WO2015005630A1 - Composition capable of inhibiting tslp secretion and alleviating allergic diseases - Google Patents

Abstract

The present invention relates to a pharmaceutical composition, a cosmetic composition, or a health functional food, which are capable of effectively alleviating allergic diseases by inhibiting the secretion of Thymic stromal lymphopoietin (TSLP) and inhibiting TSLP, and which include, as an active ingredient, a compound represented by chemical formula 1 of the present invention or a pharmaceutically acceptable salt. Accordingly, the composition has an excellent effect for inhibiting the secretion of TSLP, which is an immune reaction factor, and thus is superior for alleviating allergic diseases caused by an imbalance in the immune system.

Description

Composition having TSLP inhibitory activity and allergic disease improving ability

The present invention includes a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, has a TSLP (Thymic stromal lymphopoietin) secretion ability, by the TSLP secretion inhibitory ability, atopic dermatitis, asthma, allergic rhinitis A pharmaceutical composition, cosmetic composition or nutraceutical composition effective for improving allergic diseases including allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, gallbladder or food allergy.

Recently, skin diseases have increased significantly due to the increase in indoor living chemicals caused by the mass distribution of artificial fibers as well as new environmental pollutants caused by industrial development. In particular, urban people have recently been exposed to a variety of incidences of hypersensitivity, such as mites living on carpets in their homes, increased dust due to lowered humidity, hair from dogs, pollen, new fruits and foods, and food additives. The chances of exposure to allergens are increasing. Allergic diseases, such as atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, gallbladder or food allergy, have recently increased significantly and become a social problem.

Allergic disease refers to a disease caused by an immune hypersensitivity reaction and includes atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, gall margin or food allergy.

Allergic rhinitis is the most common allergic disease, and it is increasing gradually, affecting the quality of life, socioeconomic problems due to the decrease in production capacity and the increase in the cost of treatment, but there is no clear treatment yet. Currently used pharmacotherapy is a basic treatment for allergic rhinitis, but recurrence is common and can cause serious side effects when the drug is discontinued. Immunotherapy can be the only treatment that restores the only modified immune system, but there are no cost problems. have.

On the other hand, asthma is a typical allergic disease, such as allergic rhinitis, chronic chronic inflammation of the airway due to the airway is irritable and intermittent airway contraction is a chronic disease causing symptoms of respiratory distress. Asthma is caused by allergens (allergens) such as house dust mites and pollen in the external environment, resulting in excessive immune reactions (allergic reactions), which causes inflammation of the airway mucosal tissues. Symptoms of asthma occur (Lemanske RF Jr. JAMA 1997, 278, 1855-1873). With the recent advances in immunology and molecular genetics, the prevalence of asthma is increasing despite the understanding of the pathophysiology of asthma and the development of new therapeutic agents. In particular, steroids or bronchodilators, which are used as conventional therapeutics, should be used for a lifetime as a medicament for the control and prevention of symptoms rather than the fundamental cure of a disease, which causes a significant economic burden on individuals and society.

In addition, atopic dermatitis, also called civilization or advanced intractable disease, is a worldwide disease that can occur at any age, with 70% to 95% occurring in infants under 5 years of age. Even in Korea, the problem of atopic dermatitis has reached a serious social and medical level. According to various reports, about 15% of Koreans are atopic dermatitis patients, and 18 to 22 of 100 infants aged 0 to 4 years are known as atopic patients. In addition, more than 50% of patients with atopic dermatitis develop an atopic march, which causes allergic rhinitis and asthma.

The exact pathophysiology of allergic diseases, including atopic dermatitis, is not yet fully understood, but it is thought that immunological and environmental factors may be involved with genetic predisposition, especially asthma, allergic rhinitis and atopic dermatitis. Immunity imbalances are common in allergic patients, and many studies have been conducted from an immunological point of view.

