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WO2014104681A1 - Composition pharmaceutique pour prévenir ou traiter une maladie cutanée comprenant un composé d'ériodictyol ou un sel pharmaceutiquement acceptable de celui-ci en tant que substance active - Google Patents

Composition pharmaceutique pour prévenir ou traiter une maladie cutanée comprenant un composé d'ériodictyol ou un sel pharmaceutiquement acceptable de celui-ci en tant que substance active Download PDF

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Publication number
WO2014104681A1
WO2014104681A1 PCT/KR2013/012018 KR2013012018W WO2014104681A1 WO 2014104681 A1 WO2014104681 A1 WO 2014104681A1 KR 2013012018 W KR2013012018 W KR 2013012018W WO 2014104681 A1 WO2014104681 A1 WO 2014104681A1
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Prior art keywords
skin
pharmaceutically acceptable
acceptable salt
derivative
pharmaceutical composition
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English (en)
Korean (ko)
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김택중
박세진
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Industry Academic Cooperation Foundation of Yonsei University
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Industry Academic Cooperation Foundation of Yonsei University
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Priority claimed from KR1020120153153A external-priority patent/KR20140083425A/ko
Priority claimed from KR1020120153152A external-priority patent/KR20140083424A/ko
Application filed by Industry Academic Cooperation Foundation of Yonsei University filed Critical Industry Academic Cooperation Foundation of Yonsei University
Publication of WO2014104681A1 publication Critical patent/WO2014104681A1/fr
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a composition for preventing or treating skin diseases containing an eriodictyol compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Mast cells and blood basophils are known as cells in the body that cause various allergic diseases, such as allergic rhinitis, allergic atopic dermatitis, allergic conjunctivitis, allergic asthma, food allergy and anaphylactic shock. .
  • Allergic skin diseases are caused by various allergens, which excessively stimulate the immune system, and in immune cells such as macrophages, TNF- ⁇ (tumor necrosis factor- ⁇ ), IL-6 (interleukin-6), and IL-8 ( interleukin-8), prostaglandin, leucotriene and nitric oxide (NO) to induce excessive inflammatory substances, such as allergic purpura, atopic dermatitis, chronic asthma and immunity. causes hypersensitivity symptoms.
  • immune cells such as macrophages, TNF- ⁇ (tumor necrosis factor- ⁇ ), IL-6 (interleukin-6), and IL-8 ( interleukin-8), prostaglandin, leucotriene and nitric oxide (NO) to induce excessive inflammatory substances, such as allergic purpura, atopic dermatitis, chronic asthma and immunity. causes hypersensitivity symptoms.
  • the eriodictyol compound is a type of flavanone of the plant, which is separated from the old maple ( Acer mono Max.) And Yerba santa ( Eriodictyon califonicum ). Known.
  • the erythridiol compound has a prophylactic effect in diseases such as atherosclerosis, bone disease and hypertension.
  • diseases such as atherosclerosis, bone disease and hypertension.
  • erythrothiol compound has a prophylactic effect in diseases such as atherosclerosis, bone disease and hypertension.
  • the effect of the erythrothiol compound has been no report on the effect of the erythrothiol compound on the treatment of skin-related diseases.
  • the present inventors have completed the present invention by confirming that the eriodictyol compound, which is a kind of plant flavanone, is effective in alleviating the itch of dermatitis, treating inflammation, moisturizing the skin and enhancing skin elasticity.
  • the present invention provides a pharmaceutical composition for preventing or treating skin diseases containing an eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides an external skin preparation for preventing or treating skin diseases containing an eriodictyol compound, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a cosmetic composition for improving or alleviating skin diseases containing an eriodictyol compound, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food for improving or alleviating skin diseases containing an eriodictyol compound, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • erythrothiol compound, a derivative thereof or a pharmaceutically acceptable salt thereof by inhibiting the degranulation of mast cells and by confirming the effect on relieving itching, inflammation, edema, skin moisturizing and skin elasticity excellent in allergic animal models, It is expected to be useful as a good medicine, cosmetics, external skin preparations or health functional food.
  • Figure 1 shows the chemical structure of riodic thiol.
  • 2A and 2B show the results of experiments measuring the effect of erythrothiol on IgE / Ag-induced passive dermal anaphylaxis (PCA).
