Pharmaceutical composition for preventing or treating allergic skin diseases or skin itch

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating allergic skin diseases or skin itch, and more particularly, to a pharmaceutical composition for preventing or treating allergic skin diseases or skin itch, containing ABT-751 or TN-16 as an active ingredient, a cosmetic composition for preventing or ameliorating allergic skin diseases or skin itch, which contains ABT-751 or TN-16 as an active ingredient; and a cosmetic composition for moisturizing skin, which contains ABT-751 or TN-16 as an active ingredient. The composition for preventing or improving and treating atopic dermatitis according to the present invention effectively increases the expression of silk protein in skin cells and improves the skin barrier function, thereby having the effect of effectively improving or treating the symptoms of allergic skin diseases including atopic dermatitis or skin itch. And it is confirmed that an excellent skin moisturizing effect is exhibited.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition for preventing or treating allergic skin diseases or skin itch, and the like, and more particularly, to a pharmaceutical composition for preventing or treating allergic skin diseases or skin itch containing ABT-751 or TN-16 as an effective ingredient, a cosmetic composition for preventing or improving allergic skin diseases or skin itch containing ABT-751 or TN-16 as an effective ingredient, and a cosmetic composition for skin moisturizing containing ABT-751 or TN-16 as an effective ingredient, and the like. BACKGROUND

[0002] Atopic dermatitis is a chronic and recurrent inflammatory skin disease that begins mainly in infancy or childhood, and reaches 150 million people in patients in 9 countries worldwide such as the United States, the United Kingdom, and China, and is a disease with many patients, and is expected to grow the related therapeutic agent market to about 8 trillion won in 2025.

[0003] In the case of Korea, the number of patients who received diagnosis and treatment of atopic dermatitis reaches 1 million, and in particular, the incidence rate is higher in the infant and toddler period, and the infant and toddler patients of 0-4 years old reach 30% of the whole, and the child patients under the age of 9 reach half of the whole.

[0004] The reason why atopic dermatitis shows an increasing trend in the prevalence rate at home and abroad is a high incidence rate, but the lack of a diagnostic method that can accurately diagnose the cause and an appropriate treatment method can also be mentioned. Currently, the diagnosis of atopic dermatitis is mainly made by an interview or a macroscopic examination, and therapeutic agents also use steroids or immunosuppressants regardless of the cause. In the case of immunosuppressants, the side effects are relatively not serious, but for infants under the age of 2, who have a particularly high incidence rate, it is not possible to make a prescription, and thus the treatment period of infants in the early stage of the disease is missed, and thus leads to long-term and deepening of the disease.

[0005] Until now, although antibody therapeutic agents have been developed by global pharmaceutical companies, they can only be prescribed to severe patients over the age of 12, and thus there is a limitation that infants cannot be treated, and thus there is an urgent need for a fundamental solution to this. SUMMARY

[0006] TECHNICAL PROBLEM

[0007] The research group confirmed that colchicine regulates the expression amount of filaggrin in the skin, thereby not only enhancing the inherent barrier function of the skin, but also enhancing the amount of moisture replenishment, and showed an effect of preventing, treating, and improving the disease in an atopic dermatitis model, thereby completing the present application.

[0008] To solve the above problems, the present application provides a pharmaceutical composition for preventing or treating allergic skin diseases or skin itch, containing ABT-751 or TN-16 as an effective ingredient, a cosmetic composition for preventing or improving allergic skin diseases or skin itch, containing ABT-751 or TN-16 as an effective ingredient, and a cosmetic composition for skin moisturizing, containing ABT-751 or TN-16 as an effective ingredient.

[0009] Technical Solution

[0010] The present application provides a pharmaceutical composition for preventing or treating allergic skin diseases or skin itch, containing a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] [Formula I]

[0012]

[0013] [Formula II]

[0014]

[0015] In an example of the present application, the allergic skin disease can be atopic dermatitis or contact dermatitis.

[0016] In an example of the present application, the allergic skin disease can be atopic dermatitis.

[0017] In an example of the present application, the pharmaceutical composition can be applied by skin coating.

