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WO2022108392A1 - Composition théragnostique pour la sclérodermie, contenant bifidobacterium sp. comme ingrédient actif - Google Patents

Composition théragnostique pour la sclérodermie, contenant bifidobacterium sp. comme ingrédient actif Download PDF

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Publication number
WO2022108392A1
WO2022108392A1 PCT/KR2021/017103 KR2021017103W WO2022108392A1 WO 2022108392 A1 WO2022108392 A1 WO 2022108392A1 KR 2021017103 W KR2021017103 W KR 2021017103W WO 2022108392 A1 WO2022108392 A1 WO 2022108392A1
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Prior art keywords
bifidobacterium
scleroderma
cells
composition
present
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English (en)
Korean (ko)
Inventor
문수진
조미라
박성환
전주연
최정원
이건희
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Industry Academic Cooperation Foundation of Catholic University of Korea
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Industry Academic Cooperation Foundation of Catholic University of Korea
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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
    • A61K35/745—Bifidobacteria
    • 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
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat

Definitions

  • the present invention relates to a composition for theragnosis for scleroderma comprising the genus Bifidobacterium as an active ingredient.
  • Immune diseases are diseases in which components of the mammalian immune system cause, mediate or otherwise contribute to the pathology of mammals.
  • inflammatory disorders are one of the most important health problems in the world.
  • Inflammation is generally a localized protective response of body tissues against host invasion by foreign substances or noxious stimuli. Inflammation can be caused by infectious causes such as bacteria, viruses, and parasites; physical causes such as burns or radiation; chemicals such as toxins, drugs or industrial agents; immune responses, such as allergies and autoimmune responses, or conditions associated with oxidative stress.
  • T cells are one of the cell groups that play a central role in the immune system as a biological defense system against various pathogens.
  • T cells are generated in the thymus of the human body and differentiate into T cells with unique characteristics through a series of differentiation processes. differentiated into helper cells (Th2).
  • Th2 cells helper cells
  • the main function of Th1 cells is involved in cell-mediated immunity
  • Th2 cells are involved in humoral immunity
  • these two cell populations maintain the balance of the immune system by checking each other so that they do not overactivate each other. Therefore, it can be seen that most of the immune diseases are due to the imbalance between these two immune cells. For example, if the activity of Th1 cells is abnormally increased, autoimmune diseases may occur, and the activity of Th2 cells is abnormally increased.
  • Treg cells have the characteristic of controlling the inflammatory response by suppressing the function of abnormally activated immune cells, and many studies are being conducted to treat immune diseases by increasing the activity of Treg cells.
  • Th17 cells are known to be formed through a process similar to the differentiation of Treg cells in the differentiation process of undifferentiated T cells.
  • Treg cells and Th17 cells are differentiated in the presence of TGF- ⁇ in common, but Treg cells do not require IL-6, whereas in Th17 cells, IL-6 is present together with TGF- ⁇ . differentiate in a situation where In addition, differentiated Th17 cells are characterized in that they secrete IL-17. It has been found that Th17 cells, unlike Treg cells, are involved in the forefront of the inflammatory response seen in immune diseases and accelerate disease progression by maximizing the signal of the inflammatory response. Therefore, in the case of autoimmune diseases that are not controlled by Treg cells among autoimmune diseases, the development of therapeutic agents for autoimmune diseases targeting the inhibition of Th17 cell activity has been highlighted.
  • Systemic scleroderma is a progressive, debilitating autoimmune disorder, also referred to as dermal fibrosis, characterized by excessive protein deposition into the extracellular matrix by skin fibroblasts, with widespread microvascular damage in the skin and It is characterized by progressive fibrosis.
  • dermal fibrosis characterized by excessive protein deposition into the extracellular matrix by skin fibroblasts, with widespread microvascular damage in the skin and It is characterized by progressive fibrosis.
  • the most obvious clinical symptoms are hardening of the skin and associated scarring, for example, hardening, redness, or peeling of the skin.
  • SSc is caused by activated fibroblasts that excessively produce connective tissue constituents such as collagen, and causes changes in the connective tissue of the skin, resulting in a defect in its function.
