control agent.
  • Pathogenic viruses such as influenza are a threat that human beings are always facing.
  • the innate immune system that prevents the invasion and proliferation of viruses in the body at the forefront is important, and it is known that cytokines such as interferon are involved. . Under such circumstances, substances that can control cytokine production have been searched for in various fields.
  • Patent Document 1 describes a dendritic cell activator containing an extract of Cordyceps sinensis as an active ingredient, and enhances production of interferon ⁇ by dendritic cell activation. The effect is also described.
  • JP-A-2009-256312 describes a polysaccharide produced by Cremoris having an action of inducing production of interferon ⁇ and interleukin-6.
  • an object of the present invention is to provide a cytokine production control agent that can be safely and easily ingested while having a sufficient cytokine production control action.
  • the present inventors paid attention to lactic acid bacteria and examined in detail again the physiological activity of lactic acid bacteria themselves and the utilization method of metabolites of lactic acid bacteria. And as a result, it discovered that the polysaccharide (extracellular polysaccharide (EPS)) which a predetermined
  • EPS extracellular polysaccharide
  • a cytokine production control agent comprising exopolysaccharide (EPS) as an active ingredient.
  • EPS exopolysaccharide
  • the cytokine production regulator according to any of [3] or [4], wherein the inflammatory cytokine is interleukin-6.
  • the cytokine production control agent according to any one of [1] to [6], comprising EPS produced by Lactobacillus delbrueckii subsp. Bulgaricus as an active ingredient.
  • the cytokine production control agent according to any one of [1] to [7], wherein the intake of EPS as an active ingredient is 1 mg / kg / day or more.
  • the present invention also includes the following inventions.
  • Bulgaricus is Lactobacillus delbrueckii subsp.
  • Bulgaricus OLL1073R-1 (FERM BP-10741).
  • [B-1] A method for controlling cytokine production, comprising using an extracellular polysaccharide (EPS).
  • EPS extracellular polysaccharide
  • [B-2] A method for increasing antiviral cytokine production, characterized by using extracellular polysaccharide (EPS).
  • EPS extracellular polysaccharide
  • [B-4] A method of increasing antiviral cytokine production and decreasing inflammatory cytokine production, characterized by using extracellular polysaccharide (EPS).
  • EPS extracellular polysaccharide
  • [B-5] The method according to any one of [b-2] or [b-4], wherein the antiviral cytokine is either or both of interferon ⁇ and interferon ⁇ .
  • [B-6] The method according to any one of [b-3] or [b-4], wherein the inflammatory cytokine is interleukin-6.
  • [B-7] The method according to any one of [b-1] to [b-6], wherein the EPS is an EPS produced by Lactobacillus delbrueckii subsp. Bulgaricus.
  • [C-4] Use of exopolysaccharide (EPS) in the production of a cytokine production control agent having an action of raising antiviral cytokines and a action of lowering inflammatory cytokines.
  • [C-5] The use according to any of [c-2] or [c-4], wherein the antiviral cytokine is either or both of interferon ⁇ and interferon ⁇ .
  • [C-6] The use according to any of [c-3] or [c-4], wherein the inflammatory cytokine is interleukin-6.
  • [C-7] The use according to any one of [c-1] to [c-6], wherein the EPS is an EPS produced by Lactobacillus delbrueckii subsp. Bulgaricus.
  • EPS Extracellular polysaccharide
  • Extracellular polysaccharide (EPS) for use in the production of a cytokine production control agent having an action of lowering inflammatory cytokines.
  • EPS extracellular polysaccharide
  • EPS extracellular polysaccharide
  • EPS is an EPS produced by Lactobacillus delbrueckii subsp. Bulgaricus.
  • EPS is an EPS produced by Lactobacillus delbrueckii subsp. Bulgaricus.
  • Lactobacillus delbrueckii subsp. Bulgaricus is Lactobacillus delbrueckii subsp.
  • Bulgaricus OLL1073R-1 (FERM BP-10741).
  • a cytokine production control agent having an excellent effect can be provided.
  • the cytokine production control agent of the present invention has the effect of increasing the production of beneficial antiviral cytokines and reducing the production of harmful inflammatory cytokines involved in inflammatory reactions and the like, so that cytokines are effectively produced. Production can be controlled.
  • the exopolysaccharide that is an active ingredient of the present invention is derived from lactic acid bacteria, and its safety is sufficiently supported by a long dietary experience. It can be ingested safely and conveniently.
  • the present invention is a cytokine production control agent comprising exopolysaccharide (EPS) as an active ingredient.
  • the exopolysaccharide is a polysaccharide produced by a certain lactic acid bacterium and the like and produced outside the microbial cell. For example, it is known that Lactobacillus delbrueckii subsp. In addition, Lactococcus lactis subsp. Cremoris and the like are also known to have strains that produce neutral polysaccharides.
  • the exopolysaccharide used in the present invention one kind may be used alone, or two or more kinds may be used in combination. For example, acidic polysaccharides and neutral polysaccharides may be used in combination.
