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WO2017018336A1 - Agent anti-inflammatoire - Google Patents

Agent anti-inflammatoire Download PDF

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Publication number
WO2017018336A1
WO2017018336A1 PCT/JP2016/071510 JP2016071510W WO2017018336A1 WO 2017018336 A1 WO2017018336 A1 WO 2017018336A1 JP 2016071510 W JP2016071510 W JP 2016071510W WO 2017018336 A1 WO2017018336 A1 WO 2017018336A1
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WO
WIPO (PCT)
Prior art keywords
keto
inflammatory
inflammatory agent
aldohexose
carbohydrate
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/JP2016/071510
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English (en)
Japanese (ja)
Inventor
恵三 河野
丸田　和彦
崇行 北村
章弘 藤田
森　哲也
西本　友之
惠温 福田
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Hayashibara Co Ltd
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Hayashibara Co Ltd
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Publication date
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Priority to JP2017530833A priority Critical patent/JP6729913B2/ja
Publication of WO2017018336A1 publication Critical patent/WO2017018336A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • 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
    • 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
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/14—Preparations for removing make-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/10—Washing or bathing preparations

Definitions

  • the present invention relates to an anti-inflammatory agent, and more particularly, to an anti-inflammatory agent that exerts an anti-inflammatory effect by suppressing the production of tumor necrosis factor ⁇ (TNF- ⁇ ) and interleukin 8 (IL-8). It is.
  • TNF- ⁇ tumor necrosis factor ⁇
  • IL-8 interleukin 8
  • Inflammation is a local transient reaction exhibited by the living body when a substance that causes some harmful stimulation (flame-causing substance) acts on living tissue, and is a kind of biological defense reaction. However, since it also damages biological tissues, when inflammation becomes chronic, an excessive inflammatory reaction is rather harmful. In recent years, the number of patients related to a wide variety of inflammatory diseases has been increasing as a whole due to changes in lifestyle, increased oxidative stress due to air pollution, exposure to exhaust gas and excessive ultraviolet rays, and the like.
  • Dipotassium glycyrrhizinate (hereinafter sometimes abbreviated as “GK2”) is widely used as an anti-inflammatory component in cosmetics such as skin care products, quasi-drugs such as toothpaste, and pharmaceuticals such as stomatitis treatment agents.
  • GK2 is a derivative of glycyrrhizic acid contained in the roots of licorice (licorice), a leguminous plant, and has an excellent anti-inflammatory effect, but has a steroid-like action, so the upper limit of the compounding ratio and amount used Is strictly regulated. Under such circumstances, there is a demand for an anti-inflammatory agent that can be used with peace of mind for the prevention and treatment of inflammatory diseases in addition to alleviation and improvement of inflammatory symptoms.
  • nigerose 3-O- ⁇ -glucosylglucose
  • IL-6 interleukin 6
  • Patent Document 2 a saccharide composed of neoagarobiose, neoagarotetraose and neoagarohexaose obtained by degrading agarose (agar) with ⁇ -agarase suppresses IL-6 production. It can be used as an anti-inflammatory agent. Further, Non-Patent Document 1 discloses that D-psicose, which is a kind of ketohexose, has an anti-inflammatory action. In addition, Patent Document 3 discloses an anti-inflammatory food containing trehalose and chondroitin sulfate.
  • the anti-inflammatory agent containing the above-mentioned carbohydrate as an active ingredient is highly safe, but has a relatively weak anti-inflammatory action, and the desired effect may not be obtained unless it is used in a large amount. was there. Under such circumstances, in addition to alleviating and improving inflammatory symptoms, development of safe anti-inflammatory agents that are more effective and have fewer side effects is desired for the prevention and treatment of inflammatory diseases.
  • An object of the present invention is to provide a safe anti-inflammatory agent that is effective in alleviating and improving inflammatory symptoms, and further preventing or treating inflammatory diseases and has few side effects, and contains the inflammatory agent. It is an object to provide cosmetics, quasi-drugs, foods and pharmaceuticals. It is another object of the present invention to provide a method for improving the anti-inflammatory action of a carbohydrate having an aldohexose structure in the molecule.
  • the present inventors searched for substances having an anti-inflammatory action stronger than the above-mentioned sugars that have been conventionally known to have an anti-inflammatory action for carbohydrates that are generally expected to have high safety. .
  • many of the excessive inflammatory reactions in the body are caused by excess of inflammatory cytokines such as tumor necrosis factor ⁇ (TNF- ⁇ ), interleukin 6 (IL-6), and interleukin 8 (IL-8).
  • TNF- ⁇ tumor necrosis factor ⁇
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • a carbohydrate having a ketoaldhexose structure in the molecule strongly shows the action of suppressing the production of inflammatory cytokines, but at the same time, it does not show cytotoxicity at an effective concentration, and is a safe anti-inflammatory agent with few side effects
  • the present invention was completed by finding that it can be used as an active ingredient.
  • this invention solves the said subject by providing the anti-inflammatory agent which contains the carbohydrate which has keto aldohexose structure in a molecule
  • the present invention solves the above problems by providing a cosmetic, quasi-drug, food, and pharmaceutical containing an anti-inflammatory agent containing a carbohydrate having a ketoaldhexose structure in the molecule as an active ingredient. It is.
  • the present invention provides a molecule characterized in that in a saccharide having an aldohexose structure in the molecule, a free hydroxyl group not bonded to another saccharide or substituent in the aldhexose structure is converted to a keto group.
  • a safe anti-inflammatory agent that suppresses the production of inflammatory cytokines and has few side effects can be provided.
  • the production of inflammatory cytokines such as TNF- ⁇ and IL-8 can be remarkably suppressed, so that the inflammatory symptoms caused by the overproduction of these inflammatory cytokines can be alleviated. It can be used for improvement, and further for prevention and treatment of inflammatory diseases.
  • the anti-inflammatory agent of the present invention can be advantageously used as an oral preparation or an external preparation for cosmetics, quasi-drugs, foods, pharmaceuticals, etc., and in particular, as an anti-inflammatory agent for skin inflammation, sufficient anti-inflammatory action Since it has high safety, it can be advantageously used.
  • the present invention relates to an anti-inflammatory agent containing a carbohydrate having a ketoaldhexose structure in the molecule as an active ingredient.
  • the “saccharide having a ketoaldhexose structure in the molecule” as used in the present invention is a free carbohydrate that is not bonded to other carbohydrates or substituents in aldohexose (hexose sugar having an aldehyde group at the 1-position). It means a saccharide having a structure in which any one of hydroxyl groups is oxidized and converted into a keto group in the molecule and derivatives thereof.
  • a “carbohydrate having a ketoaldhexose structure in the molecule” is a method (enzyme) that causes a microbial enzyme to act on a raw sugar or a derivative thereof, even if it is synthesized organically, regardless of its origin or production method.
  • hexose (hexose) is classified into aldohexose having an aldehyde group at the 1st position and ketohexose having a ketone group at the 2nd position, and as the aldohexose, allose, altrose, glucose, mannose, gulose, Eight kinds of idose, galactose and talose are known. Also, four types of ketohexose are known: psicose, fructose, sorbose and tagatose.
  • the “carbohydrate having a ketoald hexose structure in the molecule” as used in the present invention is usually constituted by a D-form having a high abundance ratio in nature.
  • the “carbohydrate having a keto aldohexose structure in the molecule” used as an active ingredient in the anti-inflammatory agent of the present invention is not particularly limited, the hydroxyl group at the 3-position or 2-position of the aldohexose is oxidized and converted to a keto group.
  • a carbohydrate having a ketoaldhexose structure or a 2-ketoaldhexose structure in the molecule and a derivative thereof are preferably used.
  • a saccharide having a 3-ketoaldhexose structure in the molecule and a derivative thereof (hereinafter abbreviated as “3-ketosaccharide” in the present specification) or a saccharide having a 2-ketoaldhexose structure and a derivative thereof (Hereinafter, abbreviated as “2-ketosugar” in the present specification) can be suitably used whether it is a monosaccharide, a homo- or hetero-oligosaccharide or higher oligosaccharide, or a polysaccharide. it can.
  • Examples of monosaccharides included in the 3-keto sugar in the present invention include 3-ketoglucose in which the hydroxyl group at the 3-position of glucose is oxidized and converted into a keto group, and the hydroxyl group at the 3-position in galactose is oxidized and converted into a keto group. And 3-ketogalactose.
  • Examples of monosaccharide derivatives include methyl ⁇ -3-ketoglucoside or methyl ⁇ -, which is obtained by oxidizing the hydroxyl group at the 3-position of each glucose residue of methyl ⁇ -glucoside or methyl ⁇ -glucoside into a keto group.
  • Examples include methyl ⁇ -3-ketogalactoside or methyl ⁇ -3-ketogalactoside in which the 3-position hydroxyl group of each galactose residue of 3-ketoglucoside, methyl ⁇ -galactoside or methyl ⁇ -galactoside is oxidized and converted to a keto group Can be mentioned.
