JP2022119110A - Barrier function improving agent - Google Patents

Abstract

To provide a barrier function improving agent that can effectively improve a barrier function, and a composition for improving a barrier function containing the barrier function improving agent.SOLUTION: A barrier function improving agent contains tocopherol phosphoric acid ester and/or a salt thereof as an active ingredient, and a composition for improving a barrier function contains the barrier function improving agent and a pharmaceutically acceptable carrier.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a barrier function improving agent and a barrier function improving composition.

One of the most important physiological functions of the epidermis is its protective function against external dryness, ultraviolet rays, and other physical and chemical stimuli, and the stratum corneum plays a role in this protective function. Corneocytes forming the stratum corneum are formed through a differentiation process called turnover of epidermal keratinocytes. When this skin differentiation is inhibited or abnormally accelerated for some reason, normal skin turnover is no longer performed, resulting in deterioration of barrier function (Non-Patent Documents 1 and 2).

A decrease in skin barrier function increases the amount of transepidermal water loss, causing dry skin, desquamation, itching, and the like, resulting in so-called dry skin. In patients with aged skin, atopic dermatitis associated with barrier disorders, and psoriasis, reduction and compositional changes in intercellular lipids including stratum corneum ceramide have been reported (Non-Patent Documents 3 and 4).

In addition, amino acids involved in water retention in the stratum corneum are degradation products of the filaggrin protein of the granular layer cells, and in atopic dermatitis that presents with strong dry symptoms, profilaggrin, a filaggrin precursor, is reduced in the stratum corneum. It has been known. Since a decrease in filaggrin causes a decrease in the water retention capacity of the stratum corneum and dry skin due to it, it is widely known that filaggrin is also important for maintaining and improving the skin barrier function (Non-Patent Document 5). , 6).

Besides filaggrin, involucrin, loricrin, and transglutaminase 1 are known as factors called differentiation markers involved in the process of normal skin turnover and barrier formation. In addition, aquaporin 3 (AQP3), which is abundant in skin keratinocytes, is important for improving the physiological barrier function of the skin by promoting transport of water and glycerol (Non-Patent Document 7). In addition, the expression of aquaporin 3 is remarkably reduced at sites of skin inflammation, suggesting that this is closely related to the formation of dry symptoms associated with various skin diseases (Patent Document 1).

JP 2011-32191 A

Mina Yaar et al., Retinoic Acid Delays the Terminal Differentiation of Keratinocytes in Suspension Culture. J Invest Dermatol 76:363-366, 1981. Akemi Ishida-Yamamoto et al., Structural organization of cornified cell envelopes and alterations in inherited skin disorders. Exp Dermatol 1998: 7: 1-10. Kayoko Akimoto et al., Quantitative Analysis of Stratum Corneum Lipids in Xerosis and Asteatotic Eczema. The Journal of Dermatology Vol.20: 1-6, 1993. 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. Tokuji Seguchi et al., Decreased expression of filaggrin in atopic skin. Arch Dermatol Res 288, 442-446, 1996. Hiroshi Fujita et al., "Palo Azul to prevent filaggrin and amino acid loss due to drying" J. Soc. Cosmet. Chem. Jpn. 37(2), 84-91, 2003. Mariko Hara-Chikuma et al., Aquaporin-3 functions as a glycerol transporter in mammalian skin. Biol. Cell (2005) 97, 479-486.

As described above, it is known that the barrier function of the skin is lowered in rough skin, dry skin, psoriasis, atopy, etc., and a drug capable of effectively improving the barrier function is desired. However, it can be said that conventionally known drugs are still insufficient in their effects.

Accordingly, an object of the present invention is to provide a barrier function-improving agent capable of effectively improving the barrier function, and a barrier function-improving composition containing the barrier function-improving agent.

