KR20190018108A - Composition Comprising Thymol for Preventing or Treating in Skin Wrinkle or Atopic Dermatitis as Active Ingredient - Google Patents

Abstract

The present invention relates to a composition for preventing or treating skin wrinkles or atopic dermatitis containing thymol as an active component. The composition of the present invention increases the expression of type I procollagen protein, inhibits the expression of MMP-1 and MMP-3 proteins in human dermal fibroblasts, and makes an effective inhibition of the expression of IL-6, which is an inflammatory cytokine, and thymus and activation-regulated chemokine (TARC), which is a biomarker for atopic dermatitis, in human skin keratinocyte cell lines treated with TNF-a and IFN-r, thereby being able to prevent and greatly alleviate atopic dermatitis.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing or treating skin wrinkles or atopic dermatitis comprising thymol as an active ingredient. More particularly, the present invention relates to a composition for preventing or treating atopic dermatitis,

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.

On the other hand, over-production of reactive oxygen species (ROS) has been reported in the UVB exposure environment, and the signaling pathways associated with UVB exposure include mitogen-activated protein kinases (MAPKs), extracellular signal- p38 kinase, and JNK (c-Jun amino-terminal kinase), which induce increased expression of NF-κB and AP-1 transcription factors. In addition, the AP-1 protein is associated with the activity of the MMP (matrix metalloproteinase) gene, and the NF-κB protein affects the expression of proinflammatory cytokines such as interleukins.

Collapse of collagen and elastin in aged skin is mainly caused by increased expression of its degrading enzyme such as MMP protein. In addition, proinflammatory cytokines interfere with the synthesis of collagen and promote collagen collapse. 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-β / Smad signaling pathway. In addition, the TGF-β1 signaling system is one of the important factors controlling the synthesis of extracellular matrix in human dermal fibroblasts.

Thus, the production of reactive oxygen species (ROS) regulated by AP-1 and MAPKs factors, and the expression of MMPs, ILs, TGF-ss, and type I procollagen serve as markers useful in skin photoaging studies.

Thus, there have been various attempts to discover natural substances that inhibit collagen reduction and are effective in improving skin wrinkles. In order to utilize the effect of improving the wrinkles of collagen, products containing collagen as an external composition for skin such as cosmetics or ointment have been marketed. However, since these products are coated with collagen itself on the skin surface, collagen, which is a polymer substance, The improvement effect could not be shown. To solve this problem, there has been a growing interest in collagen synthesis promoting substances. 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. However, there is a problem in that the use amount of the substance is limited or its effect is insufficient due to safety problems such as irritation and reddening when applied to the skin, so that the effect of improving wrinkles can not be expected substantially. Therefore, it is urgently required to develop a novel wrinkle-improving composition which is safer for a living body than a conventional wrinkle-improving composition and has a high wrinkle-reducing effect.

On the other hand, atopic dermatitis (chronic 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.

The direct cause of the development of atopic dermatitis has not been clarified yet. In order to treat such atopy, conventionally used ingredients such as ceramide, linoleic acid, vegetable oil or mineral oil, steroid preparations such as hydrocortisone, or substances having enhanced antimicrobial and anti-inflammatory properties have been proposed. However, the above steroid preparations may cause adverse effects such as suppression of epidermal growth or side effects, and urea peroxide may cause excessive skin irritation and may cause side effects such as resistance to bacteria and photosensitivity There is a high problem. In addition, when applied to long-term skin, serious side effects such as increased capillary vasodilatation and / or stratum corneum thickening or expansion may occur. Gamma-linoleic acid, which is recently used for atopic dermatitis, is easily oxidized However, there is a problem that it is difficult to use for sensitive skin due to relatively strong skin irritation.