  • Examples of other monosaccharide derivatives include 1,5-anhydro-3-ketoglucitol in which the 3-position hydroxyl group of 1,5-anhydroglucitol is oxidized and converted to a keto group.
  • Examples of the disaccharides included in the 3-ketosaccharide in the present invention include cordibiose (2-O- ⁇ -glucosylglucose) and nigerose (3-O- ⁇ , which are reducing glucodisaccharides in which two glucose molecules are bound.
  • 3-ketosucrose O- ⁇ -3-ketoglucosyl (1 ⁇ 2) ⁇ -fructoside
  • 3-ketoisomaltulose (6-O- ⁇ -3-ketoglucosyl fructose)
  • 3-keto sugar examples include maltose, maltitol, which is a sugar alcohol obtained by reducing the aldehyde group of the reducing terminal glucose of isomaltose, or the hydroxyl group at the 3-position of the glucose residue of isomaltol Of 3-ketomaltitol (4-O- ⁇ -3-ketoglucosyl sorbitol) or 3-ketoisomaltitol (6-O- ⁇ -3-ketoglucosyl sorbitol) in which is further converted to a keto group; 3-ketolactitol (4-O- ⁇ -3-ketogalactosylsorbitol) in which the hydroxyl group at the 3-position of the galactose residue is further converted to a keto group in lactitol, which is a sugar alcohol in which the aldehyde group of the reducing end glucose is reduced; Etc.
  • maltose maltitol
  • maltitol which is a sugar alcohol obtained by reducing the aldeh
  • Examples of the trisaccharide included in the 3-ketosaccharide in the present invention include 3 of the terminal glucose residues of meletitol (3 F- O- ⁇ -glucosyl sucrose) and erulose (4 G -O- ⁇ -glucosyl sucrose). 3-ketomeletitol (3 F- O- ⁇ -3-ketoglucosyl sucrose) and 3-keto effetose (4 G- O- ⁇ -3-ketoglucosyl sucrose) in which the hydroxyl group is converted to a keto group, maltotriose And 3-ketomaltotriose (4-O- ⁇ -3-ketoglucosyl maltose) in which the hydroxyl group at the 3-position of the non-reducing terminal glucose residue is converted to a keto group.
  • the hydroxyl group at the 1-position can take the structure of an aldehyde group and thus exhibits a reducing power, and the keto group at the 3-position further exhibits a reducing power and is highly reactive. As a compound, it becomes unstable.
  • a more stable 3-keto sugar is desirable, and when it is a monosaccharide, the hydroxyl group at the 1-position is bonded to a substituent other than the sugar, thereby changing the structure of the aldehyde group. It is more preferable that only the keto group at the 3 position shows a reducing power without taking it.
  • Examples of such 3-ketosaccharide monosaccharides include methyl ⁇ -3-ketoglucoside and methyl ⁇ -3-ketoglucoside in which the hydroxyl group at the 1-position is methylated.
  • the 3-keto sugar is a reducing disaccharide
  • 3-ketotrehalose and 3-ketosucrose obtained from trehalose and sucrose, which are non-reducing disaccharides, and 3,3′-diketotrehalose obtained from trehalose are also preferably used.
  • a sugar alcohol obtained by reducing the aldehyde group of the reducing terminal glucose of the disaccharide can be suitably used because it does not show reducibility and is more stable as a compound.
  • Examples of such a dike sugar alcohol of 3-keto sugar include 3-keto maltitol, 3-keto isomaltitol, and 3-ketolactitol.
  • the 3-keto sugar in the present invention is not particularly limited as long as it is a saccharide having a 3-keto aldohexose structure, but many saccharides having a glucose structure or a galactose structure in the molecule exist in nature, and From these carbohydrates, the production rate of 3-ketosugar by enzymatic method or fermentation method is high. Therefore, for the purpose of carrying out the present invention advantageously in the industry, 3-ketoglucose structure or A carbohydrate having a 3-ketogalactose structure is particularly preferably used.
  • 3-ketosugar is prepared by enzymatic oxidation or fermentation using a 3-ketosugar-forming enzyme that can selectively oxidize the 3-position hydroxyl group of aldohexose to produce the desired 3-ketosugar. Done by law.
  • microorganisms capable of producing glucoside 3-dehydrogenase include Rhizobium radiobacter (formerly Agrobacterium tumefaciens), Flavobacterium saccharophilum, and Flavobacterophyllum. Examples thereof include microorganisms belonging to the genus Sphaingobacterium faecium, the genus Halomonas, the genus Cytophaga, and the genus Agaricus.
  • microorganisms capable of producing a pyranose dehydrogenase include Agaricus bisporus, Agaricus meleagris, Agaricus xanthododerma, and Macrolepiota a crocod. .
  • pyranose dehydrogenase not only oxidizes the hydroxyl group at the 3-position of the saccharide aldhexose depending on the reaction conditions and the substrate to be reacted, but may oxidize the hydroxyl groups at the 2- and 4-positions.
  • glucoside 3-dehydrogenase that selectively oxidizes only the hydroxyl group at the 3-position of aldohexose is more preferably used.
  • 3-Ketosugar is usually converted (oxidized) by enzymatic reaction by causing the above-mentioned glucoside 3-dehydrogenase or pyranose dehydrogenase to act on a solution containing the raw sugar or its derivative.
  • the produced 3-keto sugar is recovered from the reaction solution and purified by a method, or the above glucoside 3-dehydrogenase is used in a liquid medium containing a saccharide as a raw material or a derivative thereof as a carbon source.
  • a microorganism capable of producing a 3-ketosugar-producing enzyme such as pyranose dehydrogenase is cultured, and the 3-ketosugar produced by microbial conversion (oxidation) of the raw material carbohydrate or its derivative in the culture solution is cultured in the culture solution. It is manufactured by a method of further recovery and purification. Recovery and purification of 3-ketosugar from the reaction solution or culture solution include removal of cells and enzymes by centrifugation, removal of proteins and the like that are insolubilized by heat treatment of the culture solution and reaction solution supernatant, alcohol precipitation treatment, etc.
  • 3-keto disaccharides such as 3-keto maltose, 3-keto sucrose, 3-ketolactose, and 3-keto trehalose are particularly versatile, such as maltose, sucrose, lactose, and trehalose. It is obtained from disaccharides and has a 3-ketoglucose structure or 3-ketogalactose structure in the molecule, both of which are known to be obtained in crystalline form. It can be more suitably used as an active ingredient of the anti-inflammatory agent of the present invention.
  • the 2-keto sugar in the present invention is not particularly limited as long as it is a saccharide having a 2-keto aldohexose structure.
  • Examples of the 2-keto monosaccharide or 2-keto disaccharide suitably used in the present invention include: 2-ketoglucose (2-dehydro-D-glucose), 2-ketotrehalose, 2-ketoneotrehalose, 2-ketoisotrehalose and the like.
  • pyranose 2-oxidase (EC 1.1.3.10) that can selectively produce 2-ketoglucose by selectively oxidizing the 2-position hydroxyl group of glucose was used. Enzymatic method is used. Examples of the microorganism having the ability to produce pyranose 2-oxidase include mushrooms such as Kawaratake (Trametes versicolor, Trametes multicolor) and basidiomycetes fungus.
  • 2-Ketosugars such as 2-ketoglucose and 2-ketotrehalose obtained by transglycosylation using 2-ketoglucose as an acceptor are also purified in the same manner as described above in the section of 3-ketosugar. It can be isolated.
  • the 3-keto disaccharides 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose, 3-ketoisomaltose, 3-ketomaltose, 3-ketosucrose, 3 -Ketodisaccharide sugar alcohol 3-keto maltitol and 2-keto sugars 2-ketoglucose and 2-ketotrehalose significantly exert TNF- ⁇ or IL-8 production inhibitory action Since the concentration does not adversely affect cell proliferation and cell viability, carbohydrates having a ketoaldhexose structure in the molecule such as 3-ketosaccharide and 2-ketosugar are safe to apply to living bodies. It is considered to be a simple carbohydrate.
  • TNF- ⁇ tumor necrosis factor ⁇
  • IL-6 interleukin 6
  • IL-8 interleukin 8
  • TNF- ⁇ is an inflammatory cytokine mainly produced from activated macrophages. When TNF- ⁇ is excessively produced, the inflammatory reaction is strengthened, and cytotoxic cells such as neutrophils are strongly active. It has also been reported that vascularization induces damage to vascular endothelial cells and tissues, leading to organ dysfunction. TNF- ⁇ is also produced from fat cells enlarged due to obesity, and it is known that it is involved in the onset and pathogenesis of type II diabetes by inducing insulin resistance. In general, overproduction of TNF- ⁇ is said to be involved in inflammation such as dermatitis, rheumatoid arthritis, psoriasis and inflammatory bowel disease.
  • IL-8 is known as an inflammatory cytokine that causes neutrophils to infiltrate the inflamed area.