  • 3A and 3B are graphs showing the results of experiments measuring the effect of erythrothiol on IgE / Ag-activated mast cell degranulation, 3a is the result of measuring the secretion amount of ⁇ -hexosaminidase, and 3b is cell survival Indicates the level measurement result.
  • Figure 4 shows the results of measuring the effect of the expression of TNF- ⁇ and IL-4 erythrothiol in IgE / Ag-sensitized mast cells.
  • Figure 5 shows the experimental results of measuring the effect of the cerioid thiol compound on ceramide kinase (CERK) in IgE / Ag-sensitized mast cells.
  • Figure 6 shows the experimental results of measuring the effect of the erythrothiol compound on ceramide levels in IgE / Ag-sensitized mast cells.
  • Figure 7 shows the results of a change measurement test of the scratching behavior of the dorsal epidermis of mice induced with allergic contact dermatitis according to the treatment of the erythrothiol compound.
  • FIGS. 8A and 8B show skin sensory evaluation photographs (A) and results (B) of the dorsal epidermis of mice induced with allergic contact dermatitis according to the treatment of the erythrothiol compound, respectively.
  • Figures 9a and 9b is taken after the hematoxylin and eosin staining process after the tissue of the dorsal epidermis of the mouse induced allergic contact dermatitis in accordance with the treatment of the erythrodiol thiol compound of the present invention was taken under a microscope (A) and a graph showing the experimental results numerically. (It is about microscope picture which enlarged 40 times (a, b, c), 100 times (d, e, f).)
  • Figure 10 shows the results of the measurement of the change in serum IgE following the treatment with the eriodithiol compound.
  • Figure 11 is a graph showing the results of measuring the skin moisturizing effect of the cream-type cosmetics containing erythridiol with MY-808S Moisture Checker (Scalar, Japan).
  • Figure 12 is a graph showing the results of measuring the skin moisturizing effect of the serum type cosmetics containing erythridiol with MY-808S Moisture Checker (Scalar, Japan).
  • the present invention relates to a pharmaceutical composition for preventing or treating skin diseases containing an eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to an external preparation for skin disease prevention or treatment containing an eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to a cosmetic composition for improving or alleviating skin diseases containing an eriodictyol compound, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to a health functional food for improving or alleviating skin diseases containing an eriodictyol compound, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention is characterized by providing a pharmaceutical composition for preventing or treating skin diseases containing an eriodictyol compound represented by Formula 1, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. :
  • Erie ohdik thiol (eriodictyol) compounds IUPAC name as a kind of flavanone (flavanone) are (2 S) -2- and (3,4-dihydroxyphenyl) -5,7-dihydroxy -4-chromanone, a
  • the molecular formula of the material is C 15 H 12 O 6 , with a molecular weight of 288.25.
  • the eriodithiol compound according to the present invention may be used in the form of a salt, preferably a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid.
  • the free acid may be an organic acid or an inorganic acid.
  • the organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
  • the eriodithiol compound of the present invention can be isolated from natural products or prepared and used by chemical synthesis methods known in the art, and commercially available riodicthiol compounds can be obtained commercially.
  • the pharmaceutical composition of the present invention is hardly toxic and harmless to the human body since the active ingredient is a component isolated from a natural product extract or a derivative thereof.
  • the pharmaceutical dosage forms of erythridiol according to the present invention may be used in the form of their pharmaceutically acceptable salts, and may also be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.
  • the pharmaceutical composition may exhibit an itching relief, inflammatory response inhibition, edema inhibition, skin moisturizing and skin elasticity effect, the composition is characterized in that for the prevention or treatment of contact dermatitis Can be.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the composition comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and such solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. Mix is prepared. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like can also be used.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the pharmaceutical composition is any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories. It can have one formulation.
  • the eriodictyol compound, derivative thereof or pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.0001 to 50% by weight of the total pharmaceutical composition, more specifically 0.005 to 25% by weight, more specifically may be included in an amount of 0.001 to 10% by weight.
  • the eriodicthiol compound, derivative thereof, or pharmaceutically acceptable salt thereof does not affect the skin disease and will be effective. It may not be possible. In addition, when it exceeds 50% by weight, it does not show an effect similar to or higher than that of 50% by weight.
  • a skin external preparation for preventing or treating skin diseases containing an eriodictyol compound represented by Formula 1 below, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is provided. It is characterized by:
  • the external skin preparation has an effect selected from the group consisting of alleviation of itching, inhibition of inflammatory response, edema inhibition, skin moisturization and skin elasticity, wherein the external skin preparation is for the prevention or treatment of contact dermatitis It is characterized by.
