WO2019031655A1 - Composition comprenant du thymol comme principe actif pour prévenir ou traiter les rides de la peau ou la dermatite atopique - Google Patents

Composition comprenant du thymol comme principe actif pour prévenir ou traiter les rides de la peau ou la dermatite atopique Download PDF

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WO2019031655A1
WO2019031655A1 PCT/KR2017/013373 KR2017013373W WO2019031655A1 WO 2019031655 A1 WO2019031655 A1 WO 2019031655A1 KR 2017013373 W KR2017013373 W KR 2017013373W WO 2019031655 A1 WO2019031655 A1 WO 2019031655A1
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atopic dermatitis
composition
skin
pharmaceutically acceptable
acceptable salt
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PCT/KR2017/013373
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English (en)
Korean (ko)
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이태후
박설웅
황은선
양정은
박상용
이원석
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(주)에스디생명공학
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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • 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 preventing or treating skin wrinkles or atopic dermatitis, and more particularly to a composition for preventing or treating skin wrinkles or atopic dermatitis containing a thymol compound as an active ingredient.
  • Skin wrinkles are known to be influenced by various factors such as skin moisture content, collagen content and immunity to the external environment. Among them, collagen production and collagenase, collagenase It is the expression and activity of Nath.
  • Collagen is present in the dermal layer of the skin and is known to be the main ingredient that imparts elasticity to the skin along with elastin, which accounts for about 70 to 80% of the dry weight of the skin. Collagen is reduced by internal factors such as decreased cell activity due to natural aging, and biosynthesis is reduced or accelerated by external factors such as increased stress in various harmful environments and increase of active oxygen species by sunlight have.
  • ROS reactive oxygen species
  • Type I collagen is the most abundant protein in the extracellular matrix of connective tissue. Extracellular matrix includes other types of proteins such as type III, V, and VII collagen, elastin, proteoglycan, and fibronectin.
  • Controlling the expression level of type I collagen protein is the most important factor in preventing skin photoaging.
  • UVB irradiation reduces the expression of the collagen precursor procollagen in skin fibroblasts by inhibiting the TGF- ⁇ / Smad signaling pathway.
  • the TGF- ⁇ 1 signaling system is one of the important factors controlling the synthesis of extracellular matrix in human dermal fibroblasts.
  • ROS reactive oxygen species
  • Examples of known collagen synthesis promoting substances include vitamin C, retinoic acid, transforming growth factor (TGF), animal placenta-derived proteins -231370), betulinic acid (JP8-208424), chlorella extract (JP9-40523, JP10-36283, fibroblast proliferation promoting action) and the like.
  • TGF transforming growth factor
  • JP8-208424 chlorella extract
  • JP9-40523, JP10-36283 fibroblast proliferation promoting action
  • atopic dermatitis is a chronic itchy dermatitis that occurs frequently during infancy and is associated with itching, dry skin or characteristic eczema in the patient or family.
  • Typical symptoms of atopic dermatitis occur in the hands, scalp, face, neck, elbow, and knee. The skin becomes very dry, itching and inflammation occurs, and scratched and scratched severely wrinkles deeply as the skin thickens.
  • Thymol (2-isopropyl-5-methylphenol) is a phenolic compound found in essential oils of many medicinal plants. It is used as a raw material for the synthesis of menthol. It is used as a preservative and disinfectant in toothpaste, soap, It is used as analytical reagent for the analysis of titanium, ammonia, etc., and has been used as a medicine for insect repellent. Thymol is Ria nodin receptor (ryanodine receptors) a greater activation, skeletal, and induces the release of calcium from the smooth muscle, transient outward in mammalian ventricular cardiomyocytes K + and L-type Ca 2 + is known as a powerful compounds to be used in order to suppress the current have.
  • the present inventors have made intensive efforts to develop a therapeutic agent for skin wrinkles or atopic dermatitis derived from natural products or new compounds, and as a result, it has been confirmed that thymol or derivatives thereof can be effectively used for preventing or treating skin wrinkles or atopic dermatitis Thus completing the present invention.