  • Neutrophils that have infiltrated the inflamed area cause degranulation, thereby releasing enzymes having a tissue damaging action such as myeloperoxidase and elastase. Therefore, when the inflammatory reaction is prolonged, tissue damage is also observed.
  • overproduction of IL-8 is said to be involved in inflammation such as rheumatoid arthritis, psoriasis, bronchial asthma, sepsis, vascular inflammation, and hepatitis. That is, suppressing excessive production of inflammatory cytokines that cause the onset or exacerbation of inflammation is expected to be effective for the prevention and treatment of inflammatory diseases, in addition to alleviation and improvement of inflammatory symptoms.
  • the carbohydrate having a ketoaldhexose structure in the molecule according to the present invention is used in human skin fibroblasts, epidermal keratinocytes, gingival fibroblasts, intestinal epithelial cells, etc. Inhibits the production of IL-8, etc., and exerts its effects even when ingested or applied to the skin, and involves overproduction of inflammatory cytokines such as TNF- ⁇ and IL-8 It can be advantageously used as an anti-inflammatory agent against inflammation.
  • inflammation In general, inflammation is roughly divided into acute inflammation and chronic inflammation. Acute inflammation is caused by redness, swelling, fever, and pain as main signs in response to external invasion stimuli, if the causative agent and infection of the inflammation disappear and the damaged tissues and cells are restored to their original state. Symptoms end in a short period of time as they move toward convergence. On the other hand, since chronic inflammation causes structural changes and functional defects of tissues due to incomplete or excessive biological immune responses, symptoms are maintained for a long time compared to acute inflammation.
  • Diseases corresponding to chronic inflammation include, for example, allergies such as hay fever, chronic respiratory disease, asthma, sepsis, rheumatoid arthritis, ARDS (acute respiratory distress syndrome), hepatitis, gastritis, inflammatory bowel disease, pancreatitis, Arthritis, arteriosclerosis, ischemia-reperfusion injury, uveitis, endotoxin shock, burn, viral myocarditis, idiopathic dilated cardiomyopathy, SIRS (systemic inflammatory response syndrome), multiple organ failure, hemolytic uremic syndrome Diseases caused by vascular endothelial cell disorders such as hemorrhagic colitis and hypergammaglobulinemia, systemic lupus erythematosus (SLE), atherosclerosis, multiple sclerosis, monoclonal B cell abnormality, polyclonal Nephritis such as B cell abnormality, atrial myxoma, castorman syndrome, primary glomerulonephritis
  • examples of the hepatitis include alcoholic hepatitis, viral hepatitis, drug-induced hepatitis, non-alcoholic fatty liver, autoimmune hepatitis, liver fibrosis, cirrhosis, and fulminant hepatitis.
  • examples of inflammatory bowel diseases include ulcerative colitis and Crohn's disease.
  • examples of neurodegenerative diseases caused by nerve cell inflammation include Parkinson's disease and Alzheimer's disease. Chronic inflammation is not limited to inflammatory diseases as described above, but is a common basis for lifestyle-related diseases such as obesity, metabolic syndrome, diabetes, and arteriosclerotic diseases.
  • the carbohydrate having a ketoaldhexose structure in the molecule which is an active ingredient of the anti-inflammatory agent of the present invention, is a highly safe substance and can be advantageously used as an oral preparation or an external preparation for a long period of time. It can be effectively used as an anti-inflammatory agent against When a carbohydrate having a keto aldohexose structure is blended in the molecule as an active ingredient, 0.1 to 90% by mass (hereinafter referred to as “% by mass” unless otherwise specified) with respect to the anti-inflammatory agent. It is desirable to contain it, and it is more desirable to contain 10 to 90%.
  • the carbohydrate having a ketoaldhexose structure in the molecule which is an active ingredient of the anti-inflammatory agent of the present invention, has an effect on safety, anti-inflammatory effect, and production-suppressing action of inflammatory cytokines such as TNF- ⁇ and IL-8.
  • it may be a preparation containing components derived from the production raw materials and by-products generated in the production process.
  • a material having a purity as high as possible.
  • a material having a purity of 80% or more, desirably 90% or more, more desirably 95% or more in terms of solid is suitably used.
  • the anti-inflammatory agent of the present invention can be blended in various compositions such as cosmetics, quasi drugs, foods, and pharmaceuticals.
  • the compounding amount of the carbohydrate having a ketoaldhexose structure in the molecule as the active ingredient in the various compositions is not particularly limited as long as it is an amount capable of exerting an anti-inflammatory action. It is preferable to contain 0.01% or more, preferably 0.1% or more, particularly preferably 0.2% or more, in terms of anhydride, with respect to the total mass of the product, food or medicine. Usually, if it is less than 0.01%, it may be insufficient for exerting an anti-inflammatory effect.
  • the anti-inflammatory agent of the present invention can exhibit an anti-inflammatory effect even when used alone, it can be advantageously used in combination with known components having an anti-inflammatory effect.
  • Known components having anti-inflammatory activity include, for example, allantoin or a derivative thereof, glycyrrhetin or a derivative thereof, pantothenic acid or a derivative thereof, vitamin E or a derivative thereof, L-ascorbic acid or a derivative thereof, pyridoxine hydrochloride, menthol, biotin, Camphor, turpentine oil, zinc oxide, azulene, guaiazulene and derivatives thereof, mefenamic acid and derivatives thereof, phenylbutazone and derivatives thereof, indomethacin and derivatives thereof, ibuprofen and derivatives thereof, ketoprofen and derivatives thereof, ⁇ -aminocaproic acid, diclofenac sodium Diphenhydramine, tranexamic acid and its derivatives, dexamethasone, cortisone and its ester, hydrocortisone and its ester, prednisone, prednisolone, etc.
  • Renal cortex hormone indigo, asenyaku, acha,retea, arnica, aloe, ibutranoo, nettle, turmeric, ages, pear, entomop, ogon, oat, barley, hypericum, virginia, orange, valerian, burrowing, ducks , Licorice, cucumber, goldfish, gardenia, kumazasa, watercress, gentian, gentian pepper, hawkfish, burdock, comfrey, salvia, salamander, shikon, perilla, citrus, peonies, birch, horsetail, oleum Alaska spruce, anteater, sage senkyu, assembly, sokuhi, taiso, thyme, tea, chimpi, tencha, hot pepper, touki, shinkin senka, tonin, do Kudami, tormentilla, elderberry, carrot, parsley, mint,
  • composition containing the anti-inflammatory agent of the present invention at least one kind of carbohydrate having a ketoald hexose structure in the molecule as an active ingredient, cosmetics, quasi drugs, foods, pharmaceuticals, etc. What is necessary is just to mix
  • the form of the agent is not particularly limited and can be an external preparation or an oral preparation.
  • composition containing the anti-inflammatory agent of the present invention is a cosmetic, as optional components, purified water, pH adjuster, lower alcohol, polyhydric alcohol, fats and oils, waxes, hydrocarbons, fatty acids, esters , Organic solvents, silicones, surfactants, thickeners, softeners, emulsifiers, antifoaming agents, humidifiers, fragrances, sequestering agents, dyes, coloring materials, water-soluble polymers, preservatives, buffers Liquids, pigments, ultraviolet absorbers, astringents, bactericides / antibacterial agents, moisturizers, cell activators, anti-inflammatory / antiallergic agents, antioxidant / active oxygen removers, fragrances, various medicinal ingredients, and the like can be blended.
  • purified water pH adjuster, lower alcohol, polyhydric alcohol, fats and oils, waxes, hydrocarbons, fatty acids, esters , Organic solvents, silicones, surfactants, thickeners, softeners, emulsifier
  • Cosmetic products containing the anti-inflammatory agent of the present invention include cosmetic soaps, facial cleansing creams, facial cleansing foams, cleansing creams, cleansing milks, cleansing lotions, cleansing oils, massage creams, cold creams, moisturizing creams, vanishing creams, hand creams, moisturizers.
  • composition containing the anti-inflammatory agent of the present invention is a quasi-drug, as optional components, excipients, bases, surfactants, dispersants, solubilizers, solvents, alkaline agents, viscosity modifiers , Thickener, film agent, foaming agent, defoaming agent, flavoring agent, coloring agent, stabilizer, preservative, bactericidal agent, anti-fading agent, antioxidant, hair treatment agent, wetting agent, hair protection agent , Hair follicle activator, antistatic agent, auxiliary agent, solvent, solubilizer, solubilizer, fluidizer, suspending agent, buffering agent, binder, adsorbent, propellant, coating agent, chewing agent, filler Conventional additives such as softeners, modifiers, sequestering agents, anti-fading agents, fats and oils, oil-soluble polymers, analgesics, disintegrants, lubricants, emulsifiers, isotonic agents, and the like can be blended. .
  • a quasi-drug used for the oral cavity for example, toothpaste, mouthwash, mouth rinse, drink, quasi-drug used for scalp, such as a hair nourishing agent , Hair restorer, hair loss prevention agent, hair removal agent, massage agent, other than that, insect repellent, trauma treatment ointment, antibacterial cream, steroid ointment, sheet-like or film-like paste to be applied to the affected area of oral cavity or skin Agents, cosmetic liquids, medicated soaps, clean cotton, bath preparations, baby powders, soft contact lens disinfectants, and the like.