  • SSc is a limited type in which skin hardening occurs only on the hands below the elbow, feet below the knee, and face, depending on the site of the onset, and skin in more areas, i.e., above the elbow, above the knee, and the body, as well as the skin It is broadly classified as a diffuse type accompanied by invasion of internal organs such as the kidneys and lungs with changes in hardness. Patients with restricted SSc have a 5-year survival rate of more than 90%, but the prognosis of patients with diffuse SSc is poor, showing a 5-year survival rate of only 50 to 70%. Patients with diffuse skin disease often show upregulation of unique markers in the skin, such as type I interferon (IFN)-induced genes.
  • IFN type I interferon
  • the hypothesis that IFN plays a role in skin fibrosis is supported by a recent report of scleroderma in patients treated with IFN for chronic viral infection (Varga & Abraham (2007) J. Clin. Invest. 117:557- 567 and Coelho et al. (2008) Immunol. Lett. 118:110-115).
  • the lesion of SSc can be characterized by symptoms such as tissue fibrosis, vasculopathy of small blood vessels, and autoimmune disease specific to autoantibodies. .
  • Probiotics are probiotics that are distributed as dominant bacteria in the human intestine where various microorganisms exist and promote the growth of beneficial bacteria in the body. do. In addition, it maintains the pH of the intestine to be acidic, inhibits the growth of harmful bacteria such as E. coli and Chlostridum sp, improves diarrhea and constipation, and plays a role in vitamin synthesis and lowering blood cholesterol.
  • probiotics have the ability to bind strongly to the intestinal mucosa and epithelial cells, and thus help the intestinal tract.
  • probiotics promote the proliferation of macrophages, thereby enhancing the recognition and sterilization ability of macrophages against harmful intestinal bacteria.
  • the present inventors analyzed the intestinal flora of normal people and patients with scleroderma, and as a result, it was confirmed that the difference between the Bifidobacterium strain, one of the probiotics, was significant, and when treated, it was effective in preventing and treating scleroderma. It was confirmed that In addition, after treatment with the conventional skin sclerosis treatment drug, the increase/decrease degree of intestinal bifidobacterium was effectively confirmed, and based on this, it was confirmed that the therapeutic drug can be used as a therapeutic level discrimination and diagnostic index, The present invention was completed by confirming that the terium sp. strain has a high value applicable to a new concept diagnosis/treatment technology for diagnosing diseases at an early stage and performing treatment at the same time.
  • the present invention is a Bifidobacterium sp. strain; its culture; Or it may provide a pharmaceutical composition for preventing or treating skin sclerosis (Scleroderma) comprising the dry powder as an active ingredient.
  • the present invention is a Bifidobacterium sp. strain; its culture; Or it can provide a food composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
  • the present invention is a Bifidobacterium sp. strain; its culture; Or it can provide a quasi-drug composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
  • the present invention is a Bifidobacterium genus ( Bifidobacterium sp.) strain; its culture; Or it can provide a method for treating sclerosis (Scleroderma) comprising; administering to the subject a pharmaceutically effective amount of the dry powder.
  • the present invention is a Bifidobacterium sp. strain; its culture; Or it provides a pharmaceutical composition for the prevention or treatment of skin sclerosis (Scleroderma) comprising the dry powder as an active ingredient.
  • the present invention is a Bifidobacterium sp. strain; its culture; Or its dry powder; provides a food composition for preventing or improving skin sclerosis comprising as an active ingredient.
  • the present invention is a Bifidobacterium sp. strain; its culture; Or it provides a quasi-drug composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
  • the present invention is a Bifidobacterium genus ( Bifidobacterium sp.) strain; its culture; Or administering a pharmaceutically effective amount of the dry powder to the subject; provides a method for treating sclerosis (Scleroderma) comprising a.
  • the Bifidobacterium sp. strain of the present invention regulates immune function by reducing Th1 cells, Th2 cells and Th17 cells, and in the intestinal flora analysis, the total number of Bifidobacterium is reduced in scleroderma patients. When administered, the effect of inducing an increase in intestinal flora is excellent. Therefore, it was confirmed that the Bifidobacterium sp. strain of the present invention is excellent in preventing and treating skin sclerosis by reducing the thickness of the skin and inhibiting skin fibrosis.
  • the Bifidobacterium spp. strain of the present invention is applicable to "Theragnosis" technology applicable to a new concept diagnosis/treatment technology for diagnosing and simultaneously treating immune diseases such as scleroderma at an early stage, and its value By confirming that is high, the present invention was completed.
