Barrier function improver

Abstract

A barrier function improver which contains methylhesperidin as an active ingredient, and a barrier function improver composition which contains said barrier function improver and a pharmaceutically acceptable carrier.

Description

[Technical Field]

[0001] The present invention relates to a barrier function improver and a barrier function improving composition. This application claims priority based on Japanese Patent Application No. 2021-016111, filed on February 3, 2021, the contents of which are incorporated herein by reference. [Background technology]

[0002] One of the most important physiological functions of the epidermis is its defense against external dryness, ultraviolet rays, and other physical and chemical stimuli, and the stratum corneum is responsible for this defense. The keratinocytes that make up the stratum corneum are formed through a differentiation process known as epidermal keratinocyte turnover. If this differentiation of the skin is inhibited or abnormally accelerated for some reason, normal skin turnover will not occur, resulting in a decline in the barrier function (Non-Patent Documents 1 and 2).

[0003] A decline in the skin's barrier function increases transepidermal water loss, causing dry skin, including dryness, scaling, and itching. A decrease in intercellular lipids, including stratum corneum ceramides, and changes in their composition have been reported in aging skin and in patients with atopic dermatitis and psoriasis, which are accompanied by barrier disorders (Non-Patent Documents 3 and 4).

[0004] Furthermore, amino acids involved in the water retention of the stratum corneum are degradation products of filaggrin protein in granular layer cells, and it is known that in atopic dermatitis, which presents with severe dryness, profilaggrin, the precursor of this filaggrin, is reduced in the stratum corneum. A reduction in filaggrin reduces the water retention capacity of the stratum corneum and causes dry skin, so it is becoming widely known that filaggrin is also important for maintaining and improving the skin's barrier function (Non-Patent Documents 5 and 6).

[0005] In addition to the above-mentioned filaggrin, factors known as differentiation markers involved in the process of normal skin turnover and barrier formation include involucrin, loricrin, and transglutaminase 1. Aquaporin 3 (AQP3), which is abundant in skin keratinocytes, is also important for improving the physiological barrier function of the skin by promoting the transport of water and glycerol (Non-Patent Document 7). Furthermore, aquaporin 3 expression is significantly reduced at sites of skin inflammation, and this has been suggested to be closely related to the development of dryness symptoms associated with various skin diseases (Patent Document 1).

[0006] Furthermore, it is known that tight junctions also play an important role in the skin's barrier function, as the skin's barrier function collapses when the proteins that make up the tight junctions present in the granular layer of the epidermis are genetically deleted (Non-Patent Document 8). If the proteins that make up the tight junctions, such as claudin 1 and occludin, are reduced for some reason, their function as a structural barrier to the permeability of substances is impaired, causing skin symptoms such as dry skin, rough skin, atopic dermatitis, and various infections. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-32191 [Non-patent literature]

[0008] [Non-Patent Document 1] Mina Yaar et al., Retinoic Acid Delays the Terminal Differentiation of Keratinocytes in Suspension Culture. J Invest Dermatol 76:363-366, 1981. [Non-patent document 2] Akemi Ishida-Yamamoto et al., Structural organization of cornified cell envelopes and alterations in inherited skin disorders. Exp Dermatol 1998: 7: 1-10. [Non-patent document 3] Kayoko Akimoto et al., Quantitative Analysis of Stratum Corneum Lipids in Xerosis and Asteatotic Eczema. The Journal of Dermatology Vol.20: 1-6, 1993. [Non-patent document 4] Genji Imokawa et al., Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin?. J Invest Dermatol 96:523-526, 1991. [Non-patent document 5] Tokuji Seguchi et al., Decrease expression of filaggrin in atopic skin. Arch Dermatol Res 288, 442-446, 1996. [Non-patent document 6] Hiroshi Fujita et al., "Palo Azul prevents the loss of filaggrin and amino acids due to dryness," J. Soc. Cosmet. Chem. Jpn. 37(2), 84-91, 2003. [Non-Patent Document 7] Mariko Hara-Chikuma et al., Aquaporin-3 functions as a glycerol transporter in mammalian skin. Biol. Cell (2005) 97, 479-486. [Non-patent document 8] Takuo Yuki et al., Tight junction proteins in keratinocytes: localization and contribution to barrier function. Experimental Dermatology 16, 324-330, 2007. Summary of the Invention [Problem to be solved by the invention]

[0009] As described above, it is known that the barrier function of the skin is impaired in conditions such as rough skin, dry skin, psoriasis, and atopy, and therefore there is a demand for drugs that can effectively improve the barrier function. However, the effects of conventionally known drugs are still insufficient.

[0010] Therefore, an object of the present invention is to provide a barrier function improver that can effectively improve the barrier function, and a barrier function improving composition containing the barrier function improver. [Means for solving the problem]

[0011] The present invention includes the following aspects. [1] A skin barrier function improver containing methylhesperidin as an active ingredient. [2] The barrier function improver according to [1], wherein the methylhesperidin is at least one selected from the group consisting of chalcone methylhesperidin represented by the following general formula (1) and flavanone methylhesperidin represented by the following general formula (2).