  • composition containing the anti-inflammatory agent of the present invention is a food, water, alcohol, starch, protein, fiber, saccharide, lipid, vitamin, mineral, flavor, colorant, sweetener as optional ingredients
  • Ingredients or materials usually blended in foods such as seasonings, stabilizers and preservatives can be blended.
  • Examples of the food containing the anti-inflammatory agent of the present invention include beverages, soups, alcoholic beverages, jelly, hard candy, soft candy, gummy candy, chewing gum, chocolate, tablets, and frozen desserts.
  • the food includes functional food, health food, health-oriented food, and the like.
  • Examples of pharmaceutical forms containing the anti-inflammatory agent of the present invention include solid preparations such as powders, tablets, pills, capsules, fine granules, granules, liquids such as liquids, suspensions, emulsions, and gels. Etc. If necessary, the granules of capsules containing tablets, pills, granules, granules can be sugar-coated with sugars such as sucrose, sugar alcohols such as maltitol, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. A coating may be applied, or a film of gastric or enteric material may be coated. Moreover, in order to improve the solubility of a formulation, the said formulation can also be given a known solubilization process. Based on a conventional method, the solution may be used in an injection or a drip.
  • the dose or intake thereof is not particularly limited as long as the desired improvement, treatment or prevention effect can be obtained. It is appropriately selected according to the age, sex, constitution and other conditions, the type and degree of disease.
  • a saccharide having a ketoaldhexose structure in the molecule as an active ingredient is blended in the pharmaceutical so as to have a content of 0.01 to 30% in terms of anhydride, and the ketoaldhexose structure is incorporated in the molecule. What is necessary is just to ingest in the range of about 0.1 mg-1,000 mg per day as a carbohydrate to have.
  • the anti-inflammatory agent of the present invention is excellent in safety, not only for humans, for example, non-human animals such as rats, mice, guinea pigs, rabbits, sheep, pigs, cows, You may mix
  • feed or feed for example, livestock feed used for sheep, pigs, cows, horses, chickens, etc., feed for small animals used for rabbits, rats, mice, etc., feed for fish and shellfish used for eels, Thailand, hamachi, shrimp, etc. Examples include pet food used for dogs, cats, small birds, squirrels, and the like.
  • the method for improving anti-inflammatory action of the present invention by converting a free hydroxyl group that is not bonded to another carbohydrate or substituent in a carbohydrate having an aldohexose structure in the molecule to a keto group. Since the anti-inflammatory action of a carbohydrate having a weak anti-inflammatory action can be improved, it is also useful as a method for improving the anti-inflammatory action of a sugar having an aldohexose structure.
  • a method suitable for improving the anti-inflammatory action there is a method in which the hydroxyl group at the 3-position or the hydroxyl group at the 2-position in the aldohexose structure is converted to a keto group by an enzymatic method or a fermentation method.
  • the 3-position hydroxyl group or the 2-position hydroxyl group of the non-reducing end aldhexose of the saccharide is oxidized, and the anti-inflammatory action of the saccharide is improved as compared with that before the conversion.
  • ⁇ Experiment 1 Preparation of various 3-keto sugars> Trehalose, cordobiose, isomaltose, lactose, maltose, sucrose, and maltitol are used as raw materials, respectively, and 3-ketotrehalose, 3-ketocodibiose, 3-ketoisomaltose, 3-ketolactose, 3- Ketomaltose, 3-keto sucrose and 3-keto maltitol were prepared. In addition, 3,3′-diketotrehalose and methyl ⁇ -3-ketoglucoside were prepared by enzymatic methods using trehalose and methyl ⁇ -glucoside as raw sugars, respectively.
  • Trehalose registered trademark “Treha”, sold by Hayashibara Co., Ltd., trehalose purity 98.0% or more
  • 20 w / v)%
  • polypeptone manufactured by Nippon Pharmaceutical Co., Ltd.
  • yeast extract S Japan 3 mL of liquid culture medium (pH 6.8) consisting of 0.2 (w / v)%, magnesium sulfate heptahydrate 0.01 (w / v)%, and water is manufactured by Pharmaceutical Co., Ltd.
  • 50 liquid culture media having the same composition as above 50 mL in a 500 mL Erlenmeyer flask are prepared, adjusted to pH 6.8, sterilized at 121 ° C. for 20 minutes, cooled, and then the above seed culture solution is added. After inoculating 0.5 mL each of each Erlenmeyer flask, it was subjected to rotary shaking tow culture at 27 ° C. for 72 hours at 240 rpm to obtain a main culture solution. When the sugar composition of the culture broth was analyzed by HPLC, a new carbohydrate peak other than trehalose as a raw material was confirmed.
  • the collected solution is concentrated to 1,100 mL under reduced pressure using an evaporator, filtered through a 0.2 ⁇ m membrane filter, and then removed using an electrodialyzer (trade name “Microacylizer G0”, manufactured by Asahi Kasei Kogyo Co., Ltd.). Salted.
  • the obtained electrodialysate was filtered through a 0.2 ⁇ m membrane filter, and subjected to preparative HPLC under the following conditions.
  • the peak fraction of carbohydrate newly produced from the raw trehalose was collected, concentrated, and freeze-dried. Powdered to obtain 76.5 g of a standard product.
  • the obtained sample was subjected to HPLC analysis under the following conditions, and the purity was determined to be 98.1% based on the HPLC chromatogram (FIG. 1). Further, when the sample was subjected to LC / MS analysis, it was found to have a molecular weight 340 that is 2 (two hydrogen atoms) smaller than the molecular weight 342 of trehalose. Further, NMR ( 1 H-NMR and 13 C-NMR) spectra were measured using the sample as a sample. In the 13 C-NMR spectrum (FIG. 2), one glucose of two glucose residues constituting trehalose was measured.
  • the collected solution is concentrated to 300 mL under reduced pressure using an evaporator, centrifuged at 11,000 rpm, the supernatant is collected, filtered through a 0.2 ⁇ m membrane filter, and then electrodialyzed (trade name “Micro Acylizer”). G1 ”, manufactured by Asahi Kasei Kogyo Co., Ltd.) for desalting.
  • the obtained electrodialysis solution is concentrated to about 20 mL under reduced pressure using an evaporator, filtered through a 0.2 ⁇ m membrane filter, and subjected to preparative HPLC under the following conditions to obtain a peak of newly produced saccharide from the raw material cordobiose.
  • ⁇ Experiment 1-3 Preparation of 3-keto isomaltose> Rhizobium radiobacter strain G37 was cultured in the same manner as in Experiment 1-2, except that the sugar in the liquid medium used for main culture was changed to isomaltose (Hayashibara Co., Ltd., purity: 97.7%). As a result of purification, crystals were precipitated from the concentrated solution after desalting. Crystals were collected from the crystal suspension by centrifugation, washed with special grade ethanol, and dried in an oven (40 ° C.) to obtain 6.0 g of a standard product. The purity of the obtained sample was analyzed by HPLC and found to be 98.5%. Analysis by the same method as that performed for 3-ketotrehalose in Experiment 1-1 revealed that the obtained sample was 3-ketoisomaltose (6-O- ⁇ -3-ketoglucosylglucose). .
  • Example 1-4 Preparation of 3-ketolactose> A liquid medium (pH 6.8) comprising lactose 2.0% (w / v), yeast extract (manufactured by Difco) 0.1 (w / v)%, and water is used for seed culture and main culture.
  • Rhizobium radiobacter strain G37 was cultured in the same manner as in Experiment 1-2, except that three flasks containing 100 mL of medium were used in an Erlenmeyer flask. When the sugar composition of the culture solution was analyzed by HPLC, a new carbohydrate peak other than lactose as a raw material was confirmed.
  • the Zobiumu radiobacter G37 strain was a platinum loop inoculation, a material obtained by tow culture shaking for 48 hours at 27 °C was a seed culture solution.
  • the cells were removed by centrifuging about 1 L of the obtained culture solution at 10,000 rpm.
  • the obtained supernatant was heat-treated at 100 ° C. for 10 minutes, and then again at 10,000 rpm. Centrifuged. Ethanol 2,700mL was added to the obtained centrifugation supernatant, and also centrifuged at 10,000 rpm. Subsequently, the centrifugal product was concentrated to 500 mL under reduced pressure using an evaporator, and the obtained concentrated solution was filtered through a 0.22 ⁇ m membrane filter, and then preparative HPLC was repeated under the same conditions as in Experiment 1-1 to obtain raw material maltose.
  • the newly produced carbohydrate peak fraction was collected, concentrated and powdered by freeze-drying to obtain 5.1 g of a standard product.
  • the purity of the obtained sample was analyzed by HPLC and found to be 96.2%.