On the other hand, exogenous atopic dermatitis, which accounts for most of atopic dermatitis, is caused by an immune mechanism associated with IgE, and there are many reports that a delayed immune response due to T cell abnormality is involved rather than an immediate immune response to a specific allergen. The main skin symptom of atopic dermatitis is eczema, which is not erythema and swelling on skin terminal test. Therefore, it is still controversial to evaluate the direct correlation of atopic dermatitis with skin terminal test result. In addition, it has been reported that cell-mediated immune dysfunction is associated with an increase in IgE in patients with atopic dermatitis, and is reported to be involved in delayed immune responses caused by T cell abnormalities rather than immediate immune responses to specific allergens.

In patients with atopic dermatitis, cell-mediated autoimmune disorders are known to occur up to about 80%, and susceptibility to skin infections caused by viruses and dermatophytes is increased, and sensitivity to contact allergens tends to decrease. The cause of this has been reported in the past T cell maturation deficiency, a decrease in the number of CD8 + inhibitory T cells, but recently the role of CD4 + T cells is known to be more important. That is, T cells secreting IL-4, which induces IgE production from B cells, IL-5, which promotes IgE production from B cells, and IL-6, which amplifies IgE production, are Th2 cells among CD4 + T cells. Antigen-specific T cell clones isolated from peripheral blood and skin lesions of dermatitis patients were found to be Th2, and IL-4 and IL-13 secreted from these cells promote IgE production and IL-5 is a basophil response (Source: Immunopathology of atopic dermatitis, Lee Kwang-hoon). According to recent reports, the immune response varies according to the condition of atopic dermatitis. Th2 is involved in acute atopic dermatitis and Th1 is involved in chronic atopic dermatitis. Initially, IL-2 and IL-13, which are secreted by Th2, play an important role, and when itching begins to scratch, it moves to Th1 cells.

Recently, the increase in atopic dermatitis in children as well as in adults is becoming serious, and in severe cases, it causes serious social problems such as employment and marriage. In such cases, severe mental stress may cause extreme avoidance and depression. Although atopic dermatitis has become a serious social and medical problem, there is no effective treatment to date.

Existing atopic dermatitis treatments, such as cyclosporin and FK506 (tacrolimus), which reduce the expression of cytokines by inhibiting calcineurin, have been developed and used, but they have reduced the resistance of secondary infections by weakening the immune system during long-term use. In addition, steroid-based external treatments that relieve skin itching and pruritus also have problems such as reduced immunity and growth inhibition when children are used for a long time. Therefore, there is a need for an effective therapeutic agent that is safe for long-term use and that can alleviate or eliminate the root cause of atopic dermatitis.

As a result, many researchers in Korea have been researching and commercializing improvement agents for improving atopic dermatitis, and most of the products developed are disappearing at the beginning of the market. The reason for this is that cosmetics that enhance the skin's moisturizing effect or hypoallergenic skin are being developed as atopic dermatitis products rather than the development of products corresponding to pathological mechanisms that cause and worsen atopic dermatitis.

On the other hand, the underlying cause of allergic diseases is known as immune imbalance, which is the result of various biological signal transductions. The top level protein for this abnormal signaling is the TSLP (Thymic stromal lymphopoietin) cytokine. When the allergen penetrates into the body, substances such as TSLP stimulate dendritic cells to respond. In this process, symptoms of allergic diseases such as atopic dermatitis and asthma appear.

According to known literature, increased levels of TSLP protein and mRNA in lesions of patients with atopic dermatitis have been found, indicating severe allergic diseases in humans and animal models (mouse) with increased TSLP expression in the skin (Steven F. Ziegler et al., J Allergy Clin Immunol, 2012; 130: 845-52). In addition, TSLP was detected in bronchial lavage fluid of asthma patients, and it was reported that there was a correlation between the sensation of disease and increased TSLP expression in airway epidermal cells. This has been found to be accelerated (Juan et al., Journal of Investigative Dermatology, 2012).