  • the external skin preparation is formulated into any one selected from the group consisting of ointments, creams, lotions, solutions, dressings, patches, blisters, tapes, aerosols, external preparations and sprays. Can be.
  • the eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof in the external preparation for skin is 0.00001 to 25% by weight of the total external skin composition, more specifically 0.0005 To 10% by weight, more specifically, may be included in an amount of 0.0001 to 5% by weight.
  • any ingredient generally used in external preparations for skin may be used.
  • ointments creams, gels and lotions, white and petrolatum (waceline), yellow and petrolatum, lanolin, refined beeswax, cetanol, stearyl alcohol, stearic acid, hydrogenated oil, hydrocarbon gel, polyethylene glycol, liquid paraffin and squalane Base such as; Oleic acid, isopropyl myristate, glycerol triisooctanoate, crotamiton, diethyl sebacate, diisopropyl sebacate, diisopropyladipate, hexylulaate, fatty acids, fatty acid esters, vegetable oils, fatty alcohols and Solvents or stabilizers such as alcohols; Antioxidants such as tocopherol derivatives, L-ascorbic acid, dibutylhydroxytoluene and butylhydroxyanisol;
  • adhesives such as a polyacrylic acid and a polyacrylic acid copolymer
  • Crosslinking agents such as aluminum sulfate, aluminum potassium sulfate, aluminum chloride, magnesium aluminosilicate and dihydroxyaluminum aminoacetate
  • Thickeners such as sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose
  • Polyhydric alcohols such as glycerin, polyethylene glycol (macrogol), polyethylene glycol and 1,3-butanediol
  • Surfactants such as polyoxyethylene derivatives
  • flavorings such as l-menthol
  • preservatives such as p-hydroxybenzoate
  • Purified water And other suitable fillers may be added.
  • adhesives such as a styrene-isoprene- styrene block copolymer and an acrylate resin
  • Adhesive resins such as acrylic saturated hydrocarbon resins, hydrogenated rosine resins and terpene resins
  • Softeners such as liquid gums and liquid paraffins
  • Antioxidants such as dibutylhydroxytoluene
  • Polyhydric alcohols such as polyethylene glycol
  • Adsorption promoters such as oleic acid
  • Surfactants such as polyoxyethylene derivatives
  • other suitable fillers may be added.
  • water-absorbing polymers such as sodium polyacrylate and polyvinyl alcohol and a small amount of purified water may be added to the preparation of the tape agent containing water.
  • bases such as white and petrolatum (waceline), yellow and petrolatum, lanolin, purified beeswax, cetanol, stearyl alcohol, stearic acid, hydrogenated oil, hydrocarbon gel, polyethylene glycol, liquid paraffin and squalane; Oleic acid, isopropyl myristate, glycerol triisooctanoate, crotamiton, diethyl sebacate, diisopropyl sebacate, isopropyl adipate, hexyl laurate, fatty acids, fatty acid esters, vegetable oils, aliphatic alcohols and alcohols Solvents or stabilizers such as; Antioxidants such as tocopherol derivatives, L-ascorbic acid, dibutylhydroxytoluene and butylhydroxyanisol; preservatives such as p-hydroxybenzoate; Curb agents such as glycerin, propylene glycol and sodium
  • potato starch For external acids, potato starch, rice starch, corn starch, fillers such as talc and zinc oxide, and other suitable additives may be added.
  • the external skin preparation of the present invention may be prepared by well mixing each component with a suitable base as necessary according to a well-known method for preparing the external skin preparation, and the preparation thus prepared is applied to the lesion as necessary.
  • a cosmetic composition for improving or alleviating skin diseases containing an eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof represented by the following formula (1) as an active ingredient It is characterized by:
  • the cosmetic composition for improving or alleviating skin diseases exhibits an effect selected from the group consisting of alleviating itching, inhibiting inflammatory reactions, suppressing edema, skin moisturizing and skin elasticity, and improving or alleviating the skin disease.
  • Cosmetic composition for is characterized in that for the prevention or treatment of contact dermatitis.
  • the eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof in the cosmetic composition is 0.0000001 to 10% by weight of the total cosmetic composition weight, more specifically from 0.0000005 to 5% by weight, more specifically, it may be included in an amount of 0.000001 to 1% by weight.