  • Rhizobium / Rhizobium was the same as in Experiment 1-5 except that the sugar in the liquid medium used for seed culture and main culture was changed to maltitol (Tokyo Chemical Industry Co., Ltd., purity 93.0% or more) and the concentration was changed to 3%. Radiobacter G37 strain was cultured. When the sugar composition of the culture broth was analyzed by HPLC, a new carbohydrate peak other than maltitol as a raw material was confirmed. After completion of the culture, purification was carried out in the same manner as 3-ketomaltose to obtain 9.4 g of a standard product.
  • maltitol Tokyo Chemical Industry Co., Ltd., purity 93.0% or more
  • Radiobacter G37 strain was cultured. When the sugar composition of the culture broth was analyzed by HPLC, a new carbohydrate peak other than maltitol as a raw material was confirmed. After completion of the culture, purification was carried out in the same manner as 3-ketomaltose to obtain 9.4
  • the purity of the obtained sample was analyzed by HPLC and found to be 90.2%. Analysis by the same method as that performed for 3-ketotrehalose in Experiment 1-1 revealed that the obtained sample was 3-keto maltitol (4-O- ⁇ -3-ketoglucosyl sorbitol). .
  • Um Saccharophilum NBRC15944 strain was inoculated with 30 ⁇ L from a glycerol stock. A seed culture was obtained by shaking and culturing at 27 ° C. for 96 hours.
  • liquid culture media having the same composition as described above were prepared by putting 100 mL in a 500 mL Erlenmeyer flask, adjusted to pH 6.8, sterilized at 121 ° C. for 20 minutes, and cooled. Next, 1 mL each of the above seed culture solution was inoculated into each Erlenmeyer flask, and then the shaker tow culture was performed at 27 ° C. for 24 hours to obtain a main culture solution.
  • the main culture solution was centrifuged at 10,000 rpm.
  • the centrifugation supernatant was removed, and Triton X-100 and lysozyme were added to the obtained cells, followed by stirring at room temperature for 1 hour. Subsequently, it was frozen by being placed at ⁇ 80 ° C. for 1 hour and thawed in a 38 ° C. water bath for 1 hour. Subsequently, ultrasonic crushing was performed, and centrifugation was performed at 10,000 rpm. The obtained centrifugal supernatant was used as a crude enzyme solution of glucoside 3-dehydrogenase.
  • glucoside 3-dehydrogenase The activity of glucoside 3-dehydrogenase was roughly measured based on the following principle. That is, flavin which is a coenzyme of glucoside 3-dehydrogenase when methyl ⁇ -glucoside is used as a substrate and glucoside 3-dehydrogenase oxidizes methyl- ⁇ -glucoside and converts it to methyl- ⁇ -3-ketoglucoside Since adenine dinucleotide (FAD) is reduced and reduced FAD (FADH 2 ) is produced, phenazine methosulfate (PMS) and dichloroindophenol (DCIP) are conjugated, and finally reduction of oxidized DCIP ( The oxidation activity of methyl- ⁇ -glucoside was evaluated by measuring the absorbance at a wavelength of 660 nm.
  • FAD adenine dinucleotide
  • FAD FAD
  • DCIP dichloroindophenol
  • 195 ⁇ L of an appropriately diluted enzyme solution is placed in a well of a microplate, and 50 ⁇ L of a substrate solution containing methyl- ⁇ -glucoside, PMS, DCIP, and phosphate buffer (pH 7.0) is added thereto.
  • the reaction volume was adjusted to 200 ⁇ L, and the final concentrations of methyl- ⁇ -glucoside, PMS, DCIP, and phosphate buffer were adjusted to 10 mM, 1 mM, 60 ⁇ M, and 50 mM, respectively.
  • the enzyme reaction was carried out at pH 7.0, 30 ° C. in the dark for 10 minutes, and the absorbance at a wavelength of 660 nm was measured with a plate reader over time.
  • One unit of activity of glucoside 3-dehydrogenase was defined as the activity of oxidizing 1 ⁇ mol of substrate per minute under the above conditions.
  • the final concentrations of trehalose, potassium ferricyanide, and phosphate buffer (pH 7.0) were 40 mM, 100 mM, and 250 mM, respectively, and 390 mL of a reaction solution prepared so that the crude enzyme solution obtained above was 18 units per gram of trehalose. Was reacted at 27 ° C. for 8 hours.
  • 910 mL of ethanol was added and centrifuged at 10,000 rpm. The centrifugal supernatant was concentrated to 60 mL under reduced pressure with an evaporator, and the obtained concentrated solution was filtered with a 0.22 ⁇ m membrane filter.
  • ⁇ Experiment 1-9 Preparation of methyl ⁇ -3-ketoglucoside>
  • the final concentrations of methyl ⁇ -glucoside, potassium ferricyanide, and phosphate buffer (pH 7.0) were 40 mM, 100 mM, and 250 mM, respectively.
  • the crude enzyme solution prepared in the same manner as in Experiment 1-8 was methyl ⁇ -glucoside.
  • 240 mL of a reaction solution prepared to be 8.1 units per 1 g was reacted at room temperature for 2 hours. 560 mL of ethanol was added to the resulting reaction solution and centrifuged at 10,000 rpm.
  • 2-ketoglucose is prepared from D-glucose by an enzymatic method using pyranose 2-oxidase, and the obtained 2-ketoglucose is used as a receptor to produce ⁇ -glucose-1-phosphate (hereinafter referred to as “ ⁇ -G1P”).
  • 2-ketotrehalose was prepared by transglycosylation of trehalose phosphorylase using glucosyl donor.
  • the reason for the combined use of catalase is that hydrogen peroxide is produced in the reaction process in which pyranose 2-oxidase acts on D-glucose to produce 2-ketoglucose. It is for decomposing. After the enzyme reaction, the resulting reaction solution was heated at 100 ° C. for 10 minutes to deactivate the enzyme. When the purity of 2-ketoglucose in the obtained reaction liquid was analyzed by HPLC, it was 96.4%. It was confirmed that the obtained standard was 2-ketoglucose by comparing the chromatogram obtained by HPLC analysis with a commercially available 2-ketoglucose standard (reagent, Sigma-Aldrich Japan). Finally, 2.86 g of 2-ketoglucose was obtained from 3 g of D-glucose.
  • ⁇ Experiment 2-2 Preparation of 2-ketotrehalose> ⁇ -G1P (Hayashibara Preparation) and 50 mM acetate buffer (pH 5.5) were added to the 2-ketoglucose-containing reaction solution obtained by the method of Experiment 2-1, and the final concentration of 2-ketoglucose was 1% ( w / v), to 200 mL of substrate solution adjusted to a final concentration of ⁇ -G1P of 10%, trehalose phosphorylase (derived from Thermoanaerobacter), 10 units / g ⁇ -G1P (100 units per 2-ketoglucose) Hayashibara preparations) were added and reacted at 40 ° C. for 24 hours.
  • trehalose phosphorylase derived from Thermoanaerobacter
  • 10 units / g ⁇ -G1P 100 units per 2-ketoglucose
  • the resulting reaction solution was heated at 100 ° C. for 10 minutes to deactivate the enzyme.
  • the reaction solution was subjected to LC / MS analysis, and the production of 2-ketotrehalose having a molecular weight 2 smaller than that of trehalose was confirmed.
  • the 2-ketotrehalose content in the reaction solution was 0.37 g.
  • preparative HPLC was performed under the same conditions as in Experiment 1-1, and the 2-ketotrehalose fraction was recovered and analyzed under the same analysis conditions as in Experiment 1-1. The purity of ketoretrehalose was measured and found to be 95.0%. Finally, 0.36 g of 2-ketotrehalose was obtained using 2 g of 2-ketoglucose.
  • THP-1 cells a human monocytic cell line
  • LPS lipopolysaccharide
  • IFN- ⁇ interferon- ⁇
  • THP-1 cells used in this experiment have increased responsiveness to LPS when treated with sodium butyrate, which is also known as a cell differentiation inducer, and therefore 4 to 5 with 2 mM sodium butyrate in advance. What was cultured for one day was used.
  • 0.1 mL of THP-1 cells treated with sodium butyrate prepared at a cell concentration of 1 ⁇ 10 6 cells / mL using RPMI 1640 medium containing 10% fetal bovine serum was added to a 96-well microplate.
  • 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose, 3-ketoisomaltose, 3-ketomaltose, 3-ketosucrose, 3-ketomaltitol, 3 , 3′-diketotrehalose, methyl ⁇ -3-ketoglucoside, 2-ketoglucose obtained in Experiment 2 and 2-ketotrehalose were added at 0.05 mL per well so that the final concentrations shown in Table 1 were obtained. Adjust and incubate at 37 ° C. for 2-3 hours.
  • Table 1 shows the effect of 3-keto sugar or 2-keto sugar on TNF- ⁇ production of THP-1 cells. The experiment was performed in triplicate and Dunnett's multiple comparison test was performed on the control. Table 1 shows the average values of three experiments. When the risk rate is p ⁇ 0.01, it is determined that there is a significant difference, and is indicated by *.