TSLP (Thymic stromal lymphopoietin) is an IL-7-like cytokine first discovered in culture of thymic stromal cells. TSLP is an important factor regulating the immune response at the interface between the body and the environment (skin, respiratory, digestive, eye, etc.) and is mainly secreted by skin epidermal and skin epithelial cells. Recent studies have shown that TSLP is secreted from mast cells, airway smooth muscle, fibroblasts, and dendritic cells in addition to epidermal and epidermal keratinocytes to regulate immune responses. Overexpression is known to cause immune imbalance.

Promoting TSLP secretion includes viruses, bacteria and bacterial products, protease allergens, inflammatory cytokines, chemicals, and physical irritation (scratching). Overexpression can lead to immune imbalances. The mechanism causing the imbalance is as described below.

The TSLP receptor (TLSPR) is mainly expressed in hematopoietic cells and is most frequently expressed in dendritic cells (DC). Dendritic cells have increased survival by TSLP, which increases the expression of major histocompatibility complex II, co-stimulatory molecules CD86 and CD40, and Th2 CD4 + T cells and naive CD4. CCL17 and CCL22 secretion are increased, which increases + T cell influx, respectively. In addition, OX40L expression, which increases Th2 differentiation, is increased, and IL-12 expression, which is involved in Th1 differentiation, is decreased. As a result, TSLP increases dendritic cells inducing Th2 responses. It also increases the influx of eosinophils, mast cells, and natural killer T cells, and promotes cytokine secretion such as IL-13 to deepen immune imbalances.

In order to effectively treat allergic diseases, the inventors of the present invention have been studying a substance capable of improving the imbalance, which is a fundamental cause of the imbalance, by inhibiting the overexpression of TSLP secretion by the compound represented by the following formula (1) to regulate the immune response. The present invention was completed by confirming that it effectively alleviates allergic diseases such as atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, gallbladder or food allergy.

[Formula 1]

An object of the present invention is to provide a pharmaceutical composition for inhibiting TSLP (Thymic stromal lymphopoietin) secretion comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of allergic diseases caused by immune imbalance, comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a cosmetic composition having an ability to improve allergic diseases by inhibiting TSLP secretion, including the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a health functional food composition having a TSLP secretion inhibitory activity, including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a nutraceutical composition having the ability to prevent or ameliorate allergic diseases, including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for inhibiting TSLP secretion or a method for treating allergic diseases, comprising administering to a subject a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. To provide.

The composition comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention is excellent in inhibiting the secretion of TSLP, an immune response factor.

In addition, the composition of the present invention has an excellent activity in inhibiting TSLP secretion, thereby regulating the immune response and having an excellent alleviating effect on allergic diseases caused by immune imbalance.

Therefore, the composition comprising the compound represented by the formula (1) according to the present invention or a pharmaceutically acceptable salt thereof is a TSLP secretion inhibitor or atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact It can be usefully applied as a therapeutic agent for allergic diseases including dermatitis, gallbladder or food allergy.

1 is a graph showing the inhibitory effect of the concentration (Rhein) of the compound represented by the formula (1) for TSLP secretion in human keratinocytes according to an embodiment of the present invention.

Figure 2 shows the results of cytotoxicity analysis of the compound (Rhein) of the compound represented by Formula 1 for human keratinocytes according to an embodiment of the present invention.

In one aspect, the present invention provides a pharmaceutical composition for inhibiting TSLP (Thymic stromal lymphopoietin) secretion comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

The term "thymic stromal lymphopoietin" (TSLP) used in the present invention is an IL-7-like hematopoietic cytokine, which is produced in epithelial cells, stromal cells, and mast cells and is an important factor regulating the immune response of the human body. Therefore, when TSLP is overexpressed (oversecreted) in the human body, including skin cells, it causes immune imbalance, which may cause the onset and deepening of allergic diseases. Therefore, the pharmaceutical composition may have the ability to prevent or treat allergic diseases caused by immune imbalance by inhibiting TSLP secretion.

