Pharmaceutical composition for preventing or treating inflammatory diseases comprising pegylated bilirubin

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases, the pharmaceutical composition comprising a compound of Chemical Formula 1, and to a cosmetic composition comprising the compound. By comprising the compound of Chemical Formula 1, the present invention can scavenge reactive oxygen species and inhibit inflammatory cytokines in a non-toxic manner, thereby protecting protective cells and reducing inflammation.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases, comprising pegylated bilirubin. Background Art

[0002] Reactive oxygen or reactive oxygen species (ROS) refers to chemically reactive molecules containing oxygen atoms. ROS are compounds of oxygen produced in living organisms, including peroxide ions and hydrogen peroxide, and have unpaired electrons. Therefore, it is equivalent to highly reactive oxygen with very strong oxidative power, which can attack biological tissues and damage cells. This ROS can also be produced during normal metabolism, and it is reported that ROS plays a role in regulating cell signal transduction and homeostasis.

[0003] The damage caused to normal cells due to the increase in ROS concentration is called oxidative stress. Oxidative stress reflects the imbalance between the production of ROS and the ability of the organism to detoxify reaction intermediates or to restore the damage caused by ROS. If the imbalance caused by oxidative stress is very severe, cell death may occur. In addition, the increase in ROS may cause direct damage to the DNA present in the organism. This leads to various inflammatory reactions, aging, hyperlipidemia, chronic fatigue, vascular diseases, etc., and may also worsen existing diseases. Summary of the invention

[0004] Problems to be solved by the present invention The object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases, which comprises pegylated bilirubin.

[0005] Another object of the present invention is to provide a cosmetic composition comprising pegylated bilirubin.

[0006] Means used to solve problems 1. A pharmaceutical composition for preventing or treating inflammatory diseases, comprising a compound represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Formula 1]

[0007] (In the above formula 1, R1 and R4 are vinyl or methyl, and R2 and R3 are methyl or vinyl, but they are not all vinyl or methyl; and R5 is polyethylene glycol (PEG) or its derivatives).

[0008] 2. The pharmaceutical composition according to 1 above, wherein the compound is a compound represented by any one of Formula 2 to Formula 7: [Formula 2]

[0009] [Formula 3]

[0010] [Formula 4]

[0011] [Formula 5]

[0012] [Formula 6]

[0013] [Formula 7]

[0014] 3. The pharmaceutical composition according to 1 above, comprising nanoparticles formed by self-assembly of the compound represented by Formula 1.

[0015] 4. The pharmaceutical composition according to 3 above, wherein the size of the nanoparticles is 1-5000 nm.

[0016] 5. The pharmaceutical composition according to item 1 above, wherein the derivative of polyethylene glycol is selected from the group consisting of methoxy polyethylene glycol (methoxy PEG), succinimide of PEG propionic acid, succinimide of PEG butanoic acid, branched PEG-NHS, PEG succinimidyl succinate, succinimide of carboxymethylated PEG, benzotriazole carbonate of PEG, PEG-glycidyl ether, PEG-oxycarbonylimidazole, PEG nitrophenyl carbonates, PEG-aldehyde, PEG succinimidyl carboxymethyl ester and PEG succinimidyl ester.

[0017] 6. The pharmaceutical composition according to item 1 above, wherein the inflammatory disease is at least one selected from the group consisting of inflammatory skin diseases, osteoarthritis, hepatitis, pneumonia, keratitis, gastritis, nephritis, tuberculosis, bronchitis, pleurisy, peritonitis, spondylitis, pancreatitis, inflammatory bowel disease, urethritis, cystitis, inflammatory arteriosclerosis, sepsis, periodontitis, gingivitis and autoinflammatory diseases.

[0018] 7. The pharmaceutical composition according to 6 above, wherein the inflammatory skin disease is at least one selected from the group consisting of atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, pruritus, parapsoriasis, urticaria, lichen planus, sunburn, radiation dermatitis, erythema multiforme, erythema nodosum, granuloma annulare, keratosis follicularis, xeroderma, seborrheic membrane inflammation, pyoderma gangrenosum, acne, rosacea, lupus erythematosus, pemphigus, diaper dermatitis, pityriasis rosea, alopecia areata, androgenic alopecia, vitiligo and bedsores.

[0019] 8. The pharmaceutical composition according to 1 above, wherein the inflammatory disease is caused by increased oxidative stress.

[0020] 9. A cosmetic composition comprising a compound represented by Formula 1, a solvate thereof or a cosmetically acceptable salt thereof: [Formula 1]

[0021] (In the above formula 1, R1 and R4 are vinyl or methyl, and R2 and R3 are methyl or vinyl, but they are not all vinyl or methyl; and R5 is polyethylene glycol (PEG) or its derivatives).

[0022] 10. The cosmetic composition according to 9 above, wherein the compound is a compound represented by any one of Formula 2 to Formula 7 above.

[0023] 11. The cosmetic composition according to 9 above, comprising nanoparticles formed by self-assembly of the compound represented by Formula 1.

[0024] 12. The cosmetic composition according to 11 above, wherein the size of the nanoparticles is 1-5000 nm.

[0025] 13. The cosmetic composition according to item 9 above, wherein the derivative of polyethylene glycol is selected from the group consisting of methoxy polyethylene glycol (methoxy PEG), PEG propionate succinimidyl ester, PEG butyrate succinimidyl ester, branched PEG-NHS, PEG succinimidyl succinate, carboxymethyl PEG succinimidyl ester, PEG benzotriazole carbonate, PEG-glycidyl ether, PEG-oxycarbonyl imidazole, PEG nitrophenyl carbonate, PEG-aldehyde, PEG succinimidyl carboxymethyl ester and PEG succinimidyl ester.

[0026] 14. The cosmetic composition according to 9 above, wherein the cosmetic composition is used for anti-inflammatory or anti-oxidation.

[0027] 15. The cosmetic composition according to 9 above, wherein the cosmetic composition is used to prevent or improve skin inflammation caused by increased oxidative stress.

[0028] 16. The cosmetic composition according to 15 above, wherein the skin inflammation caused by increased oxidative stress is at least one selected from the group consisting of atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, pruritus, parapsoriasis, urticaria, lichen planus, sunburn, radiation dermatitis, erythema multiforme, erythema nodosum, granuloma annulare, keratosis follicularis, xeroderma, seborrheic membrane inflammation, pyoderma gangrenosum, acne, rosacea, lupus erythematosus, pemphigus, diaper dermatitis, pityriasis rosea, alopecia areata, androgenic alopecia, vitiligo and bedsores.

[0029] 17. The cosmetic composition according to 9 above, wherein the cosmetic composition is used to moisturize the skin, restore the skin barrier function or prevent skin aging.

[0030] Beneficial Effects The composition of the present invention may include pegylated bilirubin to effectively remove ROS that cause inflammation by selectively targeting inflamed tissues and cells without causing cytotoxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The results of molecular weight analysis (QTOF mass spectrometry) data of the synthesized compounds of Formula 2 to Formula 7 are shown.

[0032] 2A and 2B show the results of confirming whether PEGylated bilirubin nanoparticles were formed using dynamic light scattering (DLS).

[0033] 3A to 3C show the results of confirming whether the Dil dye is loaded and whether PEGylated bilirubin nanoparticles are formed using dynamic light scattering (DLS) and absorbance changes.

[0034] 4A and 4B show the results of confirming the increased intracellular influx of Brixelle in a human keratinocyte cell line (HaCaT) according to inflammation-inducing conditions (house dust mite (HDM) antigen stimulation).

[0035] 5A to 5D show the results of treating a human keratinocyte cell line (HaCaT) with Brixelle under inflammation-inducing conditions (HDM or C48 / 80 stimulation), thereby confirming that Brixelle can scavenge reactive oxygen species within skin cells and protect the cells.

[0036] Figures 6A to 6F show the results confirming that Brixelle dose-dependently inhibits the production of cytokines (TSLP, IL-25, IL-33) in a human keratinocyte cell line (HaCaT) under inflammation-inducing conditions (HDM or C48 / 80 stimulation).

[0037] Figures 7A, 7B (7ba to 7bd), and 7C show the expression of inflammatory factors under inflammatory induction conditions (UVB irradiation) by using a reconstructed human epidermis model (KeraSkin TM ) were treated with Brixelle and confirmed that the skin barrier function was restored while the inflammatory response was suppressed in a dose-dependent manner.

[0038] 8A to 8E show the results of confirming the dose-dependent efficacy of Brixelle on atopic dermatitis in a mouse model of atopic dermatitis induced by house dust mite antigen by daily topical Brixelle treatment for 3 weeks.

[0039] 9A to 9D show the results of confirming the efficacy of daily topical Brixelle treatment for 3 weeks in a mouse model of atopic dermatitis induced by house dust mite antigens by comparison with drugs used to treat atopic dermatitis (Elidel, Dexamethasone, Eucrisa).

[0040] 10A to 10D show the results of confirming the efficacy of Brixelle on psoriasis in an imiquimod (IMQ)-induced psoriasis mouse model by daily topical treatment for 7 days.