  • GK2 known as an anti-inflammatory agent, suppresses TNF- ⁇ production of THP-1 cells in a concentration-dependent manner, and 53 mM and 2.0 mM of the control at 1.0 mM. To 17.4%.
  • the 3-keto disaccharides 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose, 3-ketoisomaltose, 3-ketomaltose, 3-ketosucrose, 3-ketomaltitol and 3, 3'-diketotrehalose also suppressed TNF- ⁇ production in THP-1 cells to 1.5-87.8% of the control in the concentration range of 0.5 mM to 2.0 mM. Was also concentration-dependent and significant.
  • Methyl ⁇ -3-ketoglucoside which is a derivative of 3-keto monosaccharide, has a weak TNF- ⁇ production inhibitory effect and did not show significant inhibition even at 4.0 mM, but it was 79.7% at 8.0 mM, 16 It was suppressed to 49.5% at 0.0 mM.
  • 2-ketoglucose suppresses TNF- ⁇ production to 69.0% at 2.0 mM and 53.8% at 4.0 mM
  • 2-ketotrehalose has a concentration range of 0.5 to 2.0 mM. It was suppressed to 69.6 to 41.3%.
  • the number of cells was also measured at each concentration of each test sample.
  • maltose, 3-ketomaltose, 3-ketosucrose, 3-ketomaltitol and methyl ⁇ -3-ketoglucoside, 2-ketosugars 2-ketoglucose and 2-ketotrehalose are used at any concentration
  • the number of cells was almost the same as the control, and it was confirmed that the addition of these 3-keto sugars or 2-keto sugars did not reduce the number of viable THP-1 cells.
  • the results of this experiment are the 3-ketosugars 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose, 3-ketoisomaltose, 3-ketomaltose, 3-ketosucrose, 3-keto maltitol 3,3'-diketotrehalose and methyl ⁇ -3-ketoglucoside, and 2-ketosugar 2-ketoglucose and 2-ketotrehalose all inhibit the production of TNF- ⁇ , an inflammatory cytokine And it is useful as an active ingredient of anti-inflammatory agents.
  • the inflammatory cytokine TNF- ⁇ secreted by THP-1 cells is diabetes, chronic respiratory disease, rheumatoid arthritis, gastritis, inflammatory bowel disease, atherosclerosis, cardiovascular disorder, acne, atopic dermatitis, It has been found that it is deeply involved in the pathogenesis of neurodegenerative diseases and the like, and the results of this experiment show that 3-keto sugar or 2-keto is an effective ingredient of anti-inflammatory agents against a wide range of inflammation including these diseases. It shows that sugar can be used.
  • the concentration of each test sample in the medium was 4.8 mM, 19.2 mM and 57.2 mM, methyl- ⁇ -glucoside, D- for trehalose, lactose, cordobiose, isomaltose, maltose, sucrose, and maltitol.
  • the three stages were 4.8 mM, 14.4 mM and 43.2 mM.
  • Table 2 shows the effects of 3-ketosugar raw sugar and D-psicose on TNF- ⁇ production in THP-1 cells. The experiment was performed in triplicate and Dunnett's multiple comparison test was performed on the control. Table 2 shows the average values of three experiments. When the risk rate p ⁇ 0.01, it was determined that there was a significant difference, and indicated by *.
  • D-psicose which has been reported to have an anti-inflammatory effect, and methyl- ⁇ -glucoside exhibited a TNF- ⁇ production inhibitory effect at a concentration of 43.2 mM.
  • the action of D-psicose and methyl- ⁇ -glucoside is the 3-ketodisaccharide 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose, 3-ketoisomaltose, 3-ketomaltose, 3 -It was weaker than the action of ketosucrose, 3-ketomaltitol, 3,3'-diketotrehalose and the action of 2-ketoglucose, 2-ketoglucose and 2-ketotrehalose.
  • NHDF cells prepared at a concentration of 1 ⁇ 10 5 cells / mL using Dulbecco's modified Eagle's medium containing 10% fetal bovine serum was added until the entire surface of the well was occupied. Cultured. After aspirating and removing the culture supernatant, 0.1 mL of fresh Dulbecco's modified Eagle medium containing 10% fetal calf serum was added per well. Next, add 0.05 mL of 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose or 3-ketoisomaltose diluted appropriately in the same medium, and adjust the final concentration to the concentration shown in Table 3.
  • human IL-1 ⁇ that stimulates IL-8 production was added to a final concentration of 1 ng / mL and further cultured for 24 hours.
  • GK2 which is known as an anti-inflammatory agent.
  • the amount of IL-8 in the culture supernatant was detected using a specific ELISA kit (manufactured by Affymetrix), developed with tetramethylbenzidine, and the absorbance at 450 nm was measured.
  • a sample treated in the same manner except that the test sample was not added was used as a control, and the production amount of IL-8 in the culture supernatant in the control was regarded as 100%, and the production amount of IL-8 was relatively evaluated by the following formula.
  • Table 3 shows the effect of 3-keto sugar on the production of IL-8 in NHDF cells. The experiment was performed three times, and Dunnett's multiple comparison test was performed on the control. Table 3 shows the average value of three experiments. When the risk rate is p ⁇ 0.01, it is determined that there is a significant difference, and is indicated by *.
  • 3-ketosugars 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose and 3-ketoisomaltose all inhibited the production of IL-8, an inflammatory cytokine. It is useful as an active ingredient in anti-inflammatory drugs. More specifically, since 3-ketosugar suppressed IL-8 production from normal human skin fibroblasts, alleviation of skin inflammatory symptoms such as allergic dermatitis, atopic dermatitis, acne and psoriasis In addition to improvement, it is useful for the prevention and treatment of various inflammatory diseases.
  • Normal NHEK cells prepared at a concentration of 5.0 ⁇ 10 4 cells / mL were added to a collagen-coated 96-well microplate using a growth factor-containing keratinocyte culture medium (trade name “EpiLife”, manufactured by Life Technologies). 2 mL was added, and the cells were cultured at 37 ° C. for 3 days while changing the medium every 1-2 days. Thereafter, the cells were prepared by replacing the medium with a keratinocyte medium containing no growth factor and further culturing for 24 hours.
  • a growth factor-containing keratinocyte culture medium trade name “EpiLife”, manufactured by Life Technologies
  • the amount of IL-8 in the culture supernatant was detected using a specific ELISA kit (manufactured by Affymetrix), developed with tetramethylbenzidine, and the absorbance at 450 nm was measured.
  • the same treatment except that the test sample was not added was used as a control, and the production of IL-8 was relatively evaluated in the same manner as in Experiment 4.
  • Table 4 shows the effect of 3-keto sugar on IL-8 production in NHEK cells. The experiment was performed three times, and Dunnett's multiple comparison test was performed on the control. Table 4 shows the average values of three experiments. When the risk rate p ⁇ 0.01, it was determined that there was a significant difference, and indicated by *.
  • 3-ketosugars 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose and 3-ketoisomaltose all inhibited the production of IL-8, an inflammatory cytokine. It is useful as an active ingredient in anti-inflammatory drugs. More specifically, since 3-ketosugar suppressed IL-8 production from human epidermal keratinocyte cells, alleviation and improvement of skin inflammatory symptoms such as allergic dermatitis, atopic dermatitis, acne and psoriasis In addition, it is useful for the prevention and treatment of various inflammatory diseases.
  • HGF cells prepared at a concentration of 5 ⁇ 10 4 cells / mL were added to a collagen-coated 96-well microplate (ASAHI Glass Co., Ltd.) using Dulbecco's modified Eagle's medium containing 10% fetal bovine serum. Incubation was performed until the entire bottom surface of the well was occupied. After aspirating and removing the culture supernatant, 0.15 mL of fresh Dulbecco's modified Eagle medium containing 10% fetal bovine serum was added per well. Next, 0.05 mL of 3-ketotrehalose, 2-ketoglucose or GK2 appropriately diluted with the same medium was added, and cultured at 37 ° C. for 24 hours. Thereafter, human IL-1 ⁇ was added to a final concentration of 1 ng / mL and further cultured for 24 hours.
  • PGE2 and IL-6 in the culture supernatant were each detected using a specific ELISA kit (PGE2; manufactured by Enzo Lifesciences, IL-6; manufactured by R & D), and developed with tetramethylbenzidine. Quantification was performed by measuring absorbance. The same treatment except that the test substance was not added was used as a control, and PGE2 and IL-6 in the culture supernatant in the control were taken as 100%. The relative production of PGE2 and IL-6 was evaluated. The experiment was performed three times, and Dunnett's multiple comparison test was performed on the control. The risk factor p ⁇ 0.01 was considered significant and indicated by *. The results are shown in Table 5.
  • 3-ketototrehalose showed a concentration-dependent and significant PGE2 production inhibitory action as compared to the control to which no test substance was added. Moreover, a PGE2 production inhibitory action stronger than that of GK2 was observed at a concentration of 1 mM or less.
  • 2-ketoglucose showed a significant PGE2 production inhibitory effect at a concentration of 2 mM.