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating allergic diseases, including the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

As used herein, the term "allergic disease" means an allergic predisposition, that is, a disease that develops by an allergic reaction (immune hypersensitivity reaction). Although the exact cause of the disease has not yet been identified, immunity imbalances have been observed in most allergic disease patients, and thus therapeutic agents or methods of treatment through immune imbalance control have been actively studied.

Allergic diseases of the present invention include atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis This includes contact dermatitis, hives or food allergy.

The atopic dermatitis of the present invention is a chronic recurrent inflammatory skin disease that begins mainly in infancy or childhood and is accompanied by pruritus (itch), dry skin, and characteristic eczema.

The asthma of the present invention, the bronchus in the lungs is very sensitive, sometimes the bronchus narrows and the symptoms of severe breathing cough while listening to the breathing and crotch breathing, due to allergic inflammation of the bronchus It is an allergic disease.

In the allergic rhinitis of the present invention, the nasal mucosa exhibits hypersensitivity to a specific substance, and allergens (antigens) causing allergy are exposed to the nasal mucosa. Means a disease in which the inflammatory cells are caused by the various mediators secreted by the inflammatory cells through the media.

The allergic conjunctivitis of the present invention refers to conjunctivitis caused by local sensations, ranging from mild hyperemia of the conjunctiva to bleeding, bleeding, and conjunctival edema, especially related to hereditary predisposition. It is called allergic conjunctivitis.

The allergic dermatitis of the present invention refers to a disease showing symptoms of inflammation on the skin due to an immune hypersensitivity reaction to an allergen.

The allergic contact dermatitis of the present invention refers to a skin disease in which erythematous papules, keratinous proliferation, or blisters appear along with pruritus on the skin of the abdomen, the periphery of the face, the facial part, etc. in response to the skin caused by the contact of the allergen. do.

The thin margin (tick) of the present invention refers to a skin disease in which plasma components are temporarily accumulated in tissues as the permeability of blood vessels present in the skin or mucosa increases, causing the skin to swell red or white and accompanied by severe itching.

The food allergy of the present invention is an allergic reaction caused by food, and the symptoms often appear immediately after ingesting a food (causal allergen) causing most allergic reactions, or may appear after several hours.

The compound represented by Formula 1 of the present invention and also referred to as Rhein may be obtained by extraction or separation from natural products, such as rhubarb, but is not limited thereto and may be chemically synthesized by a method known in the art, or commercially available. You can use what is sold at. It is known that the pharmacological activity of lanes is effective in antipyretic, lowering body temperature, antibacterial and edema.

In addition, the composition of the present invention preferably comprises from 0.0001% to 10% by weight of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof relative to 100% by weight of the total composition. In addition, the composition may be a pharmaceutical composition. If the content is less than 0.0001% by weight, the effect is too weak, whereas if it is included in excess of 10% by weight, the increase in effect due to the increase of the content is insufficient and the stability of the formulation is not secured. This can happen.

According to an embodiment of the present invention, as a result of treating the compound represented by Chemical Formula 1 with human keratinocytes induced with TSLP secretion by concentration, it was confirmed that inhibiting TSLP secretion in a concentration-dependent manner, represented by Chemical Formula 1 A cream containing the compound was applied to patients with atopic dermatitis for a period of time and showed excellent improvement. This means that the composition comprising the compound represented by Formula 1 of the present invention has an excellent effect on atopic dermatitis caused by immune imbalance by inhibiting TSLP secretion that modulates the immune response. It is shown that the compound can be usefully used as a TSLP secretion inhibitor or a therapeutic agent for allergic diseases.

