WO2022139531A1 - Composition pour améliorer, prévenir ou traiter une stéatose hépatique comprenant des vésicules extracellulaires dérivées de leuconostoc citreum en tant que principe actif - Google Patents

Composition pour améliorer, prévenir ou traiter une stéatose hépatique comprenant des vésicules extracellulaires dérivées de leuconostoc citreum en tant que principe actif Download PDF

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WO2022139531A1
WO2022139531A1 PCT/KR2021/019782 KR2021019782W WO2022139531A1 WO 2022139531 A1 WO2022139531 A1 WO 2022139531A1 KR 2021019782 W KR2021019782 W KR 2021019782W WO 2022139531 A1 WO2022139531 A1 WO 2022139531A1
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Prior art keywords
fatty liver
preventing
pharmaceutical composition
extracellular vesicles
leuconostoc citreum
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PCT/KR2021/019782
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English (en)
Korean (ko)
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진화섭
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주식회사 리스큐어바이오사이언시스
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Priority claimed from KR1020210186080A external-priority patent/KR20220091428A/ko
Publication of WO2022139531A1 publication Critical patent/WO2022139531A1/fr

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    • 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
    • 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

Definitions

  • the present invention relates to a composition for improving, preventing or treating fatty liver.
  • Fatty liver is a disease in which fat is accumulated in hepatocytes due to the ingestion of fat and consequent accumulation of fat in the liver, increase in synthesis, decrease in decomposition, and excessive alcohol intake.
  • the number of patients with fatty liver is increasing rapidly due to a westernized high-fat, high-calorie diet and lack of exercise. If fat is continuously accumulated in the liver, it progresses to steatohepatitis accompanied by inflammation, and it progresses to necrosis or fibrosis of the liver tissue, which is known as a major cause of cirrhosis and liver cancer.
  • the fatty liver can be classified into alcoholic fatty liver disease (Alcoholic Steatosis, Alcoholic Fatty Liver Disease) and nonalcoholic fatty liver disease (NAFLD, Nonalcoholic Fatty Liver Disease) caused by chronic drinking, and non-alcoholic fatty liver disease is generally a two-stage disease can be distinguished as First, as the most common type, there is nonalcoholic simple fatty liver (NAFL, Nonalcoholic Fatty Liver), and secondly, there is nonalcoholic steatohepatitis (NASH, Nonalcoholic Steatohepatitis) as a type of severe disease.
  • NASH Nonalcoholic Steatohepatitis
  • Such nonalcoholic steatohepatitis is a disease in which inflammation is induced in liver cells by fatty liver.
  • Another object of the present invention is to inhibit the accumulation of fat in hepatocytes and promote the expression of Claudin 1, a close junction-related gene, to strengthen the close junction between enterocytes, thereby inhibiting the movement of inflammatory substances to prevent or improve fatty liver. to provide a composition, and a feed or feed additive.
  • a pharmaceutical composition for preventing or treating fatty liver comprising Leuconostoc citreum-derived extracellular vesicles as an active ingredient is provided.
  • the fatty liver may be any one selected from alcoholic fatty liver (Alcoholic Fatty Liver), alcoholic steatohepatitis (ASH), nonalcoholic simple fatty liver (NAFL, Nonalcoholic Fatty Liver) and nonalcoholic steatohepatitis (NASH, Nonalcoholic Steatohepatitis). .
  • the pharmaceutical composition for preventing or treating fatty liver may be for inhibiting fatty acid accumulation in hepatocytes.
  • the pharmaceutical composition for preventing or treating fatty liver may be for promoting expression of a tight junction gene in enterocytes.
  • the tight junction gene may be Claudin 1.
  • the leuconostoc citrium may be leuconostoc citreum WiKim0104 (Leuconostoc citreum WiKim0104) deposited with accession number KCCM12420P.
  • a food composition for preventing or improving fatty liver comprising Leuconostoc citreum-derived extracellular vesicles as an active ingredient.
  • a feed or feed additive for preventing or improving fatty liver comprising Leuconostoc citreum-derived extracellular vesicles as an active ingredient is provided.
  • the pharmaceutical composition for preventing or treating fatty liver of the present invention inhibits fat accumulation in hepatocytes and promotes the expression of Claudin 1, a tight junction gene, to strengthen tight junctions between intestinal cells, thereby moving inflammatory substances By inhibiting fatty liver, it is possible to prevent or treat fatty liver.
  • the food composition for preventing or improving fatty liver of the present invention, and feed or feed additive inhibit fat accumulation in hepatocytes and promote the expression of Claudin 1, a tight junction gene, to form a tight junction between intestinal cells. By strengthening it, it is possible to prevent or improve fatty liver by inhibiting the movement of inflammatory substances.
  • FIG. 1 is an electron micrograph of an extracellular vesicle derived from Leukonostok citrium isolated according to Example 1.
  • the pharmaceutical composition for preventing or treating fatty liver of the present invention includes Leuconostoc citreum-derived extracellular vesicles as an active ingredient.
  • the leukonostok citrium is not limited, but is preferably a leukonostok citrium derived from kimchi, and more preferably a leukonostok citrium deposited with accession number KCCM12420P.
  • the fatty liver may be any one selected from alcoholic fatty liver (Alcoholic Fatty Liver), alcoholic steatohepatitis (ASH), nonalcoholic simple fatty liver (NAFL, Nonalcoholic Fatty Liver) and nonalcoholic steatohepatitis (NASH, Nonalcoholic Steatohepatitis). .
  • the pharmaceutical composition for preventing or treating fatty liver may be for inhibiting fatty acid accumulation in hepatocytes.