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 release of stored intracellular calcium from neurons and thymol enhances GABA-A receptor properties have been reported. Recent studies have also reported activity as an alpha 1-adrenergic agonist in circulating smooth muscle cells isolated from guinea pigs, suggesting that the transient receptor potential channel (TRPV3) of the tongue and nasal epithelium And is known to inhibit acetylcholinesterase activity in vitro. In addition, it has been known that the anti-inflammatory effect exhibits the property of neutralizing COX-1 enzyme activity or elastase secreted by neutrophils (Boudry G et al., J Physio Pharmacol 2008; 59 (3): 543552 ). However, the effect of thymol or its derivatives on skin wrinkles or atopic dermatitis has not yet been disclosed.

Accordingly, 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.

Accordingly, it is a main object of the present invention to provide a composition comprising thymol as an active ingredient, which has an excellent effect in preventing or treating skin wrinkles or atopic dermatitis.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, there is provided 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 :

[Chemical Formula 1]

.

.

The compound of Formula 1 is Thymol (2-isopropyl-5-methylphenol).

The term "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. As the free acid, organic acid and inorganic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As 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.

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. In this case, 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.

In one embodiment of the present invention, it has been observed that 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. In addition, 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, or a pharmaceutically acceptable salt thereof, is characterized in that it increases the expression of type I procollagen gene and inhibits the expression of MMP-1 and MMP-3 genes.

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.

Therefore, collagen of skin fibroblasts may be directly related to restoration or regeneration of tissue during skin regeneration, skin elasticity, wrinkle formation and skin damage.

That is, when the synthesis of collagen or procollagen of skin fibroblast is promoted or the synthesis of matrix metallo-proteinase (hereinafter, referred to as 'MMP'), which degrades collagen, is inhibited, skin elasticity improvement, skin regeneration, Improvement of skin wrinkles, wound healing, restoration and regeneration of damaged skin tissue; And prevention of skin aging can be obtained.

It is obvious that 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, or a pharmaceutically acceptable salt thereof, 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.

Many studies have investigated whether a particular chemokine present in serum or lesion tissue can be used as a marker in atopic dermatitis-related studies in patients with atopic dermatitis and NC / Nga mice (a mouse model of atopic dermatitis) Numerous studies have been accumulated on TARC (Fujisawa et al., J. Allergy Clin. Immunol., 110 (1), 139-146, 2002; H. Furukawa et al., J. Dermatol. Sci. Y. Shimada et al., J. Dermatol. Sci., 34, 201-208, 2004, Jahns-Rozyk et al., J. Immunol., 36, 165-172, 2004, Pediatr Allergy Immunol., 14,296-301, et al., Allergy, 60, 685-688, 2005). 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). In other words, serum TARC concentration in patients with atopic dermatitis is high and treatment with ciclosporin A or topical corticosteroids has been shown to significantly reduce TARC concentration and improve disease (Hijnen et. al., J. Allergy Clin. Immunol. 113 (2) 334-340).

It is clear that 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.

The term " 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, and " 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.

In the present invention, 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.

As used herein, the term " 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. In acute lesions of atopic dermatitis, a significant increase of serum immunoglobulin E (IgE) was noted. In addition, histopathologic changes of lesions and evaluation of dermatitis lesions were performed to evaluate the diagnosis and severity of atopic dermatitis . Although the exact cause of atopic dermatitis has not yet been fully understood, it is believed that immunologic and nonphysiologic mechanisms are involved with genetic predisposition.

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. In the case of formulation, 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. Various 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.

The composition of the present invention may be administered in a pharmaceutically effective amount.

The term " pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will vary depending on the species and severity, age, sex, The type of drug, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The 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. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art. 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. For example, 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. For example, transdermal administration through topical application may be used, but is not limited thereto.

In another aspect, 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 .

[Chemical Formula 1]

Specifically, the compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, may be incorporated into a health functional food composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.

The above-mentioned compounds, pharmaceutically acceptable salts, skin wrinkles and atopic dermatitis are as described above.

In the present invention, 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.

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. Generally, 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. However, in the case of long-term intake for the purpose of health control and hygiene, 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.