[0018] In an example of the present application, the atopic dermatitis is caused by a decrease in the expression of filaggrin.

[0019] In an example of the present application, when the expression amount of the filaggrin is decreased by 5.0% or more relative to that of a normal person, the pharmaceutical composition can be administered to a patient.

[0020] In an example of the present application, the pharmaceutical composition can be in a dosage form selected from the group consisting of an ointment, a cream, an emulsion, a gel, a solution for external use, a paste, a liniment, and an aerosol.

[0021] In addition, the present application provides a cosmetic composition for preventing or improving allergic skin diseases or skin itch, containing a compound represented by the following Chemical Formula I or Chemical Formula II as an effective ingredient.

[0022] In an example of the present application, the cosmetic composition can be in a dosage form selected from the group consisting of a solution, an external ointment, a cream, a foam, a nourishing lotion, a softening lotion, a pack, a skin toner, a milk, a primer, an essence, a soap, a liquid cleanser, a body wash, a sunscreen, a sunscreen oil, a suspension, an emulsion, a paste, a gel, a milk, a powder, a soap, a surfactant-containing cleanser, an oil, a foundation, an emulsion-type foundation, a wax-type foundation, a patch, and a spray.

[0023] In addition, the present application provides a skin-moisturizing cosmetic composition containing a compound represented by the following Chemical Formula I or Chemical Formula II as an effective ingredient.

[0024] [Formula I]

[0025]

[0026] [Formula II]

[0027]

[0028] In addition, the present application provides a skin-moisturizing medical external preparation composition containing a compound represented by the following Chemical Formula I or Chemical Formula II as an active ingredient.

[0029] [Formula I]

[0030]

[0031] [Formula II]

[0032]

[0033] Advantages of the Invention

[0034] The atopic dermatitis-preventing or -improving, treating composition of the present application effectively increases the expression of filaggrin in skin cells and improves skin barrier function, thereby having an effect of effectively improving or treating the symptoms of allergic skin diseases including atopic dermatitis or skin itch, and is confirmed to exhibit an excellent skin-moisturizing effect. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 a and 1b indicate the increase in the expression level of filaggrin by ABT-751 and TN-16 treatment, respectively.

[0036] Figure 2 indicates the increase in the differentiation rate of cells by ABT-751 treatment.

[0037] Figures 3a to 3cIndicate the increase of filaggrin expression in the skin of HR-1 mice treated with ABT-751 (a, b) and TN-16 (c), respectively.

[0038] Figures 4a to 4d Indicate the decrease of transepidermal water loss and the increase of skin barrier index in HR-1 mice treated with ABT-751 (a, b) and TN-16 (c, d) by applying 4% dosage, respectively. DETAILED DESCRIPTION

[0039] Hereinafter, the present application will be described in detail with reference to the tables or drawings.

[0040] In order to fully convey the idea of the present application to those skilled in the art, the drawings are provided. Therefore, the present application is not limited to the suggested drawings, but can be embodied in other forms, and the above drawings can be exaggerated to clarify the idea of the present application.

[0041] At this time, unless otherwise defined, the technical terms and scientific terms used have meanings commonly understood by those skilled in the art to which the present application belongs, and in the following description and drawings, the description of well-known functions and structures that can unnecessarily obscure the main idea of the present application is omitted.

[0042] In addition, the singular form used in the specification of the present application is intended to include the plural form unless the context clearly indicates otherwise.

[0043] In addition, the units used in the specification of the present application are based on weight, and as an example, the units of % or ratio mean weight % or weight ratio.

[0044] In addition, it will also be understood that when the term "include" is used in the specification of the present application, it is an open-ended description recorded with the same meaning as "have", "contain", "possess", or "characterized by" and the like, and does not exclude elements, materials or processes not otherwise recited. In addition, the term "consisting essentially of" means that other elements, materials or processes not listed together with a specific element, material or process can exist in an amount that does not significantly affect at least one basic and new technical idea of the present application. In addition, the term "consisting of" means that only the recited elements, materials or processes exist.