  • the pharmaceutical composition for preventing or treating fatty liver may be for promoting expression of a tight junction gene in enterocytes.
  • the tight junction gene may be Claudin 1.
  • a tight junction is a type of cell junction that limits the movement of substances between connected cells, and is wound around the cell in the form of a band.
  • a tight junction can be formed by partially fusion of the cell membrane of an adjacent cell by a protein called claudin and occludin. It is mainly present in humans and vertebrates, and it can also play a role in preventing harmful substances in the blood from reaching the cerebrospinal fluid by creating a blood-brain barrier.
  • extracellular vesicle refers to a vesicle having a lipid bilayer structure with a diameter ranging from 20 to 1,000 nm that is secreted into the extracellular environment through the fusion of polycystic bodies and plasma membranes in various cells.
  • the average diameter of the extracellular vesicles produced by the method of the present invention may be in the range of 20 to 500 nm, preferably 50 to 300 nm, more preferably 100 to 200 nm. .
  • Extracellular vesicles having a microdiameter within this range are called exosomes.
  • step a culturing Leuconostoc citreum
  • Leukonostok citrium can be obtained from the stock solution of the kimchi extract.
  • the culture supernatant is recovered by centrifugation of the culture medium in which the Leukonostok citrium is cultured (step b).
  • the culture supernatant is mixed with a solution containing sodium chloride and an organic solvent and reacted, followed by centrifugation to obtain an extracellular vesicle pellet (step c).
  • the culture supernatant and the solution containing sodium chloride and the organic solvent may be mixed in a volume ratio of 1:0.5 to 1:1.5, preferably in a volume ratio of 1:0.8 to 1:1.2, more preferably the same amount can be mixed with
  • the organic solvent may be polyethylene glycol.
  • the solution containing sodium chloride and the organic solvent preferably has a sodium chloride concentration of 0.5 to 1 M.
  • centrifugation may be performed, and then the mixing and centrifugation may be repeated.
  • extracellular vesicle pellet is resuspended in extracellular vesicle extraction buffer to prepare a suspension, and the extracellular vesicles are isolated from the suspension (step d).
  • the term 'comprising as an active ingredient' means including an amount sufficient to achieve the efficacy or activity of leukonostok citrium-derived extracellular vesicles.
  • the leukonostok citrium-derived extracellular vesicles in the composition of the present invention are, for example, 0.001 mg/kg or more, preferably 0.1 mg/kg or more, more preferably 10 mg/kg or more. kg or more, even more preferably 100 mg/kg or more, even more preferably 250 mg/kg or more, and most preferably 1 g/kg or more.
  • Leuconostok citrium-derived extracellular vesicles are natural products, and since there is no side effect to the human body even when administered in excess, the upper quantitative limit of the leuconostok citrium-derived extracellular vesicles contained in the composition of the present invention is selected and carried out by those skilled in the art within an appropriate range can do.
  • the pharmaceutical composition of the present invention may be prepared by using a pharmaceutically suitable and physiologically acceptable adjuvant in addition to the active ingredient, and the adjuvant includes an excipient, a disintegrant, a sweetener, a binder, a coating agent, a swelling agent, a lubricant, and a lubricant. agent or flavoring agent, etc. may be used.
  • the pharmaceutical composition may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the active ingredients described above for administration.
  • Formulations of the pharmaceutical composition may be granules, powders, tablets, coated tablets, capsules, suppositories, solutions, syrups, juices, suspensions, emulsions, drops or injectables.
  • the active ingredient may be combined with an orally, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrants and color-developers may also be included in the mixture.
  • Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • acceptable pharmaceutical carriers are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostats may be added as needed.
  • diluents, dispersants, surfactants, binders and lubricants may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets.
  • the pharmaceutical composition of the present invention may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc., preferably oral administration.
  • a suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration mode, age, weight, pathological condition, food, administration time, route of administration, excretion rate, and response sensitivity of the patient, usually skilled A trained physician can readily determine and prescribe an effective dosage for the desired treatment or prevention.
  • the daily dose of the pharmaceutical composition of the present invention is 0.001-10 g/kg.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. Alternatively, it may be prepared by being introduced into a multi-dose container. At this time, the formulation may be in the form of a solution, suspension, or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
  • the present invention provides a food composition for preventing or improving fatty liver comprising Leuconostoc citreum-derived extracellular vesicles as an active ingredient.
  • the leuconostok citrium is not limited, but is preferably a leukonostok citrium derived from kimchi, and more preferably a leuconostok citrium deposited under the accession number KCCM12420P.
  • the content of the leuconostok citrium-derived extracellular vesicles is the same as the description in the pharmaceutical composition for preventing or treating fatty liver comprising the above-described leuconostok citrium-derived extracellular vesicles as an active ingredient. to refer.
  • the food composition according to the present invention may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.