As used herein, the term "prevention" refers to any action that inhibits or delays a disease by administration of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. In addition, the term "treatment" used in the present invention means all the actions that improve or cure the symptoms of the disease by administration of a composition comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

Compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, such salts are formed by acid addition salts or bases formed by pharmaceutically acceptable free acid (free acid) There is a metal salt. An inorganic acid and an organic acid may be used as the free acid, and hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid, or phosphoric acid may be used as the inorganic acid. The metal salts include alkali metal salts or alkaline earth metal salts, and sodium, potassium or calcium salts are useful.

The composition of the present invention may contain a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-mentioned active ingredient for administration. The carrier, excipient and diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

The compositions of the present invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral formulations, suppositories, or sterile injectable solutions, respectively, according to conventional methods. In detail, when formulated, it may be prepared by using diluents or excipients such as fillers, weights, binders, wetting agents, disintegrating agents, and surfactants which are commonly used. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like with the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. In addition to simple excipients, lubricants such as magnesium stearate, talc can also be used. It may be prepared by adding various excipients such as humectants, sweeteners, fragrances, preservatives and the like in addition to liquid oral liquids or liquid paraffin for oral use. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and tasks. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like can be used. As the base of the suppository, utopsol, macrosol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Suitable dosages of the compositions of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, and the time of day, but may be appropriately selected by those skilled in the art. The daily dosage of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is preferably 1 mg / kg to 500 mg / kg, and may be administered once to several times daily if necessary.

As another aspect, the present invention comprises a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, cosmetic composition having the ability to improve allergic diseases by inhibiting the secretion of TSLP (Thymic stromal lymphopoietin) secretion To provide.

[Formula 1]

It is known that TSLP can cause serious allergic diseases (atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, contact dermatitis or diarrhea) when TSLP is overexpressed on the skin of humans and animals. May affect the onset and progression of sexual skin inflammation (such as atopic dermatitis, etc.) (Steven F. Ziegler et al., J Allergy Clin Immunol, 2012; 130: 845-52). In addition, allergic inflammatory reactions are exacerbated by TSLP secreted from skin cells and promote the development of asthma (Juan et al., Journal of Investigative Dermatology, 2012).

Therefore, the cosmetic composition comprising a compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis by inhibiting overexpression of TSLP in the skin It can ameliorate allergic diseases of allergic dermatitis, allergic contact dermatitis, gallbladder or food allergy.

The cosmetic composition of the present invention may include conventionally acceptable ingredients in addition to the active ingredient, and may include, for example, conventional auxiliaries such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavors, and carriers.

Cosmetic compositions of the present invention may be prepared in any formulation conventionally prepared in the art and include, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing , Oils, powder foundations, emulsion foundations, wax foundations and sprays, and the like, but are not limited thereto. More specifically, it may be prepared in the form of a flexible lotion (skin), nourishing lotion (milk lotion), nourishing cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder. .

When the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components. Can be.

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polaramide powder may be used, especially in the case of spray, additionally chloro fluoro hydrocarbon, propane Propellant such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, liquid carrier diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, and microcrystals are used as carrier components. Soluble cellulose, aluminum metahydroxy, bentonite, agar or tracant and the like can be used.

When the formulation of the present invention is a surfactant-containing cleansing, the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, isethionate, an imidazolinium derivative, a methyltaurate, a sarcositate, a fatty acid amide. Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.

As another aspect, the present invention provides a health functional food composition having a TSLP (Thymic stromal lymphopoietin) secretion ability comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

The health functional food composition of the present invention has the ability to prevent or ameliorate allergic diseases including atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, contact dermatitis, or d margin caused by immune imbalance. It is preferable.

The dietary supplement composition includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and salts thereof. , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. Others may contain pulp for the production of natural fruit juices, synthetic fruit juices and vegetable drinks. These components can be used independently or in combination. In addition, the nutraceutical composition is in the form of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverages, tea, functional water, drinks, alcohol and vitamin complexes Can be.