[0045] The terms "ingredient", "composition", "composition of compounds", "compound", "drug", "pharmaceutically active agent", "active agent", "cure", "therapeutic method", "treatment" or "medicament" used in the specification of the present application are used interchangeably to indicate a compound or a combination of compounds or substances that induce the desired pharmacological and / or physiological effects by local and / or systemic action when administered to a subject (human or animal).

[0046] The term "treatment", "method of treatment" (and its different forms) used in the specification of the present invention includes prophylactic (e.g. prophylactic treatment), curative or alleviative treatment. The term "therapeutic" used in the present invention includes alleviating or reducing at least one deleterious or enhancing effect or symptom of a state, disease or disorder. The terms "prevention", "amelioration" and "treatment" of the present invention should be interpreted in the broadest concept, "prevention" refers to an act of preventing, although possibly exposed to a disease or susceptible to a disease, but not yet experienced the disease, or preventing one or more of the clinical symptoms of the disease in an unexposed patient. "Treatment" refers to all acts of inhibiting or reducing the development of a disease or one or more of its clinical symptoms.

[0047] In the present invention, "sample" or "specimen" means an object for analysis, and is used in the same meaning in the specification.

[0048] The present invention provides a pharmaceutical composition for preventing or treating an allergic skin disease or skin itch, comprising a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an active ingredient.

[0049] [Formula I]

[0050]

[0051] [Formula II]

[0052]

[0053] Compound I is a compound of CAS Registry Number 141430-65-1, which is ABT-751 (N-[2-[(4-Hydroxyphenyl]amino]pyridin-3-yl]-4-methoxybenzenesulfonamide).

[0054] ABT-751 is an anticancer agent for oral administration, which is a sulfonamide-containing mitotic inhibitor. It exhibits antitumor activity against a wide range of tumor cells, and was developed as a therapeutic agent for breast cancer and non-small cell lung cancer, etc., but the development was discontinued thereafter.

[0055] The compound II is a compound of CAS Registry Number 33016-12-5, which is TN-16 (3-[1-(phenylamino)ethylidene]-5-(phenylmethyl)-2,4-pyrrolidinedione).

[0056] TN-16 is a new microtubule inhibitor having an anti-tumor activity, which is synthesized by modifying Tenuazonic acid (3-acetyl-5-sec-butyltetraic acid) isolated and characterized from a culture of Alternaria tenuis. It was found that TN-16 has a strong anticancer efficacy in 1967, but no stronger drugs have been found through subsequent studies. In addition, it is known that the mechanism of action of TN-16 is to inhibit microtubule formation and to act by binding at the sensitive site in 1983. It is known that the structure of TN-16 is similar to cytochalasin B, which is a standard inhibitor of actin polymerization, induces cell cycle arrest at the M phase, and inhibits the cytotoxicity of T lymphocytes and natural killer cells.

[0057] In the present application, the pharmaceutically acceptable salt refers to a salt generally used in the medical field, and as an example, inorganic ion salts prepared from calcium, potassium, sodium, and magnesium, etc., inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, and sulfuric acid, etc., organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydrogen iodide, etc., sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid, etc., amino acid salts prepared from glycine, arginine, lysine, etc., and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, methylpyridine, etc., but is not limited thereto.

[0058] According to the results of one embodiment of the present application, the pharmaceutical composition enhances the skin moisturizing effect by increasing the expression amount of filaggrin associated with the onset of allergic skin diseases, thereby not only improving the skin barrier function, but also having an excellent effect on allergic skin diseases, skin itching, or all of them by adjusting the inflammatory response of allergic skin diseases, reducing the itching of the skin, etc.

[0059] The allergic skin disease refers to a pathological symptom caused by an allergic reaction mediated by the activation of mast cells such as degranulation of mast cells, and representative examples of such allergic skin disease include atopic dermatitis, contact dermatitis, etc.

[0060] The skin itching is a disease including pruritus caused by external stimuli such as itching caused by a decrease in the content of lipids in the stratum corneum of the skin, a decrease in antibacterial activity, and itching caused by a blockage dysfunction, temperature changes, chemical substances, electrical stimulation, etc.