  • the cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, skin cosmetic ointment, essence, whitening cream, lotion, emulsion, pack, general cosmetics, skin milk, cream, It can be prepared in various forms, such as serum, cosmetic soap, soft cosmetics, medicinal cosmetics, hair tonic, systemic cleanser and oil gel.
  • the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide are used as carrier components.
  • animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide are used as carrier components.
  • tragacanth cellulose derivative
  • polyethylene glycol silicone
  • bentonite silica
  • talc talc
  • zinc oxide cellulose derivative
  • Can bentonite silica
  • talc talc
  • zinc oxide cellulose derivative
  • Can bentonite silica
  • talc talc
  • zinc oxide zinc oxide
  • lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane or dimethyl ether.
  • a solvent, solubilizer or emulsifier is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.
  • liquid carrier diluents such as water, ethanol or propylene glycol
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Sung cellulose, aluminum metahydroxy, bentonite, agar or tragacanth and the like can be used.
  • the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide.
  • Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
  • a health functional food for improving or alleviating skin diseases containing an eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient
  • the eriodictyol compound, a derivative thereof or a pharmaceutically acceptable salt thereof in the dietary supplement is 0.0001 to 10% by weight of the total dietary supplement, more specifically 0.0005 to 5% by weight, more specifically may be included in an amount of 0.001 to 1% by weight.
  • Eriodithiol was purchased from Elcomb Science (Seoul, South Korea), and mouse monoclonal anti-DNP IgE antibody, dinitriphenol-conjugated human serum albumin (DNP-HSA), and Evans Blue were sigma -N -Oleoyl-D-erythro-spingosin (C 17 base) was purchased from Aldrich (St. Louis, Mo.) and p -nitrophenyl- N -acetyl-- from Avantiola Lipid (Alabaster, AL). D-glucosaminid was purchased from MP Biomedical (Solon, OH).
  • Rat mast cell line RBL-2H3 was purchased from the American Type Culture Collection (ATCC, Rockville, MD). Cells were cultured in Eagle minimal minimal medium (WelGENE, Daegu, Korea) containing 10% (v / v) fetal bovine serum and 100 units / mL penicillin-streptomycin (Lonza Walkersville, Walkersville, MD). Incubated at 5% CO 2 . Cells were aliquoted in trypsin-EDTA solution and resuspended in fresh medium for use in the experiment.
  • mice Male BALB / C mice (7 weeks old) were purchased from Orient Bio (Gangneung, South Korea) and bred at 40-50% relative humidity at 20-22. Animals were given free access to diet and water purchased from Samyang (Wonju, South Korea). The animal testing protocol has been approved by the Yonsei Institutional Animal Care and Use Committee. This experiment was confirmed by the NIH guidelines for the use and care of laboratory animals (NIH publication no. 85-23, revised 1996).
  • One ear of each mouse was injected into the skin with an anti-DNP-specific IgE antibody (0.5 ⁇ g).
  • mice were injected intravenously with 200 ⁇ L of DNP-HSA (200 ⁇ g; antigen) dissolved in PBS 3% Evans Blue. After one hour, eriodithiol was orally administered in an amount of 10-50 mg / kg. Two hours after antigen challenge, the mice were euthanized and the treated ears were removed to determine the amount of die to determine the amount of antigen response. The extracted ears were immersed in 500 ⁇ L of formamide and left overnight at 63 ° C. to extract the die, and quantified by measuring die absorbance at 620 nm.
  • RBL-2H3 cells were aliquoted into 24-well plates in 2 ⁇ 10 5 cells / well and sensitized with anti-DNP-specific IgE 200 ng / mL overnight. IgE-sensitized cells were washed twice with PIPES buffer (25 mM PIPES, pH 7.2, 110 mM NaCl, 4 mM KCl, 0.4 mM MgCl, 40 mM HCl, 5.6 mM glucose, 1 mM CaCl 2 , and 0.1% BSA).
  • PIPES buffer 25 mM PIPES, pH 7.2, 110 mM NaCl, 4 mM KCl, 0.4 mM MgCl, 40 mM HCl, 5.6 mM glucose, 1 mM CaCl 2 , and 0.1% BSA).