[0012] [ka] [In formula (1), R 1 ~R 9 are each independently a methyl group or a hydrogen atom, provided that R 1 ~R 9 At least one of these is a methyl group. In formula (2), R11 ~R 18 are each independently a methyl group or a hydrogen atom, provided that R 11 ~R 18 At least one of these is a methyl group. [3] The barrier function improver according to [2], wherein the methylhesperidin is at least one selected from the group consisting of chalcone methylhesperidin represented by the following general formula (3) and flavanone methylhesperidin represented by the following general formula (4).

[0013] [ka] [In formula (3), R 20 ~R 23 are each independently a methyl group or a hydrogen atom. In formula (4), R 24 ~R 25 are each independently a methyl group or a hydrogen atom. [4] The chalcone methylhesperidin represented by the general formula (3) is R 20 ~R 23 The barrier function improver according to [3], wherein the combination of the above is one or more selected from the group consisting of chalcone bodies 1 to 3.

[0014] [Table 1] [5] The flavanone methylhesperidin represented by the general formula (4) is selected from the group consisting of R 24 ~R 25 The barrier function improver according to [3] or [4], wherein the combination of the above is one or more selected from the group consisting of flavanones 1 to 4.

[0015] [Table 2] [6] The barrier function improver according to any one of [1] to [5], which is for promoting filaggrin production. [7] The barrier function improver according to any one of [1] to [5], which is for promoting the production of involucrin. [8] The barrier function improver according to any one of [1] to [5], which is for promoting the production of loricrin. [9] The barrier function improver according to any one of [1] to [5], which is for promoting the production of transglutaminase 1.

[10] The barrier function improver according to any one of [1] to [5], which is for promoting the production of aquaporin 3.

[11] The barrier function improver according to any one of [1] to [5], which is for promoting the production of claudin-1.

[12] A composition for improving barrier function, comprising the barrier function improver according to any one of [1] to

[11] and a pharmaceutically acceptable carrier.

[13] The composition for improving barrier function according to

[12] , wherein the total content of the methylhesperidin is 0.01 to 2% by mass. [Effects of the Invention]

[0016] According to the present invention, it is possible to provide a barrier function improver that can effectively improve barrier function, and a barrier function improving composition containing the barrier function improver. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows photographs of skin tissues stained with immune antibodies in Test Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0018] (Barrier function improver) In one embodiment, the present invention provides a skin barrier function improving agent comprising methylhesperidin as an active ingredient. Here, the term "barrier function" refers to the skin's function of preventing evaporation of moisture from the inside due to external dryness, ultraviolet rays, and other physical and chemical stimuli, and protecting against the intrusion of foreign substances from the outside world. The barrier function improving agent of this embodiment can effectively improve barrier function by promoting the production of differentiation markers filaggrin, involucrin, loricrin, and transglutaminase 1, aquaporin 3, a water channel in the cell membrane, and claudin 1, a structure of tight junctions.

[0019] <Methylhesperidin> The barrier function improver of the present embodiment is not particularly limited as long as it contains methylhesperidin as an active ingredient. The methylhesperidin used in the barrier function improver of the present embodiment is preferably hesperidin that has been methylated and solubilized in water.

[0020] Methylhesperidin is known to mainly include chalcone-type compounds (chalcone-type methylhesperidin) represented by the following general formula (1) and flavanone-type compounds (flavanone-type methylhesperidin) represented by the following general formula (2).

[0021] [ka] [In formula (1), R 1 ~R 9 are each independently a methyl group or a hydrogen atom, provided that R 1 ~R 9 At least one of these is a methyl group. In formula (2), R 11 ~R 18 are each independently a methyl group or a hydrogen atom, provided that R 11 ~R 18 At least one of these is a methyl group.

[0022] The methylhesperidin used in the barrier function improving agent of the present embodiment is preferably one or more types selected from the group consisting of chalcone methylhesperidin represented by the general formula (1) and flavanone methylhesperidin represented by the general formula (2).

[0023] In the general formula (1), R1 ~R 9 are each independently a methyl group or a hydrogen atom, and R 1 ~R 9 At least one of the R is a methyl group. 1 ~R 9 Among these, it is preferable that any one to six of them are methyl groups, and it is more preferable that any two to five of them are methyl groups.

[0024] In the general formula (2), R 11 ~R 18 are each independently a methyl group or a hydrogen atom, and R 11 ~R 18 At least one of the R is a methyl group. 11 ~R 18 Among these, it is preferable that any one to four of them are methyl groups, and it is more preferable that any one to three of them are methyl groups.

[0025] Among the compounds represented by the general formula (1), the chalcone methylhesperidin is preferably a compound represented by the following general formula (3): Among the compounds represented by the general formula (2), the flavanone methylhesperidin is preferably a compound represented by the following general formula (4):

[0026] [ka] [In formula (3), R 20 ~R 23 are each independently a methyl group or a hydrogen atom. In formula (4), R 24 ~R 25 are each independently a methyl group or a hydrogen atom.