[0061] In the present application, the term "anti-allergic" is used as a meaning including improvement (reduction of symptoms), treatment, prevention (onset inhibition or delay) of allergic skin diseases.

[0062] As an example, the allergic skin disease can be atopic dermatitis, which exhibits symptoms such as dry eczematous skin, papules, and the like, and in which epidermal hyperplasia, epidermal proliferation, and accumulation of lymphocytes and mast cells are confirmed in a lesion sample of a patient with atopic dermatitis. A patient with atopic dermatitis can suffer from severe skin itching, thereby causing inflammation of the skin lesion, further worsening the clinical symptoms.

[0063] Skin is located anatomically at the outermost side of the body to block direct in vivo influx of pathogenic microorganisms or viruses, chemicals, and the like in the air, thereby protecting the body from the external environment, and plays an important barrier function of preventing excessive leakage of water in the body. Skin tissue is composed of a layer structure of a basal layer, a spinous and granular layer, and a cornified layer, and in each layer structure, specific expression markers are known. Among them, keratin 1 (K1) and keratin 10 (K10) are expressed in the spinous and granular layer, and filaggrin is expressed in the uppermost epithelium including the cornified layer, and is one of the main proteins indispensable for forming the above-mentioned intrinsic barrier function of the skin.

[0064] Recently, an association between atopic dermatitis and abnormality of the filaggrin gene has been found in patients with atopic dermatitis as described above, and in particular, in the case of Europe, mutations in the filaggrin gene were detected in more than half of the total atopic patients. In Japan, it was found that mutations in the filaggrin gene exist in more than about 25% of atopic patients, and in many Asian countries including China and Korea, mutations in the filaggrin gene were detected in patients with atopic dermatitis. It is reported that such abnormality of the filaggrin gene causes a decrease in expression of filaggrin protein in the skin and a loss of skin barrier function, and penetration of antigens such as allergic stimulant substances becomes easy, thereby causing dermatitis. In fact, in patients with allergic dermatitis, the development of allergic diseases such as asthma and rhinitis is very easy, and thus there is a need to develop a diagnostic method and a therapeutic agent capable of judging whether the filaggrin is abnormal or not.

[0065] The atopic dermatitis can be caused by a decrease in expression of the filaggrin, and when the decrease in expression of the filaggrin is 5.0% or more relative to a normal person, the pharmaceutical composition can be administered to the patient.

[0066] In a specific embodiment of the present application, the compound represented by the above Chemical Formula I enhances the expression of filaggrin, enhances the moisturizing effect of the skin, and exhibits an excellent improvement effect in terms of the skin barrier index and the skin comprehensive index. Also, in an allergic skin disease model, not only does it suppress the inflammatory response, but it also suppresses epidermal hyperplasia, epidermal proliferation, and the like, regulates inflammatory cytokines, and reduces the itching of the skin, thereby exhibiting an excellent preventive, therapeutic, and improvement effect on allergic skin diseases and / or skin itching. Here, the inflammatory cytokine refers to a cytokine that induces an inflammatory response occurring in the body, and is used in the usual meaning in the technical field to which the present application pertains. For example, IL-2, IL-4, and IL-13 can be used as an inflammatory cytokine of allergic skin diseases.

[0067] For example, when the expression of filaggrin is reduced by 5.0% or more, preferably 5.3% or more, and more preferably 5.6% or more, compared to that of a normal person, it can be judged that the patient has atopic dermatitis, and thus, the patient can be administered with the pharmaceutical composition according to the present application to treat atopic dermatitis.

[0068] The pharmaceutical composition can further include a suitable carrier, excipient, and diluent, which are generally used for pharmaceutical compositions, in addition to the compound represented by Chemical Formula I or a pharmaceutically acceptable salt thereof.

[0069] Non-limiting examples of the carriers, excipients, and diluents that can be included in the composition include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil, etc. When the above composition is formulated into a dosage form, a diluent or an excipient such as a common filler, extender, binder, wetting agent, disintegrating agent, surfactant, etc. can be used for preparation.