  • composition comprising thymol as an active ingredient, which has an excellent effect in preventing or treating skin wrinkles or atopic dermatitis.
  • a pharmaceutical composition for preventing or treating skin wrinkles or atopic dermatitis comprising, as an active ingredient, a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof :
  • the compound of Formula 1 is Thymol (2-isopropyl-5-methylphenol).
  • Thymol in the present invention is a colorless crystal and has a molecular weight of 150.22, a specific gravity of 0.97, a melting point of 51 ° C, and a boiling point of 232.8 ° C.
  • the inventors of the present invention searched for a substance effective for the prevention of skin wrinkles and atopic dermatitis and found that the thymol compound has an effect of preventing and improving wrinkles of the skin and at the same time, And it was confirmed that there is no problem in safety when applied to the skin.
  • Pharmaceutically acceptable salts of the thymol compounds may be acid addition salts formed by pharmaceutically acceptable free acids.
  • the free acid organic acid and inorganic acid can be used.
  • the inorganic acid hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used.
  • the organic acid citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid.
  • the addition salt according to the present invention can be obtained by a conventional method, that is, by dissolving the above compound in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, adding an equivalent amount or excess amount of an organic acid, Precipitation or crystallization, or by evaporating a solvent or excess acid, followed by drying or precipitation of the precipitated salt by suction filtration.
  • a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile or the like
  • the present invention includes all of the solvates, hydrates and stereoisomers which exhibit the same potency as the above compound or a pharmaceutically acceptable salt thereof, which can be prepared therefrom, all within the scope of the present invention.
  • the pharmaceutical composition comprising the thymol compound of the present invention, or a pharmaceutically acceptable salt thereof may further comprise an appropriate carrier, adduct or diluent conventionally used in the production of a pharmaceutical composition.
  • the content of the thymol compound represented by the formula (1) or a pharmaceutically acceptable salt thereof contained in the composition is not particularly limited, but may be 0.01 to 50.0% by weight, preferably 0.05 % To 20% by weight, and most preferably 0.1% to 10% by weight.
  • the thymol compound has an effect of increasing the expression of type I procollagen protein and suppressing the expression of MMP-1 and MMP-3 protein in UVB-irradiated human dermal fibroblasts.
  • the thymol compound inhibits the expression of IL-6, an inflammatory cytokine, and TARC (thymus and activation-regulated chemokine), a specific factor in atopic dermatitis, in human dermal keratinocytes treated with TNF-a and IFN- I have confirmed.
  • the thymol compound of the present invention is characterized in that it increases the expression of type I procollagen gene and inhibits the expression of MMP-1 and MMP-3 genes.
  • dermal fibroblasts The major function of dermal fibroblasts is extracellular matrix synthesis and regeneration of injured skin tissue through proliferation.
  • the factors of extrinsic aging such as photoaging, accumulation of damage by free oxygen, and endogenous aging by cell aging due to telomere breakage Reduce the physiological activity of dermal fibroblasts in the dermal layer.
  • Type I collagen which accounts for more than 95% of the extracellular matrix and plays a major role in the physiological activity of fibroblasts through interactions and signal interactions with adhesion molecules and cytoskeletons of cells, Is reduced, the amount of collagen in the skin tissue is reduced, whereby the surface tension is reduced, so that the skin elasticity is lowered and the skin wrinkles are formed, and the physiological activity including cell proliferation and regeneration is decreased This causes a vicious circle.
  • collagen of skin fibroblasts may be directly related to restoration or regeneration of tissue during skin regeneration, skin elasticity, wrinkle formation and skin damage.
  • 'MMP' matrix metallo-proteinase
  • the thymol compound has an effect of preventing or treating wrinkles of skin by increasing the expression of type I procollagen protein, which is an inflammatory cytokine, and suppressing the expression of MMP-1 and MMP-3 genes.
  • the thymol compound of the present invention is characterized by having an effect of preventing or treating atopy by inhibiting the expression of IL-6 (interleukin-6) and TARC (Thymus and activation regulated chemokine) genes.
