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WO2025053495A1 - Composition pour la prévention ou le traitement de la dermatite atopique ou du psoriasis comprenant du candésartan - Google Patents

Composition pour la prévention ou le traitement de la dermatite atopique ou du psoriasis comprenant du candésartan Download PDF

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Publication number
WO2025053495A1
WO2025053495A1 PCT/KR2024/012414 KR2024012414W WO2025053495A1 WO 2025053495 A1 WO2025053495 A1 WO 2025053495A1 KR 2024012414 W KR2024012414 W KR 2024012414W WO 2025053495 A1 WO2025053495 A1 WO 2025053495A1
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candesartan
psoriasis
atopic dermatitis
cells
skin
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Korean (ko)
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임동순
손소은
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Kyung Hee University
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Kyung Hee University
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • 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
    • 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
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • 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
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds

Definitions

  • the present invention relates to the use of candesartan for treating skin diseases, and more specifically, to a composition for preventing, improving or treating atopic dermatitis or psoriasis containing candesartan or a pharmaceutically/foodstuffally acceptable salt thereof as an active ingredient.
  • Angiotensin II receptor blockers or AT 1 receptor antagonists are drugs that regulate the renin-angiotensin system. They are mainly used to treat hypertension, but are also used to treat diabetic nephropathy and congestive heart failure.
  • ARBs have been shown to have anti-inflammatory effects in animal models of inflammatory diseases, including multiple sclerosis, autoimmune encephalomyelitis, and arthritis, and the potential benefits of ARBs in systemic inflammation and allergic reactions have been studied recently, but their efficacy in inflammatory skin diseases such as atopic dermatitis and psoriasis has not yet been elucidated.
  • Atopic dermatitis or psoriasis is caused by genetic, environmental, and immunological factors, and is an allergic disease that worsens in dry climates, with abnormalities in the stratum corneum, the outermost protective layer of the skin.
  • Atopic dermatitis and psoriasis have a prevalence of about 10-20% worldwide, and mainly occur in infants between 1 month and 1 year of age, and are somewhat alleviated by the age of 3, but can relapse again depending on living environment and individual differences.
  • Prescriptions for atopic dermatitis or psoriatic dermatitis mainly include drug therapy such as steroids, antihistamines, and antibiotics.
  • drug therapy such as steroids, antihistamines, and antibiotics.
  • Steroids adrenal cortex hormones
  • the purpose of the present invention is to provide a novel use of candesartan, an angiotensin II receptor blocker conventionally used as a treatment for hypertension, which has an excellent effect in improving or treating atopic dermatitis or psoriasis.
  • the present invention provides a pharmaceutical composition for preventing or treating atopic dermatitis or psoriasis, containing candesartan or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a cosmetic composition for preventing or improving atopic dermatitis or psoriasis, containing candesartan or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food composition for preventing or improving atopic dermatitis or psoriasis, containing candesartan or a food-wise acceptable salt thereof as an active ingredient.
  • the composition according to the present invention has excellent anti-inflammatory or anti-allergic activity by inhibiting differentiation of T cells into helper T cell 17 (Th17) cells, and can be utilized as a pharmaceutical composition, cosmetic composition, and health functional food composition for preventing, improving, or treating atopic dermatitis or psoriasis.
  • Th17 helper T cell 17
  • composition according to the present invention has been found to have an inhibitory activity on differentiation of T cells into Th17 cells, and can be further utilized as a therapeutic agent for diseases related thereto.
  • FIG. 1 Effect of angiotensin II receptor blocker (ARB) on atopic dermatitis-like response of ear tissue.
  • A is a schematic diagram showing the experimental plan
  • B is a macroscopic observation image of the ear on day 49 of the experiment
  • C is a hematoxylin and eosin (H&E) staining image of mouse ear skin tissue on day 49
  • H&E hematoxylin and eosin
  • D is a graph of ear skin thickness measurement in tissue sections.
  • FIG. 1 Effects of ARB on mast cell accumulation and inflammatory cytokine levels in the ear.