  • the exopolysaccharide used in the present invention may be used without purifying the culture of lactic acid bacteria containing the exopolysaccharide as it is, for example, using the method described in JP-A-2000-247895, An exopolysaccharide isolated from a culture of lactic acid bacteria containing an exopolysaccharide or further purified as necessary may be used.
  • a culture of lactic acid bacteria is crushed into a concentrate, pasted product, spray dried product, freeze dried product, vacuum dried product, drum dried product, liquid material dispersed in a medium, diluted product, dried product. You may use as a to-be-processed object which obtained the process process, such as the crushed material.
  • the cytokine production control agent of the present invention exhibits its function when ingested by mammals including humans.
  • the “intake” as used herein is not limited to the administration route as long as it enters the human body, and is realized by all known administration methods such as oral administration, tube administration, enteral administration and the like. obtain. In this case, typical examples include oral intake and enteral intake via the digestive tract, but oral intake is preferable, and intake by eating and drinking is more preferable.
  • the dose of the cytokine production control agent of the present invention containing exopolysaccharide as an active ingredient can be appropriately set in consideration of various factors such as administration route, age, weight, and symptoms.
  • the dose of the cytokine production control agent of the present invention is not particularly limited, but is preferably 1 mg / kg / day or more, more preferably 5 mg / kg / day or more, particularly preferably as the amount of exopolysaccharide as an active ingredient. Is 10 mg / kg / day or more. However, when ingested over a long period of time, the amount may be smaller than the above preferred amount.
  • the dosage of the cytokine production control agent of the present invention is the active ingredient.
  • the amount of a certain exopolysaccharide may be an amount greatly exceeding the above amount (for example, 100 mg / kg / day or more).
  • the weight per unit package of the cytokine production control agent of the present invention is not particularly limited.
  • the weight is preferably in the range of 10 g to 500 g, and more preferably in the range of 25 g to 250 g. , More preferably in the range of 50 g to 200 g, most preferably in the range of 75 g to 150 g.
  • the unit packaging is not limited to unit packaging per bag, box, or container, but may be unit packaging per one time included therein or unit packaging per day. It should be noted that a plurality of days, for example, a quantity suitable for intake for one week may be packaged together, or may include a plurality of individual packages.
  • the cytokine production control agent of the present invention is preferably taken continuously for 3 weeks or longer, more preferably 5 weeks or longer, and even more preferably 8 weeks or longer.
  • an ingestion period is not specifically limited, It can be continued permanently. From the viewpoint of obtaining a sufficiently effective cytokine control effect, the intake period is preferably 8 weeks.
  • the cytokine production control agent of the present invention can be used as a food or drink.
  • the food or drink is useful in that it has a cytokine production control effect, and can be used as, for example, a food or drink having an antiviral effect.
  • the cytokine production control agent of the present invention can be used as a health functional food or a food for the sick.
  • the functional health food system is intended for not only regular foods but also foods in the form of tablets, capsules, etc., taking into account trends in Japan and overseas and the consistency with conventional food systems for specified health use. .
  • two types of foods for specific health use (individual permission type) and functional foods (standard specification type) are defined.
  • it is possible to prevent various infections by administering the cytokine production control agent of the present invention to animals such as humans as special-purpose foods such as foods for specified health use or nutritional functional foods.
  • the cytokine production control agent of the present invention preferably displays a description of its use, efficacy, function, type of active ingredient, type of functional ingredient, intake method, and the like.
  • “Indication” as used herein refers to pharmaceuticals, quasi drugs, health functional foods, foods for specified health use, functional foods for nutrition, general foods, health supplements, health foods, supplements, enteral nutrition, oral cosmetics, and feed Each should be a suitable display.
  • the “display” here includes all displays for informing the consumer of the above description. This display only needs to be a display that allows the above-described display contents to be recalled / analogized, and may include any display regardless of the purpose of display, the display contents, the object / medium to be displayed, and the like. For example, display the above description on product packaging / containers, display the above description on product advertisements / price lists or transaction documents, or display or distribute the information, electromagnetically (such as the Internet) ) By a method.