[0070] The above pharmaceutical composition can be used in various forms according to a general method of formulation, and in the case of being formulated into a transdermal administration agent, as a suitable dosage form, for example, an ointment, a cream, an emulsion, a gel, an external solution, a paste, a liniment, an aerosol, etc. are preferred, but are not limited thereto.

[0071] In addition to the above carriers, the pharmaceutical composition according to the present application can further include a preservative, a stabilizer, a wetting agent, an emulsifying agent, a solubilizing agent, a sweetening agent, a coloring agent, an osmotic pressure adjusting agent, an antioxidant, etc.

[0072] The formulation of the pharmaceutical composition is well known in the art, and can be found in, for example, "Remington's Pharmaceutical Sciences (19th ed., 1995)". The above document is incorporated herein by reference.

[0073] The pharmaceutical composition according to the present application can be administered in a pharmaceutically effective amount.

[0074] In the present application, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level can be determined according to factors including the kind of disease, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, treatment period, drugs used simultaneously, and other factors well known in the medical field. The pharmaceutical composition according to the present application can be administered as a sole therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered once or multiple times. In consideration of all the above factors, it is important to administer an amount capable of obtaining the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.

[0075] The pharmaceutical composition of the present application can be administered to an individual by various routes. The administration method can be, for example, oral or non-oral in various dosage forms, and in the case of formulation, can be prepared using the above excipients commonly used, and preferably, in the present application, as a non-oral agent, can be used as a smearing agent for smearing the skin. The administration method of the pharmaceutical composition of the present application is determined according to the kind of drug as an active ingredient in consideration of various related factors such as the disease to be treated, route of administration, age, sex and body weight of the patient, and severity of the disease.

[0076] In addition, the present application provides a cosmetic composition for preventing or improving allergic skin diseases or skin itch, comprising a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0077] [Formula I]

[0078]

[0079] [Formula II]

[0080]

[0081] The cosmetic composition can be in any dosage form selected from the group consisting of a solution, an external ointment, a cream, a foam, a nourishing cosmetic water, a softening cosmetic water, a pack, a skin softener, a lotion, a primer, an essence, a soap, a liquid cleanser, a body wash, a sunscreen, a sunscreen oil, a suspension, an emulsion, a paste, a gel, a milk, a powder, a soap, a surfactant-containing cleanser, an oil, a foundation, an emulsion-type foundation, a wax-type foundation, a patch, and a spray, but is not limited thereto.

[0082] In addition, the cosmetic composition of the present application can further include one or more cosmetically acceptable carriers conventionally used in skin cosmetics, and as general ingredients, for example, oil, water, a surfactant, a humectant, a lower alcohol, a thickening agent, a chelating agent, a pigment, a preservative, a fragrance, etc. can be appropriately included, but is not limited thereto.

[0083] The cosmetically acceptable carrier included in the cosmetic composition of the present application varies depending on the dosage form.

[0084] When the dosage form of the present application is an ointment, a paste, a cream, or a gel, as a carrier ingredient, animal oil, vegetable oil, wax, paraffin, starch, tragacanth gum, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, or a mixture thereof can be used.

[0085] When the dosage form of the present application is a powder or a spray, as a carrier ingredient, lactose, talc, silica, aluminum hydroxide, calcium silicate, a polyamide powder, or a mixture thereof can be used, and in the case of a spray, a propellant such as chlorofluorocarbon, propane / butane, or dimethyl ether can be further included.

[0086] In the case where the dosage form of the present application is a solution or an emulsion, as a carrier ingredient, a solvent, a solubilizer, or an emulsifier can be used, for example, water, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, and especially, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol fatty ester, polyethylene glycol, or a fatty acid ester of sorbitan can be used.

[0087] When the dosage form of the present application is a suspension, as a carrier ingredient, a liquid diluent such as water, ethanol, or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, and microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, or tragacanth gum can be used.

[0088] When the dosage form of the present application is a soap, as a carrier ingredient, an alkali metal salt of a fatty acid, a fatty acid half ester salt, a fatty acid protein hydrolysate, a hydroxyethyl sulfonate, a lanolin derivative, a fatty alcohol, a vegetable oil, glycerol, a sugar, etc. can be used.