The present invention includes the following aspects.
[1] A skin barrier function-improving agent containing a tocopherol phosphate and/or a salt thereof as an active ingredient.
[2] The barrier function improving agent according to [1], wherein the tocopherol phosphate and/or its salt is α-tocopherol phosphate and/or its salt.
[3] The barrier function improving agent according to [1] or [2], which contains the salt of tocopherol phosphate as an active ingredient, and the salt of tocopherol phosphate is a sodium salt of tocopherol phosphate. .
[4] The barrier function-improving agent according to any one of [1] to [3], which is for promoting the production of filaggrin.
[5] The agent for improving barrier function according to any one of [1] to [3], which is for promoting the production of involucrin.
[6] The barrier function-improving agent according to any one of [1] to [3], which is for promoting loricrin production.
[7] The agent for improving barrier function according to any one of [1] to [3], which is for promoting transglutaminase-1 production.
[8] The barrier function-improving agent according to any one of [1] to [3], which is for promoting the production of aquaporin-3.
[9] A barrier function-improving composition comprising the barrier function-improving agent according to any one of [1] to [8] and a pharmaceutically acceptable carrier.
[10] The composition for improving barrier function according to [9], wherein the total content of the tocopherol phosphate and/or salt thereof is 0.01 to 10% by mass.

ADVANTAGE OF THE INVENTION According to this invention, the barrier function improving composition which contains the barrier function improving agent which can improve a barrier function effectively, and the said barrier function improving agent can be provided.

1 is a photograph of skin tissue subjected to immuno-antibody staining in Test Example 1. FIG.

(Barrier function improving agent)
In one embodiment, the present invention provides a skin barrier function-improving agent containing a tocopherol phosphate and/or a salt thereof as an active ingredient.
Here, the term "barrier function" refers to the ability of the skin to prevent evaporation of moisture from the inside due to dryness, ultraviolet rays, and other physical and chemical stimuli from the outside world, and to protect against the invasion of foreign substances from the outside world. .
The barrier function-improving agent of the present embodiment effectively improves the barrier function by promoting the production of filaggrin, involucrin, loricrin, and transglutaminase 1, which are differentiation markers, and aquaporin 3, which is a cell membrane water channel. can be done.

<Tocopherol phosphate>
The barrier function improving agent of the present embodiment is not particularly limited as long as it contains tocopherol phosphate or a salt thereof as an active ingredient. Examples of the tocopherol phosphate used in the barrier function improving agent of the present embodiment include compounds represented by the following general formula (1).

［式中、Ｒ^１、Ｒ^２及びＲ^３は、互いに独立に、水素原子又はメチル基を表す。］

[In the formula, R ¹ , R ² and R ³ each independently represent a hydrogen atom or a methyl group. ]

The tocopherol phosphate includes α ^{-tocopherol phosphate (R 1 ,} R ^{2 , R 3 =} CH ³ ), β _- tocopherol phosphate, and ester (R ¹ , R ³ = CH ₃ , R ² = H), γ-tocopherol phosphate (R ¹ , R ² = CH ₃ , R ³ = H), δ-tocopherol phosphate (R ¹ = CH ₃ , R ² , R ³ = H), ζ ₂ -tocopherol phosphate (R ² , R ³ = CH ₃ , R ¹ = H), η-tocopherol phosphate (R ² = CH ₃ , R ¹ , R ³ =H) and the like.

The tocopherol phosphate is not particularly limited and may be any of these tocopherol phosphates. Among these, α-tocopherol phosphate and γ-tocopherol phosphate are preferred, and α-tocopherol phosphate is more preferred.

Since the compound represented by the above general formula (1) has an asymmetric carbon atom at the 2-position of the chroman ring, it exists in d- and l-stereoisomers and dl-stereoisomers. The tocopherol phosphate may be any of these stereoisomers, but the dl form is preferred.

Among the above, as the tocopherol phosphate, dl-α-tocopherol phosphate and dl-γ-tocopherol phosphate are preferred, and dl-α-tocopherol phosphate is more preferred.

The salt of tocopherol phosphate is not particularly limited, but examples thereof include salts with inorganic bases and salts with organic bases.

Salts with inorganic bases include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; ammonium salts;
Salts with organic bases include, for example, alkylammonium salts and salts with basic amino acids.

Among the above, the salt of tocopherol phosphate is preferably an alkali metal salt, more preferably a sodium salt. Alkali metal salts of tocopherol phosphates, particularly sodium salts, have the advantage of being highly soluble in water and easy to handle because they are powdery.

Preferred embodiments of the tocopherol phosphate include alkali metal salts (eg, sodium salts) of the compounds represented by the general formula (1), alkali metal salts (eg, sodium salts) of α-tocopherol phosphates, γ - alkali metal salt of tocopherol phosphate (e.g., sodium salt), alkali metal salt of dl-α-tocopherol phosphate (e.g., sodium salt), alkali metal salt of dl-γ-tocopherol phosphate (e.g., sodium salt) sodium salt) and the like.