  • the type of food or drink is not particularly limited.
  • Foods and beverages include, for example, milk, processed milk, soft drinks, fermented milk, yogurt, cheese, other dairy products, bread, biscuits, crackers, pizza crusts, prepared powdered milk, liquid food, food for the sick, infant milk powder, etc. It may be food, food such as powdered milk for pregnant women and lactating women, and nutritional food.
  • normal food compositions such as using the exopolysaccharide as an active ingredient of the cytokine production control agent of the present invention as it is or mixing with other foods or drinks or food ingredients The manufacturing method can be used.
  • the shape of food / beverage products used normally may be sufficient.
  • any shape such as solid (including powder and granule), paste, liquid, and suspension may be used, but not limited thereto.
  • milk drink, fermented milk, soft drink, jelly drink, tablet, and powdered food are more preferable, and yogurt is particularly preferable.
  • the cytokine production control agent of the present invention has an action of increasing the expression level of antiviral cytokines.
  • antiviral cytokines include interferon ⁇ and interferon ⁇ , but the present invention is not limited thereto.
  • the cytokine production control agent of the present invention has an action of reducing the expression level of inflammatory cytokines.
  • antiviral cytokines include interleukin-6, but the present invention is not limited thereto.
  • the cytokine production control agent of the present invention is effective because it increases the production of antiviral cytokines beneficial to humans and reduces the production of inflammatory cytokines that are involved in inflammatory reactions and are harmful to humans. In addition, cytokine production can be controlled.
  • the cytokine production control agent of the present invention can be used as a pharmaceutical product.
  • the dose of the cytokine production control agent of the present invention in the pharmaceutical product is not particularly limited, but for example, the amount of exopolysaccharide as an active ingredient is preferably 1 mg / kg / day or more, more preferably 5 mg / kg / day or more, particularly preferably 10 mg / kg / day or more.
  • the amount may be smaller than the above amount.
  • the above-mentioned pharmaceutical dosage form is preferably a dosage form that can be administered orally in order to allow the cytokine production control agent of the present invention to reach the intestine.
  • Examples of preferable dosage forms of the pharmaceutical product according to the present invention include tablets, coated tablets, capsules, granules, powders, liquids, syrups, lozenges and the like.
  • These various preparations are prepared according to conventional methods, such as exopolysaccharide, which is the main agent, excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, solubilizing agents, suspension agents, coating agents, etc.
  • the pharmaceutical composition can be formulated by mixing with adjuvants that can be usually used in the pharmaceutical preparation technical field.
  • exopolysaccharide was prepared from yogurt prepared using Lactobacillus delbrueckii subsp.
  • Bulgaricus OLL1073R-1 deposit number: FERM BP-10741
  • the product purified by the method described in -923 was used.
  • Porcine intestinal epithelial cells were obtained according to the method described in Biochimica et Biophysica Acta (BBA) -General Subjects, 1780 (2), 134-144. The obtained cells were cultured for 3 days on a 12-well plate coated with type I collagen to form a monolayer. As the medium, DMEM medium supplemented with 10% fetal calf serum, 100 mg / mL penicillin, and 100 U / mL streptomycin was used. After culturing, EPS was added to the monolayered cells at a concentration of 100 ⁇ g / mL, allowed to act for 48 hours under conditions of 37 ° C. and 5% CO 2 , and then the cells were washed 3 times with a fresh medium.
  • BBA Biochimica et Biophysica Acta
  • TLR3 is a Poly (I: C) receptor, and production of IFN- ⁇ and IFN- ⁇ by Poly (I: C) stimulation is performed via TLR3. Therefore, it was clarified that EPS increases TLR3 expression, thereby increasing the sensitivity to Poly (I: C) and, as a result, exerting an effect of promoting production of IFN- ⁇ and IFN- ⁇ .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Le problème abordé par la présente invention est de pourvoir à un régulateur de production de cytokines qui est facile à ingérer et sans danger et a une activité de régulation de production de cytokines satisfaisante. La solution selon l'invention concerne un régulateur de production de cytokines, ayant une activité d'accroissement des cytokines antivirales, ainsi qu'une activité de réduction des cytokines inflammatoires, et contient un polysaccharide extracellulaire à titre de principe actif.
PCT/JP2018/016228 2017-04-21 2018-04-20 Régulateur de production de cytokines Ceased WO2018194149A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2017084318A JP7017864B2 (ja) 2017-04-21 2017-04-21 サイトカイン産生制御剤
JP2017-084318 2017-04-21