  • 1 is a diagram confirming the distribution of Bifidobacterium genus by analyzing the intestinal flora in 28 normal subjects and 24 patients.
  • Figure 2 is a diagram confirming the distribution of species (Species) of the genus Bifidobacterium (genus) by analyzing the intestinal flora in 28 normal and 24 patients.
  • 3 is a diagram showing the comparison of the distribution of various genera including the genus Bifidobacterium at the genus level by analyzing the intestinal flora in 28 normal patients and 24 patients.
  • Figure 4 is a diagram showing the comparison of the distribution of various species (Species) including Bifidobacterium longum ( Bifidobacterium longum ) at the level of the species (Species) by analyzing the intestinal flora in 28 normal and 24 patients.
  • species including Bifidobacterium longum ( Bifidobacterium longum ) at the level of the species (Species) by analyzing the intestinal flora in 28 normal and 24 patients.
  • Figure 5 is a diagram showing the comparison of the distribution of various species (Species) including Bifidobacterium catenulatum at the species level by analyzing the intestinal flora in 28 normal and 24 patients.
  • FIG. 6 is a diagram showing the comparison of the distribution of various species (Species) including Bifidobacterium adolescentis at the species level by analyzing the intestinal flora in 28 normal people and 24 patients.
  • species including Bifidobacterium adolescentis at the species level by analyzing the intestinal flora in 28 normal people and 24 patients.
  • 7a is a view confirming the decrease in skin thickness according to the administration of Bifidobacterium longum to an animal model of scleroderma.
  • 7B is a diagram illustrating quantification of the reduction in skin thickness according to the administration of Bifidobacterium longum to an animal model of scleroderma.
  • FIG. 8 is a view showing the results of confirming the degree of skin thickness reduction according to the administration of Bifidobacterium longum to an animal model of scleroderma by MT (masson's trichrome stain) staining.
  • 9a is a diagram showing the Th1 inhibitory effect according to the administration of Bifidobacterium longum to an animal model of scleroderma.
  • 9B is a diagram showing the Th2 inhibitory effect according to the administration of Bifidobacterium longum to an animal model of scleroderma.
  • 9c is a diagram showing the Th17 inhibitory effect according to the administration of Bifidobacterium longum to an animal model of scleroderma.
  • Figure 10a is a diagram showing the CD8+IL-17+ inhibitory effect according to the administration of Bifidobacterium longum to an animal model of scleroderma.
  • 10B is a diagram showing the CD8+IFN-r enhancement effect according to the administration of Bifidobacterium longum to an animal model of scleroderma.
  • FIG. 11 is a diagram for diagnosing the degree of therapeutic effect of conventional therapeutic drugs by confirming an increase in the genus of Bifidobacterium after treatment of a conventional therapeutic drug (Metfomin or tacrolimus (FK506)) in an animal model of scleroderma .
  • a conventional therapeutic drug Metalfomin or tacrolimus (FK506)
  • the present invention is a Bifidobacterium sp. strain; its culture; Or it provides a pharmaceutical composition for the prevention or treatment of skin sclerosis (Scleroderma) comprising the dry powder as an active ingredient.
  • Bifidobacterium is Bifidobacterium longum ( Bifidobacterium longum ), Bifidobacterium is Bifidobacterium catenulatum ( Bifidobacterium catenulatum ) , Bifidobacterium adolescentis ( Bifidobacterium adolescentis ) It was confirmed that there is a difference in the distribution of normal people and patients. Therefore, in the present invention, Bifidobacterium genus, preferably Bifidobacterium longum, can be used as an active ingredient.
  • the scleroderma is characterized by an increase in Th1 cells, Th2 cells and Th17 cells, an increase in CD8+IL17+ T cells, and a decrease in CD8+IFN-r+ cells, resulting in thickening of the skin, and advanced skin fibrosis. .
  • the genus Bifidobacterium of the present invention reduces Th1 cells, Th2 cells and Th17 cells, inhibits CD8+IL17+ T cells, and increases CD8+IFN-r+ cells, thereby reducing the thickness of the skin and reducing skin fibrosis. By suppressing it, skin sclerosis can be treated and prevented.
  • the increase/decrease degree of intestinal bifidobacterium can be effectively checked, and based on this, it can be used as a therapeutic level discrimination and diagnostic index of the treatment drug.