There is no particular limitation on the kind of health functional food that can contain the composition of the present invention, and 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.

In addition, when the health functional food composition of the present invention is 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.

In addition to the above, 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.

In another aspect, 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.

[Chemical Formula 1]

Specifically, the compound of the present invention, or a pharmaceutically acceptable salt thereof, may be included in the quasi-drug composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.

The above-mentioned compounds, pharmaceutically acceptable salts, skin wrinkles and atopic dermatitis are as described above.

The term " 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.

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.

In another aspect, the present invention provides a cosmetic composition for preventing or improving skin wrinkles or atopic dermatitis, which comprises a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

Specifically, the compound of the present invention, or a pharmaceutically acceptable salt thereof, may be included in the cosmetic composition for the purpose of preventing or improving skin wrinkles or atopic dermatitis.

The above-mentioned compounds, pharmaceutically acceptable salts, skin wrinkles and atopic dermatitis are as described above.

The cosmetic composition for preventing or improving skin wrinkles or atopic dermatitis according to the present invention 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.

In addition, 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.

In addition, 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.

When the formulation of the present invention is an ointment, a paste, a cream or a gel, 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.

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.

When the formulation of the present invention is a solution or emulsion, 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.

When 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.

When 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, .

When the formulation of the present invention is an interface-active agent-containing cleansing, 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.

In another embodiment, the present invention provides a transdermal preparation for the treatment of atopic dermatitis comprising the above pharmaceutical composition.

Specifically, the pharmaceutical composition can be used for treatment of skin wrinkles or atopic dermatitis by transdermal administration.

The term " 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. In 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. However, there are advantages in ease of use such as efficiency of drug, control of administration rate, possibility of direct application to affected part, maintenance of relatively constant blood concentration, minimization of side effects of substances showing gastrointestinal toxicity, And reducing the burden on the liver. In order to facilitate skin permeation of the active ingredient, 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. For example, preparations such as ointments, creams, gels, lotions, solutions, emulsions, suspensions, warnings (sticks), pastes, liniments, papings, tapes, aerosols or external powders Can be used. To this end, it may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of conventional transdermal dosage forms.

In the case of ointments, creams, gels and lotions, 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 glycerin, propylene glycol and sodium hyaluronate; Surfactants such as polyoxyethylene derivatives, glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, and lecithin; Carboxyvinyl polymer, xanthan gum, carboxymethylcellulose, carboxymethylcellulose sodium salt, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. In addition, a stabilizer, a preservative, an absorption promoter, a pH adjuster, and other suitable additives may be added as desired. In the case of a liquid or an emulsion, 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.

In the case of a suspension agent, 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.

In the case of a warning agent, lead monoxide, olive oil and lard are used. In case of pasta starch, zinc sulfate, salicylic acid and starch and petroleum jelly are used. In case of liniment oil, ginger oil, olive oil, methyl salicylate, Sodium carboxymethyl cellulose, glycerin, and zinc oxide.

In the case of the PAPE agent, 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; And purified water. In addition, a stabilizer, a preservative, an absorption promoter, a pH adjuster, and other suitable additives may be added as desired.

In the case of the tape, 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. In this case as well, a stabilizer, a preservative, an absorption promoter, a pH adjuster, and other suitable additives may be added as desired.

In the case of the aerosol preparation, 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, propylene glycol and sodium hyaluronate; Surfactants such as polyoxyethylene derivatives, glycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, and lecithin; Thickening agents such as carboxyvinyl polymer, xanthan gum, carboxymethyl cellulose, carboxymethyl cellulose sodium salts, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like; In addition, various stabilizers, buffers, mating agents, suspending agents, emulsifiers, fragrances, preservatives, solubilizers, and other suitable additives may be added. In particular, it may additionally include propellants such as fluoro-hydrocarbons, propane / butane or dimethyl ether.