  • both 3-ketotrehalose and 2-ketoglucose showed IL-6 production inhibitory action comparable to GK2 at a concentration of 2 mM. Note that no cytotoxic effect was observed in the concentration range tested.
  • 3-ketotrehalose and 2-ketoglucose have an action of suppressing the production of inflammatory mediators from activated gingival fibroblasts and are effective in preventing or treating periodontal disease. .
  • IL-8 production as an inflammatory mediator from intestinal epithelial cells by IL-1 or TNF- ⁇ is considered to lead to reduction or treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Therefore, the effect of 3-ketosugar on IL-8 production from human intestinal epithelial cells was examined.
  • 0.2 mL of Caco-2 cells prepared at a concentration of 3 ⁇ 10 4 cells / mL using collagen-coated 96-well microplate (IWAKI Glass Co., Ltd.) using Dulbecco's modified Eagle medium containing 10% fetal bovine serum After addition, the cells were cultured at 37 ° C. for 3 days. After aspirating and removing the culture supernatant, 0.1 mL of fresh Dulbecco's modified Eagle medium containing 1% fetal bovine serum was added per well. Next, 0.05 mL of 3-ketotrehalose, 3-ketomaltitol, or GK2 appropriately diluted in the same medium was added per well and incubated at 37 ° C. for 7 hours.
  • a medium containing IL-1 ⁇ adjusted to a concentration of 2.5 ng / mL and TNF- ⁇ adjusted to a concentration of 62.5 ng / mL in the same medium was added and stimulated by adding 0.1 mL per well. 16-18 hours after stimulation, the amount of IL-8 produced in the culture supernatant was detected using a specific ELISA kit (manufactured by R & D), developed with tetramethylbenzidine, and the absorbance at 450 nm was measured. .
  • the amount of IL-8 produced was the same as that used in Experiment 4, with the control being the same treatment except that the test substance was not added, and the amount of IL-8 produced in the culture supernatant in the control being 100%. evaluated.
  • GK2 did not show any inhibition of IL-8 production by stimulation with IL-1 ⁇ and TNF- ⁇ .
  • 3-ketotrehalose and 3-keto maltitol showed a concentration-dependent and significant inhibitory effect on IL-8 production.
  • NHDF cells prepared at a concentration of 1 ⁇ 10 5 cells / mL using Dulbecco's modified Eagle's medium containing 10% fetal bovine serum was added until the entire surface of the well was occupied. Cultured. After aspirating and removing the culture supernatant, 0.1 mL of fresh Dulbecco's modified Eagle medium containing 10% fetal calf serum was added per well. Next, 0.1 mL of 3-ketotrehalose, 3-ketolactose, 3-ketocodibiose or 3-ketoisomaltose appropriately diluted with the same medium was added, and the mixture was cultured at 37 ° C. for 24 hours. For comparison, the same procedure was performed for GK2, which is known as an anti-inflammatory agent.
  • the culture supernatant was removed by aspiration, 0.2 mL of hydrogen peroxide prepared to a concentration of 150 ⁇ M with HANKS buffer was added per well, and incubated at 37 ° C. for 2 hours. Subsequently, the hydrogen peroxide solution was removed by suction, 0.2 mL of Dulbecco's modified Eagle medium containing 10% fetal calf serum was added per well, and further cultured at 37 ° C. for 48 hours.
  • the number of cells after culturing was measured using a cell counting kit (manufactured by Doujin Chemical Laboratory Co., Ltd.). Specifically, after removing the culture supernatant of cells cultured for 48 hours, 0.1 mL of Dulbecco's modified Eagle's medium containing fresh 10% fetal bovine serum was added per well, and further diluted 10-fold in the same medium. The kit was added at 0.1 mL per well and incubated at 37 ° C. for 2 hours. Finally, the absorbance at 450 nm corresponding to the number of cells was measured with a spectrophotometer. The cells were similarly treated with hydrogen peroxide except that no pretreatment with the test substance (3-ketosugar) was performed as a control, the absorbance in the control was 100%, and the number of cells was evaluated as a relative cell number by the following formula. .
  • Table 5 shows the effect of pretreatment in the presence of 3-ketosugar on the resistance of human skin fibroblasts to cell damage caused by treatment with hydrogen peroxide. The experiment was performed three times, and Dunnett's multiple comparison test was performed on the control. Table 7 shows the average values of three experiments. When the risk rate is p ⁇ 0.01, it is determined that there is a significant difference, and is indicated by *.
  • the anti-inflammatory agent of the present invention containing a carbohydrate having a ketoaldhexose structure in the molecule as an active ingredient suppresses the production of inflammatory cytokines at a low concentration and has an antioxidative effect as compared with GK2. It can be said to be a safe anti-inflammatory agent that is effective and has few side effects.
  • composition (mass%) 3-Ketotrehalose 10.0 Trehalose 90.0 Magnesium stearate 0.2
  • this product contains 3-ketotrehalose as an active ingredient of anti-inflammatory action, it can be used to improve oral anti-inflammatory agents that can improve sepsis, rheumatoid arthritis, ARDS, hepatitis, inflammatory bowel disease, diseases involving active oxygen, etc. It is an inflammatory agent.
  • composition (mass%) Stearic acid 2.0 Stearyl alcohol 3.0 Lipophilic glyceryl monostearate 2.0 Beeswax 1.5 Vaseline 6.0 Liquid paraffin 40.0 Dimethylpolysiloxane (100CS) 0.5 Sorbitan sesquioleate 1.0 Preservative Appropriate amount Triethanolamine 1.0 Propylene glycol 10.0 Polyethylene glycol 20000 0.5 Carboxyvinyl polymer 0.05 Purified water remaining amount 3-ketotrehalose 5% (w / v) aqueous solution 1.0 Perfume
  • this product is formulated with 3-ketotrehalose, it can suppress the production of inflammatory cytokines in dermal fibroblasts in human skin and keratinocytes in the epidermis, thereby suppressing and improving skin inflammation.
  • this product is a cleansing cream that smoothes the skin.
  • composition (mass%) Lauric acid 5.0 Myristic acid 18.5 Stearic acid 6.0 Glycerin 12.0 Polyethylene glycol 1500 5.0 Potassium hydroxide 6.5 Purified water remaining amount Palm oil fatty acid diethanolamide 5.0 Palm oil fatty acid methyl taurine sodium 1.8 Polyoxyethylene lauryl ether (7.5E.O.) 2.0 Distearate ethylene glycol lauryl ether 1.0 Hydroxypropyl methylcellulose 1% (w / v) aqueous solution 5.0 3-ketolactose 5% (w / v) aqueous solution 2.0 Perfume
  • this product is formulated with 3-ketolactose, it can suppress the production of inflammatory cytokines in dermal fibroblasts in human skin and keratinocytes in the epidermis, thereby suppressing and improving skin inflammation.
  • this product is a facial cleanser that keeps the skin fine and has a rich lather and a refreshing feel.
  • composition (mass%) Polyvinyl alcohol 15.0 Polyethylene glycol 3.0 Propylene glycol 7.0 Ethanol 10.0 Royal Jelly Extract 1.0 3-keto cordobiose 0.5 Preservative appropriate amount Fragrance appropriate amount Purified water remaining
  • This product contains 3-keto cordobiose, it can suppress the production of inflammatory cytokines in dermal fibroblasts in human skin and keratinocytes in the epidermis, thereby suppressing and improving skin inflammation. .
  • This product is a pack that can improve skin inflammation and maintain a good skin condition according to its typical usage, and is also excellent in whitening effect.
  • ⁇ Gel cream for sunscreen> A gel cream for sunscreen having the following composition was prepared by a conventional method.
  • Compounding ingredients (mass%) Octyl paramethoxycinnamate 4.0
  • Oxybenzone 3.0 Liquid paraffin 16.0 Olive oil 9.0
  • 3-keto isomaltose 1.0
  • Acrylic acid / alkyl methacrylate copolymer 0.6
  • Carboxyvinyl polymer 0.4 Ascorbic acid 2-glucoside 2.0
  • Allantoin 1.0 Triethanolamine 1.0 Preservative Appropriate amount Purified water Remaining
  • this product is formulated with 3-keto isomaltose, it can suppress the production of inflammatory cytokines in the dermal fibroblasts and the keratinocytes of the human skin, thereby suppressing and improving the inflammation of the skin.
  • this product is an excellent anti-inflammatory effect that suppresses sunburn and suppresses hot flashes by the anti-inflammatory action of 3-keto isomaltose and allantoin.
  • ⁇ Emulsion> 0.5 parts by mass of polyoxyethylene behenyl ether, 1 part by mass of polyoxyethylene sorbitol tetraoleate, 1 part by mass of lipophilic glyceryl monostearate, 0.5 parts by mass of pyruvic acid, 0.5 parts by mass of behenyl alcohol, avocado oil 1 part by weight, 1 part by weight of 3-ketomaltose, appropriate amounts of vitamin E and preservatives are dissolved by heating according to a conventional method, and 1 part by weight of L-sodium lactate, 5 parts by weight of 1,3-butylene glycol, carboxyvinyl 0.1 parts by weight of polymer and 85.3 parts by weight of purified water were added, emulsified with a homogenizer, an appropriate amount of a fragrance was added, and the mixture was stirred and mixed to produce an emulsion.