  • A Toluidine blue O (TBO) staining of ear skin samples on day 49,
  • B mast cell counts in different tissue sections,
  • C interleukin (IL)-4,
  • D IL-13,
  • E interferon (IFN)- ⁇ , and
  • F IL-17A expression levels.
  • FIG. 3 Effects of ARB on lymph node size and inflammatory cytokine levels in lymph nodes.
  • A The photograph of the isolated cervical lymph node on day 49,
  • B The weight of the isolated lymph node,
  • C The expression levels of IL-4,
  • D IL-13,
  • E IL-17A, and
  • F IFN- ⁇ are shown.
  • FIG. 4 Effect of ARB on the differentiation of na ⁇ ve T cells into T helper (Th)-17 cells.
  • A is the result of flow cytometry
  • B is a histogram of the CD4 + IL-17A + cell population.
  • the Gaussian distribution assumption of the data was made using the Kolmogorov-Smirnov (KS) test.
  • Figure 5 shows the effect of ARB on psoriasis-like skin reactions.
  • A is a schematic diagram showing the experimental plan
  • B is a macroscopic observation image of the skin of the back of the mouse 6 days after treatment
  • C is a graph of thickness, erythema, scaling, and total psoriasis area and severity index (PASI) scores on day 7.
  • FIG. 6 Effects of ARB on histological changes in psoriatic skin.
  • A H&E staining image of back skin, showing elongation of the epidermal ridge and clubbing as well as moderate to severe dermal lymphocytic infiltration in the imiquimod-treated group.
  • B Ki-67 staining image, red arrows indicate Ki-67 positive cells.
  • C Histogram of epidermal thickness,
  • FIG. 7 qRT-PCR analysis of the mRNA expression levels of cytokines related to Th17 (IL-17A, IL-23, and IL-22) and Th1 (IFN- ⁇ , tumor necrosis factor [TNF]- ⁇ , and IL-1 ⁇ ) in skin tissues isolated from imiquimod-induced and ARB-treated mice to confirm the effect of ARB on the levels of Th17 and Th1-related cytokines in the skin.
  • the relative mRNA levels of cytokines were quantified by calculating the ratio of the levels to the GAPDH transcript level.
  • Figure 9 shows the effect of ARB on the levels of Th17 and Th1-related cytokines in lymph nodes.
  • the levels of (A) IL-17A, (B) IL-23, (C) IL-22, (D) IFN- ⁇ , (E) TNF- ⁇ , and (F) IL-1 ⁇ are shown.
  • Figure 10 is a schematic diagram showing the atopic and psoriatic dermatitis therapeutic effects of candesartan and telmisartan.
  • Candesartan inhibits atopic dermatitis and psoriasis by inhibiting the differentiation of naive T cells into Th17 cells, thereby reducing IL-17 production and simultaneously inhibiting Th1/Th2/Th22 cytokines
  • telmisartan inhibits atopic dermatitis and psoriasis by activating PPAR- ⁇ , inhibiting NF-kB activation, and consequently inhibiting the production of inflammatory cytokines.
  • the present inventors completed the present invention by confirming the in vivo anti-inflammatory effect of angiotensin II receptor blockers (ARBs) on skin diseases, by confirming the effects of candesartan and telmisartan on atopic dermatitis induced by 1-chloro-2,4-dinitrobenzene (CDNB) and on psoriasis-like skin models induced by imiquimod.
  • ARBs angiotensin II receptor blockers
  • prevention means any act of inhibiting or delaying the occurrence of atopic dermatitis, psoriasis or at least one symptom thereof by administering a pharmaceutical composition, cosmetic composition or health functional food composition according to the present invention. It also includes treatment of a subject suffering from the disease to prevent or prevent recurrence.
  • treatment means any act of improving or beneficially altering the symptoms of atopic dermatitis, psoriasis, or at least one symptom thereof, such as alleviating, reducing, or eliminating the symptoms, by administering a pharmaceutical composition according to the present invention.
  • “improvement” means any act of alleviating or beneficially changing the symptoms of atopic dermatitis, psoriasis or at least one symptom thereof, such as alleviating, reducing or eliminating the symptoms, by administering a cosmetic composition or health functional food composition according to the present invention.