[0027] In the general formula (3), R 20 ~R 23 are each independently a methyl group or a hydrogen atom. The chalcone methylhesperidin represented by the general formula (3) can be prepared by adding R 20 ~R 23It is preferable that the compound is one or more selected from the group consisting of chalcone compounds-1 to 3 having the combination of the above.

[0028] [Table 3]

[0029] In the general formula (4), R 24 ~R 25 are each independently a methyl group or a hydrogen atom. The flavanone methylhesperidin represented by the general formula (4) includes those represented by R 24 ~R 25 It is preferable that the compound is one or more selected from the group consisting of flavanones-1 to 4 having the combination of the following:

[0030] [Table 4]

[0031] The methylhesperidin used in the barrier function improving agent of this embodiment may be a single type or a mixture of two or more types. The methylhesperidin may contain both or only one of the chalcone methylhesperidin represented by the general formula (1) or the chalcone methylhesperidin represented by the general formula (3), and the flavanone methylhesperidin represented by the general formula (2) or the flavanone methylhesperidin represented by the general formula (4). The methylhesperidin may contain both the chalcone methylhesperidin represented by the general formula (3) and the flavanone methylhesperidin represented by the general formula (4). Furthermore, the methylhesperidin may contain one or more of the chalcone-1 to -3, or one or more of the flavanone-1 to -4. Furthermore, the barrier function improving agent of the present embodiment may contain a mixture of chalcone-1 to -3 and flavanone-1 to -3 as methylhesperidin.

[0032] Methylhesperidin can be produced by known methods, such as dissolving hesperidin produced from citrus peels in an aqueous sodium hydroxide solution, reacting the alkaline solution with a corresponding amount of dimethyl sulfate, neutralizing the reaction solution with sulfuric acid, extracting with n-butyl alcohol, distilling off the solvent, and then recrystallizing with isopropyl alcohol (Sakiyoku, Nippon Kagaku Zasshi, (1958) Vol. 79, pp. 733-736; Japanese Patent Publication No. 6312333), but the production method is not limited thereto.

[0033] Alternatively, commercially available products (e.g., those distributed as pharmaceutical additives, food additives, and cosmetic ingredients, or "methyl hesperidin" (Showa Denko K.K.), "methyl hesperidin" (Tokyo Chemical Industry Co., Ltd.), "hesperidin methyl chalcone" (Sigma), etc.) can be purchased and used.

[0034] The barrier function improver of this embodiment can be administered to a patient by itself for the purpose of treating rough skin, dry skin, psoriasis, atopic dermatitis, etc. The barrier function improver of this embodiment can also be incorporated into pharmaceuticals or cosmetics for the purpose of improving barrier function. The barrier function improver of this embodiment may also be incorporated into a barrier function-improving composition, which will be described later.

[0035] The barrier function improving agent of the present embodiment can effectively improve the barrier function by promoting the production of filaggrin. The barrier function improving agent of the present embodiment can effectively improve barrier function by promoting the production of involucrin. The barrier function improving agent of the present embodiment can effectively improve barrier function by promoting the production of loricrin. The barrier function improving agent of this embodiment can effectively improve barrier function by promoting the production of transglutaminase 1. The barrier function improving agent of this embodiment can effectively improve the barrier function by promoting the production of aquaporin 3. The barrier function improving agent of this embodiment can effectively improve barrier function by promoting the production of claudin-1. The barrier function improving agent of the present embodiment can effectively improve the barrier function, and therefore can be used to prevent or treat rough skin, dry skin, psoriasis, and atopic dermatitis.

[0036] (filaggrin) Filaggrin is a basic protein produced by granular cells in the epidermis, and promotes the fibrosis reaction of keratin fibers that occurs within stratum corneum cells. As stratum corneum cells migrate from the lower to the upper layers, filaggrin is further broken down into amino acids by the action of proteases, and the free amino acids in the stratum corneum function as natural moisturizing factors (NMF). Promoting the production of filaggrin increases the amount of NMF, enhancing the moisturizing power of the stratum corneum and improving the skin's barrier function.

[0037] (Involucrin) Involucrin is one of the major proteins that make up the cornified envelope of stratum corneum cells and is used as an indicator of the early stages of keratinocyte (epidermal keratinocyte) differentiation. Promoting the production of involucrin promotes the formation of the cornified envelope, a structure responsible for the stratum corneum's moisturizing power, thereby improving the skin's barrier function.

[0038] (Loriklin) Loricrin is a hydrophobic protein rich in glycine, serine, cysteine, etc., and is the main component of the cornified envelope. By promoting the production of involucrin, the formation of the cornified envelope is promoted, thereby improving the skin's barrier function.

[0039] (Transglutaminase 1) Transglutaminase 1 is an enzyme that forms isopeptide bonds between glutamine and lysine in proteins and is involved in the formation of the cornified envelope. By promoting the production of transglutaminase 1, the formation of the cornified envelope is promoted, thereby improving the skin's barrier function.