Among the alkali metal salts of tocopherol phosphate, the sodium salt of α-tocopherol phosphate and the sodium salt of γ-tocopherol phosphate are preferred, and the sodium salt of α-tocopherol phosphate is more preferred.

The sodium salt of dl-α-tocopherol phosphate is commercially available from Showa Denko under the product name of TPNa (registered trademark) (display name: sodium tocopheryl phosphate). The TPNa is exemplified as a preferred example of the tocopherol phosphate.

As the barrier function-improving agent of the present embodiment, one selected from tocopherol phosphates and salts thereof may be used alone, or two or more thereof may be used in combination. The barrier function improving agent of the present embodiment preferably contains a salt of tocopherol phosphate, and more preferably an alkali metal salt (eg, sodium salt) of tocopherol phosphate is used alone.

A tocopherol phosphate or a salt thereof can be produced by known production methods such as those described in JP-A No. 59-44375 and International Publication No. 97/14705.
For example, a tocopherol phosphate can be obtained by allowing a phosphorylating agent such as phosphorus oxychloride to act on tocopherol dissolved in a solvent, followed by appropriate purification after completion of the reaction. Furthermore, by neutralizing the obtained tocopherol phosphate with a metal oxide such as magnesium oxide, a metal hydroxide such as sodium hydroxide, or ammonium hydroxide or alkylammonium hydroxide, tocopherol phosphate A salt of the ester can be obtained.

Hereinafter, tocopherol phosphates and salts thereof may be collectively referred to as "tocopherol phosphates, etc.".

The barrier function-improving agent of the present embodiment can be used by administering itself to a patient for the purpose of treating rough skin, dry skin, psoriasis, atopic dermatitis, and the like. In addition, the barrier function-improving agent of the present embodiment can also be used by being blended in pharmaceuticals and cosmetics for the purpose of improving the barrier function. In addition, it may be used by blending with the composition for improving barrier function described below.

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 the barrier function by promoting the production of involucrin.
The barrier function-improving agent of the present embodiment can effectively improve the barrier function by promoting the production of loricrin.
The barrier function-improving agent of the present embodiment can effectively improve the barrier function by promoting the production of transglutaminase-1.
The barrier function-improving agent of the present embodiment can effectively improve the barrier function by promoting the production of aquaporin-3.
Since the barrier function-improving agent of the present embodiment can effectively improve the barrier function, it can be used for prevention or treatment of rough skin, dry skin, psoriasis, and atopic dermatitis.

(filagrin)
Filaggrin is a kind of basic protein produced in epidermal granule cells, and has the function of promoting the fibrogenesis reaction of keratin fibers progressing in stratum corneum cells. Filaggrin is further decomposed into amino acids by the action of protease during the process of migration of stratum corneum cells from the lower layer to the upper layer, and the free amino acids function as natural moisturizing factors (NMF) in the stratum corneum. By promoting the production of filaggrin, the amount of NMF increases and the moisturizing power of the stratum corneum increases, thus improving the barrier function of the skin.

(Involucrin)
Involucrin is one of the major proteins that constitute the cornified envelope of stratum corneum, and is used as an indicator of the early stages of differentiation of keratinocytes (epidermal keratinocytes). By promoting the production of involucrin, the formation of the cornified envelope, which is a structure responsible for the moisturizing power of the stratum corneum, is promoted, thereby improving the barrier function of the skin.

(loricrin)
Loricrin is a hydrophobic protein rich in glycine, serine, cysteine, etc., and is a major component of the cornified envelope. By promoting the production of involucrin, the formation of cornified envelopes is promoted, thereby improving the barrier function of the skin.

(Transglutaminase 1)
Transglutaminase 1 is an enzyme that forms an isopeptide bond between glutamine and lysine in proteins and participates in the cornified envelope formation reaction. By promoting the production of transglutaminase 1, the formation of the cornified envelope is promoted, so that the barrier function of the skin is improved.

(Aquaporin 3)
Aquaporin 3 is a protein with pores present in cell membranes, and functions as a water channel that regulates intracellular water content. By promoting the production of aquaporin 3, the water content in epidermal cells increases, thereby improving the barrier function of the epidermis.