[0041] 11A to 11D show the results of confirming the efficacy of Brixelle on contact dermatitis in a DNFB (2,4-dinitrofluorobenzene)-induced contact dermatitis mouse model by daily topical treatment for 5 days.

[0042] Figures 12A to 12C, 12D (12da and 12db) and 12E show how the human epidermis was reconstructed using a KeraSkin TM ) and reconstructed human corneal epithelial model (MCTT HCE TM ) to conduct skin irritation tests, eye irritation tests, skin micronucleus tests, skin sensitization tests and skin phototoxicity tests using alternative animal testing methods to confirm that Brixelle is a substance with very low risk of skin toxicity. DETAILED DESCRIPTION

[0043] The present invention is described in detail below.

[0044] The present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases, which comprises: a compound represented by Formula 1, a solvate thereof or a pharmaceutically acceptable salt thereof.

[0045] [Formula 1]

[0046] In the above Formula 1, R1 and R4 are vinyl groups or methyl groups, and R2 and R3 are methyl groups or vinyl groups, but they are not all vinyl groups or methyl groups, and R5 is polyethylene glycol (PEG) or a derivative thereof.

[0047] The molecular weight of the polyethylene glycol or its derivative may be 500 to 10000, 500 to 9000, 500 to 8000, 500 to 7000, 500 to 6000 or 500 to 5000, but is not limited thereto.

[0048] The polyethylene glycol or its derivatives may be linear or branched.

[0049] For example, the derivative of polyethylene glycol can be selected from the group consisting of methoxy polyethylene glycol (methoxy PEG), PEG propionate succinimidyl ester, PEG butyrate succinimidyl ester, branched PEG-NHS, PEG succinimidyl succinate, carboxymethyl PEG succinimidyl ester, PEG benzotriazole carbonate, PEG-glycidyl ether, PEG-oxycarbonyl imidazole, PEG nitrophenyl carbonate, PEG-aldehyde, PEG succinimidyl carboxymethyl ester and PEG succinimidyl ester.

[0050] Specifically, the compound may be a compound represented by any one of the following Formulae 2 to 7.

[0051] [Formula 2]

[0052] [Formula 3]

[0053] [Formula 4]

[0054] [Formula 5]

[0055] [Formula 6]

[0056] [Formula 7]

[0057] The pharmaceutical composition of the present invention may include nanoparticles formed by self-assembly of the compound represented by the above formula 1.

[0058] The size of the nanoparticles may be 1-5000 nm, more specifically 50-1000 nm, 50-500 nm, or 50-300 nm, but is not limited thereto.

[0059] The inflammatory disease may be at least one selected from the group consisting of inflammatory skin diseases, osteoarthritis, hepatitis, pneumonia, keratitis, gastritis, nephritis, tuberculosis, bronchitis, pleurisy, peritonitis, spondylitis, pancreatitis, inflammatory bowel disease, urethritis, cystitis, inflammatory arteriosclerosis, sepsis, periodontitis, gingivitis and autoinflammatory diseases, but is not limited thereto.

[0060] The inflammatory skin disease may be at least one selected from the group consisting of, for example, atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, pruritus, parapsoriasis, urticaria, lichen planus, sunburn, radiation dermatitis, erythema multiforme, erythema nodosum, granuloma annulare, keratosis follicularis, xeroderma, panniculitis, pyoderma gangrenosum, acne, rosacea, lupus erythematosus, pemphigus, diaper dermatitis, pityriasis rosea, alopecia areata, androgenic alopecia, vitiligo, and bedsores.

[0061] The cause of the inflammatory disease may be, but is not limited to, immune system abnormality, infection, external stimulation or injury, environmental factors, genetic factors, etc. For example, the inflammatory disease may be caused by increased oxidative stress.

[0062] The term "oxidative stress" refers to the phenomenon that oxidative substances such as reactive oxygen species are overproduced or antioxidant substances are insufficient, resulting in imbalance and damage or destruction of cells or tissues. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen atoms, which are compounds of oxygen produced in living organisms. Because oxygen has a strong oxidizing ability, it can attack biological tissues and damage cells. ROS are produced during the normal metabolism of oxygen, but their concentration may increase rapidly due to environmental stress, etc., causing damage to cells.

[0063] The causes of excessive production of ROS or oxidative stress may include various internal and external causes, such as, for example, improper eating habits, nutritional imbalance, irregular lifestyle, excessive exercise, smoking, drinking, overwork, immune response, surgery, administration of anticancer drugs, exhaust gas, heavy metals, radiation, ultraviolet rays, ultrasound, electromagnetic waves, chemical substances (detergents, pesticides, etc.), etc., but are not limited thereto.

[0064] In addition, inflammatory skin diseases may occur due to impaired barrier function of the epidermis and stratum corneum caused by oxidative stress, resulting in dry skin, increased sensitivity, pigmentation, and local inflammation of the skin.

[0065] The term "prevention" refers to any action of inhibiting or delaying the occurrence of the relevant disease by administering the composition of the present invention. Those skilled in the art to which the present invention belongs can determine that the relevant disease can be prevented by administering the composition of the present invention before the occurrence of symptoms or at an early stage.

[0066] The term "treatment" refers to any action that improves or beneficially changes the symptoms of the relevant disease by administering the composition of the present invention, and treatment includes alleviating or improving the disease. Those skilled in the art to which the present invention belongs will be able to know the exact criteria of the disease and determine the degree of improvement, enhancement and treatment of the disease.

[0067] The term "pharmaceutically acceptable" refers to properties that will not cause severe irritation to individuals, cells, tissues, etc. to which the compound or composition is administered, nor will it impair the biological activity and physical properties of the compound.

[0068] The expression "pharmaceutically acceptable salt" refers to salts prepared using specific compounds according to the present invention and relatively non-toxic acids or bases. Pharmaceutically acceptable salts may include, for example, acid addition salts or metal salts.

[0069] Acid addition salts can be formed with inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, nitrous or phosphorous acids, aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and alkanedioic acids, and nontoxic organic acids such as aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically nontoxic salts can include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butine-1,4-dioates, nucleoside-1,6-dioates, and the like. acid-1,6-dioate), benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate.

[0070] The metal salt may be a sodium salt, a potassium salt or a calcium salt. The metal salt may be prepared using a base, for example, an alkali metal salt or an alkaline earth metal salt may be obtained by dissolving the compound in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the undissolved compound salt and evaporating or drying the filtrate.

[0071] The administration route of the pharmaceutical composition of the present invention can be oral or parenteral administration, including intraneural, intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, but not limited thereto. The administration route of the pharmaceutical composition of the present invention can be, for example, parenteral administration, specifically, topical administration, such as skin creams, nasal drops, eye drops, ear drops, vaginal tablets, rectal suppositories, etc., more specifically, it can be the administration of topical skin application.

[0072] The term "administering" means introducing a predetermined substance into a subject by an appropriate method, and the term "subject" means animals such as rats, mice, livestock, and humans who suffer from or may develop a relevant disease.

[0073] The pharmaceutical composition of the present invention may contain a carrier, an excipient and a diluent, and may be formulated and used in the form of oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injections, but is not limited thereto.

[0074] Carriers, excipients and diluents may include, for example, lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil, but are not limited thereto. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants commonly used in the art may be used for preparation, but are not limited thereto.

[0075] Solid preparations for oral administration may include tablets, capsules, pills, granules, etc., which may be prepared by mixing at least one excipient such as sucrose, lactose, starch, gelatin, calcium carbonate, etc. In addition, lubricants such as magnesium stearate and talc may be used in addition to the above excipients.

[0076] Liquid preparations for oral administration may include aqueous solutions, suspensions, syrups, emulsions, etc., and these liquid preparations may be prepared using various excipients such as wetting agents, sweeteners, flavoring agents and preservatives in addition to simple diluents such as water and liquid paraffin.

[0077] Preparations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents or suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween61, cacao, laurin, glycerogelatin, etc. may be used.

[0078] Preparations for parenteral administration may include, for example, sterile injectable preparations. Sterile injectable preparations may be aqueous or oily suspensions. Suspensions may be prepared using suitable dispersants, wetting agents (e.g., Tween 80) or suspending agents according to techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents. Here, solvents such as mannitol, water, Ringer's solution or isotonic sodium chloride solution may be used. In addition, sterile, non-volatile oils may be used as solvents or suspension media as long as they are less irritating, and may be used without restriction, such as synthetic monoglycerides or diglycerides, etc.

[0079] Preparations for topical administration during parenteral administration may include topical preparations (film coatings), eye drops, nasal drops, inhalation preparations, vaginal tablets, suppositories, and oral rinses. For example, when formulated for topical preparations, they may contain fatty substances, organic solvents, solubilizers, thickeners and gelling agents, emollients, antioxidants, suspending agents, stabilizers, foaming agents, fragrances, surfactants, water, ionic emulsifiers, nonionic emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, hydrophilic active agents, lipophilic active agents or lipid vesicles, and other adjuvants commonly used in topical preparations for skin. These topical preparations may be in the form of ointments, patches, gels, creams, or sprays, but are not limited thereto.