[0040] (Aquaporin 3) Aquaporin 3 is a protein with pores present in the cell membrane that functions as a water channel to regulate the amount of water inside the cell. By promoting the production of aquaporin 3, the amount of water inside the epidermal cells increases, improving the epidermal barrier function.

[0041] (Claudin 1) Claudin 1 is a major protein in tight junctions, which are intercellular junctions and form an intercellular barrier. Promoting the production of claudin 1 promotes the formation of tight junctions, thereby improving the barrier function of the epidermis.

[0042] The barrier function improver of the present embodiment may be administered to patients at high risk of developing rough skin, dry skin, psoriasis, atopic dermatitis, etc., and used to prevent rough skin, dry skin, psoriasis, atopic dermatitis, etc. The barrier function improver of the present embodiment may also be administered to patients who have developed rough skin, dry skin, psoriasis, atopic dermatitis, etc., and used to suppress the progression or worsening of rough skin, dry skin, psoriasis, atopic dermatitis, etc.

[0043] The barrier function improving agent of the present embodiment can be administered to a patient in the same manner as the barrier function improving composition described below, and may be administered orally, parenterally, intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intraperitoneally, etc., or may be administered rectally as a suppository, or may be administered to the skin as an external preparation for skin.

[0044] (Composition for improving barrier function) The barrier function improving composition of the present embodiment contains the above-mentioned barrier function improving agent containing methylhesperidin and a pharmaceutically acceptable carrier.

[0045] The barrier function improving composition of this embodiment can be produced by mixing the above-mentioned barrier function improving agent, a pharmaceutically acceptable carrier, and, if necessary, other ingredients, and formulating the mixture according to a conventional method (e.g., a method described in the Japanese Pharmacopoeia).

[0046] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier that does not inhibit the physiological activity of an active ingredient and that does not exhibit substantial toxicity to a subject to which it is administered. The phrase "not substantially toxic" means that the component does not exhibit toxicity to the subject at the doses normally used. Pharmaceutically acceptable carriers are not particularly limited, and examples thereof include excipients, binders, disintegrants, lubricants, stabilizers, diluents, solvents for injections, humectants, texture enhancers, surfactants, polymers, thickeners, gelling agents, solvents, propellants, antioxidants, reducing agents, oxidizing agents, chelating agents, acids, alkalis, powders, inorganic salts, water, metal-containing compounds, unsaturated monomers, polyhydric alcohols, polymer additives, wetting agents, thickeners, tackifiers, oil-based raw materials, liquid matrices, fat-soluble substances, and polymeric carboxylates.

[0047] Specific examples of these components include those described in International Publication No. 2016 / 076310. Furthermore, specific examples of polymers, thickeners, and gelling agents include methacryloyloxyethyl phosphorylcholine, butyl methacrylate, and polymers thereof. In the barrier function-improving composition of this embodiment, one type of pharmaceutically acceptable carrier may be used alone, or two or more types may be used in combination.

[0048] Other ingredients include, but are not limited to, preservatives, antibacterial agents, UV absorbers, whitening agents, vitamins other than methylhesperidin and their derivatives, anti-inflammatory agents, hair growth agents, blood circulation promoters, stimulants, hormones, anti-wrinkle agents, anti-aging agents, firming agents, cooling agents, warming agents, wound healing promoters, irritation soothing agents, analgesics, cell activators, plant, animal, and microbial extracts, seed oils, antipruritics, exfoliants, Examples of ingredients include solubilizers, antiperspirants, cooling agents, astringents, enzymes, nucleic acids, fragrances, dyes, colorants, dyes, pigments, anti-inflammatory and analgesic agents, antifungals, antihistamines, hypnotics, sedatives, tranquilizers, antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antibacterial substances, antiepileptic drugs, coronary vasodilators, herbal medicines, antipruritics, keratin softening and exfoliating agents, UV protection agents, disinfectants, antioxidants, pH adjusters, additives, and metal soaps. Specific examples of these ingredients include those described in International Publication No. 2016 / 076310. Specific examples of plant, animal, and microbial extracts include Lapsana communis flower / leaf / stem and tea leaves. Specific examples of seed oils include Moringa oleifera seed oil. Specific examples of fragrances include perillaldehyde. The other components may be used alone or in combination of two or more.

[0049] The barrier function improving composition of this embodiment can contain a therapeutically effective amount of the barrier function improving agent. The term "therapeutically effective amount" refers to the amount of a drug that is effective for treating or preventing a disease in a patient. The therapeutically effective amount may vary depending on the disease state, age, sex, weight, etc. of the subject to be administered. In the barrier function-improving composition of this embodiment, the therapeutically effective amount of the barrier function improving agent may be an amount of methylhesperidin capable of improving barrier function and promoting the production of at least one enzyme selected from the group consisting of filaggrin, involucrin, loricrin, transglutaminase 1, aquaporin 3, and claudin 1.