  • the present invention provides a pharmaceutical composition for preventing or treating atopic dermatitis or psoriasis, containing candesartan or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Candesartan is a compound represented by the following chemical formula 1, and is an angiotensin II receptor blocker (ARB) mainly used for the treatment of hypertension and heart failure.
  • ARB angiotensin II receptor blocker
  • the candesartan may be contained and act in the form of candesartan cilexetil represented by the following chemical formula 2, but is not limited thereto.
  • candesartan can be synthesized by a method well known in the art, and a commercially available one can be selected and used, but the method or material is not particularly limited.
  • candesartan can be used in the form of a pharmaceutically or food-wise acceptable salt within the range of the same efficacy.
  • pharmaceutically or food-wise acceptable means a salt that is non-toxic to cells or humans exposed to the composition and has a safety and efficacy profile suitable for administration to humans.
  • the above salt can be used in the form of either a basic salt or an acid salt acceptable from a pharmaceutical or food perspective.
  • the basic salt can be used in the form of either an organic basic salt or an inorganic basic salt, and can be selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a lithium salt, a magnesium salt, a cesium salt, an aluminum salt, an ammonium salt, a triethylaminium salt, and a pyridinium salt.
  • Acid salts are useful as acid addition salts formed by free acids.
  • Inorganic acids and organic acids can be used as free acids, and inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, diphosphoric acid, nitric acid, etc.
  • organic acids include citric acid, acetic acid, maleic acid, malic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, stearic acid, etc., but are not limited thereto, and all salts formed using various inorganic acids and organic acids commonly used in the art can be included.
  • the candesartan may include not only the above salts, but also all salts, hydrates, solvates, derivatives, etc. that can be prepared by a conventional method.
  • the addition salt may be prepared by a conventional method, and may be prepared by dissolving in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic base, or adding an aqueous base solution of an inorganic base, and then precipitating or crystallizing.
  • the addition salt may be obtained by evaporating the solvent or the excess amount of base from the mixture and then drying, or the precipitated salt may be prepared by suction filtration.
  • composition according to the present invention can improve or suppress atopic dermatitis, psoriasis or symptoms thereof by inhibiting differentiation of T cells into helper T cell 17 (Th17) cells, thereby exhibiting anti-allergic or anti-inflammatory activity.
  • Th17 helper T cell 17
  • IL-17 production can be reduced, and further, production of Th1, Th2, Th22 or Th17-related cytokines can be suppressed.
  • candesartan reduces the mRNA expression level of IL-4, IL-13, IFN- ⁇ , or IL-17A, which are Th1, Th2, or Th17-related cytokines associated with atopic dermatitis.
  • candesartan reduces the mRNA expression level of IL-17A, IL-23, IL-22, IFN- ⁇ , TNF- ⁇ , or IL-1 ⁇ , which are Th1, Th22, or Th17-related cytokines associated with psoriasis.
  • the composition can inhibit the infiltration of mast cells and inhibit the proliferation of Ki-67 positive cells.
  • candesartan according to the present invention has a superior therapeutic effect on atopic dermatitis or psoriasis than telmisartan, which is another angiotensin II receptor blocker.
  • telmisartan which acts on atopic dermatitis or psoriasis through the activation of PPAR ⁇ (peroxisome proliferator-activated receptor)
  • candesartan has a different mechanism of action due to its effect by inhibiting differentiation into Th17 cells.
  • pharmaceutical composition means a composition administered for a specific purpose, and for the purpose of the present invention, it means administered to prevent or treat atopic dermatitis, psoriasis or at least one symptom thereof.
  • the pharmaceutical composition according to the present invention can be applied in any dosage form, and more specifically, it can be formulated and used as an oral dosage form, an external preparation, a suppository, and a parenteral dosage form of a sterile injection solution according to a conventional method.
  • liquid dosage forms include suspensions, solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and without causing adverse effects.
  • the pharmaceutical composition according to the present invention can be used alone for the prevention or treatment of atopic dermatitis or psoriasis, or can be used in combination with surgery or other drug treatments.