  • the Bifidobacterium sp. strain of the present invention refers to a fermentation broth obtained by culturing in a culture medium, a concentrated fermentation broth, a dried product of the fermentation broth, a culture filtrate, a concentrated culture filtrate, or a dried product of the culture filtrate, including the strain It may be a culture filtrate from which the strain is removed after culturing.
  • the formulation of the culture is not limited, and may be, for example, a liquid, an emulsion, or a solid.
  • cultivation means to grow microorganisms in an appropriately artificially controlled environmental condition.
  • the strain can grow in a normal medium, and the medium contains nutrients required by the microorganism to be a culture target, that is, a culture body in order to culture a specific microorganism. have.
  • the medium is also referred to as an incubator or culture medium, and is a concept including all of natural medium, synthetic medium or selective medium, and can be cultured according to a conventional culture method.
  • the medium used for culture must meet the requirements of a specific strain in an appropriate manner while controlling temperature, pH, etc. in a conventional medium containing an appropriate carbon source, nitrogen source, amino acids, vitamins, and the like.
  • a carbon source that can be used a mixed sugar of glucose and xylose is used as the main carbon source, in addition to sugars and carbohydrates such as sucrose, lactose, fructose, maltose, starch, cellulose, soybean oil, sunflower oil, castor oil, coconut Oils and fats such as oil, fatty acids such as palmitic acid, stearic acid and linoleic acid, alcohols such as glycerol, ethanol, and organic acids such as acetic acid are included.
  • nitrogen source examples include inorganic nitrogen sources such as ammonia, ammonium sulfate, ammonium chloride, ammonium acetate, ammonium phosphate, anmonium carbonate, and ammonium nitrate; Amino acids such as glutamic acid, methionine, glutamine, and organic nitrogen sources such as peptone, NZ-amine, meat extract, yeast extract, malt extract, corn steep liquor, casein hydrolyzate, fish or its degradation products, defatted soybean cake or its degradation products, etc. can These nitrogen sources may be used alone or in combination.
  • inorganic nitrogen sources such as ammonia, ammonium sulfate, ammonium chloride, ammonium acetate, ammonium phosphate, anmonium carbonate, and ammonium nitrate
  • Amino acids such as glutamic acid, methionine, glutamine
  • organic nitrogen sources such as peptone, NZ-amine, meat extract, yeast extract, malt extract, corn steep liquor, casein hydroly
  • the medium may contain monopotassium phosphate, dipotassium phosphate and the corresponding sodium-containing salt as phosphorus.
  • the phosphorus that may be used includes potassium dihydrogen phosphate or dipotassium hydrogen phosphate or the corresponding sodium-containing salt.
  • sodium chloride, calcium chloride, iron chloride, magnesium sulfate, iron sulfate, manganese sulfate, calcium carbonate, etc. may be used as the inorganic compound.
  • essential growth substances such as amino acids and vitamins can be used.
  • precursors suitable for the culture medium may be used.
  • the above-mentioned raw materials may be added in a batch, fed-batch or continuous manner by an appropriate method to the culture during the culturing process, but is not particularly limited thereto.
  • Basic compounds such as sodium hydroxide, potassium hydroxide, ammonia or acid compounds such as phosphoric acid or sulfuric acid may be used in an appropriate manner to adjust the pH of the culture.
  • the pharmaceutical composition of the present invention may further include an adjuvant in addition to the active ingredient.
  • the adjuvant may be used without limitation as long as it is known in the art, for example, Freund's complete adjuvant or incomplete adjuvant may be further included to increase the immunity thereof.
  • the pharmaceutical composition according to the present invention may be prepared in a form in which the active ingredient is incorporated into a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. .
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose, lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
  • Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc.
  • compositions for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
  • base of the suppository witepsol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • composition according to the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
  • the dosage of the pharmaceutical composition according to the present invention is selected in consideration of the individual's age, weight, sex, physical condition, and the like. It is self-evident that the concentration of the active ingredient included in the pharmaceutical composition can be variously selected depending on the subject, and is preferably included in the pharmaceutical composition at a concentration of 0.01 to 5,000 ⁇ g/ml. If the concentration is less than 0.01 ⁇ g/ml, pharmaceutical activity may not appear, and if it exceeds 5,000 ⁇ g/ml, it may be toxic to the human body.
  • the pharmaceutical composition may be formulated in various oral or parenteral dosage forms.
  • Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like. crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol).