Publications (1)

Publication Number Publication Date
WO2018194149A1 true WO2018194149A1 (fr) 2018-10-25

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WO (1) WO2018194149A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019087993A1 (fr) * 2017-10-31 2019-05-09 株式会社 明治 Lait fermenté et polysaccharide ayant une action inhibitrice de la cachexie cancéreuse

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7529394B2 (ja) * 2019-11-15 2024-08-06 株式会社明治 ウイルス増殖を抑制するための組成物
CN116075312A (zh) 2020-05-22 2023-05-05 森永乳业株式会社 肠道发育促进用组合物、肺功能改善用组合物和免疫功能增强用组合物
CN118973409A (zh) 2022-04-20 2024-11-15 株式会社明治 抗人冠状病毒用组合物

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ARENA, ADRIAN A ET AL.: "Antiviral and immunoreguratory effect of a novel exopolysaccharide from a marine thermotolerant Bacillus licheniformis", INT IMMUNOPHARMACOL, vol. 6, 2006, pages 8 - 13, XP024976731 *
GANESH KUMAR, C. ET AL.: "Kocuran, an exopolysaccharide isolated from Kocuria rosea strain BS-1 and evaluation of its in vitro immunosuppression activities", ENZYME MICROB TECHNOL, vol. 55, 2014, pages 113 - 120, XP028812858 *
LI, S. ET AL.: "Characterization, anti- inflammatory and antiproliferative activities of natural and sulfonated exo-polysaccharides from Streptococcus thermophilus ASCC 1275", JFOOD SCI, vol. 81, no. 5, 2016, pages M1167 - M1176, XP055542877 *
MAKINO, SEIYA ET AL.: "Immunoregulatory effects of Lactobacillus delbrueckii ssp. Bulgaricus OLL1073R-1.", JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRYPROCEEDINGS OF THE ANNUAL MEETING OF THE JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRY, 2011, pages 55 *
MAKINO, SEIYA ET AL.: "Immunostimulatory effects of exopolysaccharides produced by Lactobaccillus delbrueckii ssp. Bulgaricus OLL1073R-1", MILK SCIENCE, vol. 64, no. 3, 2015, pages 271 - 277 *
MAKINO, SEIYA: "Immunostimulatory Effects of Yogurt Fermented with Lactobacillus delbrueckii ssp . Bulgaricus OLL1073R-1 and its EPS", JOURNAL OF INTESTINAL ICROBIOLOGY, vol. 29, 2015, pages 163 - 167, XP055542864 *
MATSUZAKI, CHIAKI ET AL.: "Immunomodulating activity of exopolysaccharides produced by Leuconostoc mesenteroides strain NTM 048.", JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRYANNUAL MEETING OF THE JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRY, 2015, XP055272799 *
WACHI, SATOSHI ET AL.: "Lactobacillus delbrueckii TUA4408L and its extracellular polysaccharides attenuate enterotoxigenic Escherichia coli-induced inflammatory response in porcine intestinal epitheliocytes via Toll-like receptor-2 and 4", MOL NUTR FOOD RES, vol. 58, 2014, pages 2080 - 2093, XP055542870 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019087993A1 (fr) * 2017-10-31 2019-05-09 株式会社 明治 Lait fermenté et polysaccharide ayant une action inhibitrice de la cachexie cancéreuse
CN111201026A (zh) * 2017-10-31 2020-05-26 株式会社明治 具有癌性恶病质抑制作用的发酵乳和多糖类
US11638431B2 (en) 2017-10-31 2023-05-02 Meiji Co., Ltd. Fermented milk and polysaccharide with cancerous cachexia inhibitory effect
CN111201026B (zh) * 2017-10-31 2023-09-19 株式会社明治 具有癌性恶病质抑制作用的发酵乳和多糖类

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JP2018177740A (ja) 2018-11-15
JP7017864B2 (ja) 2022-02-09

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