[0050] The therapeutically effective amount of the barrier function improving agent in the barrier function improving composition of this embodiment (total content of methylhesperidin) may be, for example, 0.01 to 2 mass%, for example, 0.05 to 1.5 mass%, or for example, 0.1 to 1.0 mass%, relative to the total amount of the barrier function improving composition. The total content of methylhesperidin means the content of one type of methylhesperidin when used alone, and means the total content of these compounds when used in combination of two or more types of methylhesperidin.

[0051] Specific preferred examples of the barrier function improving composition of this embodiment include those having the following compositions. (Example 1) A composition for improving barrier function containing 0.01 to 2% by mass of methylhesperidin, 0.04 to 1% by mass of dipotassium glycyrrhizinate, and 0.01 to 10% by mass of sodium hyaluronate. (Example 2) A barrier function improving composition containing 0.01 to 2 mass % of methylhesperidin, 0.05 to 10 mass % of isononyl isononanoate, 0.05 to 10 mass % of octyldodecyl myristate, and 0.001 to 5 mass % of tocopherol.

[0052] The barrier function-improving composition of the present embodiment may be a pharmaceutical composition or a cosmetic.

[0053] (Pharmaceutical composition) In one embodiment, the present invention provides a pharmaceutical composition for improving barrier function, comprising the barrier function improving agent described above and a pharmaceutically acceptable carrier.

[0054] In the pharmaceutical composition of this embodiment, the pharmaceutically acceptable carrier is not particularly limited, and in addition to the above-mentioned carriers, carriers commonly used in pharmaceuticals can be used. For example, common raw materials described in the Japanese Pharmacopoeia, Japanese Pharmacopoeia Non-Drug Standards, Pharmaceutical Additive Standards 2013 (Yakuji Nipposha, 2013), Pharmaceutical Additives Dictionary 2016 (edited by the Japan Pharmaceutical Additives Association, Yakuji Nipposha, 2016), Handbook of Pharmaceutical Excipients, 7th edition (Pharmaceutical Press, 2012), etc. can be used. One type of pharmaceutically acceptable carrier may be used alone, or two or more types may be used in combination.

[0055] The pharmaceutical composition of this embodiment may contain other ingredients in addition to the barrier function improver and a pharmaceutically acceptable carrier. The other ingredients are not particularly limited, and common pharmaceutical additives can be used. Active ingredients other than the barrier function improver can also be used as the other ingredients. In addition to those listed above, other pharmaceutical additives and active ingredients that can be used as the other ingredients include, for example, common raw materials described in the Japanese Pharmacopoeia, Japanese Pharmacopoeia Non-Drug Standards, Pharmaceutical Additive Standards 2013 (Yakuji Nipposha, 2013), Pharmaceutical Additives Dictionary 2016 (edited by the Japan Pharmaceutical Additives Association, Yakuji Nipposha, 2016), and Handbook of Pharmaceutical Excipients, 7th edition (Pharmaceutical Press, 2012). The other ingredients may be used alone or in combination of two or more.

[0056] The dosage form of the pharmaceutical composition of this embodiment is not particularly limited and can be any dosage form commonly used for pharmaceutical preparations. Examples include oral dosage forms such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions; and parenteral dosage forms such as injections, suppositories, and topical skin preparations. Pharmaceutical compositions in these dosage forms can be formulated according to standard methods (e.g., methods described in the Japanese Pharmacopoeia).

[0057] The method of administration of the pharmaceutical composition of this embodiment is not particularly limited, and can be administered by a method commonly used for administering pharmaceuticals. For example, it may be orally administered as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, etc., or as injections, infusion preparations, etc., administered alone or mixed with common infusions such as glucose solutions and Ringer's solutions, intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intraperitoneally, etc., or rectally as suppositories, or administered to the skin as topical skin preparations.

[0058] The dosage of the pharmaceutical composition of this embodiment can be a therapeutically effective amount, which may be determined appropriately depending on the symptoms, weight, age, sex, etc. of the patient, as well as the dosage form and administration method of the pharmaceutical composition. For example, the dosage of the pharmaceutical composition of this embodiment may be, for oral administration, a total methylhesperidin content of 0.01 to 500 mg per dosage unit; for injections, a total methylhesperidin content of 0.02 to 250 mg per dosage unit; for suppositories, a total methylhesperidin content of 0.01 to 500 mg per dosage unit; and for topical skin preparations, a total methylhesperidin content of 0.01 to 500 mg per dosage unit.

[0059] The administration interval of the pharmaceutical composition of this embodiment may be appropriately determined depending on the symptoms, weight, age, sex, etc. of the patient, as well as the dosage form of the pharmaceutical composition, the administration method, etc. For example, it can be once or about two to three times a day.

[0060] The pharmaceutical composition of the present embodiment can be used for the treatment or prevention of symptoms or diseases caused by impaired barrier function, such as rough skin, dry skin, psoriasis, atopic dermatitis, etc.