  • Foods to which the composition of the present invention can be added include, for example, beverages, alcoholic beverages, sweets, diet bars, dairy products, meat, chocolate, pizza, ramen, other noodles, gums, ice cream, vitamin complexes, health supplements etc.
  • the food composition of the present invention may include not only the active ingredients, but also ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents.
  • examples of the above-mentioned carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • flavoring agents natural flavoring agents [taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
  • stevia extract eg, rebaudioside A, glycyrrhizin, etc.
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the present invention provides a health functional food comprising a food composition for preventing or improving fatty liver comprising the leuconostok citrium-derived extracellular vesicles as an active ingredient.
  • Health functional food is a food prepared by adding Leukonostok citrium-derived extracellular vesicles to food materials such as beverages, teas, spices, gum, and confectionery, or by encapsulating, powdering, or suspension, etc. It means to bring a specific effect, but unlike general drugs, it has the advantage that there are no side effects that may occur when taking the drug for a long time using food as a raw material.
  • the health functional food of the present invention obtained in this way is very useful because it can be ingested on a daily basis.
  • the amount of leukonostok citrium-derived extracellular vesicles added in such health functional food varies depending on the type of health functional food and cannot be uniformly defined, but it can be added within a range that does not impair the original taste of the food. , It is usually in the range of 0.01 to 50% by weight, preferably 0.1 to 20% by weight, based on the target food.
  • a health functional food in the form of pills, granules, tablets or capsules it is usually added in an amount of 0.1 to 100% by weight, preferably 0.5 to 80% by weight.
  • the health functional food of the present invention may be in the form of pills, tablets, capsules or beverages.
  • the leukonostok citrium-derived extracellular vesicles according to the present invention or a composition comprising the same as an active ingredient may be used as a feed additive or feed.
  • the composition When used as a feed additive, the composition may be 20 to 90% highly concentrated or prepared in powder or granular form.
  • the feed additives include organic acids such as citric acid, humic acid, adipic acid, lactic acid, and malic acid, phosphates such as sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, rosemary Extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, any one or more of natural antioxidants such as phytic acid may be further included.
  • the composition When used as a feed, the composition may be formulated in the form of a conventional feed, and may include common feed ingredients together.
  • the feed additive and feed include grains such as milled or crushed wheat, oats, barley, corn and rice; plant protein feeds, such as feeds based on rape, soybean, and sunflower; animal protein feeds such as blood meal, meat meal, bone meal and fish meal; Sugar and dairy products, for example, may further include dry ingredients made of various powdered milk and whey powder, and may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.
  • the feed additive may be administered alone or in combination with other feed additives in an edible carrier.
  • the feed additive can be easily administered to the animal as a top dressing, directly mixing them with animal feed, or in an oral formulation separate from the feed.
  • a pharmaceutically acceptable edible carrier as well known in the art, and may be prepared into an immediate release or sustained release formulation.
  • Such edible carriers may be solid or liquid, for example cornstarch, lactose, sucrose, soybean flakes, peanut oil, olive oil, sesame oil and propylene glycol.
  • the feed additive may be a tablet, a capsule, a powder, a troche or a sugar-containing tablet, or a top dressing in a microdispersed form.
  • the feed additive may be in the form of a gelatin soft capsule, or a syrup, suspension, emulsion, or solution.
  • the feed additives and feed may contain auxiliary agents, for example, preservatives, stabilizers, wetting or emulsifying agents, solution accelerators, and the like.
  • the feed additive may be used by adding to animal feed by immersion, spraying, or mixing.
  • the feed or feed additive of the present invention can be applied to a number of animal diets including mammals, poultry and fish.
  • the mammal it can be used for pigs, cattle, sheep, goats, laboratory rodents, and laboratory rodents, as well as pets (eg, dogs, cats), etc., as the poultry, chickens, turkeys, ducks, geese, pheasants, and quail, and the like, and may be used as the fish such as trout, but is not limited thereto.
  • the present invention provides a use of the leukonostok citrium-derived extracellular vesicles for the manufacture of a medicament or food for preventing, treating or improving fatty liver.
  • the leukonostok citrium-derived extracellular vesicles can be used for the treatment or improvement of fatty liver.
  • the present invention provides a method for improving, preventing or treating fatty liver comprising administering to a mammal an effective amount of an extracellular vesicle derived from leukonostok citrium.
  • mammal refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
  • the term "effective amount” refers to the amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human as conceived by a researcher, veterinarian, physician or other clinician, which is the disease in question. or an amount that induces alleviation of the symptoms of the disorder.
  • the effective amount and frequency of administration for the active ingredient of the present invention may vary depending on the desired effect.