The barrier function-improving agent of the present embodiment is administered to patients at high risk of developing rough skin, dry skin, psoriasis, atopic dermatitis, etc., and is used to prevent rough skin, dry skin, psoriasis, atopic dermatitis, etc. You may In addition, the barrier function-improving agent of the present embodiment is administered to a patient who has developed rough skin, dry skin, psoriasis, atopic dermatitis, etc., and suppresses the progression or deterioration of rough skin, dry skin, psoriasis, atopic dermatitis, etc. may be used to

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 later, and may be administered orally or parenterally. It may be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intraperitoneally, or the like, or may be administered intrarectally as a suppository, or administered to the skin as an external preparation.

(Composition for improving barrier function)
The barrier function-improving composition of the present embodiment contains a barrier function-improving agent containing the above-described tocopherol phosphate and/or salt thereof, and a pharmaceutically acceptable carrier.

The barrier function-improving composition of the present embodiment is prepared by mixing the barrier function-improving agent described above, a pharmaceutically acceptable carrier, and optionally other ingredients according to a conventional method (for example, the method described in the Japanese Pharmacopoeia). It can be produced by formulating as

As used herein, the term "pharmaceutically acceptable carrier" means a carrier that does not inhibit the physiological activity of the active ingredient and that does not exhibit substantial toxicity to the subject to which it is administered.
The term "substantially non-toxic" means that the component does not show toxicity to the administration subject at the dosage normally used.
Pharmaceutically acceptable carriers are not particularly limited, and include excipients, binders, disintegrants, lubricants, stabilizers, diluents, solvents for injections, moisturizers, texture improvers, and surfactants. , polymer/thickening/gelling agent, solvent, propellant, antioxidant, reducing agent, oxidizing agent, chelating agent, acid, alkali, powder, inorganic salt, water, metal-containing compound, unsaturated monomer , polyhydric alcohols, polymer additives, wetting agents, thickeners, tackifiers, oily raw materials, liquid matrices, fat-soluble substances, polymer carboxylates, and the like.

Specific examples of these components include those described in International Publication No. 2016/076310. Furthermore, specific examples of the polymer/thickening/gelling agent include methacryloyloxyethylphosphorylcholine, butyl methacrylate, and polymers thereof.
The pharmaceutically acceptable carriers in the barrier function-improving composition of the present embodiment may be used singly or in combination of two or more.

In addition, other ingredients are not particularly limited, and include preservatives, antibacterial agents, ultraviolet absorbers, whitening agents, vitamins other than tocopherol phosphate and derivatives thereof, antiphlogistic agents, anti-inflammatory agents, and hair growth agents. , blood circulation promoters, stimulants, hormones, anti-wrinkle agents, anti-aging agents, tightening agents, cooling agents, warming agents, wound healing agents, stimulants, pain relievers, cell activators, plants, animals, Microorganism extract, seed oil, antipruritic agent, exfoliating/dissolving agent, antiperspirant, cooling agent, astringent, enzyme, nucleic acid, fragrance, pigment, coloring agent, dye, pigment, anti-inflammatory analgesic, antifungal agent, antihistamine, Hypnotic sedatives, tranquilizers, antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antibacterial substances, antiepileptic agents, coronary vasodilators, herbal medicines, antipruritic agents, exfoliating agents, UV blockers, Bactericides, antioxidants, pH adjusters, additives, metal soaps and the like can be mentioned. Specific examples of these components include those described in International Publication No. 2016/076310. Furthermore, specific examples of plant/animal/microorganism extracts include Lapsana communis flower/leaf/stem, tea leaves, and the like. Specific examples of seed oils include moringa seed oil. Specific examples of perfumes include perillaldehyde.
Other components may be used singly or in combination of two or more.

The barrier function-improving composition of the present embodiment can contain a therapeutically effective amount of the barrier function-improving agent. By "therapeutically effective amount" is meant an amount of an agent effective to treat or prevent disease in a patient. A therapeutically effective dose may vary depending on the disease state, age, sex, body weight, etc. of the administration subject.
In the barrier function-improving composition of the present embodiment, the therapeutically effective amount of the barrier function-improving agent may be an amount in which the tocopherol phosphate or the like can improve the barrier function. In addition, the therapeutically effective amount of the barrier function-improving agent can promote the production of at least one selected from the group consisting of filaggrin, involucrin, loricrin, transglutaminase 1, and aquaporin 3. can be an amount.