  • the treatment was performed by the solution of erythridiol solution dissolved in PIPES buffer for each concentration, the temperature was set to 37 °C, was treated for 30 minutes. It was then activated with DNP-HSA (25 ng / mL) at 37 ° C. for 15 minutes and cooled with ice to stop activation. Supernatants from antigen-activated cells and P -hexosaminidase substrate ( p -nitrophenyl- N -acetyl-D-glucosaminid) in PIPES buffer were measured to determine ⁇ -hexosaminidase release. Well plates were mixed in 0.1 M citrate buffer (pH 4.5) and incubated at 37 ° C. for 1 hour. 0.1 M carbonate buffer (pH 10.5) was added to terminate the reaction, and the absorbance was measured at 405 nm using a microplate reader.
  • Cytotoxicity measurement of eriodic thiol was measured using the Ez-Cytox Enhanced Cell Viability Kit (Daily Lab Service, Seoul, Korea), and the protocol was followed.
  • RBL-2H3 cells were dispensed into 96 ⁇ well plates at 2 ⁇ 10 4 cells / well, inoculated with 200-ng / mL anti-DNP-specific IgE, and left overnight. After incubation, the medium was replaced with serum-free medium and treated for 23 hours with various concentrations of eriodicthiol and 20 ng / mL DNP-HSA.
  • Ez-Cytox kit reaction was added to the medium and cells were incubated at 37 ° C. for 1 hour. Cell survival levels were determined by measuring absorbance at 450 nm using a microplate reader.
  • RBL-2H3 cells were seeded in 6-well plates at 8 ⁇ 10 5 cells / well and incubated overnight in medium containing 200 ng / mL anti-DNP-specific IgE. After washing twice, they were resuspended in PIPES buffer and activated for 1 hour with DNP-HSA (25 ng / mL) in the absence of erythrothiol and in the presence of erythoxythiol. After incubation, the cells were washed twice with ice-cold PBS. Total RNA was isolated using TRI reaction solution (Sigma-Aldrich, St. Louis, MO), but followed protocol. The concentration of total RNA was measured using a spectrophotometer. Total RNA (1 ⁇ g) was used as a template for cDNA synthesis and PCR using AccuPower RT / PCR premix kit (Bionia, Daejeon, Korea). The following primers were used:
  • rat IL-4 sense 5'-ACCTTGCTGTCACCCTGTTC-3 ';
  • beta-actin sense 5'- ATGCCATCCTGCGTCTGGACCTGGC-3 ';
  • PCR products were electrophoresed on 2% agarose gels and visualized by addition of ethidium bromide. Gels were tested using a transilluminator (Vilber Lourmat, France).
  • Inflammatory cytokines IL-4 and TNF- ⁇ are cytokines used as experimental indicators in allergic reactions.
  • IL-4 induces IgE production in B cells to promote na ⁇ ve T cells into Th2 cells.
  • TNF- ⁇ is an inflammatory mediator secreted from mast cells via IgE challenge.
  • IgE / Ag-induced expression of IL-4 mRNA was shown to be significantly inhibited, and the effect was concentration dependent.
  • the experimental results show that erythrodiol inhibits IgE production in B cells by down-regulating Il-4 expression, and also inhibits IgE / Ag-mediated degranulation.
  • Ca 2+ -dependent trigger in mast cell degranulation appears to be present in the enzyme CERK, which phosphorylates ceramide to C1P. Formation of C1P induces arachidonic acid release, synthesis of inflammatory metabolites, and Ca 2+ -dependently activates MAPK.
  • CERK mRNA was found to be increased and measured by RT-PCR. However, in the cells treated with erythridiol, CERK mRNA levels were significantly lower than those in cells activated only with IgE / Ag (see FIG. 5). It can be seen that it inhibits the 2 + -dependent process.
  • RBL-2H3 cells were washed twice and harvested. Cell pellets were lysed with 0.2 N NaOH. Total lipids were extracted with ethanol and incubated at 37 ° C. for 1 hour with C 17 ceramide ( N -oleoyl-D-erythro-sphingosine) as internal standard. The extract was centrifuged at 12,000 rpm for 10 minutes. The supernatant was dried in a vacuum centrifuge. The dried residue was dissolved in methanol, spotted on a high performance thin layer chromatography silica gel plate (Merck, Darmstadt, Germany), and isopropylether / methanol / 29% NH 4 OH (40/10/1, v / v / v).
  • the plate was immersed in 10% H 2 SO 4 and dried at 180 ° C.
  • the region of the sample lane corresponding to the ceramide standard band was then cut out and the ceramide was eluted with methanol.