In the case of external preparations, excipients such as potato starch, rice starch, corn starch, talc and zinc oxide or other suitable additives may be added. In this case as well, 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, . In the preparation of 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. In the case of a papermaking or a tape preparation, these preparations can be used by directly attaching them to the skin affected portion.

When used as the transdermal preparation of the present invention, the application amount can be set in consideration of the transdermal permeation rate, the cell absorption capacity, and the like. Preferably 1 mg / cm < ² > To 50 mg / cm ^2, or from 2 mg / cm ² to 20 mg / cm ² , based on the weight of the total composition, or a pharmaceutically acceptable salt thereof, May be determined by those skilled in the art, taking into consideration the salt content. 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.

In another aspect, 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.

The term " administering " in the present invention 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. For purposes of the present invention, however, 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.

As described above, the 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.

In addition, the 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.
2 is a graph showing changes in the expression of MMP-1 protein in human fibroblasts treated with thymol compound.
3 is a graph showing changes in the expression of MMP-3 protein in human fibroblasts treated with thymol compound.
4 is a graph showing changes in the expression of procollagen protein in human fibroblasts treated with thymol compound.
5 is a graph showing changes in the expression of TARC in keratinocyte lineage treated with thymol compound.
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.
8 is a graph showing the results of measurement of skin erythema 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.
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. FIG.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention, and thus the scope of the present invention is not construed as being limited by these embodiments.

Experimental Example 1. Cytotoxicity determination

Cytotoxicity was measured using a colorimetric assay of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide. MTT (Methyl thiazol tetrazolium) assay is used to measure cell viability, and MTT converts to purple-forming Fomarzan stain. After 72 hours of incubation, the volume of the medium was reduced to 1 ml, and 100 μl 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 μl 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).

As a result, as shown in FIG. 1, it was confirmed that the human dermal fibroblasts treated with the thymol compound before UVB irradiation and after UVB irradiation did not inhibit cell survival but rather promoted cell growth.

Example 2. Inhibition of MMP-1 and MMP-3 protein expression

40mm cell into the culture medium of DMEM 2㎖ a Petri dish, and then inoculated with human fibroblasts in a concentration of about 1.2x10 ^5, and incubated for 24 hours at 37 ℃, 5% CO ₂ environment. Thereafter, UVB was irradiated under conditions of 144 mJ / cm ² , and the medium was replaced with a medium containing thymol (0.1, 1, and 10 / / ml, respectively) and cultured for 3 days. The cultures were then harvested and centrifuged at 7500 rpm for 5 minutes at 4 ° C to obtain MMP-1 and MMP-3 (Human Total MMP-1 kit, R & D Systems, Inc., Minneapolis, MN, USA).

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 μg / And showed the inhibitory effect on the production of MMP-1 protein (Fig. 2). In addition, the increase in the production of MMP-3 protein due to ultraviolet irradiation treatment was reduced by the treatment with thymol, which was improved by 18%, 28%, and 40% at 0.1, 1, and 10 μg / Indicating the inhibitory effect of MMP-3 protein (Fig. 3).

From the above results, it can be seen that 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.

Example 3. Promoting the synthesis of type 1 procollagen protein

40mm cell into the culture medium of DMEM 2㎖ a Petri dish, and then inoculated with human fibroblasts in a concentration of about 1.2x10 ^5, and incubated for 24 hours at 37 ℃, 5% CO ₂ environment. Thereafter, UVB was irradiated under conditions of 144 mJ / cm ² , and then the medium was replaced with medium containing thymol (1 and 10 μg / ml, respectively) and cultured for 3 days. Then, the culture was harvested and centrifuged at 7500 rpm for 5 minutes at 4 ° C. The protein expression level of type 1 procollagen (ICP Peptide EIA Kit, Takara, Shiga, Japan) was changed by ELISA (See Fig. 4).

First, in human fibroblast experiments without ultraviolet irradiation, it was found that the thymol-treated group increased the production of type 1 procollagen protein in a concentration-dependent manner. In the thymol treated group, 146% and 177% improved in the 1 and 10 / / ㎖ capacities, respectively, compared to the untreated group And increased production of type 1 procollagen protein (FIG. 4).