The therapeutically effective amount (total content of tocopherol phosphate and the like) of the barrier function improving agent in the composition for improving barrier function of the present embodiment is, for example, 0.01 to 0.01 with respect to the total amount of the composition for improving barrier function. It may be 10% by mass, for example 0.1 to 10% by mass, for example 0.1 to 5% by mass, for example 0.1 to 3% by mass. , for example 0.1 to 2% by mass, for example 0.3 to 2% by mass, for example 0.6 to 1.5% by mass.
In addition, the total content of tocopherol phosphates and the like means the content of the compound when one type of tocopherol phosphates or salts thereof is used alone, and tocopherol phosphates and/or salts thereof. is used in combination of two or more, it means the total content of these compounds.

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

(Pharmaceutical composition)
In one embodiment, the present invention provides a barrier function-improving pharmaceutical composition containing the above-described barrier function-improving agent and a pharmaceutically acceptable carrier.

In the pharmaceutical composition of the present embodiment, the pharmaceutically acceptable carrier is not particularly limited, and in addition to those listed above, carriers generally used for pharmaceuticals can be used. For example, Japanese Pharmacopoeia, Japanese Non-Pharmacopoeia Pharmaceutical Standards, Pharmaceutical Excipients Standards 2013 (Yakuji Nippo, 2013), Pharmaceutical Excipients Dictionary 2016 (Edited by Japan Pharmaceutical Excipients Association, Yakuji Nippo, 2016), Handbook of Common raw materials described in Pharmaceutical Excipients, 7th edition (Pharmaceutical Press, 2012) and the like can be used.
One type of pharmaceutically acceptable carrier may be used alone, or two or more types may be used in combination.

The pharmaceutical composition of this embodiment may contain other components in addition to the barrier function-improving agent and the pharmaceutically acceptable carrier. Other ingredients are not particularly limited, and general pharmaceutical additives can be used. In addition, active ingredients other than the barrier function-improving agent described above can also be used as other ingredients. Pharmaceutical excipients and active ingredients as other ingredients include, in addition to those listed above, for example, the Japanese Pharmacopoeia, Japanese Pharmaceutical Standards Outside the Pharmacopoeia, Pharmaceutical Excipients Standards 2013 (Yakuji Nipposha, 2013), pharmaceutical additives Common raw materials described in Monozukuri 2016 (edited by Japan Pharmaceutical Excipients Association, Yakuji Nippo, 2016), Handbook of Pharmaceutical Excipients, 7th edition (Pharmaceutical Press, 2012), etc. can be used. Other components may be used singly or in combination of two or more.

The dosage form of the pharmaceutical composition of the present embodiment is not particularly limited, and may be a dosage form generally used as a pharmaceutical formulation. For example, orally administered dosage forms such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions; and parenteral forms such as injections, suppositories, and skin preparations Examples include a dosage form that is administered in a targeted manner. Pharmaceutical compositions in these dosage forms can be formulated according to standard methods (eg, methods described in the Japanese Pharmacopoeia).

The administration method of the pharmaceutical composition of the present embodiment is not particularly limited, and administration can be performed by a method generally used as a pharmaceutical administration method. For example, it may be administered orally as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions, etc.; It may be administered intravenously, intraarterially, intramuscularly, intradermally, subcutaneously, intraperitoneally, etc. by mixing with a general infusion solution such as It may also be administered to the skin.

The dosage of the pharmaceutical composition of this embodiment can be a therapeutically effective amount. A therapeutically effective amount may be appropriately determined depending on the symptoms, body weight, age, sex, etc. of the patient, dosage form of the pharmaceutical composition, administration method, and the like.
For example, the dosage of the pharmaceutical composition of the present embodiment is 0.01 to 500 mg per dosage unit form as tocopherol phosphate etc. in the case of oral administration, and tocopherol phosphate etc. in the case of injection. Examples include 0.02 to 250 mg per dosage unit form, and 0.01 to 500 mg per dosage unit form as tocopherol phosphate and the like in the case of suppositories. In the case of an external preparation for skin, for example, tocopherol phosphate and the like can be exemplified in an amount of 0.15 to 500 mg, for example, 0.15 to 300 mg, for example, 0.15 mg, per dosage unit form. It may be up to 200 mg, for example 0.2-100 mg.