[0080] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit / risk ratio suitable for medical treatment, and the effective dosage level can be determined based on the patient's condition and weight, the type and severity of the patient's disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, factors including concurrently used drugs, and other factors well-known in the medical field. The pharmaceutical composition of the present invention can be administered as a separate therapeutic agent, or in combination with other therapeutic agents, for the treatment of inflammatory diseases or skin diseases associated with oxidative stress. In addition, the composition of the present invention can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered in a single dose or multiple doses. Taking all of the above factors into account, it is important to administer the lowest dose that can achieve the maximum effect without side effects, and such an amount can be easily determined by those skilled in the art.

[0081] The effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, weight, etc. For example, an amount of 0.01 to 1000 mg / kg / day, more preferably 0.1 to 500 mg / kg / day, may be administered in one or more divided doses. However, since the effective amount may be increased or decreased depending on the administration route, the number of doses administered, the severity of the disease, age, sensitivity to the drug, etc., the above dosage does not limit the scope of the present invention in any way.

[0082] The present invention relates to a cosmetic composition comprising a compound represented by Formula 1, a solvate thereof or a cosmetically acceptable salt thereof.

[0083] [Formula 1]

[0084] In the above Formula 1, R1 and R4 are vinyl groups or methyl groups, and R2 and R3 are methyl groups or vinyl groups, but they are not all vinyl groups or methyl groups, and R5 is polyethylene glycol (PEG) or a derivative thereof.

[0085] The polyethylene glycol or its derivative may be within the above range.

[0086] The compound may be a compound represented by any one of Formula 2 to Formula 7 above.

[0087] The cosmetic composition of the present invention may include nanoparticles formed by self-assembly of the compound represented by Formula 1 above.

[0088] The content regarding nanoparticles may be within the above range.

[0089] The cosmetic composition of the present invention can be used for anti-inflammatory or anti-oxidative effects.

[0090] Furthermore, the cosmetic composition of the present invention can be used to prevent or improve skin inflammation caused by increased oxidative stress.

[0091] Skin inflammation caused by increased oxidative stress may occur due to impaired barrier function of the epidermis and stratum corneum caused by oxidative stress, resulting in dry skin, increased sensitivity, pigmentation, and local inflammation of the skin.

[0092] For example, the skin inflammation caused by increased oxidative stress can be at least one selected from the group consisting of, for example, atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, pruritus, parapsoriasis, urticaria, lichen planus, sunburn, radiation dermatitis, erythema multiforme, erythema nodosum, granuloma annulare, keratosis follicularis, xeroderma, panniculitis, pyoderma gangrenosum, acne, rosacea, lupus erythematosus, pemphigus, diaper dermatitis, pityriasis rosea, alopecia areata, androgenic alopecia, vitiligo and bedsores.

[0093] Furthermore, the cosmetic composition of the present invention can be used to moisturize the skin, restore the skin barrier function, or prevent skin aging.

[0094] Damage to the skin barrier may occur due to skin aging, ultraviolet rays, hormones, etc. If the skin barrier is damaged, it may even be accompanied by skin inflammation caused by increased oxidative stress, such as atopic dermatitis and psoriasis.

[0095] Skin aging may be induced by ultraviolet rays, ROS, dryness, etc. Since the compound of Formula 1 included in the cosmetic composition of the present invention can scavenge ROS, the cosmetic composition of the present invention can have the effect of preventing or restoring skin aging caused by ROS and skin barrier damage caused by skin aging.

[0096] The cosmetic composition of the present invention can be prepared in various formulations, such as solution, external ointment, cream, foam, nourishing lotion, softening lotion, pack, softening water, emulsion, makeup base, essence, soap, liquid cleanser, bath agent, sunscreen cream, sun oil, suspension, emulsion, paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch or spray, but is not limited thereto.

[0097] The cosmetic composition may contain one or more additives selected from the following: aqueous additives, such as purified water, stabilizers, emulsifiers, thickeners, moisturizers, liquid crystal film strengtheners, pH adjusters, antibacterial agents, water-soluble polymers, coating agents, masking agents, amino acids, organic amines, polymer emulsions, skin nutrients, antioxidants and antioxidant additives, preservatives, flavoring agents, etc.; and oil-based additives, such as fats and oils, waxes, hydrocarbon oils, higher fatty acid oils, higher alcohols, synthetic ester oils and silicone oils, etc.

[0098] The aqueous additive is not limited as long as it is a raw material commonly used in the art, and specific examples can be selected from glycerol, dipropylene glycol, butylene glycol, pentylene glycol, methyl propanediol, sorbitol, diglycerol, erythritol, pentaerythritol, polybutylene glycol-10, polyglycerol-3, polyglycerol-4, polyglycerol-6, polyglycerol-10, polyglycerol-20, polyglycerol-40, sorbeth-5, sorbeth-6, sorbeth-20, sorbitol Polyether-30, Sorbitol Polyether-40, Inositol, Maltitol, Maltose, Mannan, Mannitol, Mannitol, Lactitol, Lactose, Dihydroxypropyl PG-glucoside, Dithioctanediol, Fructose, Glucosamine, Methylglucamine, Glucose, 1,2,6-Hexanethiol, Methylgluceth-10, Methylgluceth-20, Ozonized Glycerin glycerin), phytantriol, thioglycerol, threitol, trimethylolpropane, xylitol, EDTA, guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylhydroxypropylcellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, sulfated mucopolysaccharide, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratan sulfate sulfate), locust bean gum, succinoglucan, caronicacid, chitin, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium polyacrylate, polyethylene glycol, bentonite, methyl paraben, propyl paraben, phenoxyethanol, 1,2-hexanediol, ethylhexylglycerin, etc.

[0099] The oil-based additive is not limited, as long as it is a raw material commonly used in the art, and its example can include liquid oils, such as olive oil, camellia oil, jojoba oil, triglyceride, tricaprylin, triisopalmitin, etc., solid fats, such as coconut oil, hydrogenated coconut oil, palm oil, hydrogenated oil, hydrogenated castor oil, etc., beeswax, candelilla wax, carnauba wax, lanolin, jojoba wax, etc. The example of hydrocarbon oil can include liquid paraffin, squalene, vaseline and microcrystalline wax. The example of higher fatty acid can include wax, such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, etc., and cetyl alcohol, stearyl alcohol, behenyl alcohol, myristyl alcohol, cetearyl alcohol, etc. The synthetic ester oil may be selected from higher alcohols such as isopropyl myristate, cetyl octanoate, octyl dodecyl myristate, isopropyl palmitate, hexyl laurate, myristyl myristate, cetyl lactate, isocetyl isostearate, neopentyl glycol dicaprate, ethylhexylglycerin, cetylethylhexanoate, ethylhexyl palmitate, cetostearyl alcohol, alcohol), etc., chain silicone oils such as dimethylpolysiloxane, methylphenylpolysiloxane, methylhydrogenpolysiloxane, etc., and cyclic silicone oils such as dodecamethyl cyclohexasiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, etc., but not limited thereto.

[0100] The cosmetic composition of the present invention may also include a cosmetically acceptable carrier, which is usually mixed with a typical skin cosmetic in the art. The cosmetically acceptable carrier may include, for example, oil, water, a surfactant, a humectant, a lower alcohol, a thickener, a chelating agent, a colorant, a preservative, a fragrance, etc., but is not limited thereto.

[0101] The formulation of the cosmetic composition according to the present invention may include various cosmetically acceptable carriers.

[0102] When the cosmetic composition is formulated as an ointment, cream, emulsion or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicon dioxide, talc, zinc oxide or a mixture thereof may be used as a carrier component.

[0103] When the formulation of the cosmetic composition is a powder or spray, lactose, talc, silicon dioxide, aluminum hydroxide, calcium silicate, polyamide powder or a mixture thereof can be used as a carrier component. In particular, in the case of a spray, the composition may also include a propellant such as chlorofluorocarbons, propane / butane or dimethyl ether.

[0104] When the formulation of the cosmetic composition is a solution or an emulsion, a solvent, a solubilizer or an emulsifier is used as a carrier component. For example, water, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid ester can be used.

[0105] When the preparation of the cosmetic composition is a suspension, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth gum, etc. can be used as a carrier component.

[0106] When the formulation of the cosmetic composition is a surfactant-containing cleanser, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamido betaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, ethoxylated glycerol fatty acid ester, etc. can be used as the carrier component.

[0107] In addition to the above-mentioned compounds and carrier components, the ingredients included in the cosmetic composition of the present invention may also include components commonly included in cosmetic compositions, such as common adjuvants, such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances.

[0108] The cosmetic composition can be used alone or applied multiple times, or applied multiple times together with other cosmetic compositions other than the composition of the present invention. In addition, the cosmetic composition according to the present invention can be used according to any conventional use method, and the number of times it is used can vary according to skin conditions or user preferences.

[0109] The present invention is described in detail below with reference to the embodiments.