[0089] In the case where the dosage form of the present application is a surfactant-containing cleanser, as the carrier component, a fatty alcohol sulfate, a fatty alcohol ether sulfate, a sulfosuccinic acid monoester, a isethionate, an imidazoline derivative, a methyl taurate, a sarcosinate, a fatty acid amide ether sulfate, an alkyl amido betaine, a fatty alcohol, a fatty acid glyceride, a fatty acid diethanolamide, a vegetable oil, a lanolin derivative, or an ethoxylated glycerol fatty acid ester, or the like can be used.

[0090] The cosmetic composition according to the present application can contain 0.01 to 20% by weight of colchicine, relative to the total weight of the composition.

[0091] In addition, the present application provides a skin-moisturizing cosmetic composition containing a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an effective ingredient.

[0092] [Formula I]

[0093]

[0094] [Formula II]

[0095]

[0096] The skin moisturization can mean an increase in the moisture sensation of the skin, a maintenance of a moist state, and the skin-moisturizing cosmetic composition of the present application is excellent in the skin-moisturizing effect of inhibiting or reducing the loss of moisture from the skin, and exhibits excellent effects in skin moisturization by regulating the expression of factors such as filaggrin, phospholipid, and loricrin, which are moisture-related factors.

[0097] In addition, the present application provides a skin-moisturizing medical external preparation composition containing a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an active ingredient.

[0098] [Formula I]

[0099]

[0100] [Formula II]

[0101]

[0102] The medical external preparation composition is a skin-moisturizing medical external preparation composition.

[0103] The above medical external product refers to an article whose effect is weaker than that of a pharmaceutical product among articles used for the diagnosis, treatment, amelioration, alleviation, management, or prevention of a disease of a human or an animal, for example, according to the Pharmaceutical Affairs Act, the medical external product can include, in addition to an article used for the purpose of a pharmaceutical product, a fiber, a rubber product, an article that has a slight effect on the human body or does not directly act on the human body, a case of a non-instrument or a machine, and the like, a sterilizing agent, an insecticide, and the like used for the treatment or prevention of a disease of a human or an animal, but is not limited thereto.

[0104] The kind or dosage form of the medical external product composition of the present application is not particularly limited, and preferably, can be a disinfecting cleaner, a shower foam, a mouthwash, a wet wipe, a lotion soap, a hand sanitizer, a humidifier filler, a mask, an ointment, or a filter filler, or the like.

[0105] In the case where the composition of the present application is included in a medical external product for skin moisturizing use, the above composition can be directly included or used together with other medical external product ingredients, and can be appropriately used according to a general method. The mixing amount of the active ingredient can be appropriately determined according to the purpose of use, and the medical external product composition according to the present application can contain 0.01 to 20% by weight of the compound represented by the above Chemical Formula I or Chemical Formula II, relative to the total weight of the composition.

[0106] Also, the present application provides a method of treating an allergic skin disease or skin itch, which comprises the step of administering to a patient a pharmaceutical composition containing a compound represented by the above Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof.

[0107] [Formula I]

[0108]

[0109] [Formula II]

[0110]

[0111] As an example, the above treatment method can administer the pharmaceutical composition to a patient by a) the step of measuring the filaggrin expression amount of the patient; and b) the step of determining that the patient needs to administer the above pharmaceutical composition when the above filaggrin expression amount is reduced by 5.0% or more relative to that of a normal person, but is not limited thereto, and the amount of the pharmaceutical composition administered to the patient and the administration period can vary depending on the amount of reduction in the filaggrin, and as an example of an embodiment of the present application, the pharmaceutical composition can be administered at a concentration of 0.5 to 2.5 μM at an interval of 1 day for 1 to 4 cycles, but is not limited thereto.

[0112] The present application will be described in more detail by examples. These examples are only for illustrating the present application, and the scope of the present application is not limited to these examples, which will be apparent to those skilled in the art.

[0113] [Materials, reagents, strains, and devices, etc.]

[0114] - Human epidermal cell line (Normal Human Epidermal Keratinocyte; NHEK) is a human fetal hard skin cell line, which is obtained from ATCC and used.