The administration interval of the pharmaceutical composition of the present embodiment may be appropriately determined according to the symptoms, body weight, age, sex, etc. of the patient, dosage form of the pharmaceutical composition, administration method, and the like. For example, it can be done once a day or about 2 to 3 times a day.

The pharmaceutical composition of this embodiment can be used for treatment or prevention of symptoms or diseases caused by decreased barrier function. Such symptoms or diseases include, for example, rough skin, dry skin, psoriasis, atopic dermatitis, and the like.

The pharmaceutical composition of the present embodiment is used, for example, to suppress the progression of rough skin, dry skin, psoriasis, or atopic dermatitis by administering to patients with rough skin, dry skin, psoriasis, or atopic dermatitis. be able to. In addition, the pharmaceutical composition of the present embodiment can be administered to patients with rough skin, dry skin, psoriasis, or atopic dermatitis to treat rough skin, dry skin, psoriasis, or atopic dermatitis. can. In addition, the pharmaceutical composition of this embodiment can be used to treat symptoms or diseases caused by decreased production of filaggrin, involucrin, loricrin, transglutaminase-1, or aquaporin-3.

The pharmaceutical composition of the present embodiment is used to prevent rough skin, dry skin, psoriasis, or atopic dermatitis by administering to patients at high risk of developing rough skin, dry skin, psoriasis, or atopic dermatitis. can also

(cosmetics)
In one embodiment, the present invention provides a cosmetic for improving barrier function, containing the barrier function-improving agent described above and a pharmaceutically acceptable carrier.

In the cosmetics of the present embodiment, the pharmaceutically acceptable carrier is not particularly limited, and in addition to those listed above, carriers commonly used in cosmetics can be used. For example, the second edition commentary on the Standards for Cosmetic Ingredients (edited by Japan Kozokusho Kyokai, Yakuji Nippousha, 1984), Standards for Ingredients Outside the Standards for Cosmetic Ingredients (supervised by the Examination Division of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nippousha, 1993), Standards for Cosmetic Ingredients Supplement to external ingredient standards (supervised by the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nippousha, 1993), Permit criteria for each cosmetic type (supervised by the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, Yakuji Nipposha, 1993), Dictionary of Cosmetic Ingredients (Nikko Chemicals, Inc., 1993) 1991), 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.

The cosmetic of this embodiment may contain other ingredients in addition to the barrier function improving agent and the pharmaceutically acceptable carrier. Other ingredients are not particularly limited, and general cosmetic additives can be used. In addition, active ingredients other than the barrier function-improving agent described above can also be used as other ingredients. Cosmetic additives and active ingredients as other ingredients, in addition to those listed above, include, for example, Cosmetic Ingredients Standard 2nd Edition Commentary (edited by Nippon Kosho Kyokai, Yakuji Nippousha, 1984), Cosmetic Ingredients Outside Standards Standards (Ministry of Health and Welfare Pharmaceutical Affairs Bureau, Examination Division Supervision, Yakuji Nippo, 1993), Cosmetic Ingredient Standards Supplementation (Ministry of Health and Welfare Pharmaceutical Affairs Bureau, Examination Division, Yakuji Nippo, 1993) Bureau Examination Division, Yakuji Nippousha, 1993), Cosmetic Ingredients Dictionary (Nikko Chemicals, 1991), International Cosmetic Ingredient Dictionary and Handbook 2002 Ninth Edition Vol. 1 to 4, by CTFA, etc., can be used. Other components may be used singly or in combination of two or more.

The form of the cosmetic of the present embodiment is not particularly limited, and may be a form commonly used as a cosmetic. Hair cosmetics such as shampoos, rinses, and hair styling products; basic cosmetics such as facial cleansers, cleansing agents, lotions, milky lotions, lotions, creams, gels, sunscreens, packs, masks, and serums; foundations , make-up bases, lipsticks, lip glosses, blushes, and other makeup cosmetics; body cleansers, body powders, deodorants, and other body cosmetics. These cosmetics can be manufactured according to a conventional method.

In addition, the dosage form of the cosmetic of the present embodiment is not particularly limited. Emulsified type such as /O type, emulsified polymer type, oily, solid, liquid, paste, stick, volatile oil, powder, jelly, gel, paste, cream, sheet, film , mist type, spray type, aerosol type, multilayer type, foam type, flake type and the like.