  • the present invention provides a cosmetic composition for preventing or improving atopic dermatitis or psoriasis, containing candesartan or a pharmaceutically acceptable salt thereof as an active ingredient.
  • composition above has an excellent improvement effect on atopic dermatitis or psoriasis by inhibiting the differentiation of T cells into helper T cell 17 (Th17) cells, and thus can be utilized as a cosmetic composition for preventing or improving atopic dermatitis or psoriasis.
  • Th17 helper T cell 17
  • cosmetics may include functional cosmetics having the effects of skin protection, skin moisturizing, and improving atopic dermatitis or psoriasis dermatitis.
  • the functional cosmetics unlike general cosmetics, have specialized functionality with emphasized physiological activity and effects, and mean cosmetics with emphasized specific effects and effects, such as skin protection, skin moisturizing, and atopic skin improvement.
  • the cosmetic composition according to the present invention may further include at least one of the ingredients listed in the list of cosmetic raw materials registered with the Ministry of Food and Drug Safety and the ICID (International Cosmetic Ingredient Dictionary).
  • the cosmetic composition may further include at least one auxiliary agent commonly used in the cosmetic field, such as an organic solvent, a solubilizer, a thickener, a gelling agent, a softener, an antioxidant, a suspending agent, a stabilizer, a fragrance, a surfactant, an emulsifier, a filler, a metal ion sequestering agent, a preservative, a vitamin, a blocking agent, a humectant, a dye and pigment, a hydrophilic or lipophilic active agent, or any other ingredient commonly used in cosmetics.
  • auxiliary agent commonly used in the cosmetic field such as an organic solvent, a solubilizer, a thickener, a gelling agent, a softener, an antioxidant, a suspending agent, a stabilizer, a
  • the above vitamins may include water-soluble or oil-soluble vitamins, and the water-soluble vitamins are water-soluble vitamins that can be incorporated into cosmetics, and preferably include vitamin B1, vitamin B2, vitamin B6, pyridoxine, pyridoxine hydrochloride, vitamin B12, pantothenic acid, nicotinic acid, nicotinamide, folic acid, vitamin C, vitamin H, etc.
  • salts thiamine hydrochloride, sodium ascorbate, etc.
  • derivatives sodium ascorbate-2-phosphate, magnesium ascorbate-2-phosphate, etc.
  • water-soluble vitamins can be obtained by a conventional method such as a microbial transformation method, a purification method from a microbial culture, an enzymatic method, or a chemical synthesis method.
  • the cosmetic composition according to the present invention can be prepared in any formulation commonly manufactured in the technical field to which the present invention belongs.
  • it can be formulated as a toner, emulsion, lotion, cream, paste, gel, solution, suspension, oil, wax, pack, powder, foundation, spray, surfactant-containing cleansing, etc., but is not limited thereto.
  • a flexible toner a nourishing toner, an astringent toner, a nourishing cream, a massage cream, a milk lotion, a powder, an essence, an eye cream, a sun lotion, a sunscreen, a makeup primer, a makeup base, a BB cream, a powder foundation, an emulsion foundation, a cleansing cream, a cleansing foam, a cleansing water, a soap, a pack, a stick product, a balm type product, a spray, or a powder.
  • the cosmetic composition according to the present invention when in the form of a cream or gel, it may further contain animal oil, vegetable oil, wax, paraffin, starch, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide as a carrier component.
  • the above cosmetic composition when in the form of a solution or emulsion, it may further contain a solvent, solvating agent or emulsifying agent, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, propylene glycol, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.
  • a solvent, solvating agent or emulsifying agent such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, propylene glycol, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.
  • the above cosmetic composition is in the form of a suspension formulation, it may further include a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth as a carrier component.
  • a liquid diluent such as water, ethanol or propylene glycol
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth as a carrier component.
  • the above cosmetic composition is in a powder or spray formulation, it may further contain lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder as a carrier component, and particularly in the case of a spray formulation, it may further contain a propellant such as chlorofluorohydrocarbon, propane/butane or dimethyl ether.
  • a propellant such as chlorofluorohydrocarbon, propane/butane or dimethyl ether.