[0115] The cells are cells obtained by primary culture, and are used to confirm intracellular biochemical changes based on ABT-751 or TN-16 under normal conditions, not disease conditions.

[0116] - Experimental animal: hos: HR-1 (hairless) mouse has no hair in skin disease research, so it has the advantage that drugs can be directly administered to the skin, or skin diseases can be induced by chemical or biological allergens, so that skin-related research can be performed.

[0117] In addition, the thickness of the skin of 8-10 weeks old is about 0.4 mm, which is similar to human skin, so it has the advantage of studying the pathomechanism of skin diseases and confirming the biochemical changes in skin tissue.

[0118] [Experimental Example 1]

[0119] 1.1 Determination of filaggrin expression level using RNA extraction and RT-qPCR

[0120] After dissolving human epidermal cell lines (NHEK) or mouse skin tissues coated with ABT-751, TN-16, or control samples using TRI reagent (MRC company), RNA in the cells was extracted using Rneasy Mini Kit (Qiagen company).

[0121] The extracted RNA was reverse transcribed using ImProm-II TM Reverse Transcription Kit, Promega company) and after synthesizing cDNA, the amount of filaggrin was determined using quantitative PCR (qPCR) by Real-Time PCR Detection System (Bio-Rad company, CFX96).

[0122] 1-2. Protein extraction and Western blotting

[0123] A portion of the collected tissue was homogenized using a tissue homogenizer (Korea Science Co.), dissolved using a cell lysis buffer solution (RIPA buffer, Invitrogen Co.), and centrifuged using a centrifuge (Labogene Co.), and the supernatant was moved to a new tube and used as a protein sample.

[0124] 30 μg of the protein sample was loaded into a PAGE gel (Invitrogen) having a density gradient of 4% to 12%, and SDS-PAGE was performed using a running buffer (Invitrogen Co.) and an electrophoresis apparatus (Bio-Rad Co.) to separate the proteins according to molecular weight.

[0125] After the separated proteins were transferred to a PVDF membrane (Bio-Rad Co.), blocking was performed using 5% blocking solution (Skimmilk; BD Co.).

[0126] The membrane was reacted with filaggrin antibody (Santa Cruz Co.) or GAPDH antibody (Abeam Co.) for 16 hours, washed, and again reacted with 2 times antibody for 1 hour and washed.

[0127] After the membrane was reacted with ECL solution (Thermo Fisher Co.), the reaction-finished proteins were detected using a luminescence reaction measuring apparatus (Fusion Solo, Vilber Co.).

[0128] [Experimental Example 2] Skin barrier function test

[0129] After ABT-751 or TN-16 was applied for 2 hours, the amount of skin moisture loss, the skin barrier index, and the comprehensive index of the applied site were measured and recorded for 3 weeks using a precision measuring apparatus (Courage-khazaka electronic GmbH, MPA10).

[0130] [Example 1] Filaggrin expression amount and cell differentiation degree in human epidermal cell line treated with ABT-751 or TN-16

[0131] ABT-751 and TN-16 were respectively treated to a human epidermal cell line (NHEK) in culture, the filaggrin expression amount was measured, and the change in the cell differentiation degree was confirmed.

[0132] ABT-751 and TN-16 were treated to NHEK at concentrations of 0, 0.5, 1.0, and 2.5 μM, respectively, and after 24 hours, the expression level of filaggrin and the cell differentiation degree were observed.

[0133] Results are shown in FIG. 1 and Figure 2 FIG. 2.

[0134] As such, it was confirmed that the expression amount of filaggrin was increased depending on the concentration of ABT-751 and TN-16 (refer to Figure 1 a and Figure 1 b ), and the degree of cell differentiation was significantly increased in the ABT-751-treated group compared to the ABT-751-untreated group (control group) (refer to Figure 2 ).

[0135] [Example 2] Expression amount of filaggrin and degree of cell differentiation in animal cells treated with ABT-751 or TN-16

[0136] ABT-751 and TN-16 in the form of 0, 1, 2, and 4% were applied to the skin of a hairless hos: HR-1 mouse (hereinafter, referred to as an HR-1 mouse) and the like in the same amount once a day for 3 weeks.