[0110] Preparation Example 1. Preparation of Brixelles The following PEGylated bilirubin 3α of Formulae 2 to 7 (compounds 1 to 6, respectively) were synthesized by changing the molecular weight of PEG, and their molecular weights were analyzed ( Figure 1 ). Using synthetic PEGylated bilirubin 3α, Brixelle was prepared as its self-assembled product by the following method.

[0111] [Table 1]

[0112]

[0113] To make Brixelle into uniformly sized nanoparticles, a flow chemistry approach was employed.

[0114] Specifically, 10 L of citric acid buffer solution was prepared by dissolving citric acid dihydrate and citric anhydride in water, and the pH value was confirmed to be 4.4. Then, 9.9 L of citric acid buffer solution was prepared in a 30 L reactor. The mixture was stirred at a speed of 100 rpm to 1000 rpm, while adjusting the temperature to maintain it at 4 to 15 °C.

[0115] Next, 1100 mL of acetonitrile was added dropwise to 504.4 g of PEGylated bilirubin 3α and stirred until completely dissolved. After the solution was transferred to a 2 L measuring cylinder, acetonitrile was added to make the total volume 1650 mL. The solution was filtered through a 0.20 μm PVDF filter and then transferred to the reactor. The mixture was stirred at a speed of 100 rpm to 1000 rpm while adjusting the temperature to keep it at 4 to 15 °C. The above process was carried out in a yellow light environment.

[0116] To formulate the product into nanoparticles, 1650 mL of the PEGylated bilirubin 3α solution was added to the citric acid buffer solution. First, a tube with an inner diameter of 3.2 mm was connected to a pump, and the PEGylated bilirubin 3α solution was injected into the aqueous solution at a flow rate of 10 mL / min to 50 mL / min using the pump and the tube. After the dropwise addition of the PEGylated bilirubin 3α solution was completed, the mixture was stirred for another 15 minutes at 100 rpm to 1000 rpm and 4 ℃ to 15 ℃. The above process was also carried out in a yellow light environment. After the stirring was completed, the reaction solution was filtered through a 0.20 μm PVDF filter and then transferred to a steel tray, followed by freeze drying to obtain Brixelle freeze-dried powder. The resulting Brixelle powder was re-dissolved in some distilled water, and the formation of nanoparticles was determined using dynamic light scattering (DLS) (Figures 2A and 2B).

[0117] 2. Preparation of Tetramethylindocyanine Perchlorate (Dil) @Brixelle To load the Dil dye into Brixelle, it was prepared in the following manner.

[0118] 15 mg of Dil was added to 135 mg of PEGylated bilirubin 3α completely dissolved in 6.16 mL of chloroform, filtered through a 0.20 μm PTFE filter, and then a vacuum rotary evaporator was used to obtain a thin film. The film was dried under vacuum conditions for 24 hours.

[0119] The dried reactant was dissolved in 14.6 mL of distilled water and treated with ultrasound at 20°C to 30°C for 5 to 15 minutes using an ultrasonic water bath to obtain a dispersion. The aqueous solution in which Dil@Brixelle was dispersed was purified by filtering with a 0.45 μm PVDF filter and a 0.20 μm PVDF filter, and the filtrate was lyophilized to obtain Dil@Brixelle lyophilized powder.

[0120] The obtained Dil@Brixelle powder was redissolved in some distilled water, and dynamic light scattering (DLS) was used to determine whether Dil@Brixelle nanoparticles were formed (Figures 3A and 3B). The maximum absorbance of Brixelle was compared with the maximum absorbance of Dil using a multimode plate reader to determine whether the Dil dye was loaded (Figure 3C; the graph formed after a wavelength of 500 nm is the graph of Dil@Brixelle (high concentration)).

[0121] Example The following experiments were conducted using Brixelle and Dil@Brixelle prepared in the above Preparation Examples 1 and 2.

[0122] 1. Results of confirming that Brixelle is taken up by skin cells under conditions that induce inflammation (1) Experimental methods To confirm the absorption pattern of Brixelle by skin cells according to inflammation-inducing conditions (house dust mite (HDM) antigen stimulation), human keratinocytes (HaCaT) were used for testing. HDM antigens are known to induce more reactive oxygen species (ROS) in immune cells and inflammatory cells associated with Th2 immune responses in atopic dermatitis and asthma, and are used as the main antigen stimulation source in atopic dermatitis-induced cell models. To establish an inflammation-induced ("inflammatory") cell model, HaCaT cells were treated with 500 μg / mL of HDM antigen for 24 hours. The prepared inflammatory cells were distributed into a 24-well culture plate and treated with Brixelle loaded with the fluorescent dye tetramethylindocyanine perchlorate (Dil@Brixelle). Thereafter, the intracellular fluorescence expression pattern was observed in one-hour units using the real-time fluorescence microscopy device MuviCyte for 24 hours.

[0123] (2) Experimental results The uptake of Brixelle by HaCaT cells was compared according to the inflammation-inducing conditions, and it was found that the uptake of Brixelle by inflammatory cells stimulated with HDM antigens was significantly increased compared with normal cells not stimulated with HDM antigens. Specifically, the uptake of Brixelle by inflammatory cells increased rapidly starting about 4 hours after Brixelle treatment, and it was confirmed that the uptake of Brixelle by inflammatory cells was about 6.2 times higher than that of normal cells after 24 hours (Figures 4A and 4B).

[0124] 2. Results confirming Brixelle's ability to scavenge reactive oxygen species and protect skin cells (1) Experimental methods Compound 48 / 80 (C48 / 80) is known to mediate inflammatory responses and cell differentiation, as well as its role as a mast cell degranulation agent. In particular, it has been reported that C48 / 80 is involved in skin inflammation through the production of ROS by keratinocytes and the degranulation of mast cells. Therefore, in this assay, HDM and C48 / 80 were used as antigenic and non-antigenic stimuli, respectively, in the inflammatory cell model. First, to evaluate the ability of Brixelle to scavenge ROS in skin cells, HaCaT cells were distributed into black 96-well plates and then treated with HDM and C48 / 80 at concentrations of 500 μg / mL and 20 μg / mL, respectively, to induce inflammatory stimulation. At the same time, different concentrations of the test substance Brixelle and the control substance N-acetylcysteine ​​(NAC) were applied to the cells. After 24 hours, the culture medium was removed, and the cells were washed three times with sterile phosphate-buffered saline (PBS). Again, the cells were treated with 20 μM 2',7'-dichlorofluorescein diacetate (DCF-DA) for 45 min to stain the intracellular ROS, and then the fluorescence intensity of the reaction solution was measured in the wavelength range of λex=485 / λem=535 nm.

[0125] Next, to evaluate the ability of Brixelle to protect skin cells from inflammatory stimuli, cells were treated with antigens and non-antigen stimuli at concentrations that reduced HaCaT cell viability by 90% (90% cytotoxic concentration, CC90) (HDM=2.5 mg / mL, C48 / 80=35 μg / mL). At the same time as the inflammatory stimuli treatment, different concentrations of the test substance Brixelle and the control substance NAC were applied to the cells. After 24 hours, the culture medium was removed, washed three times with sterile PBS, and then replaced with new culture medium. Then, 10 μL of Quanti-Max WST-8 solution equivalent to 1 / 10 of the culture medium volume was added to each well, and after 4 hours of reaction, the absorbance of the reaction solution was measured at a wavelength of 450 nm to evaluate cell viability.

[0126] (2) Experimental results In inflammatory cell lines induced by antigen or non-antigenic stimuli, the dose-dependent ROS scavenging effect of Brixelle was confirmed. In HDM-induced inflammatory cell lines, Brixelle was confirmed to be able to scaveng 50% of intracellular ROS (50% effective concentration, EC 50 ) was 78.8 μM, which was about 3.7 times that of the control substance NAC (Figure 5A). The EC of Brixelle's ability to scavenge intracellular ROS in the C48 / 80 induced inflammatory cell line 50 The value was 48.1 μM, which showed approximately 6.2-fold higher than that of NAC ( Figure 5B ).

[0127] Brixelle exhibited a dose-dependent cytoprotective effect against both antigenic and non-antigenic stimulation in inflammatory cell lines. 50 The EC value of Brixelle for cytoprotection in C48 / 80-induced inflammatory cell line was 93.9 μM, which was approximately 1.6-fold higher than that of NAC (Figure 5C). 50 The value was even 67.0 μM, which showed about 4.8 times higher than that of NAC ( Figure 5D ).

[0128] Thus, the role of Brixelle in scavenging intracellular ROS was confirmed in an inflammation-induced cell model, and its cytoprotective effect based on strong antioxidant effects was demonstrated.