The amount of the cosmetic used in this embodiment is not particularly limited, but it can be an effective amount for improving the barrier function.
For example, the amount of the cosmetic used in the present embodiment can be exemplified by 0.15 to 500 mg, for example, 0.15 to 300 mg per use as the amount of tocopherol phosphate, etc. For example, it may be from 0.15 to 200 mg, for example from 0.2 to 100 mg.

The use interval of the cosmetic of the present embodiment is not particularly limited, but can be, for example, about once or two to three times a day.

The cosmetic of the present embodiment can be used to alleviate symptoms caused by deterioration of barrier function. Alternatively, in order to prevent the onset of symptoms caused by the deterioration of the barrier function, it may be used in daily skin care and make-up by subjects at high risk of developing these.

(Other embodiments)
In one embodiment, the present invention provides a method of improving barrier function comprising administering a tocopherol phosphate and/or salt thereof to a subject.

In one embodiment, the present invention provides a method of promoting production of filaggrin, involucrin, loricrin, or transglutaminase 1, comprising administering tocopherol phosphate and/or a salt thereof to a subject.

In one embodiment, the present invention provides a method of promoting production of aquaporin-3, comprising administering tocopherol phosphate and/or a salt thereof to a subject.

In one embodiment, the present invention provides tocopherol phosphates and/or salts thereof for improving barrier function.

In one embodiment, the present invention provides tocopherol phosphates and/or salts thereof for promoting filaggrin, involucrin, loricrin, or transglutaminase-1 production.

In one embodiment, the present invention provides tocopherol phosphates and/or salts thereof for promoting aquaporin-3 production.

In one embodiment, the present invention provides tocopherol phosphates and/or salts thereof for preventing or treating rough skin, dry skin, psoriasis, or atopic dermatitis.

In one embodiment, the present invention provides use of a tocopherol phosphate and/or a salt thereof for manufacturing a barrier function-improving agent.

In one embodiment, the present invention provides use of a tocopherol phosphate and/or a salt thereof for producing a filaggrin, involucrin, loricrin, or transglutaminase-1 production-enhancing agent.

In one embodiment, the present invention provides use of a tocopherol phosphate and/or a salt thereof for producing an aquaporin-3 production promoter.

In one embodiment, the present invention provides use of a tocopherol phosphate and/or a salt thereof for producing a composition for improving barrier function.

In one embodiment, the present invention provides use of a tocopherol phosphate and/or a salt thereof for producing a composition for promoting the production of filaggrin, involucrin, loricrin, or transglutaminase-1.

In one embodiment, the present invention provides use of a tocopherol phosphate and/or a salt thereof for producing a composition for promoting aquaporin-3 production.

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

[Tocopherol Phosphate]
In the following test examples, α-TPNa (sodium dl-α-tocopheryl phosphate, product name: TPNa (registered trademark)) manufactured by Showa Denko K.K. was used. In Test Examples 1 and 2, an “α-TPNa solution” in which α-TPNa was dissolved in an aqueous ethanol solution was used.

[Tocopherol Acetate]
In the following test examples, tocopherol acetate manufactured by Wako Pure Chemical Industries, Ltd. was used. In Test Examples 1 and 2, a "tocopherol acetate solution" in which tocopherol acetate was dissolved in an aqueous ethanol solution was used.

[Test Example 1] Effect of Promoting Expression of Differentiation Markers and Aquaporin 3 By the following method, the effects of promoting the expression of differentiation markers (filagrin, involucrin, loricrin, transglutaminase 1) and aquaporin 3 in human three-dimensional model skin were verified.
Human 3D model skin (manufactured by Kurabo Industries) was transplanted into EPI-100 medium (manufactured by Kurabo Industries), and after 30 minutes, in Example 1, α-TPNa 1% ( V/V) was dissolved in α-TPNa solution (30 μL) was added to the surface of the skin and cultured for 6 hours. In Comparative Example 1, 30 μL of a tocopherol acetate solution prepared by dissolving 0.2% (V/V) tocopherol acetate in 0.5% (V/V) ethanol aqueous solution was added to the skin surface and cultured for 6 hours. In Reference Example 1, 0.5% (V/V) ethanol aqueous solution was added to the skin surface and cultured for 6 hours. Thereafter, the skin was washed with physiological saline, fixed with ALTFiX (registered trademark) (manufactured by Pharma Co., Ltd.), and embedded in paraffin to prepare a skin tissue section.
Immunoantibody staining was performed on skin tissue after sections were deparaffinized and dehydrated. As primary antibodies, filaggrin, involucrin, loricrin, aquaporin 3 (all manufactured by Abcam) and transglutaminase 1 (manufactured by Novus Biologicals) were used. Each antibody was administered at a concentration of filaggrin (1:200), involucrin (1:150), loricrin (1:150), transglutaminase 1 (1:500), aquaporin 3 (1:500) at 0.05% twin -20 containing phosphate buffer was used for dilution. As a secondary antibody, a horseradish-derived peroxidase-conjugated anti-rabbit IgG antibody (manufactured by Abcam) was used after being diluted to 1:200 with a phosphate buffer containing 0.05% Twin-20. After antibody reaction and washing, peroxidase coloring substrate 3,3′-diaminobenzidine tetrahydrochloride (manufactured by Wako Pure Chemical Industries, Ltd.) was used to carry out coloring reaction.
Each tissue was observed with Nikon TS1 and photographed. Fig. 1 shows an example of a photograph taken.

