Filaggrin and / or epidermal hyaluronic acid production promoter

Abstract

To provide a novel agent for promoting the production of filaggrin and / or epidermal hyaluronic acid.SOLUTION: An agent for promoting the production of filaggrin and / or epidermal hyaluronic acid contains at least one compound selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for promoting the production of filaggrin and / or epidermal hyaluronic acid. [Background technology]

[0002] In recent years, skin problems have been increasing due to various changes in living and social environments, such as increases in air pollutants and ultraviolet rays, increases in pests, pathogens, and viruses, and an increasingly stressful society. Furthermore, the number of patients in Japan suffering from chronic skin diseases such as atopic dermatitis, psoriasis, and xerosis has been increasing for over 20 years. These skin problems and diseases are known to be caused or worsened by the entry of foreign substances, such as viruses, bacteria, and chemicals, as well as allergens (hereinafter referred to as "foreign substances") into the skin from the outside world. Healthy skin has a skin barrier function that prevents the entry of foreign substances into the skin, as a function of maintaining homeostasis.

[0003] The skin barrier function, which is primarily composed of sebum present on the skin surface, ceramides filling the gaps between keratinocytes, filaggrin present in keratinocytes, and its degradation product, natural moisturizing factor (NMF), is a function that prevents the penetration of foreign substances from the skin surface and the evaporation of moisture from within the skin. A weakening or breakdown of the skin barrier function allows foreign substances to penetrate the skin surface more easily, which is known to cause or worsen skin diseases and skin problems such as allergic dermatitis, xerosis, inflammation, pruritus, and rough skin. At the same time, increased moisture evaporation from within the skin is known to cause skin problems such as dry skin, flaky skin, and rough skin, as well as the worsening of atopic dermatitis.

[0004] In recent years, one component that has attracted attention as a key component of the stratum corneum is filaggrin, a key component of the stratum corneum that plays a key role in skin barrier function. Filaggrin is first produced as profilaggrin in the granular layer of the epidermis. Profilagrin is a high molecular weight protein with a molecular weight of approximately 400 kDa, consisting of an arrangement of 10 to 12 filaggrin units, and is degraded to filaggrin within the stratum corneum. Filaggrin within the stratum corneum aggregates keratin fibers, which form the skeleton of keratinocytes, and helps maintain the physical strength and elasticity of keratinocytes and the stratum corneum. Furthermore, filaggrin is degraded into amino acids, urocanic acid, and other components in the upper layers of the stratum corneum. These are known as natural moisturizing factors (NMFs) and are responsible for retaining moisture in the stratum corneum and preventing keratinocytes from drying out, deforming, atrophying, or shedding. The gene encoding profilaggrin is the FLG gene, and mutations in the FLG gene are known to cause the loss or thinning of the granular layer, resulting in a decrease in profilaggrin production and ultimately in impaired skin barrier function (Non-patent documents 1 and 2).

[0005] It has been reported in the UK and Japan that profilaggrin gene abnormalities are found in patients with atopic dermatitis, and this gene abnormality has also been found to be involved in bronchial asthma, food allergies such as peanut allergies, hay fever, etc. Furthermore, the rate of filaggrin abnormalities is significantly higher in patients with metal allergies and hand eczema compared to healthy individuals (Non-Patent Document 3).

[0006] In many organisms, filaggrin is responsible for the skin barrier function, and in fact, it is known that filaggrin plays an important role in the barrier function of dogs (Non-Patent Document 4).

[0007] Another component responsible for skin barrier function is hyaluronic acid (epidermal hyaluronic acid) present in the epidermis. Like dermal hyaluronic acid, epidermal hyaluronic acid is a linear macromolecule with a repeating structure of N-acetylglucosamine and glucuronic acid, and is known to have extremely high water-retaining capacity. Dermal hyaluronic acid functions as a molecule that builds the extracellular matrix and is involved in the formation of deep wrinkles. Furthermore, epidermal hyaluronic acid is present in the intercellular spaces of epidermal cells to maintain the intercellular space, and by improving the moisture retention of the stratum corneum, it prevents deformation, atrophy, and shedding of keratinocytes due to dryness, thereby preventing the penetration of foreign substances from the outside. Furthermore, epidermal hyaluronic acid contributes to the proliferation and differentiation of keratinocytes, including the granular layer, where filaggrin, ceramide, and other substances are produced, thereby indirectly supporting the maintenance and improvement of skin barrier function (Non-Patent Document 5).