  • IL-6 interleukin-6
  • TARC Thymus and activation regulated chemokine
  • TARC binds to chemokine receptor 4 (CCR4), and the linkage between them is known to play an important role in the migration of Th2 cells to inflammatory tissues. It has been reported that serum concentrations of TARC are closely related to Th2 cell-related skin diseases such as atopic dermatitis (Y. Shimada et al., J. Dermatol. Sci., 34, 201-208, 2004).
  • the thymol compound has the effect of preventing or treating atopic dermatitis by inhibiting the expression of IL-6, an inflammatory cytokine, and TARC (thymus and activation-regulated chemokine), which is a specific factor in atopic dermatitis.
  • prevention in the present invention means any action that inhibits or delays the onset of skin wrinkles or atopic dermatitis upon administration of the composition of the present invention
  • treatment means that the composition of the present invention causes skin wrinkles or atopic It means all the actions that improve or change the symptoms caused by dermatitis.
  • the term " skin wrinkle” means a skin formed by decay of skin, which may be caused by a cause of a gene, a decrease in collagen existing in the skin dermis, or an external environment.
  • atopic dermatitis refers to chronic and recurrent inflammatory skin disease, which refers to a disease accompanied by itching (itching) and dry skin, characteristic erythema or eczema.
  • IgE serum immunoglobulin E
  • histopathologic changes of lesions and evaluation of dermatitis lesions were performed to evaluate the diagnosis and severity of atopic dermatitis .
  • the pharmaceutical composition may be any one selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, nonaqueous solvents, suspensions, emulsions, And may be oral or parenteral formulations of various forms.
  • a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain one or more excipients such as starch, calcium carbonate, sucrose or lactose lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like.
  • excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent.
  • Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
  • composition of the present invention may be administered in a pharmaceutically effective amount.
  • composition of the present invention may be administered as an individual therapeutic agent or in combination with another therapeutic agent, and may be administered sequentially or simultaneously with a conventional therapeutic agent. And can be administered singly or multiply.
  • the preferred dosage of the composition of the present invention will depend on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, and the appropriate total daily dose may be determined by treatment, Generally, an amount of 0.001 to 1000 mg / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / kg, can be administered in a single dose, divided into several times a day.
  • the composition is not particularly limited as long as it is an object for prevention or treatment of skin wrinkles and / or atopic dermatitis, and any object can be applied.
  • any object can be applied.
  • it can be applied to any individual such as a monkey, a dog, a cat, a rabbit, a guinea pig, a rat, a mouse, a cattle, a pig, a goat, Including without limitation.
  • transdermal administration through topical application may be used, but is not limited thereto.
  • the present invention provides a health functional food composition for preventing or ameliorating skin wrinkles or atopic dermatitis comprising, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof :
  • the compound represented by Formula 1 of the present invention may be incorporated into a health functional food composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.
  • the term " improvement" refers to any action that alleviates or alleviates the symptoms of skin wrinkles, atopic dermatitis and symptoms of onset individuals using the composition.
  • the composition of the present invention When the composition of the present invention is incorporated into a health functional food, the composition may be added as it is or may be used together with other health functional foods or health functional food ingredients and suitably used according to a conventional method.
  • the amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use.
  • the composition of the present invention may be added in an amount of preferably not more than 15 parts by weight, more preferably not more than 10 parts by weight, based on the raw material, in the production of food or beverage.
  • the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
  • health functional food that can contain the composition of the present invention
  • examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gum, Dairy products, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and may include foodstuffs used as food for animals, which may include all health functional foods in the conventional sense.
  • the health functional food composition of the present invention when used in the form of a drink, it may contain various sweetening agents, flavoring agents, or natural carbohydrates as additional components such as ordinary beverages.
  • the natural carbohydrates may be polysaccharides such as disaccharides such as monosaccharides such as glucose and fructose, maltose, sucrose, dextrin, cyclodextrins, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • the ratio of the natural carbohydrate is not limited thereto, but may be about 0.01 to 0.04 g, more preferably 0.02 to 0.03 g per 100 ml of the composition of the present invention.