  • the above cosmetic composition is a surfactant-containing cleansing formulation, it may further include, as a carrier component, an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, methyl taurate, a sarcosinate, a fatty acid amide ether sulfate, an alkyl amidobetaine, a fatty alcohol, a fatty acid glyceride, a fatty acid diethanolamide, a vegetable oil, a linolenic derivative, or an ethoxylated glycerol fatty acid ester.
  • a carrier component an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, methyl taurate, a sarc
  • the cosmetic composition according to the present invention can be used by applying it alone or in duplicate, or by applying it in duplicate with another cosmetic composition other than the present invention.
  • the cosmetic composition according to the present invention can be used according to a conventional method of use, and the number of times it is used can vary depending on the skin condition or preference of the user.
  • the present invention provides a health functional food composition for preventing or improving atopic dermatitis or psoriasis, containing candesartan or a food-wise acceptable salt thereof as an active ingredient.
  • composition above has an excellent improvement effect on atopic dermatitis or psoriasis by inhibiting the differentiation of T cells into helper T cell 17 (Th17) cells, and thus can be utilized as a health functional food composition for preventing or improving atopic dermatitis or psoriasis.
  • Th17 helper T cell 17
  • health functional food includes food manufactured and processed using raw materials or ingredients with functionality useful to the human body according to Act No. 6727 on Health Functional Foods, and means a food with high medical and healthcare effects processed so that, in addition to nutritional supply, it efficiently exhibits bioregulatory functions such as prevention of atopic dermatitis or psoriasis, biodefense, immunity, and recovery for the purpose of the present invention.
  • the health functional food can be manufactured in the form of powder, granules, tablets, capsules, syrup or beverage, etc., for the purpose of preventing or improving atopic dermatitis or psoriasis.
  • the health functional food can take, and it can be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.
  • the health functional food may include all foods in the conventional sense.
  • beverages and various drinks, fruits and processed foods thereof such as canned fruits, jams, etc.
  • fish, meat and processed foods thereof ham, bacon, etc.
  • bread and noodles, cookies and snacks, dairy products such as cheese, etc.
  • dairy products such as cheese, etc.
  • foods used as feed for animals may also be included.
  • the health functional food composition according to the present invention can be manufactured by further including food additives (food additives) and other appropriate auxiliary ingredients that are commonly used in the art and are food-relatedly acceptable. Whether or not it is suitable as a food additive can be determined by the standards and criteria for the relevant item according to the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise specified.
  • food additives food additives
  • other appropriate auxiliary ingredients that are commonly used in the art and are food-relatedly acceptable. Whether or not it is suitable as a food additive can be determined by the standards and criteria for the relevant item according to the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise specified.
  • the items listed in the 'Food Additives Codex' include, for example, chemical synthetic substances such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, calciphilic pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.
  • chemical synthetic substances such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid
  • natural additives such as persimmon pigment, licorice extract, crystalline cellulose, calciphilic pigment, and guar gum
  • mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.
  • auxiliary ingredients may additionally contain, for example, flavoring agents, natural carbohydrates, sweeteners, vitamins, electrolytes, coloring agents, pectic acid, alginic acid, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonating agents, etc.
  • natural carbohydrates monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol
  • sweetener natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame can be used.
  • the effective dose of candesartan contained in the health functional food according to the present invention can be appropriately adjusted depending on the intended use, such as prevention or improvement of atopic dermatitis or psoriasis.
  • the above health functional food composition has the advantage of being made from food and having no side effects that may occur with long-term use of general drugs, and is highly portable, so it can be taken as a supplement for preventing or improving atopic dermatitis or psoriasis.
  • telmisartan The potential effects of candesartan and telmisartan on inflammatory skin diseases were investigated using a CDNB-induced mouse atopic dermatitis-like model in BALB/c mice.
  • ARBs including telmisartan, directly bind to and activate PPAR ⁇ to exert anti-inflammatory effects.
  • GW9662 is a selective PPAR ⁇ inhibitor, the effect of PPAR ⁇ activation was investigated using a GW9662-treated mouse model in this experiment.