In addition, 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. At this time, the thymol compound-treated group exhibited a remarkable increase effect as compared with the untreated group, with? And?% At 10, and 100 μg / (Fig. 4). Fig. 4 shows the effect of increasing the production of type 1 procollagen protein.

Example 4. Promoting TARC expression

Skin horny cell line ^{(HaCaT 5 × 10 5 / well} ) and then after 24 hours incubation in FBS DMEM medium, pretreated for 30 minutes thymol compounds (each 1 and 10㎍ / ㎖) 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.

As a result, as shown in FIG. 5, it was confirmed that the amount of TARC over-expressed by TNF-a and IFN-r was significantly inhibited by thymol compound treatment.

Example 5 Inflammatory cytokine production inhibition

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.

The effect of the thymol compound on inflammation and immunosuppressive activity was verified by the following method.

In the inflammatory reaction mechanism caused by atopic dermatitis, inflammatory mediators such as IL-6 are involved, and the inflammatory response is amplified by the action of inflammatory mediators. In the case of inhibiting the expression of IL-6, It can be effectively blocked.

In order to examine the effect of atopic dermatitis on the expression of IL-6 protein, skin keratinocyte line (HaCaT) was experimented. HaCaT cells were inoculated in a 96-well plate at a concentration of 5.0 × 10 ⁵ , and thymol compounds (1 and 10 μg / ml, respectively) were pre-treated for 30 minutes in DMEM without FBS for 24 hours. TNF-α and IFN- 10 ng / mL) were diluted, co-treated, and further cultured.

After the incubation, the supernatant was taken and the amount of IL-6 protein produced was analyzed using an enzyme-linked immunosorbent assay (ELISA) kit.

As a result, it was shown that the production of IL-6 protein induced by LPS was effectively inhibited by thymol compound treatment, and the inhibitory effect on IL-6 protein production was concentration-dependent (FIG. 6).

Production example. Manufacture of thymol cream

After mixing with thymol, IPM, liquid paraffin, cetostearyl alcohol, glyceryl monostearate, Brij 58, Span 60, BHA and Methyl paraben for oil phase production, The mixture was heated to uniformly dissolve until the temperature of the mixture reached 70 to 80 占 폚. PEG1500, PEG4000, SLS, xanthan gum, and purified water were mixed and dissolved at 70 to 80 ° C for preparation of the water phase. Then, the mixture was stirred at 70 to 80 ° C for 20 minutes to mix the oil-based product and the water-based product. After cooling, the mixture was poured into purified water, and a cream preparation was prepared at room temperature.

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.

[Table 1]

Experimental Example 1. Effectiveness of thymol against atopic dermatitis (in-vivo)

The relationship between skin inflammation and atopic dermatitis was examined using 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 ℃), humidity (50 ± 10%) and light (12 hours) Replace every 3 days.

After the stabilization period of the mice, the entire back of the mouse was removed from the lower part of the ear to the upper part of the tail and allowed to stand for 24 hours. 200 μl of 1% DNCB solution (acetone: olive oil = 3: 1) 5 times. After that, 150 μl of 0.4% DNCB solution was reapplied three times a week for at least 10 weeks to induce atopic dermatitis.

At the 5th week of application of the DNCB solution, 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. As 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.

1-1. Moisture measurement

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.

As a result, as shown in Fig. 7, in the test group treated with the thymol in parallel, the skin moisture amount was measured by 157 AU (0.1 wt% treatment group) and 134 AU (1 wt% treatment group) A 3.6-fold and 3-fold improvement in skin moisture was observed in the control group compared with 44 AU, respectively. It was found that 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.

1-2. Erythema measurement

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.