  • the optimal dosage to be administered can be easily determined by those skilled in the art, and the type of disease, the severity of the disease, the content of active ingredients and other components contained in the composition, the type of formulation, and the age, weight, and general health of the patient It can be adjusted according to various factors including state, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs.
  • the extract for adults, it is preferable to administer the extract at a dose of 0.001 g/kg to 10 g/kg when administered once to several times a day.
  • the composition comprising leuconostok citrium-derived extracellular vesicles as an active ingredient is administered by oral, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, transdermal, topical, or intradermal routes. It can be administered in a conventional manner.
  • the Leukonostok Citrium Wikim0104 (Accession No. KCCM12420P) strain was tested with the permission of the Korea Food Research Institute, the depositor. 0.1% of the received leuconostok citrium strain was inoculated into 30 ml of MRS liquid medium and cultured at 30° C. for 18 hours. After incubation, centrifuged at 3000 rpm for 10 minutes, the culture medium was stored separately for nano-vesicle separation, and the cells were washed three times with a PBS (phosphate buffered saline) solution to remove the remaining medium components.
  • PBS phosphate buffered saline
  • the culture solution obtained after culturing the strain and 1M NaCl solution containing 16% PEG 6000 were mixed in equal amounts and reacted at 4°C for 15 hours. Then, the reacted solution was centrifuged at 10,000 g and 4° C. for 20 minutes to obtain an extracellular vesicle pellet.
  • the nano-ER pellet was resuspended in 0.5M NaCl solution containing 5% PEG6000 and washed, followed by centrifugation at 11,000 rpm at 4°C for 20 minutes. Thereafter, the supernatant was discarded and the pellet was resuspended in 1X PBS to finally separate the leukonostok citrium-derived extracellular vesicles.
  • An electron microscope image of the isolated leuconostok citrium-derived extracellular vesicles is shown in FIG. 1 .
  • Example 1 A leukonostok citrium strain culture solution in (1) of Example 1 was prepared .
  • a strain of leukonostok citrium (accession number KCCM12420P) cultured according to (1) of Example 1 was prepared.
  • the particles were separated in the same manner as the extracellular vesicle separation method in (2) of Example 1.
  • HT-29 cells which are human-derived colorectal cancer cells
  • HepG2 cells which are human-derived liver cancer cells
  • RPMI-1640 medium supplemented with penicillin/streptomycin and 10% fetal bovine serum (FBS) at 37° C., 5% CO 2 condition. It was prepared by culturing in HT-29 cells were plated in the upper chamber of a 12-well plate Transwell chamber (4 ⁇ m pore size), and a cover slip was put in the lower chamber, and 2X10 5 HepG2 cells were plated thereon. After 24 hours, HepG2 cells in the lower chamber were treated with 250 ⁇ M of oleic acid and palmitic acid in serum free media for 24 hours to induce adipogenesis and accumulation in hepatocytes. .
  • Each particle was treated for 24 hours. Thereafter, the upper chamber was removed and the cells in the lower chamber were washed twice with 1X PBS and then fixed with 4% paraformaldehyde at room temperature for 15 minutes. After washing twice with PBS, it was reacted at 37° C. for 15 minutes with 5 ⁇ g/ml of BODIPY dye for fat staining.
  • Primer information and PCR test conditions are as follows.
  • HT-29 cells which are human-derived colorectal cancer cells, were plated on a 6-well plate, and when the cells were sufficiently grown, 1 ⁇ g/ml of LPS and 500 ⁇ M of palmitic acid were treated in serum-free media.
  • Leukonostok citrium-derived extracellular vesicles of Example 1 the strain culture medium of Comparative Example 1, the Leukonostok citrium bacteria of Comparative Example 2 (1X10 7 CFU), and the particles derived from the culture medium of Comparative Example 3, respectively, for close contact
  • the expression level of the gene claudin 1 (Claudin 1) gene was measured, and the result is shown in FIG. 3 .
  • the above ingredients are mixed and filled in an airtight bag to prepare a powder.
  • tablets are prepared by tableting according to a conventional manufacturing method of tablets.
  • the above ingredients are mixed and filled in a gelatin capsule to prepare a capsule.
  • the content of the above ingredients per 1 ampoule is prepared.
  • each component is added to purified water to dissolve, an appropriate amount of lemon flavor is added, the above components are mixed, purified water is added, the whole is adjusted to 100 g by adding purified water, and then filled in a brown bottle to sterilize to prepare a liquid.
  • composition ratio of the vitamin and mineral mixture is relatively suitable for granules in a preferred embodiment, but the mixing ratio may be arbitrarily modified. It can be prepared and used in the preparation of a health functional food composition according to a conventional method.
  • the resulting solution is filtered and obtained in a sterilized 2 L container, sealed and sterilized, then refrigerated. It is used to prepare the functional beverage composition of the present invention.
  • composition ratio is prepared by mixing ingredients suitable for relatively favorite beverages in a preferred embodiment, the mixing ratio may be arbitrarily modified according to regional and national preferences such as demand class, demanding country, and use.
  • the pharmaceutical composition for preventing or treating fatty liver of the present invention inhibits fat accumulation in hepatocytes and promotes expression of Claudin 1, a tight junction gene, to strengthen tight junctions between intestinal cells, thereby moving inflammatory substances By inhibiting fatty liver, it is possible to prevent or treat fatty liver.
  • the food composition for preventing or improving fatty liver of the present invention, and feed or feed additive inhibit fat accumulation in hepatocytes and promote the expression of Claudin 1, a tight junction gene, to form a tight junction between intestinal cells. By strengthening it, it is possible to prevent or improve fatty liver by inhibiting the movement of inflammatory substances.