[0008] Approximately 50% of the body's hyaluronic acid is said to be present in the skin, and its metabolism is controlled by hyaluronic acid synthase (HAS) and hyaluronidase (hyaluronidase). There are three isozymes of hyaluronic acid synthase (HAS1, HAS2, and HAS3), and it has been reported that HAS1 and HAS2 contribute to hyaluronic acid synthesis in the dermis, while HAS3 contributes to hyaluronic acid synthesis in the epidermis. Expression of HAS3 is important for promoting hyaluronic acid production targeted at the epidermis (Non-Patent Document 5). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Japanese Patent Application Laid-Open No. 2008-88075 [Patent Document 2] Japanese Patent Application Laid-Open No. 2012-232920 [Patent Document 3] Japanese Patent Publication No. 2020-164456 [Patent Document 4] Japanese Patent Application Laid-Open No. 2009-46465 [Patent Document 5] Japanese Patent Application Laid-Open No. 2014-218481 [Patent Document 6] Japanese Patent Application Publication No. 2020-90544 [Non-patent literature]

[0010] [Non-Patent Document 1] Cosmetic Dermatology, 2nd Edition, "Stratum Cortex and Dry Skin", pp. 8-21, Nanzando, May 2009 [Non-patent document 2] Allergy 64(9)1189-1195 (2005) Atsushi Otsuka, Kenji Kabashima [Non-patent document 3] The Cutting Edge of Cosmetic Science, "Cell Biology of Skin Barrier Function," pp. 17-24, CMC Publishing, April 2014 [Non-patent document 4] Didier Pin et al., Journal of Histochemistrya and Cytochemistry, 67,85-97(2019) [Non-patent document 5] Tetsuya Sayo, PhD dissertation, "Elucidation of the epidermal hyaluronic acid synthesis control mechanism," Tokyo University of Pharmacy and Life Sciences (2013) [Non-patent document 6] Masahiro Ohta, Journal of the Japanese Society of Cosmetic Chemists, 53(3), 171-180(2019) Summary of the Invention [Problem to be solved by the invention]

[0011] Many plant extracts are known as filaggrin production promoters, such as Shizuka extract (Patent Document 1) and Long Pepper extract (Patent Document 2). However, most plant extracts are cultivated in small quantities, and production volume fluctuates depending on the climate of the year. There is also considerable variation in quality depending on the place of origin, cultivation method, harvest time, etc., and there are also problems with stable supply.

[0012] Known hyaluronic acid synthesis promoters include retinol (Non-Patent Document 6), its metabolite retinoic acid (Non-Patent Document 5), and the stilbene compound piceatannol (Patent Document 3). However, retinol has problems with skin irritation and stability, and its lipid solubility makes it difficult to incorporate into aqueous cosmetics. While retinoic acid is highly effective in promoting HAS3 expression, it is classified as a prescription drug in Japan due to its extreme skin irritation and is not used in cosmetics. Furthermore, piceatannol is known to have weak HAS3 expression ability, and all of these extracts have safety and efficacy issues. Meanwhile, plant extracts known to promote epidermal hyaluronic acid synthesis include Golden Bean Extract, Polygala gracilis, and Small Flower Extract (Patent Document 4), pineapple extract (Patent Document 5), and Tremella Fuciformis Fermented Extract (Patent Document 6). However, as mentioned above, these plant extracts have issues with quality and stable supply.

[0013] As such, it has been found that many of the ingredients that increase filaggrin and epidermal hyaluronic acid are plant extracts with quality and supply issues, or ingredients with safety and effectiveness issues. Therefore, further improvements are needed.