  • the eluate was incubated for 1 hour and dried in a vacuum centrifuge.
  • the ceramide residue was mixed with reaction buffer (pH 7.5) containing 25 mM Tris-HCl, 1% sodium cholate and 15% fatty acid-free BSA.
  • the mixture was incubated at 37 ° C. overnight with 500 ⁇ U of sphingolipid ceramide N-deacylase (SCDase; Takara, Ohtsu, Japan) and dried in a vacuum centrifuge.
  • SCDase sphingolipid ceramide N-deacylase
  • the resulting extract was dissolved in methanol with an OPA reaction solution (50 mg OPA, 1 mL ethanol, 200 ⁇ L ⁇ -mercaptoethanol and 50 mL 3% boric acid, pH 10.5) and 30 minutes while derivatizing Liver cultures.
  • OPA reaction solution 50 mg OPA, 1 mL ethanol, 200 ⁇ L ⁇ -mercaptoethanol and 50 mL 3% boric acid, pH 10.5
  • the isocratic mobile phase for HPLC was then composed of methanol / water / triethylamine (85: 15: 0.1, v / v / v) and the flow rate was 1 mL / min.
  • Intelligent fluorescence detectors were set to 340 nm (excitation wavelength) and 455 nm (emission wavelength).
  • Eriodicthiol was purchased from Sigma-Aldrich (St. Louis, Mo. U.S.A.). Male ICR mice (6 weeks old) were purchased from Orient Bio (Gangneung, South Korea) and were bred at 40-50% relative humidity at 20-22 ° C. Animals were given free access to diet and water purchased from Samyang (Wonju, South Korea). The animal testing protocol has been approved by the Yonsei Institutional Animal Care and Use Committee.
  • DNCB 2,4-dinitrochlorobenzene
  • acetone and olive oil mixed volume ratio 3: 1
  • Primary immunization was performed by applying 300 ⁇ L to 2 cm 2 of the dorsal region of male ICR mice. After 4 days of primary immunization, 250 ⁇ L of 0.5% DNCB was applied to the dorsal area and secondary immunization was performed by continuously treating the same concentration and the same amount for about 2 weeks. In the group to which riodic thiol was applied, 200 ⁇ L was applied to the dorsal area at the concentration of 0.2 mg / mL once every other day from the second DNCB administration.
  • the skin condition is graded as erythema, itching and dry skin, edema and hematoma, soreness, thyroiditis, no symptoms 0 points, symptom weakness 1 point, normal 2 points, severe 3 points for these 5 items
  • the total score was given a score between a minimum of 0 (no symptoms) and a maximum of 15 (all symptoms severe).
  • the score was gradually increased in the group in which contact dermatitis was induced by the application of DNCB and reached 13 or more.
  • the score was significantly lowered than that of the normal group. (See FIGS. 8A and 8B).
  • the thickness of the dorsal epidermis was confirmed by tissue extraction of the dorsal epidermis and staining with hematoxylin and eosin. Compared to the normal group, the thickness of the dorsal epidermis was increased continuously after the second application of DNCB. In the group of riodic thiol administered, the edema was significantly alleviated from the third dose, and it can be seen that there is an anti-inflammatory effect on riodic thiol due to the result (see FIGS. 9A and 9B).
  • Skin moisturizing effect experiment was performed by making a cream and serum containing 0.0006% of pure eriodictyol powder.
  • the device used for the skin moisturizing effect was MY-808S Moisture Checker (Scalar, Japan), and clinical trials were performed using the inside of the forearm of a person.
  • the skin moisturizing power before application was checked including the control group, and each sample 0.25 g / cm 2 was applied, and the skin moisturizing power after 1 hour, 2 hours, 3 hours, and 4 hours was measured.
  • Skin moisturizing power is very sensitive to temperature and humidity, so it was carried out in a constant temperature and humidity room controlled at a temperature of 20 ° C. and a humidity of 60%.
  • the test subjects were 5 males and 20s.
  • FIG. 11 the results of testing with MY-808S Moisture Checker are shown in FIG. 11.
  • a cream containing 0.0006% pure eriodictyol single powder had a skin moisturizing effect of 29.52% before application and a 32.88% increase in skin moisturizing effect after application.
  • the skin moisturizing effect was maintained to almost the same level as the right skin.