  • the cervical lymph nodes are the lymphoid organs closest to the ear and regulate the immune response to CDNB in the ear.
  • the weight of the isolated lymph nodes was found to increase by 529.87% in the CDNB treatment group.
  • Candesartan and telmisartan significantly inhibited the increase in lymph node weight by 51.32% and 39.58%, respectively.
  • GW9662 reversed the inhibitory effect of telmisartan on the increased lymph node weight, but did not reverse the inhibitory effect of candesartan.
  • Inflammatory cytokine levels were assessed by quantifying mRNA levels of IL-4, IL-13, IFN- ⁇ , and IL-17A in lymph nodes isolated from mice.
  • CDNB treatment significantly increased the mRNA expression levels of four cytokines in the lymph nodes. Although both ARBs inhibited the increase in the levels of inflammatory cytokines, GW9662 appeared to inhibit only the inhibitory effects of telmisartan, but not candesartan, on Th2, Th1, and Th17 responses.
  • Th17 cells that ultimately lead to lower IL-17A cytokine levels in lymph nodes.
  • ARB inhibits the differentiation of T lymphocytes into Th17 cells.
  • both ARBs significantly inhibited the differentiation of naive T cells into Th17 cells at a concentration of 10 ⁇ M, and candesartan showed a greater effect than telmisartan (84.5% vs. 29.4%).
  • Psoriasis is a chronic inflammatory skin disease characterized by a red rash covered with thick, silvery scales, which is associated with the IL-23/IL-17 pathway.
  • the imiquimod-induced dermatitis mouse model exhibits erythema, desquamation, and acanthosis, which are key features of psoriasis.
  • Imiquimod activates toll-like receptor 7, resulting in excessive secretion of inflammatory cytokines, including IFN- ⁇ , IL-6, and tumor necrosis factor (TNF)- ⁇ . These cytokines act on keratinocytes by increasing IL-12/IL-23 secretion and IL-17 production, ultimately inducing robust proliferation.
  • telmisartan and candesartan inhibited the differentiation of T lymphocytes into Th17 cells.
  • the effect of ARB was further confirmed in the imiquimod-induced psoriasis mouse model. Referring to Fig. 5, the thickness, erythema, and scaling of skin lesions increased along with the total PASI score 3-4 days after the start of imiquimod application, but were reduced by ARB administration. A significant change in the PASI score was observed on days 5-6 in the candesartan group and on days 6-7 in the telmisartan group, and the effect of candesartan was found to be greater than that of telmisartan (42.03% vs. 23.48%).
  • Fig. 6(A) in the skin tissue sections stained with H&E, epidermal proliferation and leukocyte recruitment into the skin were observed in the imiquimod treatment group and were inhibited by ARB. Similarly, in Fig. 6(C), the epidermal thickness was significantly increased by imiquimod, but decreased by ARB. In addition, referring to Figs. 6(B) and 6(D), the proliferation of keratinocytes observed by the number of Ki-67 positive cells was increased by imiquimod; both telmisartan and candesartan inhibited the increase of Ki-67 positive cells.
  • the mRNA levels of IL-17A, IL-23, and IL-22 were quantified along with IFN- ⁇ , TNF- ⁇ , and IL-1 ⁇ .
  • the mRNA levels of IL-17A, IL-23, and IL-22 in skin tissues were increased in the imiquimod-treated group. This suggests the activation of IL-23/IL-17 and was inhibited by ARB.
  • the inguinal lymph nodes are the lymphoid organs closest to the skin, regulating the skin's immune response to imiquimod.
  • the isolated lymph nodes and spleen in the present experiment were substantially increased in the imiquimod treatment group, and this increase in the size of the lymph nodes and spleen was inhibited by candesartan, but not by telmisartan.
  • the actual enlargement of the lymph nodes and spleen was objectively confirmed by measuring the weight of each lymph node and spleen, and as shown in Figs. 8(B) and 8(E), the weights of the isolated lymph nodes and spleen significantly increased by 300% and 90.85%, respectively.