[0014] The present invention relates to providing a novel agent for promoting the production of filaggrin and / or epidermal hyaluronic acid. [Means for solving the problem]

[0015] The present invention relates to the following [1] to [7]. [1] A filaggrin and / or epidermal hyaluronic acid production promoter comprising one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof. [2] A composition for promoting the production of filaggrin and / or epidermal hyaluronic acid, comprising one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof. [3] An agent for improving symptoms requiring suppression of transepidermal water loss, comprising one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof. [4] An agent for improving symptoms requiring an increase in stratum corneum moisture, comprising one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof. [5] A cosmetic, pharmaceutical, or quasi-drug product comprising the production promoter described in [1], the production-promoting composition described in [2], or the improving agent described in [3] or [4]. [6] A method for producing a cosmetic, pharmaceutical, or quasi-drug, comprising the step of adding one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof, to a cosmetic raw material, pharmaceutical raw material, or quasi-drug raw material. [7] A method for promoting the production of filaggrin and / or epidermal hyaluronic acid using one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof. [Effects of the Invention]

[0016] According to the present invention, a novel agent for promoting the production of filaggrin and / or epidermal hyaluronic acid can be provided. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is a graph showing the results of transepidermal water loss (TEWL) in Example 3. [Figure 2] 10 is a graph showing the results of stratum corneum moisture content in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0018] As a result of investigating the above-mentioned problems, the inventors of the present invention have surprisingly newly discovered that the production of filaggrin and epidermal hyaluronic acid can be promoted by using one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof.

[0019] Therefore, the present invention discloses a filaggrin and / or epidermal hyaluronic acid production promoter (hereinafter also referred to as "the production promoter of the present invention"), which comprises one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof.In addition, the present invention also discloses a method for promoting the production of filaggrin and / or epidermal hyaluronic acid using these components. Here, examples of "pharmaceutically acceptable salts" include salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases (triethanolamine, triethylamine, aminopropanediol, pyridine, piperidine, pyrimidine, piperazine, morpholine, azepine, etc.), amino acids, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, periodic acid, boric acid, etc.), and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, paratoluenesulfonic acid, carboxylic acids, sulfonic acids, phosphonic acids, sulfinic acids, trifluoroacetic acid, etc.). The carbon chain portion of the organic acid salt may be a linear, branched, or cyclic aliphatic acid salt or an aromatic acid salt. Furthermore, salts with organic bases or organic acids may contain one or more heteroatoms selected from oxygen atoms and nitrogen atoms, for example, in the form of hydroxyl groups. The present invention also encompasses solvates, such as hydrates and ethanol solvates, of one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof, which can be prepared according to known methods.

[0020] Citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, or salts thereof can be obtained by known production methods, for example, by the methods described in the Examples below. As such, the compounds according to the production promoter of the present invention can be prepared by organic synthesis, and therefore can be supplied stably with consistent quality.

[0021] The total content of one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof in the production promoter of the present invention is not particularly limited, and can be, for example, 0.0001 to 100% by mass, 0.001 to 10% by mass, etc.

[0022] As shown in the following examples, the production promoter of the present invention has the effect of promoting the production of filaggrin and epidermal hyaluronic acid.Here, the effect of promoting the production of filaggrin and epidermal hyaluronic acid refers to the increase of the gene of filaggrin and epidermal hyaluronic acid.More specifically, in the test of promoting the expression of profilaggrin gene (FLG) and the test of promoting the expression of epidermal hyaluronic acid synthase gene (HAS3) shown in the following examples, it refers to the effect of increasing the expression amount of gene.

[0023] The increase in the profilaggrin gene (FLG) expression level due to the production promoter of the present invention is not particularly limited, but is preferably 5% or more, more preferably 10% or more, even more preferably 20% or more, even more preferably 30% or more, even more preferably 40% or more, and even more preferably 50% or more compared to the gene expression level of a control that does not contain the production promoter of the present invention. The upper limit can be, for example, 1000% or less, 500% or less, etc.

[0024] The increase in the epidermal hyaluronic acid synthase gene (HAS3) by the production promoter of the present invention is not particularly limited, but is preferably 50% or more, more preferably 100% or more, even more preferably 150% or more, even more preferably 200% or more, and even more preferably 250% or more compared to the gene expression level of a control that does not contain the production promoter of the present invention. The upper limit can be, for example, 1000% or less, 500% or less, etc.