  • This product contains 3-ketomaltose, it suppresses the production of inflammatory cytokines in dermal fibroblasts in human skin and keratinocytes in the epidermis, and controls and improves skin inflammation. Can be maintained well.
  • This product can be advantageously used as an emulsion for sunscreen, stains and freckles prevention, beautiful skin and fair skin.
  • composition Frozen and concentrated Wenzhou orange juice 5.0 Fructose glucose liquid sugar 11.0 Citric acid 0.2 L-ascorbic acid 0.02 Fragrance 0.2 Dye 0.1 3-ketolactose 0.2 Water 89.28
  • This product is a useful juice to prevent periodontal disease and gingivitis because it contains 3-ketolactose.
  • this product is a juice that does not deteriorate the flavor of oranges for a long period of time due to its enhanced vitamin C action.
  • composition (mass%) 3-ketotrehalose 6.0 Stabilizer 1.2 Grapefruit sand 1.0 pH adjuster 0.9 Grapefruit juice (6-fold concentrated juice) 0.5 Ascorbic acid 2-glucoside 2.0 Enzyme-treated stevia 0.04 Safflower yellow 0.01 Purified water remaining
  • this product contains 3-ketotrehalose, it is a grapefruit jelly useful for preventing periodontal disease and gingivitis. Moreover, since this product has enhanced vitamin C action, it is a jelly that does not easily deteriorate the flavor of grapefruit for a long time.
  • ⁇ Chewing gum> Heat and melt 3 parts by weight of gum base until soft, add 7 parts by weight of powdered green-yellow vegetable with trehalose content of about 50% (w / w), and add 3-keto sucrose along with appropriate amount of coloring and flavoring. After adding to a solid content of 0.1%, the mixture was kneaded, molded and packaged by a conventional method to obtain a chewing gum containing 3-keto sucrose.
  • This product containing 3-keto sucrose suppresses skin inflammation and is an excellent chewing gum for preventing periodontal disease and gingivitis, and has good texture and taste.
  • composition (mass%) Sodium chloride 0.6 Potassium chloride 0.03 Calcium chloride 0.02 Sodium lactate 0.31 Trehalose 4.4 Palatinit 0.2 3-Ketotrehalose 0.05 Purified water remaining
  • This product containing 3-ketotrehalose is useful as eye drops and injections to treat conjunctivitis and inflammatory diseases, and has both vitamin, calorie and mineral supplementation.
  • composition (mass%) Glycerin 10.0 1,3-propanediol 3.0 Low molecular weight agar 5.0 Polyoxyethylene hydrogenated castor oil 0.2 3-keto isomaltose 0.5 Ascorbic acid 2-glucoside 1.0 Cetylpyridinium chloride 0.05 l-Menthol 0.05 Ranexamic acid 0.05 Saccharin sodium 0.02 Methyl paraoxybenzoate 0.01 Fragrance 0.05 Citric acid appropriate amount water 89.28
  • this product contains 3-keto isomaltose, it can be advantageously used as a mouthwash excellent in preventing periodontal disease and gingivitis.
  • composition (mass%) Dicalcium phosphate 30.0 Hydroxyapatite 10.0 Calcium carbonate 5.0 3-Ketotrehalose 30.0 Sodium lauryl sulfate 1.5 Sodium monofluorophosphate 0.7 Polyoxyethylene sorbitan laurate 0.5 Diphenhydramine hydrochloride 0.5 Preservative 0.05 Purified water 22.0
  • this product is formulated with 3-ketotrehalose, it can be advantageously used as a dentifrice excellent in prevention and treatment of inflammation in the mouth, swelling of the gums due to alveolar pus leakage, inflammation, and bleeding.
  • composition (mass%) Talc 20.0 Mica 33.0 Kaolin 7.0 Nylon powder 10.0 Titanium dioxide 10.0 Mica titanium 3.0 Zinc stearate 1.0 Red iron oxide 1.0 Yellow iron oxide 3.0 2-ketoglucose 1.5 Gardenia yellow, safflower red-treated cellulose 2.0 Glycosyl hesperidin 3.0 Squalane 6.0 Lanolin acetate 1.0 Octyldodecyl myristate 2.0 Perfume appropriate amount Preservative appropriate amount
  • this product contains 2-ketoglucose, it can be used as a foundation for suppressing skin irritation, maintaining good skin condition, preventing sunscreen, spots and freckles, beautiful skin, and fair skin. it can.
  • this product contains cellulose powder carrying gardenia yellow and safflower red, which has an antioxidant action, radical scavenging action, elastase inhibitory action, lipase inhibitory action, etc., thus suppressing the occurrence of acne and wrinkles, Can hold firm skin.
  • the anti-inflammatory agent containing a carbohydrate having a ketoaldhexose structure in the molecule as an active ingredient according to the present invention is a relieving agent or ameliorating agent for various inflammatory symptoms, and a prophylactic or therapeutic agent for various inflammations. It can be used in the fields of cosmetics, quasi drugs, foods and pharmaceuticals.

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Abstract

La présente invention aborde le problème de la fourniture d'un agent anti-inflammatoire sans action nuisible, qui soit efficace pour alléger et atténuer les symptômes inflammatoires et prévenir et traiter des maladies inflammatoires et qui présente peu d'effets secondaires. En outre, la présente invention aborde le problème consistant à fournir un produit cosmétique, un quasi-médicament, un aliment, une boisson et un médicament contenant ledit agent anti-inflammatoire. Pour résoudre ces problèmes, l'invention propose un agent anti-inflammatoire comprenant, en tant que principe actif, un saccharide comportant une structure de céto/aldohexose dans une molécule, ainsi qu'un produit cosmétique, un quasi-médicament, un aliment, une boisson et un médicament contenant ledit agent anti-inflammatoire.
PCT/JP2016/071510 2015-07-29 2016-07-22 Agent anti-inflammatoire Ceased WO2017018336A1 (fr)

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Cited By (6)

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JP2021095366A (ja) * 2019-12-18 2021-06-24 花王株式会社 液体口腔用組成物
CN113952347A (zh) * 2021-11-03 2022-01-21 南宁中诺生物工程有限责任公司 一种海藻糖酶抑制剂及其应用
FR3117359A1 (fr) * 2020-12-15 2022-06-17 L'oreal Procédé de revêtement des matières kératiniques consistant à appliquer un agent de revêtement formé par liaisons hydrogène d’un polyphénol avec un polysaccharide nonionique
WO2024043297A1 (fr) 2022-08-25 2024-02-29 株式会社明治 Procédé de production de composition, composition contenant un oligosaccharide ainsi obtenue et utilisation dudit procédé et de ladite composition
WO2024043298A1 (fr) 2022-08-25 2024-02-29 株式会社明治 Composition pour améliorer la flore bactérienne intestinale
WO2025116015A1 (fr) * 2023-12-01 2025-06-05 株式会社明治 Composition pour lutter contre la croissance de bactéries fusicatenibacter

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KR102646341B1 (ko) * 2019-10-08 2024-03-12 한국식품연구원 사철쑥 추출물을 유효성분으로 포함하는 호흡기 질환 개선용 조성물
WO2021071292A2 (fr) 2019-10-08 2021-04-15 한국식품연구원 Composition utilisant une souche de lactobacillus plantarum ou autre et destinée au soulagement de maladies respiratoires

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021095366A (ja) * 2019-12-18 2021-06-24 花王株式会社 液体口腔用組成物
JP7153007B2 (ja) 2019-12-18 2022-10-13 花王株式会社 液体口腔用組成物
FR3117359A1 (fr) * 2020-12-15 2022-06-17 L'oreal Procédé de revêtement des matières kératiniques consistant à appliquer un agent de revêtement formé par liaisons hydrogène d’un polyphénol avec un polysaccharide nonionique
WO2022128542A1 (fr) * 2020-12-15 2022-06-23 L'oreal Procédé de revêtement de matières kératiniques consistant à appliquer un agent de revêtement formé par interaction de liaison hydrogène d'un polyphénol avec au moins un polysaccharide non ionique sur lesdites matières
CN113952347A (zh) * 2021-11-03 2022-01-21 南宁中诺生物工程有限责任公司 一种海藻糖酶抑制剂及其应用
WO2024043297A1 (fr) 2022-08-25 2024-02-29 株式会社明治 Procédé de production de composition, composition contenant un oligosaccharide ainsi obtenue et utilisation dudit procédé et de ladite composition
WO2024043298A1 (fr) 2022-08-25 2024-02-29 株式会社明治 Composition pour améliorer la flore bactérienne intestinale
WO2025116015A1 (fr) * 2023-12-01 2025-06-05 株式会社明治 Composition pour lutter contre la croissance de bactéries fusicatenibacter

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