[0129] 3. Results confirming Brixelle's ability to inhibit inflammatory cytokines in skin cells (1) Experimental methods Thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 produced from keratinocytes are considered to be important mediators for inducing Th2 immune responses in atopic dermatitis. The effect of Brixelle on the expression of representative inflammatory cytokines secreted by inflammatory cell models induced by antigenic and non-antigenic stimuli was confirmed. First, HaCaT cells were distributed into 96-well culture plates and then treated with HDM and C48 / 80 at concentrations of 500 μg / mL and 20 μg / mL, respectively. At the same time, the test substance Brixelle and the control substance NAC were applied to the cells at concentrations of 5 μM, 50 μM, and 500 μM. After 24 hours of reaction, the cell supernatant was taken, and enzyme-linked immunosorbent assay (ELISA) was performed for each cytokine, and the absorbance of the reaction solution was measured in the wavelength range of 450 nm to quantify the amount of cytokines secreted by the inflammatory cell line. The results of the graphs are expressed as mean ± standard error of the mean (SEM), and statistical analysis was performed using the GraphPad program. Statistical analysis was performed using one-way ANOVA, and statistical significance compared with the negative control group was confirmed by Dunnett's multiple comparison method (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0130] (2) Experimental results In the inflammatory cell model induced by HDM and C48 / 80 stimulants, the secretion of three types of cytokines was statistically significantly increased compared with normal cells (p=0.0006, p<0.0001). This confirmed that the inflammatory cell model induced by stimulants is suitable for confirming the ability of Brixelle to regulate inflammatory cytokines.

[0131] In HDM-induced inflammatory cell lines, the expression levels of all three types of cytokines showed a concentration-dependent decrease trend compared with Brixelle. For TSLP, the reduction effect of the Brixelle 50 μM treatment group was 26.4% and the Brixelle 500 μM treatment group was 50.1% compared with the negative control group, and the 500 μM treatment group had a significant statistical difference compared with the negative control group (Figure 6A; p=0.0224). For IL-25, the reduction effect of the Brixelle 50 μM treatment group was 47.1% and the Brixelle 500 μM treatment group was 52.5% compared with the negative control group. Both concentration treatment groups had significant statistical differences compared with the negative control group (Figure 6B; p=0.0054, p=0.0018). Compared with the negative control group, IL-33 in the Brixelle 500 μM-treated group was significantly reduced by approximately 75.1%, and it was confirmed that it had a statistically significant difference (Figure 6C; p=0.001).

[0132] Even in the C48 / 80-induced inflammatory cell line, the expression levels of all three types of cytokines showed a concentration-dependent decrease trend compared with Brixelle, and an excellent decrease effect was observed compared with the same concentration of NAC. In the case of TSLP, the decrease effect in the Brixelle 50 μM treatment group was 31.3% compared with the negative control group, and the decrease effect in the Brixelle 500 μM treatment group was 38.3%. Both concentration treatment groups had significant statistical differences compared with the negative control group (Figure 6D; p=0.0143, p=0.0058). In the case of IL-25, the decrease effect in the Brixelle 50 μM treatment group was 35.2% compared with the negative control group, and the decrease effect in the Brixelle 500 μM treatment group was 40%, and in the Brixelle 500 μM treatment group, there was a significant statistical difference compared with the negative control group (Figure 6E; p=0.0231). Regarding IL-33, the reduction effect of the Brixelle 50 μM treatment group was 21.1% compared with the negative control group, and the reduction effect of the Brixelle 500 μM treatment group was 55.9%, and there was a significant statistical difference in the Brixelle 500 μM treatment group compared with the negative control group (Figure 6F; p=0.0120).

[0133] These results demonstrate that Brixelle, which has a strong antioxidant effect, has a stronger mechanism for suppressing inflammatory responses in inflammatory cell lines than the known antioxidant NAC.

[0134] 4. Results of confirming Brixelle's ability to suppress inflammation in a reconstructed human epidermis model (1) Experimental methods The aim is to reconstruct the human epidermis model (KeraSkin) as a model of human skin tissue. TM ) confirmed the inflammatory inhibition ability of Brixelle. After adding the culture medium of reconstructed human epidermis model to a 6-well culture plate, the prepared artificial skin model (0.6 cm 2 ) were placed in a cell culture incubator at 37 °C and 5% CO2 for 22 ± 2 hours. To induce an inflammatory response in the reconstructed human epidermis model, the culture plate was inserted into an ultraviolet (UVB) irradiator and then irradiated with 300 mJ / cm 2 of UV rays. After inducing inflammation, Brixelle 80 μM and 400 μM were slowly applied to the upper center of the artificial skin model using a pipette and evenly applied to the entire surface. After treatment with the test substance for 8 hours in a cell culture incubator, the test substance was removed using Dulbecco's PBS (DPBS). Thereafter, subsequent culture was performed in a cell culture incubator for 40 hours, and then the transepithelial electrical resistance (TEER) and the expression of inflammatory cytokines in the culture medium were measured, and tissue staining was performed after the test was completed to determine the effect of Brixelle in inhibiting skin barrier damage.

[0135] To evaluate the function and strength of the skin barrier, TEER was measured using an electrical resistance system (ERS-2, Millipore). In addition, to confirm changes in the inflammatory response, tumor necrosis factor-α (TNF-α), IL-6, IL-1α, and TSLP were measured using ELISA. In addition, to confirm the histological changes in the artificial skin model, hematoxylin and eosin (H&E) staining, as well as immunohistochemical staining for filaggrin, were performed to evaluate the skin barrier function. The results of TEER and inflammatory cytokines were expressed as mean ± standard deviation (SD), and statistical analysis was performed using the GraphPad program. Statistical analysis was performed using one-way ANOVA, and statistical significance between the test groups was confirmed by Tukey's multiple comparison method (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0136] (2) Experimental results The epithelial cell layer has formed tight junctions, which are a type of junction between cells, to form a membrane-like physicochemical barrier. It is known that when an inflammatory response occurs in the skin, the skin barrier function is impaired, and TEER is an indicator for measuring the strength of tight junctions and decreases as the barrier function is impaired. In this experiment, an inflammatory response was induced in an artificial skin model by UV irradiation, and then the changes in TEER were analyzed to determine the skin barrier function protective effect of Brixelle. Compared with the negative control group after UV irradiation, the TEER of the artificial skin model decreased, but in the case of the Brixelle-treated group, TEER was significantly restored in a concentration-dependent manner in the results measured at 24 hours and 48 hours (Figure 7A).

[0137] It is well known that in various inflammatory diseases occurring in the skin, the expression level of proinflammatory cytokines is higher than that in normal skin tissue. In this experiment, TNF-α, IL-6, and IL-1α were analyzed. In addition, TSLP was measured and found to play an important role in regulating inflammatory responses associated with allergies and skin immune-mediated diseases (Figure 7B (7ba to 7bd)).

[0138] The results of ELISA detection of the above four cytokines showed that TNF-α showed a statistically significant increase in the inflammation-induced group (i.e., inflammatory group) compared with the negative control group, but when treated with Brixelle 80 μM and 400 μM, the results showed that the expression of TNF-α was significantly reduced in a concentration-dependent manner (negative control vs UVB, 16.8±2.6 pg / mL vs 61.1±1.2 pg / mL, p<0.0001; UVB vs Brixelle 80 μM, 61.1±1.2 pg / mL vs 14.7±0.3 pg / mL, p<0.0001; UVB vs Brixelle 400 μM, 61.1±1.2 vs 15.6±0.0, p<0.0001).

[0139] After confirming the expression level of IL-6, the p values ​​were 0.0004 and 0.0034 in the comparison between the negative control group and the inflammation-induced group and the inflammation-induced group and the Brixelle 400 μM treatment group, respectively. The results confirmed that the expression level was significantly reduced when treated with Brixelle compared with the inflammation-induced group (negative control vs UVB, 3.2±0.0 vs 30.0±2.3, p=0.0004; UVB vs Brixelle 400 μM, 30.0±2.3 vs 15.0±2.3, p=0.0034).

[0140] By comparing the expression levels of IL-1α in the culture medium between the IL-1α negative control group and the inflammation-induced group, and between the inflammation-induced group and the Brixelle 80 and 400 μM treatment groups, it was confirmed that all p values ​​between the comparison groups were 0.0058 (p<0.01) (negative control group vs UVB, 3.9±0.0 vs 14.1±3.0, p=0.0058; UVB vs Brixelle 80μM, 14.1±3.0 vs 3.9±0.0, p=0.0058, UVB vs Brixelle 400 μM, 14.1±3.0 vs 3.9±0.0, p=0.0058).

[0141] In addition, the expression levels of TSLP, which regulates inflammatory responses, were 3.3±0.0, 23.7±1.9, 10.1±1.6, and 9.1±1.4 pg / mL in the negative control group, inflammation-induced group, and Brixelle 80 μM and 400 μM treatment groups, respectively. The p values ​​for the expression levels of the inflammation-induced group compared with each group were p<0.001, p<0.01, and p<0.01, respectively (negative control vs UVB, p=0.0004; UVB vs Brixelle 80 μM, p=0.0020; UVB vs Brixelle 400 μM, p=0.0015). Therefore, it was confirmed that the expression of TSLP was statistically significantly reduced when Brixelle was used for treatment after the induction of inflammation.