[0025] Furthermore, as will be shown in the Examples below, the production promoter of the present invention has the effect of suppressing transepidermal water loss (TEWL) and increasing the moisture content of the stratum corneum. Therefore, the present invention can be suitably used as an agent for improving symptoms that require suppression of transepidermal water loss (TEWL) and an agent for improving symptoms that require an increase in the moisture content of the stratum corneum. For example, the agent can be used to improve symptoms such as wrinkles, age spots, dullness, sagging, and irregular skin texture, as well as atopic dermatitis, contagious psoriasis (psoriasis vulgaris, psoriasis vulgaris, guttate psoriasis, pustular psoriasis, infectious erythroderma, parapsoriasis en plaque, etc.), ichthyosis vulgaris (Netherton syndrome, Dorfman-Chanarin syndrome, Refsum syndrome, KID syndrome, etc.), and other skin conditions. The composition can be suitably used as an agent for improving symptoms such as Sjögren-Larsson syndrome, Collandi-Hünermann-Happle syndrome, X-linked ichthyosis, congenital ichthyoid erythroderma, epidermolytic ichthyosis, etc.), Darier's disease, asteatotic eczema, nummular eczema, contact dermatitis (diaper dermatitis, caterpillar dermatitis, metal dermatitis, poisonous moth dermatitis, bell-rock dermatitis, etc.), alopecia areata, impetigo, Kaposi's varicelliform eruption, prurigo, lysosomal disease, herpes labialis, and common warts.

[0026] The form of the production promoter of the present invention is not particularly limited as long as it can be applied to the surface of a target or ingested into the body, and it may be formulated as is or prepared into a form that can be used as a raw material for cosmetics, pharmaceuticals, quasi-drugs, etc.

[0027] The present invention also provides a production-promoting composition containing one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof. The form of the composition is not particularly limited as long as it allows the compound of the present invention to be taken up into cells. Examples of the form of the composition include a composition for external use from the perspective of exerting its effects, and a composition for internal use from the perspective of easy ingestion. Either of these forms can be provided as a composition for use in cosmetics, pharmaceuticals, or quasi-drugs.

[0028] External compositions may be used in any form, including cosmetic compositions such as lotions, emulsions, creams, oils, packs, and gels; makeup cosmetics such as foundations, blushes, lipsticks, waxes, and hair tonics; cleansers such as soaps, shampoos, facial cleansers, cleansers, and body washes; skin fragrances such as colognes, deodorants, and perfumes; and bath additives. Pharmaceutical or quasi-drug compositions include solid, semi-solid, and liquid preparations for transdermal or transmucosal (intraoral or intranasal) administration. These include suppositories. Examples of such preparations include emulsions such as emulsions and lotions; liquid preparations such as topical tinctures and liquid preparations for transmucosal administration; ointments such as oily ointments and hydrophilic ointments; patches for transdermal or transmucosal administration such as films, tapes, and poultices; sprays such as aerosols and sprays; and bath additives.

[0029] Examples of the form of the internal composition include forms that can be easily compounded (for example, powder form, granule form), and from the viewpoint of easy ingestion, tablet form, liquid form, etc. Specifically, it can be in the form of a liquid, extract, elixir, capsule (hard capsule, soft capsule, etc.), granule, pill, suspension, emulsion, suppository, powder, spirit, tablet, syrup, infusion, decoction, tincture, lozenge, aromatic perfume, lemonade, liquid extract, etc.

[0030] The total content of one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof in the production-promoting composition of the present invention is determined by taking into account the form of use, method of use, etc. For example, when used as an external composition, the total content is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.01% by mass or more, with no particular upper limit, but preferably 10% by mass or less, more preferably 7% by mass or less, even more preferably 5% by mass or less. When used as an internal composition, the total content is preferably 0.0001% by mass or more, more preferably 0.001% by mass or more, even more preferably 0.01% by mass or more, with no particular upper limit, but preferably 50% by mass or less.

[0031] The amount of the production-promoting composition of the present invention to be used is not fixed and is determined appropriately depending on the form, method of use, purpose of use, and the age, weight, and symptoms of the patient to whom the composition is to be used. For example, in the case of a topical composition, the preferred dose is usually about 0.1 μg to 5 g per day per adult weighing about 50 kg, and the composition may be used once or in several divided doses within the desired range of doses per day. The duration of use is also optional. In this specification, "use" includes not only "use" but also "administration" and "ingestion."

[0032] The target subjects for the production-promoting composition of the present invention are preferably humans who require an increase in filaggrin and / or epidermal hyaluronic acid, but it may also be non-human animals such as monkeys, mice, rats, hamsters, horses, cows, pigs, sheep, goats, dogs, cats, and other pet animals and livestock.