  • a serum containing 0.0006% of pure eriodictyol single powder had a skin moisturizing effect of 33.54% after application on 30.2% of skin moisturizing power before application. After 4 hours, the skin moisturizing effect was maintained to the same degree as the right skin.
  • the powders are mixed and mixed, followed by filling into an airtight fabric to prepare a powder.
  • Tablets are prepared by mixing the above components according to a conventional method for preparing tablets and then compressing them.
  • the capsules are prepared by mixing the above components and filling the gelatin capsules according to a conventional capsule preparation method.
  • phase A and the water phase part of B are respectively heated to 70 ° C. and completely dissolved.
  • Phase A is added to phase B and emulsified with an emulsifier.
  • the emulsion was cooled using a heat exchanger to obtain a cream.
  • Latex A Paid Eriodichol 0.001% by weight Squalane 5 Oleyl oleate 3 Vaseline 2 Solbitan sesquioleic acid ester 0.8 Polyoxyethylene oleyl ether 1.2 Evening Primrose Oil 0.5 Spices 0.3 antiseptic Quantity B. Award Eriodichol 0.001% by weight 1,3-butylene glycol 4.5 ethanol 3 Carboxy Vinyl Polymer 0.2 Potassium hydroxide 0.1 L-asparaginate 0.01 Edetate 0.05 Purified water residual
  • the oil phase of A is added to the water phase of B to obtain an emulsion.
  • the alcohol phase of A was added to the aqueous phase of B and solubilized to obtain a lotion.
  • Latex was prepared by the conventional method by the said prescription.
  • the lotion was manufactured by the conventional method by the said prescription.
  • the cream was manufactured by the conventional method by the said prescription.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter une maladie cutanée, et une préparation cutanée topique, un produit cosmétique améliorant ou atténuant une maladie cutanée et un aliment de santé/fonctionnel, comprenant un composé d'ériodictyol, un dérivé de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci en tant que substance active, et, plus spécifiquement, l'invention supprime la dégranulation de mastocytes et, dans un modèle d'animal allergique, a été confirmée comme étant remarquablement efficace dans le soulagement des démangeaisons et sur l'inflammation, le gonflement, l'hydratation de la peau et l'élasticité de la peau et peut donc être utilisée avantageusement dans le but de prévenir, traiter ou améliorer différentes maladies cutanées.
PCT/KR2013/012018 2012-12-26 2013-12-23 Composition pharmaceutique pour prévenir ou traiter une maladie cutanée comprenant un composé d'ériodictyol ou un sel pharmaceutiquement acceptable de celui-ci en tant que substance active Ceased WO2014104681A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR1020120153153A KR20140083425A (ko) 2012-12-26 2012-12-26 에리오딕티올 화합물 또는 이의 약학적으로 허용되는 염을 유효성분으로 함유하는 접촉성 피부염 예방 또는 치료용 약학적 조성물
KR10-2012-0153152 2012-12-26
KR1020120153152A KR20140083424A (ko) 2012-12-26 2012-12-26 에리오딕티올을 유효성분으로 함유하는 피부보습 또는 피부탄력 증진용 화장료 조성물
KR10-2012-0153153 2012-12-26

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WO2014104681A1 true WO2014104681A1 (fr) 2014-07-03

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114588147A (zh) * 2022-02-25 2022-06-07 北京大学深圳医院 圣草酚在预防或治疗银屑病中的应用
WO2025035070A1 (fr) * 2023-08-09 2025-02-13 Debut Biotechnology, Inc. Formulations d'ériodictyol

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060123336A (ko) * 2003-12-18 2006-12-01 네스텍소시에테아노님 피부, 모발 및 털 건강 개선용 플라바논 함유 조성물

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20060123336A (ko) * 2003-12-18 2006-12-01 네스텍소시에테아노님 피부, 모발 및 털 건강 개선용 플라바논 함유 조성물

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEE, J. K.: "Anti-inflammatory Effects of Eriodictyol in Lipopolysaccharide- stimulated Raw 264.7 Murine Macrophages", ARCHIVES OF PHARMACAL RESEARCH, vol. 34, no. 4, 2011, pages 671 - 679 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114588147A (zh) * 2022-02-25 2022-06-07 北京大学深圳医院 圣草酚在预防或治疗银屑病中的应用
WO2025035070A1 (fr) * 2023-08-09 2025-02-13 Debut Biotechnology, Inc. Formulations d'ériodictyol

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