[0142] The aim was to confirm the histopathology and expression of inflammation and skin barrier function markers in the artificial skin model by H&E staining and immunohistochemical staining of filaggrin. Among the skin barrier function markers, filaggrin is a key factor in regulating epidermal homeostasis and is a lipid envelope component in the stratum corneum of the skin, exerting skin moisturizing and barrier functions. By H&E staining, it was confirmed that the artificial skin model consisted of four layers (stratum corneum, stratum granulosum, stratum corneum, and stratum basale) like real skin. When inflammation was induced by UV irradiation, the number of stained cell nuclei decreased compared with the negative control, and it was confirmed that the stratum corneum, which should have been stratified, had fallen off. However, in the artificial skin model treated with Brixelle, the number of stained cell nuclei did not change compared with the inflammation-induced group, and the stratum corneum showed a normal stratified form. By immunohistochemical staining, it was confirmed that filaggrin was expressed in the stratum granulosum and stratum corneum among the four layers of the artificial skin model. In the inflammation-induced group, the expression of filaggrin was reduced by UV irradiation, but in the artificial skin model treated with Brixelle, it was confirmed that the reduction in filaggrin expression was suppressed (Figure 7C).

[0143] Taken together, these results suggest that Brixelle can effectively inhibit UV irradiation-induced inflammatory responses in human skin tissue models, restore damaged skin barrier function, and help improve histology.

[0144] 5. Validation results of Brixelle in atopic dermatitis mouse model (1) (1) Experimental methods A HDM-induced atopic dermatitis mouse model was established by applying HDM antigen ointment to the back and ear skin of 6- to 10-week-old NC / Nga female mice for a total of 7 times on days 0, 7, 10, 14, 17, 21, and 24. The test substance Brixelle (7.5 mg / kg, 15 mg / kg, and 30 mg / kg) was applied to the skin daily from day 7 to evaluate its effectiveness, compared with a normal group (normal group) to which HDM antigen was not applied, a group (no treatment group) to which no additional substance was applied during the induction of atopic dermatitis as a negative control group, and a group (vehicle group) to which a vehicle was applied to the skin, and a group (dexamethasone group, 0.1% dexamethasone, 62.5 mg / animal) to which the previously approved drug Maxidex was applied as a positive group. Clinical symptoms were evaluated during the induction of atopic dermatitis, and skin tissues were preserved for further analysis after the end of the survival experiment.

[0145] To quantify the clinical symptoms of atopic dermatitis, clinical scores were scored using a Likert scale with a maximum score of 3 for four (4) clinical index items, including 1) erythema / hemorrhage, 2) scarring / dryness, 3) edema, and 4) excoriation / maceration (erosion). H&E staining was used to observe the skin histological changes of atopic dermatitis, and dihydroethidium (DHE) staining was used to measure ROS in skin tissue. In addition, to determine the infiltration of mast cells and eosinophils in skin tissue, toluidine blue staining and Congo red staining were performed, respectively. The results of the graphs are expressed as mean ± SEM. Statistical analysis was performed using the GraphPad program, and statistical significance compared with the vehicle group was confirmed by one-way ANOVA with Dunnett's multiple comparison method (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0146] (2) Experimental results The results of confirming clinical symptoms at the end of the survival trial showed that due to the induction of atopic dermatitis, crusts formed on the skin, and redness and edema appeared, and secondary skin damage due to itching was clearly observed. The results of clinical index evaluation confirmed that the clinical symptoms of the previously approved drug dexamethasone treatment group and Brixelle treatment group showed statistically significant improvement effects compared with the vehicle group. Furthermore, a concentration-dependent effect of Brixelle could be confirmed (Fig. 8A. Vehicle vs dexamethasone, 9.44 ± 0.77 vs 4.90 ± 0.76, p < 0.0001; Vehicle vs Brixelle 7.5 mg / kg, 9.44 ± 0.77 vs 5.90 ± 0.47, p < 0.0001; Vehicle vs Brixelle 15 mg / kg, 9.44 ± 0.77 vs 5.05 ± 0.32, p < 0.0001; Vehicle vs Brixelle 30 mg / kg, 9.44 ± 0.77 vs 4.40 ± 0.48, p < 0.0001).

[0147] As a result of confirming the skin histological changes by H&E staining, increased epidermal thickness and hyperkeratosis were observed when the HDM antigen ointment was used. In addition, increased angiogenesis, tissue edema, and inflammatory cell infiltration in the dermis were confirmed. When compared with the vehicle group, it could be confirmed that the dexamethasone-treated group and the Brixelle-treated group showed the effects of reduced epidermal thickness and reduced hyperkeratosis (Figure 8B).

[0148] To determine whether the antioxidant activity of Brixelle has an effect on improving atopic dermatitis symptoms, the expression of ROS in skin tissue was confirmed. The results of measuring ROS in skin tissue by DHE staining confirmed that the DHE staining intensity was stronger in the epidermis and dermis in the negative control group compared with the normal group, and a decrease in the DHE staining intensity was observed in the dexamethasone-treated group and the Brixelle-treated group (Figure 8C).

[0149] Additional staining was performed to confirm the infiltration of mast cells and eosinophils, which are well known inflammatory cells associated with atopic dermatitis symptoms. Mast cells and eosinophils secrete histamine and cytotoxic substances, respectively, and are therefore immune cells involved in allergic symptoms. Mast cells were quantified by toluidine blue staining, and the results confirmed that the dexamethasone-treated and Brixelle-treated groups showed a statistically significant reduction in mast cell infiltration compared with the vehicle group (Figure 8D, vehicle vs dexamethasone, 52.69±2.19 vs 27.38±3.19, p<0.0001; vehicle vs Brixelle 7.5 mg / kg, 52.69±2.19 vs 32.19±2.72, p<0.0001; vehicle vs Brixelle 15 mg / kg, 52.69±2.19 vs 29.81±1.11, p<0.0001; vehicle vs Brixelle 30 mg / kg, 52.69±2.19 vs 23.19±1.57, p<0.0001). Furthermore, when eosinophils were quantified by Congo red staining, it could be confirmed that the eosinophil infiltration in the dexamethasone-treated and Brixelle-treated groups showed a statistically significant decrease compared with that in the vehicle group (Fig. 8E, vehicle vs dexamethasone, 35.50 ± 1.37 vs 18.88 ± 1.64, p < 0.0001; vehicle vs Brixelle 7.5 mg / kg, 35.50 ± 1.37 vs 21.56 ± 1.44, p < 0.0001; vehicle vs Brixelle 15 mg / kg, 35.50 ± 1.37 vs 20.88 ± 1.55, p < 0.0001; vehicle vs Brixelle 30 mg / kg, 35.50 ± 1.37 vs 17.56 ± 0.92, p < 0.0001).

[0150] Based on these results, it can be confirmed that, as a strong antioxidant, Brixelle prevents clinical symptoms, skin histological changes, and inflammatory responses in atopic dermatitis in a dose-dependent manner.

[0151] 6. Brixelle validated the results in a mouse model of atopic dermatitis (2) (1) Experimental methods A HDM-induced atopic dermatitis mouse model was established by applying HDM antigen ointment to the back and ear skin of 6- to 10-week-old NC / Nga female mice for a total of 7 times on days 0, 7, 10, 14, 17, 21, and 24. The test substance Brixelle (30 mg / kg) and the approved drugs Elidel (Elidel group, 1% pimecrolimus, 62.5 mg / animal), Maxidex (dexamethasone group, 0.1% dexamethasone, 62.5 mg / animal), and Eucrisa (Eucrisa group, 2% crisaborole, 62.5 mg / animal) were applied to the skin daily from day 7 to compare their effectiveness, compared to a normal group not applied with HDM antigen (normal group), a group not applied with additional substances during the induction of atopic dermatitis as a negative control group (no treatment group), and a group applied with a vehicle to the skin (vehicle group). Clinical symptoms were assessed during the induction of atopic dermatitis, and skin tissues were preserved for further analysis after the end of the survival study.

[0152] To quantify the clinical symptoms of atopic dermatitis, clinical scores were scored using a Likert scale with a maximum score of 3 for four (4) clinical index items, including 1) erythema / hemorrhage, 2) scarring / dryness, 3) edema, and 4) exfoliation / erosion (erosion). H&E staining was performed to observe the histological changes of the skin in atopic dermatitis, and dihydroethidium (DHE) staining was used to measure ROS in the skin tissue. In addition, to determine the infiltration of mast cells and eosinophils in the skin tissue, toluidine blue staining and Congo red staining were performed, respectively. To detect IL-4 and IL-13, inflammatory mediators known to be highly associated with atopic dermatitis, ELISA tests were performed on the skin tissue. The results in the graphs are expressed as mean ± SEM. Statistical analysis was performed using the GraphPad program, and statistical significance compared with the vehicle group was confirmed by one-way ANOVA and Dunnett’s multiple comparison method (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0153] (2) Experimental results The results of confirming clinical symptoms at the end of the survival test showed that due to the induction of atopic dermatitis, crusts formed on the skin, and redness and edema appeared, and secondary skin damage due to itching was clearly observed. The results of clinical index evaluation confirmed that the clinical symptoms of the Brixelle and two previously approved drugs (dexamethasone group and Eucrisa group) treatment groups showed statistically significant improvement effects compared with the vehicle group (Figure 9A. Vehicle vs dexamethasone, 9.58±0.64 vs 3.75±0.99, p<0.0001; vehicle vs Eucrisa, 9.58±0.64 vs 3.25±0.67, p<0.0001; vehicle vs Brixelle, 9.58±0.64 vs 6.00±0.52, p=0.0034).