[0033] The production-promoting composition of the present invention can be prepared according to conventional methods by appropriately blending carriers, bases, and / or additives commonly used in the fields of cosmetics, pharmaceuticals, and quasi-drugs. The production-promoting composition of the present invention can also contain other ingredients that can be used to maintain skin homeostasis. Examples of such ingredients include known moisturizing ingredients, such as aloe vera, betaine, pullulan, petrolatum, glycerin, sodium lactate, urea, propylene glycol, sodium ribonucleic acid, 1,3-butylene glycol, chitosan, trehalol, royal jelly, niacinamide, ceramide, sodium tocopheryl phosphate, lactoferrin, oligomarin, and extensin.

[0034] Examples of carriers, bases, and / or additives used in the field of cosmetics include oils, higher alcohols, fatty acids, ultraviolet absorbers, powders, pigments, surfactants, polyhydric alcohols, sugars, polymeric compounds, antioxidants, solvents, etc. The content of these is not particularly limited, and they can be used in accordance with known techniques.

[0035] Examples of oils include butyl myristate, isobutyl myristate, butyl palmitate, isobutyl palmitate, butyl stearate, isobutyl stearate, butyl isostearate, cetyl myristate, isostearyl laurate, isostearyl myristate, propylene glycol dicaprate, isostearyl adipate, squalane, liquid paraffin, isoparaffin, beef tallow, lard, mink oil, fish oil, corn oil, cocoa butter, almond oil, beeswax, lanolin, reduced lanolin, and liquid lanolin.

[0036] Examples of higher alcohols include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, and hexadecyl alcohol.

[0037] Examples of fatty acids include caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and behenic acid.

[0038] Examples of ultraviolet absorbers include para-aminobenzoic acid, ethyl dihydroxypropyl para-aminobenzoate, amyl para-aminobenzoate, urocanic acid, sodium hydroxymethoxybenzophenone disulfonate, octyl salicylate, phenyl salicylate, and triethanolamine salicylate.

[0039] Examples of powders and pigments include Red No. 104, Red No. 201, Yellow No. 4, Blue No. 1, Black No. 401, nylon powder, silk powder, chromium oxide, carbon black, aluminum silicate, magnesium myristate, bentonite, zinc palmitate, sericite, calcium carbonate, and barium sulfate.

[0040] Examples of surfactants include fatty acid soaps, alkyl sulfonates, alkyl aryl sulfonates, alkyl amide sulfates, alkyl phosphates, alkyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium bromide, benzalkonium chloride, carboxybetaine type amphoteric surfactants, phosphobetaine type amphoteric surfactants, lecithin, saponin, glycerin fatty acid esters, and sorbitan fatty acid esters.

[0041] Examples of polyhydric alcohols and sugars include ethylene glycol, diethylene glycol, propylene glycol, mannitol, erythritol, glucose, sucrose, fructose, trehalose, maltitol, and sulfated trehalose.

[0042] Examples of the polymer compound include an acrylic acid ester / methacrylic acid ester copolymer and a vinyl acetate / crotonic acid copolymer.

[0043] Examples of antioxidants include sodium sulfite, erythorbic acid, sodium erythorbate, butylhydroxyanisole, lignan, tannin, flavonoid, carotenoid, ascorbyl stearate, and parahydroxyanisole.

[0044] Examples of the solvent include ethanol, purified water, lower alcohols, ethers, N-methylpyrrolidone, and fluoroalcohols.

[0045] Examples of carriers, bases, and / or additives used in the field of pharmaceuticals or quasi-drugs include excipients, binders, disintegrants, disintegration inhibitors, absorption enhancers, adsorbents, lubricants, etc. The content of these is not particularly limited, and they can be used in accordance with known techniques.

[0046] Examples of excipients include glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cacao butter, hardened vegetable oil, and talc.

[0047] Examples of binders include distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, potassium phosphate, and polyvinylpyrrolidone.

[0048] Disintegrants include, for example, sodium alginate, agar, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, powdered acacia, gelatin, ethanol and the like.

[0049] Examples of disintegration inhibitors include white sugar, stearin, cacao butter, and hydrogenated oils.