  • the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid. or a disintegrant such as its sodium salt or a boiling mixture and/or absorbent, coloring, flavoring and sweetening agent.
  • the formulation may be prepared by conventional mixing, granulating or coating methods.
  • a representative formulation for parenteral administration is an injection formulation
  • examples of the solvent for the injection formulation include water, Ringer's solution, isotonic saline, or suspension.
  • the sterile, fixed oil of the injectable preparation may be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides may be used for this purpose.
  • the injection preparation may use a fatty acid such as oleic acid.
  • the present invention is a Bifidobacterium sp. strain; its culture; Or its dry powder; provides a food composition for preventing or improving skin sclerosis comprising as an active ingredient.
  • the food composition of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional food composition.
  • Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • the above-mentioned flavoring agents can advantageously use natural flavoring agents (Taumatine), stevia extract (eg rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
  • the food composition of 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, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements. There is this.
  • the food composition includes, in addition to the active ingredient extract, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickeners (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • the food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages.
  • the functional food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like.
  • the term 'health functional food composition' refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and It refers to ingestion for the purpose of obtaining useful effects for health purposes, such as regulating nutrients or physiological effects.
  • the health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards.
  • the items listed in the 'Food Additives Code' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations, such as a sodium L-glutamate preparation, a noodle-added alkali agent, a preservative preparation, and a tar color preparation, etc. are mentioned.
  • chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid
  • natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum
  • Mixed preparations such as a sodium L-glutamate preparation, a noodle-added alkali agent, a preservative preparation, and a tar color preparation, etc. are mentioned.
  • a health functional food in tablet form is granulated by a conventional method by mixing a mixture of the active ingredient of the present invention with an excipient, binder, disintegrant and other additives, followed by compression molding by putting a lubricant, etc., or The mixture can be compression molded directly.
  • the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary.
  • hard capsules can be prepared by filling a mixture of the active ingredient of the present invention with additives such as excipients in a conventional hard capsule. It can be prepared by filling the mixture mixed with the capsule base such as gelatin.
  • the soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
  • a health functional food in the form of a ring can be prepared by molding a mixture of the active ingredient of the present invention and an excipient, a binder, a disintegrant, etc. by a conventionally known method, Alternatively, the surface may be coated with a material such as starch or talc.
  • the health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing a mixture of excipients, binders, disintegrants, etc. of the active ingredient of the present invention, and may contain flavoring agents, flavoring agents, etc. as necessary can
  • the present invention is a Bifidobacterium sp. strain; its culture; Or it provides a quasi-drug composition for preventing or improving skin sclerosis comprising the dry powder as an active ingredient.
  • quasi-drug refers to articles with a milder action than pharmaceuticals among articles used for the purpose of diagnosing, treating, improving, alleviating, treating or preventing diseases of humans or animals, for example, in the Pharmaceutical Affairs Act. According to the report, quasi-drugs exclude products used for medicinal purposes, and include products used for the treatment or prevention of diseases in humans and animals, and products with minor or no direct action on the human body.
  • the quasi-drug composition of the present invention is a body cleanser, disinfectant cleaner, detergent, kitchen cleaner, cleaning agent, toothpaste, gargle, wet tissue, detergent, soap, hand wash, hair cleaner, hair softener, humidifier filler, mask, ointment and filter filling It may be prepared in a formulation selected from the group consisting of agents, but is not limited thereto.
  • the present invention is a Bifidobacterium genus ( Bifidobacterium sp.) strain; its culture; Or administering a pharmaceutically effective amount of the dry powder to the subject; provides a method for treating sclerosis (Scleroderma) comprising a.
  • the present invention provides a method for treating scleroderma comprising the steps of: 1) determining the number of Bifidobacterium in a biological sample obtained from an individual; 2) comparing the number of Bifidobacterium to a control group; 3) It provides a method of treating scleroderma comprising administering Bifidobacterium to an individual having a reduced number of Bifidobacterium compared to the control group.
  • the treatment method of the present invention is the Bifidobacterium sp. strain; its culture; or administering the dry powder to the subject in a therapeutically effective amount.
  • a specific therapeutically effective amount for a particular subject will depend on the type and extent of the response to be achieved, the specific composition, including whether other agents are used, if necessary, the age, weight, general health, sex and diet of the subject, the time of administration; It is preferable to apply differently depending on various factors including the route of administration and secretion rate of the composition, the duration of treatment, the drug used together or concurrently with the specific composition, and similar factors well known in the pharmaceutical field.