From the results shown in FIG. 1, in Example 1 in which the α-TPNa solution was added, compared to Reference Example 1 in which the aqueous ethanol solution was added and Comparative Example 1 in which the tocopherol acetate solution was added, the differentiation markers filaggrin, involucrin, All of loricrin, transglutaminase 1, and aquaporin 3 were found to have expression-enhancing effects.

[Test Example 2] Effect of Improving Transepidermal Water Loss (TEWL) of Skin The following method was used to verify the effect of improving the transepidermal water loss (TEWL) of human three-dimensional model skin.
Human 3D model skin (manufactured by Kurabo Industries) was transplanted into EPI-100 medium (manufactured by Kurabo Industries), and 30 minutes later, in Example 2, α-TPNa 1% ( V/V) was dissolved in α-TPNa solution (30 μL) was added to the surface of the skin and cultured for 6 hours. In Comparative Example 2, 30 μL of a tocopherol acetate solution prepared by dissolving 0.2% (V/V) tocopherol acetate in 0.5% (V/V) ethanol aqueous solution was added to the skin surface and cultured for 6 hours. In Reference Example 2, 0.5% (V/V) ethanol aqueous solution was added to the skin surface and cultured for 6 hours. Thereafter, the skin was washed with a phosphate buffer and cultured, and the transepidermal water loss (TEWL) was measured 72 hours after the addition of each of the above samples using VAPO SCAN (manufactured by Nippon Ash Co., Ltd.). The measured values of Example 2 and Comparative Example 2 are shown as relative values when the measured value of Reference Example 2 is set to 1.00. Table 1 shows the results.

From the results shown in Table 1, in Example 2 in which the α-TPNa solution was added, transepidermal water loss (TEWL) was lower than in Reference Example 2 in which an aqueous ethanol solution was added and Comparative Example 2 in which a tocopherol acetate solution was added. It was confirmed that the barrier function was enhanced.

INDUSTRIAL APPLICABILITY The present invention provides a barrier function-improving agent capable of effectively improving barrier function, and a barrier function-improving composition containing the barrier function-improving agent.

Claims (10)

A skin barrier function-improving agent containing a tocopherol phosphate and/or a salt thereof as an active ingredient. The barrier function improving agent according to claim 1, wherein the tocopherol phosphate and/or its salt is α-tocopherol phosphate and/or its salt. 3. The barrier function improving agent according to claim 1, wherein the tocopherol phosphate salt is contained as an active ingredient, and the tocopherol phosphate salt is a sodium salt of tocopherol phosphate. The barrier function-improving agent according to any one of claims 1 to 3, which is for promoting the production of filaggrin. The barrier function-improving agent according to any one of claims 1 to 3, which is for promoting the production of involucrin. The barrier function-improving agent according to any one of claims 1 to 3, which is for promoting the production of loricrin. 4. The agent for improving barrier function according to any one of claims 1 to 3, which is for promoting the production of transglutaminase 1. The barrier function-improving agent according to any one of claims 1 to 3, which is for promoting the production of aquaporin-3. A barrier function-improving composition comprising the barrier function-improving agent according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier. 10. The composition for improving barrier function according to claim 9, wherein the total content of said tocopherol phosphate and/or salt thereof is 0.01 to 10% by mass.

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