[0050] Examples of absorption enhancers include quaternary ammonium bases and sodium lauryl sulfate.

[0051] Examples of adsorbents include glycerin, starch, lactose, kaolin, bentonite, and silicic acid.

[0052] Lubricants include, for example, purified talc, stearates, polyethylene glycol, and the like.

[0053] The production-promoting composition of the present invention may further contain antioxidants other than those mentioned above, such as tocopherol, tocopherol acetate, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene, coenzyme Q10, α-lipoic acid, fullerene, astaxanthin, organic germanium, dimethylaminoethanol, hydroxytyrosol, and platinum nanocolloid.

[0054] As described above, the present invention also discloses cosmetics, pharmaceuticals, or quasi-drugs containing the production-promoting agent, production-promoting composition, or improving agent of the present invention. The cosmetics, pharmaceuticals, or quasi-drugs of the present invention may be prepared using a pre-prepared production-promoting agent, etc. of the present invention, or may be prepared by adding one or more active ingredients selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof to a cosmetic raw material, pharmaceutical raw material, or quasi-drug raw material, according to a known production method.

[0055] Specifically, for example, one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof are mixed with a highly water-soluble solvent or compound such as purified water, ethanol, or glycerin, and the resulting solution is slowly mixed with a pre-mixed mixture of highly fat-soluble substances such as squalane, jojoba oil, or glycerin monostearate, to prepare a cosmetic liquid and / or a cosmetic cream. In addition, one or more compounds selected from the group consisting of citronellyl glucoside, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, citronellyl sophoroside, and pharmaceutically acceptable salts thereof can be dried, made into various solutions, pastes, etc., and then mixed with various additives, carriers, base materials, etc. to formulate into solid preparations such as tablets, granules, powders, powders, and capsules, or liquid preparations such as ordinary liquid preparations, suspensions, and emulsions, according to conventional methods in the art. [Example]

[0056] EXAMPLES The present invention will be specifically explained below with reference to examples and comparative examples, but the present invention is not limited to these.

[0057] Production Example 1 (Citronellyl Glucoside) A specific example of a method for synthesizing citronellyl glucoside is given below. 1-Citronellyl 2,3,4,6-tetraacetyl glucose was synthesized from 1-Bromo 2,3,4,6-tetraacetyl glucose and citronellol as raw materials according to the Koenig-Knorr method described in Tetrahedron Lett., 15, 551 (1974), and this was then deacetylated according to the method described in J. Am. Chem. Soc., 94, 8613 (1972), to obtain citronellyl glucoside in a yield of 91% (total of α and β). NMR ( 13 C) shows the results of structural confirmation. α:131.3, 124.7, 98.7, 74.4, 72.0, 71.6, 69.6, 62.6×2, 37.3, 36.4, 30.0, 26.4, 25.8, 19.5, 17.7 β:131.2, 124.7, 103.0, 75.6, 73.5, 70.8, 70.7, 62.4×2, 37.2, 36.6, 30.0, 26.7, 26.4, 19.5, 17.7

[0058] Example 1 Epidermal hyaluronic acid synthase gene (HAS3) expression promotion test using citronellyl glucoside obtained in Production Example 1 as a sample (cell) The test was carried out by culturing human-derived epidermal keratinocyte cell line HaCaT cells in a CO2 incubator (CO2 concentration 5%, 37°C). (Culture medium) Dulbecco's Modified Eagle Medium (DMEM, Wako, Japan) containing 10.0% (v / v) Fetal Bovine Serum (FBS, Hyclone, UK) and 1.0% (v / v) antifungal agent (Antibiotic-Antimycotic 100X, Invitrogen, USA) was used. (gene) Gene expression analysis was performed using TaqMan Assay (Applied Biosystems, USA), with human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the internal control gene. (probe) Assay ID: Hs02786624_g1 was used as the probe for the internal standard gene, and Assay ID: Hs00193436_m1 was used as the probe for the HAS3 gene. (Cell culture and sample addition) 6.0 x 10 cells in a 24-well plate 4HaCaT cells were seeded at 0.5 mL / mL and cultured in a CO2 incubator for 24 hours. The medium was removed and replaced with medium containing the sample, and cultured in a CO2 incubator for 48 hours. Medium without the sample was also prepared as a control.