  • the sweeteners may be natural sweeteners such as tau martin and stevia extract, and synthetic sweeteners such as saccharin and aspartame.
  • the health functional food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, , Alcohols, carbonating agents used in carbonated drinks, and the like. It may also contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks.
  • the present invention provides a quasi-drug composition for preventing or improving skin wrinkles or atopic dermatitis, which comprises, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • the compound of the present invention may be included in the quasi-drug composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.
  • quasi-drug in the present invention means a fiber, a rubber product or the like used for the purpose of treating, alleviating, treating or preventing a disease of a human or an animal, a weak action on the human body, Or products similar to those which are not machinery, preparations used for sterilization, insecticides and similar uses for the prevention of infections, for the purpose of diagnosis, treatment, alleviation, treatment or prevention of diseases of human beings or animals Machinery, or apparatus, and that is not an apparatus, machine, or apparatus of an article used for the purpose of giving pharmacological effects to the structure or function of a person or animal, It also includes supplies.
  • the composition of the present invention When the composition of the present invention is contained in a quasi-drug for the purpose of preventing or improving skin wrinkles or atopic dermatitis, the composition may be used as it is or may be used together with other quasi-drug components, and may be suitably used according to a conventional method have.
  • the amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use.
  • the external preparation for skin may be prepared and used in the form of, for example, an ointment, a lotion, a spray, a patch, a cream, a powder, a suspension or an ointment.
  • the present invention provides a cosmetic composition for preventing or ameliorating skin wrinkles or atopic dermatitis, which comprises, as an active ingredient, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • the compound of the present invention may be included in the cosmetic composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.
  • the cosmetic composition for preventing or improving skin wrinkles or atopic dermatitis may comprise 0.001 to 50% by weight of the compound or a pharmaceutically acceptable salt thereof, more preferably 0.01 to 20% by weight, By weight, most preferably from 0.1% to 10% by weight, of a compound or a pharmaceutically acceptable salt thereof.
  • the cosmetic composition of the present invention may include, without limitation, commonly accepted ingredients other than the above-mentioned effective ingredients, and includes conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, and carriers can do.
  • the cosmetic composition according to the present invention can be used as a cosmetic composition in the form of a solution, an ointment for external use, a cream, a foam, a nutritional lotion, a softening water, a pack, a soft water, an emulsion, a makeup base, But are not limited to, emulsions, pastes, gels, lotions, powders, soaps, surfactant-containing cleansers, oils, powder foundations, emulsion foundations, wax foundations, patches and sprays.
  • the cosmetic composition of the present invention may further comprise at least one cosmetically acceptable carrier to be incorporated in a general skin cosmetic composition, and examples thereof include oil, water, a surfactant, a moisturizer, A thickening agent, a chelating agent, a coloring matter, an antiseptic, a perfume, and the like may be appropriately compounded, but the present invention is not limited thereto.
  • the cosmetically acceptable carrier to be contained in the cosmetic composition of the present invention varies depending on the formulations.
  • the carrier component may be an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide Mixtures of these may be used.
  • lactose When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder or a mixture thereof may be used as the carrier component, Propellants such as fluorohydrocarbons, propane / butane or dimethyl ether.
  • a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, 1,3-butyl glycol oil may be used, in particular fatty acid esters of cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol aliphatic esters, polyethylene glycols or sorbitan may be used have.
  • the formulation of the present invention is a suspension
  • a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
  • the formulation of the present invention is a soap, an alkali metal salt of a fatty acid, a fatty acid hemiester salt, a fatty acid protein hydrolizate, isethionate, a lanolin derivative, an aliphatic alcohol, a vegetable oil, glycerol, .
  • the carrier component is selected from the group consisting of aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.
  • the present invention provides a transdermal preparation for the treatment of atopic dermatitis comprising the above pharmaceutical composition.