  • the daily dose is 0.0001 to 100 mg/kg, preferably 0.01 to 100 mg/kg, based on the amount of the pharmaceutical composition of the present invention, and may be administered 1 to 6 times a day.
  • the dose or dosage of each active ingredient should be such that the side effects do not occur by including the content of each active ingredient too high. Therefore, it is preferable to determine the effective amount of the composition suitable for the purpose of the present invention in consideration of the foregoing.
  • the subject is applicable to any mammal, and the mammal includes not only humans and primates, but also domestic animals such as cattle, pigs, sheep, horses, dogs and cats.
  • Bifidobacterium sp. strain of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • Example 1 Analysis of intestinal flora in normal persons and patients with scleroderma
  • fecal samples were collected from 28 normal subjects and 42 Korean scleroderma patients and stored at -80°C. After that, in order to perform next generation sequencing with the fecal sample, bacterial genomic DNA was isolated from the sample and the 16S rRNA gene specific to the microorganism was amplified among them to prepare a library. .
  • the 16S rRNA gene of the library was sequenced using Illumina's Misep. The decoded sequence was subjected to bioinformatic analysis using QllME1.9.1 (open-source bioinformatic pipeline).
  • Example 2 Skin thickness and fibrosis inhibitory effect according to the administration of Bifidobacterium longum in an animal model of scleroderma
  • bleomycin prepared in advance was dissolved in 0.9% sodium chloride (1 mg/ml), 100ul each daily for a total of 4 weeks from the neck to the back (square shape).
  • a scleroderma model was prepared by subcutaneous injection in each of the four corners).
  • Bifidobacterium long gum was purchased from CTC Bio.
  • the Bifidobacterium longum of the present invention was hydrodynamically injected into the mouse model, and injected a total of 3 times, once a week from 2 weeks to 5 weeks.
  • the skin of the untreated mouse group (control group) and the 400 mg/kg Bifidobacterium longum-administered scleroderma mouse group (experimental group) were fixed with 10% formalin each 35 days after sclerosis induction to prepare a block with paraffin. From this, a skin section was prepared and attached to a slide, and after deparaffinization using xylene, it was hydrated using high and low concentration ethanol, and the skin section was stained with hematoxylin and eosin. In addition, the skin sections were stained with Masson's Trichrome (MT) to determine the density of collagen fibers. Skin thickness and fibrosis degree for each treatment group were checked.
  • MT Masson's Trichrome
  • the thickness of the skin and the density of collagen fibers in the dermis of the scleroderma mouse model treated with Bifidobacterium longum were dense and space was lost, and the size of the hair follicles was significantly reduced and the location of the blood vessels was lowered.
  • the skin thickness was reduced and skin fibrosis was significantly reduced by the treatment of Bifidobacterium longum, the symptoms of scleroderma were remarkably alleviated ( FIGS. 7 and 8 ).
  • Example 3 Confirmation of Th1, Th2, Th17 inhibitory effect according to the administration of Bifidobacterium longum in an animal model of scleroderma
  • the T cell response suppresses the activity of Th1 (T helper 1 cell)/IFN-gamma, Th2 (T helper 2 cell)/IL-4 (Interleukin 4), Th17 (T helper 17 cell)/IL-17 (Interleukin 17) activity. and the IFN-gamma, IL-4, and IL-17 are classified as inflammatory cells.
  • Th1, Th2, Th17 inhibitory effect according to the administration of Bifidobacterium longum of the present invention, flow cytometry analysis of samples of untreated scleroderma mice (control group) and Bifidobacterium longum-treated scleroderma mice (experimental group) Th1, Th2, Th17 cells were analyzed in the method.
  • splenocytes from each group were obtained, and Th1 cells were analyzed as CD4+IFN-r+ cells, Th2 cells as CD4+IL-4+ cells, and Th17 cells as CD4+IL-17+ cells through flow cytometry.