[0061] The pharmaceutical composition of this embodiment can be administered to patients with rough skin, dry skin, psoriasis, or atopic dermatitis to inhibit the progression of the condition. The pharmaceutical composition of this embodiment can also be administered to patients with rough skin, dry skin, psoriasis, or atopic dermatitis to treat the condition. The pharmaceutical composition of this embodiment can also be used to treat symptoms or diseases caused by decreased production of filaggrin, involucrin, loricrin, transglutaminase 1, aquaporin 3, or claudin 1.

[0062] The pharmaceutical composition of this embodiment can also be administered to patients at high risk of developing rough skin, dry skin, psoriasis, or atopic dermatitis to prevent rough skin, dry skin, psoriasis, or atopic dermatitis.

[0063] (Cosmetics) In one embodiment, the present invention provides a cosmetic preparation for improving barrier function, comprising the barrier function improving agent described above and a pharmaceutically acceptable carrier.

[0064] In the cosmetic of this embodiment, the pharmaceutically acceptable carrier is not particularly limited, and carriers commonly used in cosmetics, in addition to those listed above, can be used. For example, common raw materials described in the Commentary on the Standards for Cosmetic Ingredients, Second Edition (edited by the Japan Compendium Association, Yakuji Nipposha, 1984), the Standards for Non-Standard Ingredients in Cosmetic Ingredients (supervised by the Inspection Division of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nipposha, 1993), the Supplement to the Standards for Non-Standard Ingredients in Cosmetic Ingredients (supervised by the Inspection Division of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nipposha, 1993), the Cosmetic Type Approval Standards (supervised by the Inspection Division of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nipposha, 1993), the Cosmetic Ingredient Dictionary (Nikko Chemicals, 1991), the International Cosmetic Ingredient Dictionary and Handbook 2002 Ninth Edition Vol. 1 to 4 by CTFA, etc. can be used. One type of pharmaceutically acceptable carrier may be used alone, or two or more types may be used in combination.

[0065] The cosmetic preparation of the present embodiment may contain other ingredients in addition to the barrier function improver and a pharmaceutically acceptable carrier. The other ingredients are not particularly limited, and general cosmetic additives can be used. Furthermore, active ingredients other than the barrier function improver described above can also be used as the other ingredients. In addition to those listed above, other cosmetic additives and active ingredients that can be used include common ingredients listed in, for example, the Commentary on Cosmetic Ingredient Standards, Second Edition (edited by the Japan Compendium Association, Yakuji Nipposha, 1984), Standards for Ingredients Other Than the Standards for Cosmetic Ingredients (supervised by the Inspection Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nipposha, 1993), Supplement to the Standards for Ingredients Other Than the Standards for Cosmetic Ingredients (supervised by the Inspection Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nipposha, 1993), Cosmetic Specification Approval Standards (supervised by the Inspection Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nipposha, 1993), Cosmetic Ingredient Dictionary (Nikko Chemicals, 1991), and the International Cosmetic Ingredient Dictionary and Handbook 2002 Ninth Edition Vol. 1-4 by CTFA. Other ingredients may be used alone or in combination of two or more.

[0066] The form of the cosmetic of this embodiment is not particularly limited and may be any form commonly used for cosmetics. Examples include hair cosmetics such as shampoo, rinse, and hair styling agent; basic cosmetics such as face wash, cleanser, lotion, emulsion, lotion, cream, gel, sunscreen, pack, mask, and serum; makeup cosmetics such as foundation, makeup base, lipstick, lip gloss, and blush; and body cosmetics such as body cleanser, body powder, and deodorant cosmetics. These cosmetics can be produced according to standard methods.

[0067] Furthermore, the formulation of the cosmetic of the present embodiment is not particularly limited, and examples thereof include emulsion types such as oil-in-water (O / W) type, water-in-oil (W / O) type, W / O / W type, and O / W / O type, emulsified polymer type, oil-based, solid, liquid, paste, stick-like, volatile oil type, powder, jelly, gel, paste, cream, sheet, film, mist, spray, aerosol, multilayer, foam, and flake-like forms.

[0068] The amount of the cosmetic composition of the present embodiment to be used is not particularly limited, but can be an amount effective for improving the barrier function. For example, the amount of the cosmetic of the present embodiment to be used is 0.01 to 500 mg per use as the total content of methylhesperidin, and may be, for example, 0.15 to 300 mg, for example, 0.15 to 200 mg, or for example, 0.2 to 100 mg.

[0069] The interval at which the cosmetic preparation of this embodiment is used is not particularly limited, but can be, for example, once a day or about two to three times a day.

[0070] The cosmetic composition of the present embodiment can be used to alleviate symptoms caused by a decrease in barrier function, or may be used in daily skin care or makeup by subjects at high risk of developing these symptoms in order to prevent the onset of these symptoms caused by a decrease in barrier function.

[0071] (Other embodiments) In one embodiment, the present invention provides a method for improving barrier function, comprising administering methylhesperidin to a subject.

[0072] In one embodiment, the present invention provides a method for promoting the production of filaggrin, involucrin, loricrin, or transglutaminase 1, comprising the step of administering methylhesperidin to a subject.

[0073] In one embodiment, the present invention provides a method for promoting the production of aquaporin 3, comprising the step of administering methylhesperidin to a subject.