[0154] As a result of confirming the skin histological changes by H&E staining, increased epidermal thickness and hyperkeratosis were observed when the HDM antigen ointment was used. In addition, increased angiogenesis, tissue edema, and inflammatory cell infiltration in the dermis were confirmed. It can be confirmed that the groups treated with Brixelle and two previously approved drugs (dexamethasone group and Eucrisa group) showed the effects of reduced epidermal thickness and reduced hyperkeratosis compared with the vehicle group (Figure 9B).

[0155] To determine whether the antioxidant activity of Brixelle has an effect on improving atopic dermatitis symptoms, the expression of ROS in skin tissue was confirmed. The results of measuring ROS in skin tissue by DHE staining confirmed that the DHE staining intensity was stronger in the epidermis and dermis in the negative control group compared with the normal group. In addition, a decrease in the DHE staining intensity was observed in the Brixelle and two previously approved drugs (dexamethasone group and Eucrisa group) treatment groups (Figure 9C).

[0156] Additional staining was performed to confirm the infiltration of mast cells and eosinophils, which are well known inflammatory cells associated with the symptoms of atopic dermatitis. Mast cells and eosinophils secrete histamine and cytotoxic substances, respectively, and are therefore immune cells involved in allergic symptoms. Mast cells were quantified by toluidine blue staining, and the results confirmed that the mast cell infiltration showed a statistically significant reduction in the Brixelle-treated group and two previously approved drugs (dexamethasone group and Eucrisa group) compared with the vehicle group. (Figure 9D, vehicle vs dexamethasone, 56.81±1.99 vs 20.69±5.25, p<0.0001; vehicle vs Eucrisa, 56.81±1.99 vs 20.31±2.55, p<0.0001; vehicle vs Brixelle, 56.81±1.99 vs 27.69±1.94, p<0.0001). Furthermore, when eosinophils were quantified by Congo red staining, it could be confirmed that the eosinophil infiltration in the Brixelle-treated group and two previously approved drugs (dexamethasone group and Eucrisa group) also showed a statistically significant reduction compared with the vehicle group (Figure 9E; vehicle vs dexamethasone, 40.06±5.95 vs 10.25±2.56, p<0.0001; vehicle vs Eucrisa, 40.06±5.95 vs 10.31±2.49, p<0.0001; vehicle vs Brixelle, 40.06±5.95 vs 21.69±2.77, p=0.0027).

[0157] Based on these results, it can be seen that as a strong antioxidant, Brixelle has a mechanism of preventing clinical symptoms, skin histological changes, and inflammatory responses in atopic dermatitis, similar to the previously approved drugs Elidel, dexamethasone, and Eucrisa.

[0158] 7. Validation results of Brixelle in psoriasis mouse model (1) Experimental methods The dorsal skin of 8-week-old C57BL / 6 male mice was coated with Aldara TMThe IMQ-induced psoriasis mouse model was established by applying IMQ cream to the skin. The test substance Brixelle (30 mg / kg) was applied to the skin every day from day 0 to evaluate its effectiveness, compared with a normal group (normal group) not applied with IMQ cream, a group (no treatment group) not applied with additional substances during the induction of psoriasis as a negative control group, and a group (vehicle group) to which an excipient was applied to the skin, and a group (clobetasol propionate group, 0.05% clobetasol propionate, 62.5 mg / animal) to which the previously approved drug Betabate was applied as a positive control group. Clinical symptoms were evaluated during the induction of psoriasis, and skin tissues were preserved for further analysis after the end of the survival experiment.

[0159] To quantify the clinical symptoms of psoriasis, clinical scores were performed on three (3) clinical index items, including 1) erythema (redness), 2) scaling, and 3) skin thickness, with a maximum score of 4 (modified Psoriasis Area and Severity Index, PASI). H&E staining was used to observe the skin histological changes caused by psoriasis, and DHE staining was used to measure ROS in skin tissue. RT-PCR and ELISA were performed on skin tissue to measure IL-17 and IL-23, two inflammatory mediators known to be highly associated with psoriasis. The results of the graphs are expressed as mean ± SEM. Statistical analysis was performed using the GraphPad program, and statistical significance compared with the vehicle group was confirmed by one-way analysis of variance and Dunnett's multiple comparison method (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0160] (2) Experimental results The results of confirming clinical symptoms at the end of the survival test showed that the formation of crusts, redness and edema were clearly observed due to the induction of psoriasis. The results of clinical index evaluation confirmed that the clinical symptoms of the clobetasol propionate-treated group and the Brixelle-treated group showed a statistically significant improvement effect compared with the vehicle group (Figure 10A. Vehicle vs. clobetasol propionate, 10.50±0.47 vs. 7.25±0.21, p<0.0001; Vehicle vs. Brixelle 30 mg / kg, 10.50±0.47 vs. 6.00±0.22, p<0.0001).

[0161] As a result of confirming the histological changes of the skin by H&E staining, increased epidermal thickness and hyperkeratosis were observed according to IMQ treatment. The Brixelle-treated group showed a decrease in epidermal thickness and reduced hyperkeratosis compared to the vehicle group ( FIG. 10B ).

[0162] To determine whether the antioxidant activity of Brixelle has an effect on improving psoriasis symptoms, the expression of ROS in skin tissue was examined. The results of measuring ROS in skin tissue by DHE staining confirmed that the DHE staining intensity was stronger in the epidermis and dermis in the negative control group compared with the normal group, and a decrease in the DHE staining intensity was observed in the Brixelle and positive control groups (Figure 10C).

[0163] IL-23 and IL-17, as immune mediators associated with Th1 and Th17 immune responses, are important mechanisms in the development of psoriasis symptoms and play a role in initiating and maintaining Th1 and Th17 immune responses and amplifying inflammation, and are therefore used as targets for the treatment of psoriasis. Macrophages infiltrating the skin tissue of patients with psoriasis express IL-23, thereby allowing γδT cells to express IL-17. Therefore, the expression of IL-23 and IL-17 in skin tissue was analyzed and compared. In terms of IL-23 mRNA expression, the Brixelle treatment group showed a similar reduction effect as the previously approved drug clobetasol propionate, although it was not statistically significant compared with the vehicle group (Figure 10D). In terms of IL-17 protein expression, Brixelle showed a statistically significant reduction effect compared with the vehicle group (Figure 10D. Vehicle vs Brixelle 30 mg / kg, 354±36.5 vs 203±15.2, P=0.0378).

[0164] Based on these results, it can be seen that as a strong antioxidant, Brixelle has a mechanism of preventing clinical symptoms, skin histological changes, and inflammatory responses in psoriasis that is similar to the previously approved drug clobetasol propionate.

[0165] 8. Validation results of Brixelle in contact dermatitis mouse model (1) Experimental methods A DNB-induced contact dermatitis mouse model was established using 6- to 10-week-old C57BL / 6 NC / Nga male mice and mouse 2,4-dinitrofluorobenzene (DNFB). On days 0 and 1, 0.5% DNFB solution (acetone: olive oil = 4:1) was applied to the back skin of mice for sensitization, and then on day 7, 0.3% DNFB solution was applied to the ear skin to induce contact dermatitis. The test substance Brixelle (30 mg / kg) was applied to the skin every day from day 0 to evaluate its effectiveness, relative to a normal group (normal group) to which DNFB solution was not applied, a group (no treatment group) to which no additional substance was applied during the induction of contact dermatitis as a negative control group, and a group (vehicle group) to which a vehicle was applied to the skin, and a group (dexamethasone group, 0.1% dexamethasone, 62.5 mg / animal) to which the previously approved drug Maxidex was applied as a positive control group. Clinical symptoms were assessed during the induction of contact dermatitis, and skin tissues were preserved for further analysis after the survival study.

[0166] Ear thickness was measured to evaluate the clinical symptoms of contact dermatitis, i.e., edema. H&E staining was used to observe the histological changes in the skin due to contact dermatitis, and DHE staining was used to measure ROS in the skin tissue. RT-PCR was performed on the skin tissue to measure TNF-α and IFN-γ, two inflammatory mediators known to be highly associated with contact dermatitis. The results of the graphs are expressed as mean ± SEM. Statistical analysis was performed using the GraphPad program, and statistical significance with the vehicle group was confirmed by one-way ANOVA and Dunnett's multiple comparison method (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001).

[0167] (2) Experimental results The results of confirming clinical symptoms at the end of the survival test showed that edema was clearly observed due to the induction of contact dermatitis. The results of measuring the thickness of the ear skin confirmed that the Brixelle treatment group showed a statistically significant effect compared with the vehicle group (Figure 11A. Vehicle vs dexamethasone, 0.94±0.01 vs 0.67±0.02, p<0.0001; Vehicle vs Brixelle 30 mg / kg, 0.94±0.01 vs 0.71±0.01, p<0.0001).