In addition, the health functional food composition may further include a food additive, and whether or not suitable as a "food additive" according to the General Regulations and General Test Methods of the Food Additives Code approved by the Food and Drug Administration unless otherwise specified It is determined by the standard and the standard.

Items listed in the "Food Additives Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, cinnamon acid, natural additives such as color pigments, licorice extract, crystalline cellulose, high-quench pigments, guar gum, L Mixed preparations, such as a sodium glutamate preparation, a noodles addition alkali agent, a preservative preparation, and a tar pigment preparation, etc. are mentioned.

At this time, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention added to the food in the process of preparing the health functional food composition may be appropriately added or decreased as necessary, preferably food It may be added to include 1% to 15% by weight in 100% by weight, but is not limited thereto.

In another aspect, the present invention provides a method for inhibiting TSLP secretion comprising administering the composition to an individual.

The term "administration" of the present invention means providing the patient with the desired substance in any suitable way, and the route of administration of the composition of the present invention may be administered via any general route as long as it can reach the desired tissue. have. Skin application, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, pulmonary administration, rectal administration, but is not limited thereto. It may be administered once or several times daily as needed, and the composition may be used alone or in combination with methods using surgery, hormonal therapy, drug treatment and biological response modifiers. Dosage is as described above.

In another aspect, the present invention provides a method for treating allergic disease, comprising administering the composition to an individual. The administration is as described above.

As used herein, the term "individual" means monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits or guineas, including humans who may or may develop the allergic disease. Means all animals, including pigs, can be effectively prevented or treated by administering a composition of the present invention to a subject.

In one embodiment of the present invention by preparing a cosmetic composition comprising the compound represented by the formula (1) was continuously applied to the skin of a patient with atopic dermatitis for 8 weeks, the results confirmed a clear atopic dermatitis improvement effect.

Hereinafter, the present invention will be described in more detail by the following experimental examples. However, the following experimental examples are intended to illustrate the present invention, and the scope of the present invention is not limited to these alone.

Compound lane (Rhein) represented by the formula (1) of the present invention used in the following experimental example was purchased from Sigma Aldrich (USA) and used.

Experimental Example 1 Evaluation of TSLP Secretion Inhibition of Human Keratinocytes

After treating and incubating Rhein, a compound represented by Chemical Formula 1, to human keratinocytes, TSLP secretion inhibitory effect was confirmed.

After replacing with a new culture medium containing the CaCl ₂ in 1.4 mM concentration when chilled human keratinocytes (keratinocyte) the 24-well over 90% and incubated 4 days then put attachment by 1 × 10 ⁴ cell to the test plate 2 The cells were further cultured for days to induce differentiation of cells. To induce TSLP secretion into differentiated cells, 20 μg / ml of poly I: C was treated. Thereafter, lanes were treated with 0.5 μg / ml, 1 μg / ml or 2 μg / ml, respectively, and after 24 hours, cell cultures were taken to measure TSLP concentration by ELISA. The results are shown in FIG.

As shown in Figure 1, the lane represented by the compound represented by the formula (1) of the present invention showed a TSLP secretion inhibitory ability in a concentration-dependent manner. This means that the lanes can effectively inhibit TSLP secretion, thereby having an immunomodulatory effect and resolving immune imbalance.

Experimental Example 2: Evaluation of Cytotoxicity of Lane, a Compound of Formula 1

In order to analyze the cytotoxicity of lanes, after treating the lanes by concentration, cell viability was confirmed by using a spectrophotometer.

After replacing with a new culture medium containing the CaCl ₂ in 1.4 mM concentration when chilled human keratinocytes (keratinocyte) the 24-well over 90% and incubated 4 days then put attachment by 1 × 10 ⁴ cell to the test plate 2 The cells were further cultured for days to induce differentiation of cells. The poly I: C 20 ㎍ / ㎖ and lanes were treated with a concentration of 0.5 ㎍ / ㎖, 1 ㎍ / ㎖ or 2 ㎍ / ㎖ respectively and incubated for 24 hours. After 24 hours, the medium was removed, 200 μl of medium and 20 μl of CCK8 solution were added to each well, followed by incubation for 20 minutes in a 37 ° C. incubator in a CO ₂ atmosphere. The effect of the lane on cell survival was evaluated based on the absorbance of the poly I: C only well, and the results are shown in FIG. 2.