[0074] In one embodiment, the present invention provides a method for promoting the production of claudin-1, comprising the step of administering methylhesperidin to a subject.

[0075] In one embodiment, the present invention provides methylhesperidin for improving barrier function.

[0076] In one embodiment, the present invention provides methylhesperidin for promoting the production of filaggrin, involucrin, loricrin, or transglutaminase 1.

[0077] In one embodiment, the present invention provides methylhesperidin for promoting the production of aquaporin 3.

[0078] In one embodiment, the present invention provides methylhesperidin for promoting the production of claudin-1.

[0079] In one embodiment, the present invention provides methylhesperidin for preventing or treating rough skin, dry skin, psoriasis, or atopic dermatitis.

[0080] In one embodiment, the present invention provides use of methylhesperidin for producing an agent for improving barrier function.

[0081] In one embodiment, the present invention provides use of methylhesperidin for producing an agent for promoting the production of filaggrin, involucrin, loricrin, or transglutaminase 1.

[0082] In one embodiment, the present invention provides use of methylhesperidin for manufacturing an agent for promoting aquaporin 3 production.

[0083] In one embodiment, the present invention provides use of methylhesperidin for manufacturing an agent for promoting claudin-1 production.

[0084] In one embodiment, the present invention provides use of methylhesperidin for producing a composition for improving barrier function.

[0085] In one embodiment, the present invention provides use of methylhesperidin for manufacturing a composition for promoting the production of filaggrin, involucrin, loricrin, or transglutaminase 1.

[0086] In one embodiment, the present invention provides use of methylhesperidin for manufacturing a composition for promoting aquaporin 3 production.

[0087] In one embodiment, the present invention provides use of methylhesperidin for manufacturing a composition for promoting claudin-1 production. [Example]

[0088] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0089] [Methylhesperidin] In the following test examples, methyl hesperidin (product name: methyl hesperidin) manufactured by Showa Denko K.K. was used. This product is a mixture in which the total content of the chalcone compounds-1 to 3 and the flavanone compounds-1 to 3 is 97.5 mass % or more of the total amount of the composition. In test examples 1 and 2, a "methyl hesperidin DMSO aqueous solution" prepared by dissolving methyl hesperidin in a DMSO aqueous solution was used.

[0090] [Hesperidin] In the following test examples, hesperidin manufactured by Tokyo Chemical Industry Co., Ltd. was used. In test examples 1 and 2, "hesperidin DMSO aqueous solution" prepared by dissolving hesperidin in a DMSO aqueous solution was used.

[0091] [Test Example 1] Effect of promoting expression of differentiation markers, aquaporin 3, and claudin 1 The effects of promoting the expression of differentiation markers (filaggrin, involucrin, loricrin, transglutaminase 1), aquaporin 3, and claudin 1 in a human three-dimensional model skin were examined using the following method. A human three-dimensional skin model (Kurabo Industries, Ltd.) was transplanted onto EPI-100 medium (Kurabo Industries, Ltd.) and cultured for 30 minutes. Next, in Example 1, 30 μL of a methyl hesperidin DMSO solution, prepared by dissolving 0.2% (V / V) methyl hesperidin in a 0.1% (V / V) DMSO aqueous solution, was added to the skin surface and cultured for 6 hours. In Comparative Example 1, 30 μL of a hesperidin DMSO solution, prepared by dissolving 0.2% (V / V) hesperidin in a 0.1% (V / V) DMSO aqueous solution, was added to the skin surface and cultured for 6 hours. In Reference Example 1, a 0.1% (V / V) DMSO aqueous solution was added to the skin surface and cultured for 6 hours. The skin was then washed with saline, fixed with ALTFiX (registered trademark) (Pharma Co., Ltd.), and embedded in paraffin to prepare skin tissue sections. After deparaffinization and dehydration, the skin tissue was subjected to immunohistochemistry. Primary antibodies used were filaggrin, involucrin, loricrin, aquaporin 3, and claudin 1 (all Abcam) and transglutaminase 1 (Novus Biologicals). Each antibody was diluted in 0.05% Tween-20 phosphate buffer at the following dilutions: filaggrin (1:200), involucrin (1:150), loricrin (1:150), transglutaminase 1 (1:500), aquaporin 3 (1:500), and claudin 1 (1:100). The secondary antibody used was horseradish peroxidase-conjugated anti-rabbit IgG antibody (Abcam) diluted 1:200 in 0.05% Tween-20 phosphate buffer. After the antibody reaction and washing, a color reaction was carried out using the peroxidase color-developing substrate 3,3'-diaminobenzidine tetrahydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.).

[0092] Each tissue was observed and photographed using a Nikon TS1. Three independent images were obtained, each of which was quantitatively analyzed for brightness values ​​correlated with protein expression levels using Image J software (NIH). The analytical results for Example 1 and Comparative Example 1 are shown as relative values, with the average analytical value for Reference Example 1 set at 1.00. Figure 1 shows examples of significant results from the photographs, and Table 5 shows the quantitative analysis results.