[0137] After each application, the amount of skin moisture loss and the skin barrier index were measured by the method of the above test example.

[0138] After 2 weeks of application, the HR-1 mouse was euthanized in a carbon dioxide chamber, and the dorsal skin tissue was collected, respectively.

[0139] 2-1 Measurement of the expression amount of filaggrin

[0140] RNA and protein were extracted from the skin tissue applied with ABT-751 or TN-16, respectively, by the method of the above test example, and the expression amount of filaggrin was measured, and the results are shown in FIG. 3.

[0141] As such, it was confirmed that the expression amount of filaggrin in the skin tissue was increased in a concentration-dependent manner after application of ABT-751 or TN-16 in other forms compared to the control group (0% form ABT-751 or 0% form TN-16) (refer to Figures 3a to 3c ).

[0142] 2-2 Measurement of the amount of skin moisture loss and the skin barrier index

[0143] The results of measuring the amount of skin moisture loss and the skin barrier index after application of the control group (0% form ABT-751 or 0% form TN-16) and 4% form ABT-751 or TN-16, respectively, are shown in FIG. 4.

[0144] As such, it was confirmed that the degree of skin moisture loss was reduced and the skin barrier index was increased in the applied part of the HR-1 mouse by application of ABT-751 or TN-16 in the form of 4% (refer to Figures 4a to 4d ).

[0145] In particular, it was confirmed that the decrease in the rate of skin moisture loss and the increase in the skin barrier index increased as the number of days of application passed.

[0146] The above detailed description of the specific part of the content of the present application is only a preferred embodiment for those skilled in the art, and the scope of the present application is not limited thereto, which is obvious. Therefore, the substantial scope of the present application is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing or treating allergic skin diseases or skin itching, comprising a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an active ingredient, [Formula I] [Formula II] 2. The pharmaceutical composition for preventing or treating allergic skin diseases or skin itching according to claim 1, wherein The allergic skin disease is atopic dermatitis or contact dermatitis.

3. The pharmaceutical composition for preventing or treating allergic skin diseases or skin itching according to claim 1, wherein The allergic skin disease is atopic dermatitis.

4. The pharmaceutical composition for preventing or treating allergic skin diseases or skin itching according to claim 1, wherein The pharmaceutical composition is administered by skin application.

5. The pharmaceutical composition for preventing or treating allergic skin diseases or skin itching according to claim 1, wherein The atopic dermatitis is caused by decreased expression of filaggrin.

6. The pharmaceutical composition for preventing or treating allergic skin diseases or skin itching according to claim 5, wherein: When the expression level of the filaggrin protein is reduced by 5.0% or more relative to that of a normal person, the pharmaceutical composition is administered to the patient.

7. The pharmaceutical composition for preventing or treating allergic skin diseases or skin itching according to claim 1, wherein The pharmaceutical composition is in any dosage form selected from the group consisting of ointments, creams, emulsions, gels, external solutions, pastes, liniments and aerosols.

8. A cosmetic composition for preventing or improving allergic skin diseases or skin itching, comprising a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an active ingredient, [Formula I] [Formula II] 9. The cosmetic composition for preventing or improving allergic skin diseases or skin itching according to claim 8, wherein: The cosmetic composition is any dosage form selected from the group consisting of solutions, external ointments, creams, foams, nourishing lotions, softening lotions, facial masks, toners, emulsions, primers, essences, soaps, liquid cleansers, bath agents, sunscreens, sunscreen oils, suspensions, emulsions, pastes, gels, emulsions, powders, soaps, surfactant-containing cleansers, oils, foundations, emulsion-type foundations, wax-type foundations, patches, and sprays.

10. A skin moisturizing cosmetic composition comprising a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof as an active ingredient, [Formula I] [Formula II] 11. A quasi-drug composition for moisturizing the skin, comprising as an active ingredient a compound represented by the following Chemical Formula I or Chemical Formula II or a pharmaceutically acceptable salt thereof, [Formula I] [Formula II]

Images