[0059] (RNA extraction, purification, quantification and purity measurement) PureLink TM RNA extraction and purification were performed using an RNA Mini Kit (Invitrogen, USA) as follows. After 24 hours of culture, the medium was removed from the 24-well plate, which was then washed three times with 0.5 mL of phosphate buffer saline (PBS(-), Nissui, Japan) preheated to 37°C. Cells were lysed by adding 600 μL of lysis buffer containing 2 M dithiothreitol (Invitrogen, USA), and the lysate was collected. Cells in the collected lysate were disrupted using a homogenizer (Invitrogen, USA). 600 μL of 70% ethanol solution was added to the cell lysate, which was then transferred to a column with a silica membrane. The column was centrifuged at 12,000 × g for 15 seconds at room temperature, and the filtrate was discarded. The silica membrane was washed with 700 μL of Wash Buffer I containing guanidine isothiocyanate and 500 μL of Wash Buffer II containing ethanol. The silica membrane was washed with ethanol-containing Wash Buffer II, centrifuged at 12,000 × g for 15 seconds at room temperature, and then dried. 30 μL of RNase-free water was added, and the membrane was left to stand at room temperature for 1 minute. Then, the membrane was centrifuged twice at 12,000 × g for 15 seconds at room temperature to elute the RNA. A portion of the eluted RNA was placed in a UV-transparent 96-well plate and diluted 10-fold with Tris-EDTA buffer (pH 8.0). The absorbance (OD ) was measured at 230 nm, 260 nm, and 280 nm using a microplate reader (SPARK® 10M TECAN, Switzerland). 230 , O.D. 260 , O.D. 280 ) was measured. 260The RNA concentration was calculated using the following formula, and the RNA was diluted with TE buffer to a concentration of 10 μg / mL. RNA concentration (μg / mL) = A × K × L × 10 (dilution factor) A: OD of sample or control 260 K: K=40, extinction coefficient of RNA L:L=0.3, optical path length (cm)

[0060] (Gene expression analysis using real-time PCR) SuperScript TM IV VILO TM RNA reverse transcription was performed using Master Mix with ezDNase (Invitrogen, USA) as follows: 1 μL of 10×zDNase Buffer, 1 μL of ezDNase enzyme, 6 μL of nuclease-free water, and 2 μL of 10 μg / mL RNA were added per well of eight tubes, and the tubes were incubated at 37°C for 2 minutes. 4 μL of SuperScript was added per well of the eight tubes. TM IV VILO TM Master Mix and 6 μL of nuclease-free water were added, and cDNA was synthesized by heating at 25°C for 10 minutes, 50°C for 10 minutes, and 85°C for 5 minutes using a real-time PCR (QuantStudio® 3, Applied Biosystems, USA). Each well of a PCR plate was filled with 10 μL of TaqMan® Fast Advanced Master Mix (Applied Biosystems, USA), 1 μL of TaqMan Gene Expressior, and 7 μL of UltraPure TMDistilled water (Invitrogen, USA) and 2 μL of cDNA were added and the plate was sealed with a plate seal. The solution was spun down using a plate centrifuge to remove air bubbles. Real-time PCR was performed using a real-time PCR system, and the threshold cycle (Ct) value, which is the cycle number at which the fluorescent signal of each gene in the sample and control reached an arbitrary threshold, was calculated. The Ct value was corrected using the internal standard gene to obtain the ΔCt value. The ΔCt value was corrected using the average ΔCt value of the controls to obtain the ΔΔCt value. Assuming that the difference in detection per cycle using the ΔΔCt method is a difference of two-fold, 2 -ΔΔCt The gene expression levels of the samples were analyzed by substituting the expression level of the control gene as 100. The results are shown in Table 1.

[0061] [Table 1]

[0062] The results in Table 1 demonstrate that citronellyl glucoside has the effect of promoting the production of epidermal hyaluronic acid.

[0063] Example 2 Profilagrin gene (FLG) expression promotion test using citronellyl glucoside of Production Example 1 as a sample The test was carried out in accordance with Example 1. Assay ID. Hs00856927_g1 was used as the probe for the FLG gene. The results are shown in Table 2.

[0064] [Table 2]

[0065] The results in Table 2 demonstrate that citronellyl glucoside has the effect of promoting filaggrin production.