As shown in Figure 2, it was confirmed that the lane does not cause cytotoxicity at the experimental concentration. This means that the lane is a safe material with low likelihood of causing skin irritation.

Experimental Example 3: Atopic dermatitis improvement effect of the cosmetic composition comprising a lane of the compound represented by the formula (1)

In order to confirm the atopic dermatitis improvement effect of the cosmetic composition including the lane, the cream was prepared in the ratio shown in Table 1 and then experimented with 20 adults men and women with atopic dermatitis.

Table 1

Composition	Example (% by weight)	Comparative Example (Weight%)
lane	1.0	-
Stearic acid	15.0	15.0
Cetanol	1.0	1.0
Potassium oxide	0.7	0.7
glycerin	5.0	5.0
Propylene glycol	3.0	3.0
antiseptic	Quantity	Quantity
incense	Quantity	Quantity
Purified water	Remaining amount so that the total weight is 100%	Remaining amount so that the total weight is 100%

15 out of 20 adult men and women were applied to the affected area for 8 weeks at intervals of 12 to 14 hours at the ratios shown in Table 1 (experimental group), and the remaining five were not containing the lanes of the comparative example. Cream was applied to the affected area for 8 weeks (control). Thereafter, the severity of atopic dermatitis was determined by questioning and visual observation, and the degree of improvement of atopic dermatitis was evaluated in three stages of distinct effects, effects, and no differences. The results are shown in Table 2 below.

TABLE 2

	Distinct Effects (persons)	Effective (persons)	No difference (persons)
Experimental group (containing lanes)	7	5	3
Control group (no lanes)	0	One	4

As shown in Table 2, the experimental group coated with the cream of the example including the lane represented by the formula (1) showed an excellent atopic dermatitis improvement effect compared to the control group coated with the cream of the comparative example without the lane. . Therefore, the compound represented by Formula 1 of the present invention can be usefully used as an atopic dermatitis improving agent.

From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, the embodiments described above are to be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.

Claims (12)

1. A pharmaceutical composition for inhibiting TSLP (Thymic stromal lymphopoietin) secretion comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

   [Formula 1]

   
2. The pharmaceutical composition of claim 1, wherein the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is included in an amount of 0.0001% to 10% by weight based on 100% by weight of the total composition.
3. A pharmaceutical composition for preventing or treating allergic diseases caused by immune imbalance, comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

   [Formula 1]

   
4. The pharmaceutical composition of claim 3, wherein the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof is included in an amount of 0.0001% to 10% by weight based on 100% by weight of the total composition.
5. 4. The pharmaceutical composition according to claim 3, wherein the allergic disease is atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis or gallazine.
6. Cosmetic composition having the ability to ameliorate allergic diseases by inhibiting the release of TSLP (Thymic stromal lymphopoietin) comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

   [Formula 1]

   
7. The cosmetic composition according to claim 6, wherein the allergic disease is atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, or gall margin.
8. A health functional food composition having a TSLP (Thymic stromal lymphopoietin) secretion ability, including a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

   [Formula 1]

   
9. A health functional food composition having the ability to prevent or ameliorate an allergic disease comprising a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

   [Formula 1]

   
10. 10. The health functional food composition according to claim 9, wherein the allergic disease is atopic dermatitis, asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, or gall margin.
11. A method for inhibiting TSLP secretion comprising administering to a subject a composition of any one of claims 1 to 10.
12. A method of treating allergic diseases, comprising administering to a subject a composition of any one of claims 1 to 10.

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