  • Example 4 CD8+IL-17+ inhibitory effect and CD8+IFN-r enhancement effect according to the administration of Bifidobacterium longum in an animal model of scleroderma
  • metformin metformin
  • tacrolimus tacrolimus
  • Conventional immunosuppressive agents metformin (Metfomin), tacrolimus (FK506), etc. are used for the treatment of scleroderma, and after treatment with the immunosuppressant, there is no confirmation of a change in a specific intestinal flora. Therefore, the scleroderma animal model was treated with metformin (Metfomin) and tacrolimus (FK506), and changes in the intestinal flora, particularly Bifidobacterium genus, were confirmed.
  • fecal samples from untreated scleroderma mice (control), metformin-treated scleroderma mice or tacrolimus-treated scleroderma mice were collected and stored at -80°C.
  • bacterial genomic DNA was isolated from the sample and the 16S rRNA gene specific to the microorganism was amplified among them to prepare a library.
  • the 16S rRNA gene of the library was sequenced using Illumina's Misep.
  • the decoded sequence was subjected to bioinformatic analysis using QllME1.9.1 (open-source bioinformatic pipeline).
  • the genus of Bifidobacterium is decreased during the progression of scleroderma, and results increased during treatment with therapeutic drugs, suggesting that the diagnosis of scleroderma will also be possible depending on the quantity of Bifidobacterium.
  • the effect on the treatment drug treatment can also be determined according to the quantity or increase of the Bifidobacterium genus, and can be used as a screening index for related candidate drugs in the future, so that the Bifidobacterium sp.
  • strain of the present invention confirmed that it can be applied to the "Theragnosis” technology, which can be applied to a new concept diagnosis/treatment technology that diagnoses immune diseases such as scleroderma at an early stage and performs treatment at the same time, and has high value.

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Abstract

La présente invention concerne une composition théragnostique pour la sclérodermie, contenant un Bifidobacterium sp. comme ingrédient actif. Une souche de Bifidobacterium sp. de la présente invention régule les fonctions immunitaires par réduction des cellules Th1, Th2 et Th17. De plus, la présente invention a un excellent effet d'augmentation des bactéries intestinales totales lorsqu'elle est administrée à un patient atteint de sclérodermie ayant un nombre total réduit de Bifidobacterium dans l'analyse de la microflore intestinale. Par conséquent, il a été déterminé que la souche de Bifidobacterium sp. de la présente invention réduit l'épaisseur de la peau, et inhibe la fibrose cutanée, présentant ainsi les excellents effets de prévention et de traitement de la sclérodermie. De plus, il a été déterminé qu'après traitement avec un médicament classique pour le traitement de la sclérodermie, le degré d'augmentation/diminution de Bifidobacterium intestinal est efficacement déterminé et peut donc être utilisable en tant qu'indicateur pour déterminer et diagnostiquer le degré de traitement du médicament thérapeutique. Ainsi, la présente invention a été achevée par détermination du fait que la souche de Bifidobacterium sp. de la présente invention est applicable à une technologie de "théragnostic", qui peut être appliqué à une technologie de diagnostic/thérapeutique de concept innovant qui permet un diagnostic et un traitement précoces simultanés d'une maladie immunitaire telle que la sclérodermie, et présente un intérêt
PCT/KR2021/017103 2020-11-20 2021-11-19 Composition théragnostique pour la sclérodermie, contenant bifidobacterium sp. comme ingrédient actif Ceased WO2022108392A1 (fr)

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Citations (4)

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US20160120915A1 (en) * 2013-06-10 2016-05-05 New York University Methods for manipulating immune responses by altering microbiota
KR20180012769A (ko) * 2015-06-15 2018-02-06 4디 파마 리서치 리미티드 박테리아성 균주를 함유한 조성물
KR20180089324A (ko) * 2017-01-31 2018-08-08 경희대학교 산학협력단 신규 유산균 및 이의 용도
KR20180136395A (ko) * 2017-06-14 2018-12-24 기초과학연구원 신규한 비피도박테리움 비피덤 균주 및 균주 유래 다당체

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US20160120915A1 (en) * 2013-06-10 2016-05-05 New York University Methods for manipulating immune responses by altering microbiota
KR20180012769A (ko) * 2015-06-15 2018-02-06 4디 파마 리서치 리미티드 박테리아성 균주를 함유한 조성물
KR20180089324A (ko) * 2017-01-31 2018-08-08 경희대학교 산학협력단 신규 유산균 및 이의 용도
KR20180136395A (ko) * 2017-06-14 2018-12-24 기초과학연구원 신규한 비피도박테리움 비피덤 균주 및 균주 유래 다당체

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