  • Candesartan significantly inhibited the increase in the weight of the lymph nodes and spleen by 57.6% and 63.2%, respectively. This inhibitory effect on the size of the lymph nodes and spleen was not observed with telmisartan.
  • telmisartan significantly suppressed the percentage of CD4 + IL17A + T cells by 61.7% in the spleen, but not in the lymph nodes.
  • Inflammatory cytokine levels were assessed by quantifying mRNA levels of IL-17A, IL-23, and IL-22, along with IFN- ⁇ , TNF- ⁇ , and IL-1 ⁇ levels in lymph nodes.
  • imiquimod induction substantially increased the levels of cytokines related to the IL-23/IL-17 pathway (i.e., IL-17A, IL-23, and IL-22) in the lymph nodes. This suggests activation of the IL-23/IL17 pathway in the lymph nodes of imiquimod-treated mice, and the activation of the IL-23/IL-17 pathway was inhibited by ARB.
  • cytokines related to the IL-23/IL-17 pathway i.e., IL-17A, IL-23, and IL-22

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Abstract

La présente invention concerne une composition pour la prévention ou le traitement de la dermatite atopique ou du psoriasis, comprenant du candésartan. Plus spécifiquement, la présente invention concerne une composition pharmaceutique, une composition cosmétique et une composition alimentaire de santé fonctionnelle pour prévenir ou traiter la dermatite atopique ou le psoriasis, comprenant du candésartan ou un sel pharmaceutiquement/cytologiquement acceptable de celui-ci en tant que principe actif. La composition, selon la présente invention, présente une excellente activité anti-inflammatoire ou anti-allergique par inhibition de la différenciation de lymphocytes T en lymphocytes T auxiliaires 17 (Th17), ce qui permet de prévenir, de soulager ou de traiter efficacement la dermatite atopique ou le psoriasis.
PCT/KR2024/012414 2023-09-08 2024-08-21 Composition pour la prévention ou le traitement de la dermatite atopique ou du psoriasis comprenant du candésartan Pending WO2025053495A1 (fr)

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WO2012119781A2 (fr) * 2011-03-10 2012-09-13 University Of Geneva Nouveaux lipides, phospholipides, compositions de phospholipides et de lipides et leur utilisation

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KR20090129025A (ko) 2008-06-12 2009-12-16 (주)네오팜 스핑고신키나제 활성화제 및 이를 포함하는 피부질환치료제

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US20060135422A1 (en) * 2003-04-17 2006-06-22 Moskowitz David W Use of angiotensin receptor blockers (ARBs) to treat diseases associated with excess ACE
WO2006018024A2 (fr) * 2004-08-18 2006-02-23 Ace Aps Compositions cosmetiques et pharmaceutiques contenant des inhibiteurs de l'eca et/ou des antagonistes des recepteurs de l'angiotensine ii
WO2012119781A2 (fr) * 2011-03-10 2012-09-13 University Of Geneva Nouveaux lipides, phospholipides, compositions de phospholipides et de lipides et leur utilisation

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NICKEL LAURA, SÜNDERHAUF ANNIKA, RAWISH ELIAS, STÖLTING INES, DERER STEFANIE, THORNS CHRISTOPH, MATSCHL URTE, OTHMAN ALAA, SINA CH: "The AT1 Receptor Blocker Telmisartan Reduces Intestinal Mucus Thickness in Obese Mice", FRONTIERS IN PHARMACOLOGY, FRONTIERS RESEARCH FOUNDATION, CH, vol. 13, CH , XP093288415, ISSN: 1663-9812, DOI: 10.3389/fphar.2022.815353 *
PLATTEN MICHAEL, YOUSSEF SAWSAN, HUR EUN MI, HO PEGGY P., HAN MAY H., LANZ TOBIAS V., PHILLIPS LORI K., GOLDSTEIN MATTHEW J., BHAT: "Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (PNAS), NATIONAL ACADEMY OF SCIENCES, vol. 106, no. 35, 1 September 2009 (2009-09-01), pages 14948 - 14953, XP093288414, ISSN: 0027-8424, DOI: 10.1073/pnas.0903958106 *
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