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Abstract

La présente invention concerne une composition pharmaceutique destinée à prévenir ou traiter une stéatose hépatique comprenant des vésicules extracellulaires dérivées de Leuconostoc citreum en tant que principe actif. En conséquence, la composition de la présente invention inhibe l'accumulation de graisse dans les hépatocytes et favorise l'expression de claudine-1, qui est un gène de jonction serrée, pour renforcer la jonction serrée entre les entérocytes, ce qui permet d'inhiber le mouvement de substances inflammatoires pour ainsi prévenir, traiter ou améliorer la stéatose hépatique.
PCT/KR2021/019782 2020-12-23 2021-12-23 Composition pour améliorer, prévenir ou traiter une stéatose hépatique comprenant des vésicules extracellulaires dérivées de leuconostoc citreum en tant que principe actif WO2022139531A1 (fr)

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KR20200181542 2020-12-23
KR10-2020-0181542 2020-12-23
KR1020210186080A KR20220091428A (ko) 2020-12-23 2021-12-23 류코노스톡 시트리움 유래 세포밖 소포체를 유효성분으로 포함하는 지방간 개선, 예방 또는 치료용 조성물
KR10-2021-0186080 2021-12-23

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KR20200053531A (ko) * 2017-09-08 2020-05-18 에벨로 바이오사이언시즈, 인크. 박테리아 세포외 소포

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Publication number Priority date Publication date Assignee Title
KR101873193B1 (ko) * 2010-06-08 2018-07-02 아사히 그룹 홀딩스 가부시키가이샤 지질 대사 개선제
KR20160110232A (ko) * 2015-03-11 2016-09-21 주식회사 엠디헬스케어 유산균 유래 세포밖 소포체를 유효성분으로 포함하는 염증질환의 예방 또는 치료용 조성물
KR20200053531A (ko) * 2017-09-08 2020-05-18 에벨로 바이오사이언시즈, 인크. 박테리아 세포외 소포
KR20190143336A (ko) * 2018-06-19 2019-12-30 주식회사 엠디헬스케어 류코노스톡속 균주를 포함하는 간 기능 개선용 조성물
KR102032982B1 (ko) * 2019-02-28 2019-10-16 한국식품연구원 류코노스톡 시트래움 WiKim0104를 포함하는 비만 또는 지방간 질환의 예방, 개선 또는 치료용 조성물

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