As a result, as shown in Fig. 8, skin erythema was measured in 9 AU (0.1 wt% treated group) and 8 AU (1 wt% treated group) in the experimental group treated with thymol in parallel, An improved level of erythema of the control compared to 12 AU was observed. These values indicate that the composition containing thymol of the present invention is highly effective in improving contact dermatitis, which is a typical symptom of atopic dermatitis.

1-3. Histological observation

Histological studies using H & E staining showed that the atopy-induced group mice had a more inflammatory state on the surface of the skin and a morphological breakdown of the skin barrier than the atopic-related non-grouped mice. However, 5 weeks after the atopy induction, the group treated with thymol for 5 weeks in parallel with the DNCB solution showed that the inflammatory state of the skin surface was similar to that of the atopic paralytic group, and the skin barrier was not broken.

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 μm. 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.

As a result of observing the histological changes of the skin, skin of the atopic dermatitis animal model has thickened epidermis compared to the control group and its thickness is greatly increased compared with the normal skin. This indicates that the atopic dermatitis animal model was not only changed in appearance but also histologically, it was judged to be appropriate to the atopic criteria. In these models, 5 weeks after the induction of atopy, when treated with 0.1 and 1% by weight of thymol in combination with DNCB solution, histological findings similar to those of the normal group were obtained. This suggests that thymol has an effect of inducing rapid regeneration of skin in an atopic dermatitis animal model (Fig. 9).

1-4. Spleen weighing

When an exogenous allergen enters the skin, it secretes a cytokine that causes an inflammatory response in a specific T lymphocyte. This leads to an increase in immunoglobulin E (IgE), which leads to an increase in eosinophils, leading to various symptoms of atopic disease. The eosinophil count was increased when the atopy was induced, and the eosinophil count was measured by measuring the weight of the spleen (Fig. 10). To examine the immune response of the mouse to DNCB, the mice were sacrificed at the end of the experiment and the spleen was excised and weighed. As a result, the weight of spleen was increased about 1.5 times as compared with that of normal group in DNCB induced group. This indicates that the eosinophil count is abnormally higher than the normal level due to atopic dermatitis. The increase in the weight of the spleen was not observed in the groups treated with 0.1 and 1 wt.% Of thymol. It was observed that the groups treated with 0.1 and 1 wt. These results indicate that the 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.

Claims (13)

A pharmaceutical composition for preventing or treating skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

. The method according to claim 1,
Wherein said composition further comprises a pharmaceutically acceptable carrier. The method according to claim 1,
Wherein the concentration of the compound, or a pharmaceutically acceptable salt thereof, is 0.1 to 10% by weight. The method according to claim 1,
Wherein said compound, or a pharmaceutically acceptable salt thereof, increases expression of a type I procollagen gene and inhibits the expression of MMP-1 and MMP-3 genes. The method according to claim 1,
Wherein said compound, or a pharmaceutically acceptable salt thereof, inhibits the expression of IL-6 (interleukin-6) and TARC (Thymus and activation regulated chemokine) genes. A health functional food composition for preventing or ameliorating skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

. A quasi-drug composition for prevention or improvement of skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

. A cosmetic composition for preventing or improving skin wrinkles or atopic dermatitis containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

. 9. The method according to any one of claims 6 to 8,
Wherein the concentration of the compound, or a pharmaceutically acceptable salt thereof, is 0.1 to 10% by weight. 9. The method according to any one of claims 6 to 8,
Wherein said compound, or a pharmaceutically acceptable salt thereof, increases expression of a type I procollagen gene and inhibits the expression of MMP-1 and MMP-3 genes. A transdermal preparation for treating skin wrinkles or atopic dermatitis comprising the composition according to any one of claims 1 to 5. 12. The method of claim 11,
Wherein the transdermal preparation is an ointment, a cream, a gel, a lotion, a liquid, an oil, a suspension, a stick, a pasta, a liniment, a papermaking, a tape, an aerosol or an external acid. Dosage formulations. A method for preventing or treating skin wrinkles or atopic dermatitis, comprising administering the composition of any one of claims 1 to 5 to a non-human individual.

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