[0168] As a result of confirming histological changes in the ear skin by H&E staining, increased skin thickness and tissue swelling were confirmed. The Brixelle-treated group was able to demonstrate the effect of reducing skin thickness and tissue swelling compared to the vehicle group ( FIG. 11B ).

[0169] To determine whether the antioxidant activity of Brixelle has an effect on improving contact dermatitis symptoms, the expression of ROS in ear skin tissue was studied. The results of measuring ROS in skin tissue by DHE staining confirmed that the DHE staining intensity was stronger in the negative control group compared with the normal group, and a decrease in the DHE staining intensity was observed in the Brixelle-treated group and the positive control group (Figure 11C).

[0170] TNF-α and IFN-γ, as immune mediators associated with Th1 immune response, are important mechanisms for the occurrence of contact dermatitis symptoms and play a role in inducing Th1 immune response and amplifying inflammation. Regarding the expression of TNF-α and IFN-γ in skin tissue, mRNA expression was compared using RT-PCR. In terms of mRNA expression of these two cytokines, statistical significance could not be confirmed in the Brixelle treatment group compared with the vehicle group, but it was confirmed that it showed a similar reduction effect as the previously approved drug dexamethasone (Figure 11D).

[0171] Based on these results, it can be seen that as a strong antioxidant, Brixelle has a mechanism of preventing clinical signs of contact dermatitis, skin histological changes, and clinical signs of inflammatory response similar to the previously approved drug dexamethasone.

[0172] 9. Confirmation of the results of Brixelle skin toxicity (1) Experimental methods Designed to use a reconstructed human epidermis model (KeraSkin TM ) and reconstructed human corneal epithelial model (MCTT HCE TM ) to determine the effect of Brixelle on skin tissue. After treating the reconstructed human epidermis model and the reconstructed human corneal epithelium model (which are artificial tissues that simulate human skin and cornea) with 3 concentrations of Brixelle (10 mM, 25 mM, and 50 mM), a skin irritation test was conducted with Brixelle to confirm whether irritation to the skin is possible; an eye irritation test was conducted to confirm whether irritation to the ocular mucosa is possible; a skin sensitization test was conducted to determine whether there is a possibility of activating the skin immune system; a skin phototoxicity test was conducted to determine whether there is a possibility of turning UVA into a substance that irritates the skin; and a skin micronucleus test was conducted to determine whether there is a possibility of causing genetic toxicity in skin tissue.

[0173] (2) Experimental results In a skin irritation test to confirm whether a test substance has the potential to irritate the skin, Brixelle showed 50% or greater cell viability at a concentration of 50 mM, confirming its non-irritating properties (Figure 12A).

[0174] In an eye irritation test conducted to confirm whether the test substance has the potential to irritate the ocular mucosa, Brixelle demonstrated 35% or greater cell viability at concentrations up to 50 mM, confirming its non-irritating properties (Figure 12B).

[0175] In the skin micronucleus test to determine whether the test substance has the potential to cause genotoxicity in skin tissue, Brixelle did not induce significant MN frequencies up to 50 mM compared to the negative control, and since the MN frequencies did not increase in a concentration-dependent manner (Figure 12C), it was confirmed to be negative for genotoxicity.

[0176] In a skin sensitization test to determine whether a test substance may have the potential to activate the skin immune system, THP-1 cells (an immune cell-derived cell line) co-cultured with a reconstructed human corneal epithelial model were evaluated for increased expression of CD54 and CD86 on the cell surface during differentiation. The results showed that THP-1 cells co-cultured with Brixelle expressed CD54 and CD86 below 200 RFI and 120 RFI, respectively, compared to the negative control at concentrations up to 50 mM, thus confirming that it is negative for skin sensitization (Figure 12D (12da and 12db)).

[0177] In the skin phototoxicity test to determine whether the test substance could become a skin irritant under the action of UVA, the cell viability of Brixelle before and after UVA irradiation was less than 30% at a concentration below 50 mM, thus confirming that its skin phototoxicity was negative (Figure 12E).

[0178] Based on these results, it can be confirmed that Brixelle, a strong antioxidant, does not irritate the skin or ocular mucosa, does not activate the skin's immune system, does not react with UV to become an irritant, or cause genotoxicity.

Claims

1. A pharmaceutical composition for preventing or treating inflammatory diseases, comprising a compound represented by Formula 1, a solvate thereof, or a pharmaceutically acceptable salt thereof: [Formula 1] In Formula 1, R1 and R4 are vinyl or methyl, and R2 and R3 are methyl or vinyl, but they are not both vinyl or methyl; and R5 is polyethylene glycol (PEG) or a derivative thereof.

2. The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 1, wherein the compound is a compound represented by any one of Formula 2 to Formula 7: [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] [Formula 7] 。 3. The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 1, comprising nanoparticles formed by self-assembly of the compound represented by Formula 1.

4. The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 3, wherein the size of the nanoparticles is 1-5000 nm.

5. The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 1, wherein the derivative of polyethylene glycol is selected from the group consisting of methoxy polyethylene glycol (methoxy PEG), PEG propionate succinimidyl ester, PEG butyrate succinimidyl ester, branched PEG-NHS, PEG succinimidyl succinate, carboxymethyl PEG succinimidyl ester, PEG benzotriazole carbonate, PEG-glycidyl ether, PEG-oxycarbonyl imidazole, PEG nitrophenyl carbonate, PEG-aldehyde, PEG succinimidyl carboxymethyl ester and PEG succinimidyl ester.

6. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 1, wherein the inflammatory disease is at least one selected from the group consisting of inflammatory skin diseases, osteoarthritis, hepatitis, pneumonia, keratitis, gastritis, nephritis, tuberculosis, bronchitis, pleurisy, peritonitis, spondylitis, pancreatitis, inflammatory bowel disease, urethritis, cystitis, inflammatory arteriosclerosis, sepsis, periodontitis, gingivitis and autoinflammatory diseases.

7. The pharmaceutical composition for preventing or treating inflammatory diseases according to claim 6, wherein: The inflammatory skin disease is at least one selected from the group consisting of atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, pruritus, parapsoriasis, urticaria, lichen planus, sunburn, radiation dermatitis, erythema multiforme, erythema nodosum, granuloma annulare, keratosis follicularis, xeroderma, panniculitis, pyoderma gangrenosum, acne, rosacea, lupus erythematosus, pemphigus, diaper dermatitis, pityriasis rosea, alopecia areata, androgenic alopecia, vitiligo and bedsores.

8. The pharmaceutical composition for preventing or treating an inflammatory disease according to claim 1, wherein the inflammatory disease is caused by increased oxidative stress.

9. A cosmetic composition comprising a compound represented by Formula 1, a solvate thereof or a cosmetically acceptable salt thereof: [Formula 1] In Formula 1, R1 and R4 are vinyl or methyl, and R2 and R3 are methyl or vinyl, but they are not both vinyl or methyl; and R5 is polyethylene glycol (PEG) or a derivative thereof.

10. The cosmetic composition according to claim 9, wherein the compound is a compound represented by any one of Formula 2 to Formula 7: [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] [Formula 7] 。 11 . The cosmetic composition according to claim 9 , comprising nanoparticles formed by self-assembly of the compound represented by Formula 1.

12. The cosmetic composition according to claim 11, wherein the size of the nanoparticles is 1 to 5000 nm.

13. The cosmetic composition according to claim 9, wherein the derivative of polyethylene glycol is selected from the group consisting of methoxy polyethylene glycol (methoxy PEG), PEG propionate succinimidyl ester, PEG butyrate succinimidyl ester, branched PEG-NHS, PEG succinimidyl succinate, carboxymethyl PEG succinimidyl ester, PEG benzotriazole carbonate, PEG-glycidyl ether, PEG-oxycarbonyl imidazole, PEG nitrophenyl carbonate, PEG-aldehyde, PEG succinimidyl carboxymethyl ester and PEG succinimidyl ester. The cosmetic composition according to claim 9 , wherein the cosmetic composition is used for anti-inflammatory or anti-oxidation.

15. The cosmetic composition according to claim 9, wherein the cosmetic composition is used to prevent or improve skin inflammation caused by increased oxidative stress.

16. The cosmetic composition according to claim 15, wherein the skin inflammation caused by the increased oxidative stress is at least one selected from the group consisting of atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, pruritus, parapsoriasis, urticaria, lichen planus, sunburn, radiation dermatitis, erythema multiforme, erythema nodosum, granuloma annulare, keratosis follicularis, xeroderma, panniculitis, pyoderma gangrenosum, acne, rosacea, lupus erythematosus, pemphigus, diaper dermatitis, trichotillomannia, alopecia areata, androgenic alopecia, vitiligo and bedsores.

17. The cosmetic composition according to claim 9, wherein the cosmetic composition is used to moisturize the skin, restore the skin barrier function, or prevent skin aging.

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