[0093] [Table 5]

[0094] The results shown in Figure 1 and Table 5 indicate that Example 1, in which methylhesperidin DMSO aqueous solution was added, had an effect of promoting the expression of all of the differentiation markers filaggrin, involucrin, loricrin, and transglutaminase 1, as well as aquaporin 3 and claudin 1, a tight junction structure, compared to Reference Example 1, in which DMSO aqueous solution was added, and Comparative Example 1, in which hesperidin DMSO aqueous solution was added.

[0095] [Test Example 2] Improvement effect on transepidermal water loss (TEWL) of the skin The effect of improving transepidermal water loss (TEWL) in a three-dimensional human skin model was verified using the following method. A human three-dimensional skin model (Kurabo Industries, Ltd.) was transplanted onto EPI-100 medium (Kurabo Industries, Ltd.) and cultured for 30 minutes. Next, in Example 2, 30 μL of a methyl hesperidin DMSO solution, prepared by dissolving 0.2% (V / V) methyl hesperidin in a 0.1% (V / V) DMSO aqueous solution, was added to the skin surface and cultured for 6 hours. In Comparative Example 2, 30 μL of a hesperidin DMSO solution, prepared by dissolving 0.2% (V / V) hesperidin in a 0.1% (V / V) DMSO aqueous solution, was added to the skin surface and cultured for 6 hours. In Reference Example 2, a 0.1% (V / V) DMSO aqueous solution was added to the skin surface and cultured for 6 hours. The skin was then washed with phosphate buffer and further cultured. Transepidermal water loss (TEWL) was measured 72 hours after the addition of each sample using a VAPO SCAN (Nippon Ash Co., Ltd.). The measured values ​​for Example 2 and Comparative Example 2 are shown as relative values, with the measured value for Reference Example 2 being set at 1.00. The results are shown in Table 6.

[0096] [Table 6]

[0097] The results shown in Table 6 confirm that in Example 2, in which a methyl hesperidin DMSO aqueous solution was added, the transepidermal water loss (TEWL) was reduced and the barrier function was enhanced compared to Reference Example 2, in which a DMSO aqueous solution was added, and Comparative Example 2, in which a hesperidin DMSO aqueous solution was added. [Industrial Applicability]

[0098] The present invention provides a barrier function improver that can effectively improve barrier function, and a barrier function improving composition containing the barrier function improver.

[0099] Although the preferred embodiments of the present invention have been described above, the present invention is not limited to these embodiments. Addition, omission, substitution, and other modifications of the configuration are possible within the scope of the spirit of the present invention. The present invention is not limited by the above description, but is limited only by the scope of the appended claims.

Claims

1. A skin barrier function improver containing methyl hesperidin as an active ingredient.

2. The barrier function improver according to claim 1, wherein the methyl hesperidin is at least one selected from the group consisting of chalcone-form methyl hesperidin represented by the following general formula (1) and flavanone-form methyl hesperidin represented by the following general formula (2). [In formula (1), R １ ~R ９ are each independently a methyl group or a hydrogen atom. However, at least one of R １ ~R ９ is a methyl group. In formula (2), R １１ ~R １８ are each independently a methyl group or a hydrogen atom. However, at least one of R １１ ~R １８ is a methyl group. ] 3. The barrier function improver according to claim 2, wherein the methyl hesperidin is at least one selected from the group consisting of chalcone-form methyl hesperidin represented by the following general formula (3) and flavanone-form methyl hesperidin represented by the following general formula (4). [In formula (3), R ２０ ~R ２３ are each independently a methyl group or a hydrogen atom. In formula (4), R ２４ ~R ２５ are each independently a methyl group or a hydrogen atom. ] 4. The barrier function improver according to claim 3, wherein the chalcone-form methyl hesperidin represented by the general formula (3) is at least one selected from the group consisting of chalcone-form -1 to 3 having the combinations of R ２０ ~R ２３ shown in Table 1 below.

5. The barrier function improver according to claim 3 or 4, wherein the flavanone-form methyl hesperidin represented by the general formula (4) is at least one selected from the group consisting of flavanone-form -1 to 4 having the combinations of R ２４ ~R ２５ shown in Table 2 below.

6. The barrier function improving agent according to any one of claims 1 to 5, which is for promoting the production of filaggrin.

7. The barrier function improving agent according to any one of claims 1 to 5, which is for promoting the production of involucrin.

8. The barrier function improving agent according to any one of claims 1 to 5, which is for promoting the production of loricrin.

9. The barrier function improving agent according to any one of claims 1 to 5, which is for promoting the production of transglutaminase 1.

10. The barrier function improving agent according to any one of claims 1 to 5, which is for promoting the production of aquaporin 3.

11. The barrier function improving agent according to any one of claims 1 to 5, which is for promoting the production of claudin 1.

12. A composition for improving barrier function, containing the barrier function improving agent according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. The composition for improving barrier function according to claim 12, wherein the total content of the methyl hesperidin is 0.01 to 2% by mass.

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