  • the pharmaceutical composition can be used for treatment of skin wrinkles or atopic dermatitis by transdermal administration.
  • transdermal dosage form of the present invention is a dosage form that exhibits an effect by administering a drug through the skin, and is formulated in the form of a drug applied to the skin or a drug attached to the skin.
  • transdermal administration the skin permeation of the active ingredient is carried out through an intracellular, intracellular, or parenchyma, hairy hole, or the like by simple diffusion according to the chemical potential, that is, the concentration gradient. It is not easy to pass through uninjured skin.
  • a skin administration promoter may be additionally formulated, and the compound of the present invention may be advantageous for transdermal administration owing to the lipophilicity characteristics.
  • the transdermal preparation of the present invention can be used without limitation as long as it is a formulation capable of directly administering the active ingredient to the surface of the diseased part of the skin.
  • preparations such as ointments, creams, gels, lotions, solutions, emulsions, suspensions, warnings (sticks), pastes, liniments, papings, tapes, aerosols or external powders can be used.
  • it may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of conventional transdermal dosage forms.
  • the base material is selected from the group consisting of white petrolatum, yellow petrolatum, lanolin, bleached beeswax, cetanol, stearyl alcohol, stearic acid, hydrogenated oil, gelled hydrocarbon, polyethylene glycol, liquid paraffin, squalane ; Solvents and dissolution aids such as oleic acid, myristic acid isopropyl, triisooctanoic acid glycerin, crotamiton, diethyl sebacate, diisopropyl adipate, hexyl laurate, fatty acid, fatty acid ester, aliphatic alcohol and vegetable oil; Antioxidants such as tocopherol derivatives, L-ascorbic acid, dibutylhydroxytoluene, and butylhydroxyanisole; Preservatives such as parahydroxybenzoic acid ester; Humectants such as gly
  • the carrier component may be water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan
  • a solvent, a solvent or an emulsifying agent may be used.
  • a liquid diluent such as water, ethanol or propylene glycol as a carrier component
  • Suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters
  • Microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
  • a tackifier such as polyacrylic acid and polyacrylic acid copolymer
  • a crosslinking agent such as aluminum sulfate, aluminum potassium sulfate, aluminum chloride, magnesium metasilicate aluminate, and dihydroxy aluminum acetate
  • Thickening agents such as sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, sodium alginate, carboxymethylcellulose, carboxymethylcellulose sodium salts, hydroxypropylcellulose, and hydroxypropylmethylcellulose
  • Polyhydric alcohols such as glycerin, polyethylene glycol (macrogol), propylene glycol and 1,3-butanediol
  • Surfactants such as polyoxyethylene derivatives
  • Fragrances such as 1-menthol
  • Preservatives such as parahydroxybenzoic acid ester
  • purified water may be added as
  • a pressure-sensitive adhesive such as styrene, isoprene, styrene block copolymer (SIS block copolymer) or acrylic resin
  • a tackifier resin such as an alicyclic saturated hydrocarbon resin, a rosin resin, and a terpene resin
  • Softeners such as liquid rubber and liquid paraffin
  • Antioxidants such as dibutyl hydroxytoluene
  • Polyhydric alcohols such as propylene glycol
  • Absorption promoters such as oleic acid
  • a surfactant such as a polyoxyethylene derivative, and other suitable additives.
  • a functional tape such as sodium polyacrylate or polyvinyl alcohol and a small amount of purified water may be added to form a functional tape.
  • a stabilizer, a preservative, an absorption promoter, a pH adjuster, and other suitable additives may be added as desired.
  • the white petrolatum, the yellow petrolatum, the lanolin, the bleached wax, the cetanol, the stearyl alcohol, the stearic acid, the stearic acid, Base oils such as hydrogenated oils, gelled hydrocarbons, polyethylene glycols, liquid paraffin, squalane and the like; Oleic acid, myristic acid isopropyl, diisopropyl adipate, isobutyl sebacate, glycerin triisooctanoate, crotamiton, diethyl sebacate, hexyl laurate, fatty acid esters, aliphatic alcohols and vegetable oils Solvents and dissolution aids; Antioxidants such as tocopherol derivatives, L-ascorbic acid, dibutylhydroxytoluene, and butylhydroxyanisole; Preservatives such as parahydroxybenzoic acid ester; Humectants such as glycerin
  • excipients such as potato starch, rice starch, corn starch, talc and zinc oxide or other suitable additives may be added.