[0066] Example 3 It is known that various skin diseases and skin problems result in increased water evaporation from the skin and a decline in the skin's moisture retention function. Transepidermal water loss (TEWL), which indicates the amount of water evaporated from the skin surface, and stratum corneum moisture content are commonly considered parameters of skin barrier function. Two healthy volunteers applied the citronellyl glucoside-containing lotion and a placebo lotion shown in Table 3 to the left and right sides of their faces twice daily for four weeks. Transepidermal water loss (TEWL) was measured using a Tewameter TM300 (Courage + Khazaka) and stratum corneum moisture content was measured using a Corneometer CM825 (Courage + Khazaka) at baseline, 2 weeks, and 4 weeks. Figure 1 shows the results of TEWL, with the baseline value set at 100, and Figure 2 shows the results of stratum corneum moisture content.

[0067] [Table 3]

[0068] The smaller the transepidermal water loss (TEWL) value, the more moisture evaporation from the skin surface is suppressed. Figure 1 confirms that the lotion containing citronellyl glucoside suppresses moisture evaporation compared to the placebo lotion. Figure 2 confirms that the lotion containing citronellyl glucoside increases the moisture content of the stratum corneum compared to the placebo lotion.

[0069] In Examples 1 to 3, citronellyl glucoside was used. However, instead of this, citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, or citronellyl sophoroside was used as the sample, and an HAS3 expression promotion test was performed in the same manner as in Example 1, and an FLG expression promotion test was performed in the same manner as in Example 2. When the gene expression level of the control was taken as 100, the gene expression level of the sample exceeded 100, indicating that citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, or citronellyl sophoroside has the effect of promoting the production of epidermal hyaluronic acid and filaggrin. Furthermore, by measuring the transepidermal water loss (TEWL) and stratum corneum moisture content in the same manner as in Example 3, it was found that citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, or citronellyl sophoroside can suppress transepidermal water loss (TEWL) and increase the moisture content of the stratum corneum.

[0070] Specific examples of formulations for cosmetics and medical preparations containing the skin barrier function improving agent of the present invention are shown below. The numbers on the right side of each formulation example indicate the mass % of each ingredient contained.

[0071] [Table 4]

[0072] [Table 5]

[0073] [Table 6]

[0074] [Table 7]

[0075] [Table 8]

[0076] [Table 9]

[0077] [Table 10]

[0078] [Table 11]

[0079] [Table 12]

[0080] Although prescription examples 1 to 9 show examples using citronellyl glucoside, prescription examples using citronellyl mannoside, citronellyl galactoside, citronellyl maltoside, citronellyl lactoside, or citronellyl sophoroside instead are also exemplified. [Industrial Applicability]

[0081] The production-promoting agent of the present invention can be suitably used in cosmetics, pharmaceuticals, or quasi-drugs.

Claims

1. An agent for promoting the production of filaggrin and / or epidermal hyaluronic acid, comprising one or more compounds selected from the group consisting of citronellyl glucoside and pharmaceutically acceptable salts thereof.

2. A composition for promoting the production of filaggrin and / or epidermal hyaluronic acid, comprising one or more compounds selected from the group consisting of citronellyl glucoside and pharmaceutically acceptable salts thereof.

3. The production-promoting composition according to claim 2, which is a composition for external use.

4. The production-promoting composition according to claim 2 or 3, which is a composition for use in cosmetics, pharmaceuticals, or quasi-drugs.

5. An agent for improving symptoms requiring suppression of transepidermal water loss, comprising one or more compounds selected from the group consisting of citronellyl glucoside and pharmaceutically acceptable salts thereof.

6. An agent for improving symptoms requiring an increase in stratum corneum moisture, comprising one or more compounds selected from the group consisting of citronellyl glucoside and pharmaceutically acceptable salts thereof.

7. A cosmetic, pharmaceutical, or quasi-drug comprising the production-promoting agent according to claim 1, the production-promoting composition according to any one of claims 2 to 4, or the improving agent according to claim 5 or 6.

8. A method for promoting the production of filaggrin and / or epidermal hyaluronic acid using one or more compounds selected from the group consisting of citronellyl glucoside and pharmaceutically acceptable salts thereof.

Images