  • various stabilizers, preservatives, absorption promoters and other suitable additives may be added as desired.
  • the means for preparing the transdermal dosage formulations provided by the present invention is not particularly limited, and a method for preparing conventional transdermal dosage forms, such as sufficiently kneading the respective components and the base components as necessary according to a desired formulation, .
  • a method for preparing conventional transdermal dosage forms such as sufficiently kneading the respective components and the base components as necessary according to a desired formulation, .
  • the papermaking agent and the tape agent it is possible to prepare the kneaded mixture by preliminarily drying it on a release paper, further kneading it with a flexible support, and cutting it to a desired size.
  • the transdermal dosage form provided by the present invention can be applied directly to the skin affected area by application or the like in the case of ointments, liquid preparations (suspensions, emulsions, lotions and the like), aerosols and external preparations, Or by applying or impregnating the support to a support of the above-mentioned composition.
  • these preparations can be used by directly attaching them to the skin affected portion.
  • the application amount can be set in consideration of the transdermal permeation rate, the cell absorption capacity, and the like.
  • the content of the compound represented by the formula (1) of the transdermal formulation of the present invention, or a pharmaceutically acceptable salt thereof, may be from 0.1 to 10% by weight, based on the weight of the total composition, 1, or a pharmaceutically acceptable salt thereof, can be determined by those skilled in the art to the extent that the effect of preventing or treating atopic dermatitis is provided.
  • the present invention provides a method for preventing or treating skin wrinkles or atopic dermatitis, comprising the step of administering the pharmaceutical composition to a subject suspected of having skin wrinkles or suspected individuals of atopic dermatitis do.
  • the individual can be efficiently treated by administering a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject suspected of causing skin wrinkles or suspect of atopic dermatitis.
  • Skin wrinkles and atopic dermatitis are as described above.
  • administering means introducing the pharmaceutical composition of the present invention into a suspected individual or atopic dermatitis susceptible to skin wrinkling in any appropriate manner, and the administration route can reach the target tissue May be administered via various routes of administration, whether oral or parenteral. Specifically, it can be administered by a transdermal administration method such as topical application, but is not limited thereto.
  • the method of treatment of the present invention may comprise administering a pharmaceutical effective amount of a pharmaceutical composition comprising a compound represented by the above-mentioned formula (1), or a pharmaceutically acceptable salt thereof.
  • Suitable total daily doses may be determined by treatment within the scope of sound medical judgment and are generally in the range of 0.001 to 1000 mg / kg, preferably 0.05 to 200 mg / kg, more preferably 0.1 to 100 mg / kg May be administered once or several times a day.
  • the specific therapeutically effective amount for a particular patient will depend upon the nature and extent of the reaction to be achieved, the particular composition, including whether or not other agents are used, the age, weight, Sex and diet of the patient, the time of administration, the route of administration and the rate of administration of the composition, the duration of the treatment, the drugs used or concurrently used with the specific composition, and similar factors well known in the medical arts.
  • composition of the present invention increases the expression of type I procollagen protein in human dermal fibroblasts, inhibits the expression of MMP-1 and MMP-3 proteins, inhibits the expression of TNF-a and IFN-r IL-6, an inflammatory cytokine, and TARC (thymus and activation-regulated chemokine), which are specific for atopic dermatitis, can be effectively inhibited in human keratinocyte cell line, thereby preventing and greatly improving atopic dermatitis.
  • composition of the present invention is a material which is separated in a natural state and is not only very safe for human body but also excellent in stability.
  • 1 is a graph showing cytotoxicity of human fibroblasts treated with thymol compound.
  • FIG. 2 is a graph showing changes in the expression of MMP-1 protein in human fibroblasts treated with thymol compound.
  • FIG. 3 is a graph showing changes in the expression of MMP-3 protein in human fibroblasts treated with thymol compound.
  • FIG. 4 is a graph showing changes in the expression of procollagen protein in human fibroblasts treated with thymol compound.
  • FIG. 5 is a graph showing changes in the expression of TARC in keratinocyte lineage treated with thymol compound.
  • FIG. 6 is a graph showing changes in expression of IL-6 in keratinocyte lines treated with thymol compound.
  • FIG. 7 is a graph showing the results of measurement of skin moisture content after treatment of thymol with NCNC / Nga mouse atopic model in parallel with DNCB solution.
  • FIG. 9 is a photograph showing histological changes of the skin after treatment of thymol with NCNC / Nga mouse atopic model in parallel with DNCB solution.
  • FIG. 10 is a graph showing the spleen extracted and its weight after treatment with thymol in parallel with the DNCB solution in the NC / Nga mouse atopic model.
  • Cytotoxicity was measured using a colorimetric assay of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide.
  • MTT Metal thiazol tetrazolium
  • the volume of the medium was reduced to 1 ml, and 100 ⁇ l of 1 mg / ml MTT was added to each wall.
  • the cells were then incubated at 37 ° C for 2 hours in the presence of 5% CO 2 and 95% O 2 .
  • the substrate-containing medium was removed, and 1 ml of DMSO was added to each wall to dissolve the formalin crystals.
  • the plate was also shaken with an orbital shaker for 30 minutes at room temperature. Absorbance of the 100 ⁇ l aliquot was quantified by measuring the absorbance at 570 nm using a microplate reader (Molecular Devices E09090; San Francisco, CA, USA). MTT analysis was performed on normal human dermal fibroblasts irradiated with UVB to confirm cytotoxicity of cells treated with chlorogenic acid, rutin, and combinations thereof (72 hours after treatment).
  • Human fibroblasts irradiated with ultraviolet rays at a dose of 144 mJ / cm 2 showed a three-fold increase in the production of MMP-1 protein as compared with the ultraviolet-untreated group.
  • the increase in the production of MMP-1 protein due to the ultraviolet irradiation treatment was reduced by thymol treatment, which was improved by 2%, 34%, and 46% at 0.1, 1, and 10 ⁇ g / And showed the inhibitory effect on the production of MMP-1 protein (Fig. 2).
  • the thymol of the present invention effectively inhibits the production of MMP-1 and MMP-3 proteins, which cause wrinkles, and can be effectively used for prevention and improvement of skin wrinkles.
  • human fibroblasts irradiated with ultraviolet rays at a dose of 144 mJ / cm 2 showed a 2.3-fold reduction in the production of type 1 collagen protein as compared with the ultraviolet-untreated group.
  • the decrease in the production of type 1 procollagen protein due to ultraviolet irradiation treatment was again increased by the treatment with thymol compound.
  • the thymol compound-treated group exhibited a remarkably increasing effect as compared with the untreated group, showing a remarkably improved type 1 procollagen protein production-increasing effect at a dose of 10 and 100 ⁇ g / ml, respectively ).
  • Skin horny cell line HaCaT 5 ⁇ 10 5 / well
  • FBS DMEM medium pretreated for 30 minutes thymol compounds (each 1 and 10 ⁇ g / ml) in DMEM without FBS, TNF-a and IFN- r (10 ng / mL) were diluted and co-treated and further cultured. After 24 hours, supernatants from each well were quantitated using a human TARC ELISA kit.
  • Atopic dermatitis is further enlarged through an inflammatory reaction, and clinical symptoms of atopic dermatitis tend to be further exacerbated through skin eruption, skin irritation, or photosensitization. Therefore, early prevention of inflammatory reaction is a very important factor in the treatment of acne symptoms in order to effectively improve the skin condition resulting from atopic dermatitis.
  • inflammatory mediators such as IL-6 are involved, and the inflammatory response is amplified by the action of inflammatory mediators.
  • IL-6 In the case of inhibiting the expression of IL-6, It can be effectively blocked.
  • HaCaT skin keratinocyte line
  • IL-6 protein produced was analyzed using an enzyme-linked immunosorbent assay (ELISA) kit.
  • ELISA enzyme-linked immunosorbent assay
  • Thymol was added as an active ingredient at two concentrations (0.1, 1% by weight), and the composition components were well emulsified by the ingredients and contents shown in the following Table 1, and deaerated, filtered and cooled to prepare a creamy composition.
  • Skin cream preparations were prepared in the same manner as above except that no thymol was added for the control experiment of cream formulations. The formulations were found to have good formulation stability and no side effects to the skin.
  • NC / Nga mouse atopic model (7 weeks old, male, 8 per group, Korea BioLink).
  • Experimental animals were kept in a conventional environment. The animals were fed free of animal feed and cages were fed at a constant temperature (23 ⁇ 2 °C), humidity (50 ⁇ 10%) and light (12 hours) Replace every 3 days.
  • the effect of thymol on the improvement of atopic symptoms of thymol in the atopic animal model was observed in parallel with the DNCB solution at the dose of 0.1 and 1 wt%, respectively.
  • a positive control group a group treated with 0.1 wt% of tacrolimus, which is used clinically as a treatment for atopic disease, was used.
  • NC / Nga Mouse Atopy Model In order to examine the effect of thymol on dry skin, a typical clinical symptom of atopic dermatitis on the 10th week, we measured skin moisture. Moisture content was measured using a skin measuring device (Dermalab combo, Cortex Technology, Denmark) possessed by SD Biotech.
  • the composition containing thymol of the present invention is very effective for the improvement of dry skin syndrome which is a typical symptom of atopic dermatitis.
  • NC / Nga mouse atopy model In order to examine the effect of thymol on contact dermatitis, a typical clinical symptom of atopic dermatitis on the 10th week, skin erythema was measured. The skin erythema measurement was performed using a skin measuring device (Dermalab combo, Cortex Technology, Denmark) possessed by SD Biotech.
  • H & E hematoxylin & Eosin staining was performed to determine the changes of skin (epiderms and dermis) of experimental animals caused by atopic dermatitis.
  • the skin tissue of the experimental animals was extracted and fixed in a 4% paraformaldehyde solution (pH 7.4) as a tissue fixative, and embedded in paraffin according to a conventional tissue preparation method and then cut into 5-6 ⁇ m.
  • Tissue samples were stained with nuclear and cytoplasm by H & E which had been treated with xylene to remove paraffin, and observed by optical microscope.
  • composition containing thymol as an active ingredient of the present invention has an excellent inhibitory effect on T lymphocytes and is effective in preventing and improving atopic dermatitis by inhibiting the production of immunoglobulin.

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Abstract

La présente invention concerne une composition comprenant du thymol comme principe actif efficace pour prévenir ou traiter les rides de la peau ou la dermatite atopique. Une composition de la présente invention stimule l'expression de la protéine procollagène de type I et inhibe l'expression des protéines MMP-1 et MMP-3 dans les fibroblastes du derme humain, et permet d'obtenir une suppression efficace de l'expression de l'IL-6, qui est une cytokine pro-inflammatoire, et de la chimiokine CCL17 (TARC), qui est un biomarqueur de la dermatite atopique, dans des lignées cellulaires de kératinocytes humains traitées par le TNF-α et l'IFN-γ, permettant ainsi de prévenir et de soulager fortement la dermatite atopique.
PCT/KR2017/013373 2017-08-11 2017-11-22 Composition comprenant du thymol comme principe actif pour prévenir ou traiter les rides de la peau ou la dermatite atopique WO2019031655A1 (fr)

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KR20070017451A (ko) * 2005-07-27 2007-02-12 경북대학교 산학협력단 항균 감염증 및 항염증 작용에 대한 예방 치료용 조성물 및이를 이용하여 얻어진 무좀치료제

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