Hyaluronidase inhibitors

Abstract

This invention provides a composition for inhibiting the activity of hyaluronidase. [Solution] A hyaluronidase inhibitor is prepared by incorporating niacinamide.

Description

Technical Field

[0001] The present invention relates to an agent for inhibiting the activity of hyaluronidase.

Background Art

[0002] Hyaluronic acid is a naturally occurring polysaccharide and is known to be distributed in various tissues such as the skin, joints, and eyeballs in the living body. Hyaluronic acid plays an important role in maintaining the moisture of the skin, for example, due to its excellent water retention ability, and is essential for maintaining and improving the flexibility and elasticity of the skin. Specifically, it is said that 1 g of hyaluronic acid can retain about 6 L of water, and it is known to prevent rough skin due to dryness and strengthen the skin barrier function. Thus, since hyaluronic acid plays an important role in the living body, various technologies aimed at retaining hyaluronic acid in the living body have been studied.

[0003] On the other hand, hyaluronidase, an enzyme that hydrolyzes hyaluronic acid, is known to inhibit the water retention of the skin by decomposing hyaluronic acid. In addition, hyaluronidase is also known to promote the inflammatory reaction of the skin. Therefore, by inhibiting the activity of hyaluronidase, enhancement of skin moisturization and prevention / reduction of inflammation are expected. Conventionally, mucopolysaccharides including heparin analogs are known to inhibit the activity of hyaluronidase (for example, Patent Document 1), but there is still room for examination regarding their effects.

[0004] Incidentally, niacinamide, a kind of vitamin B, is known to act on the skin such as promoting ceramide synthesis (for example, Patent Document 2) and having a collagen-producing effect (for example, Patent Document 3). However, there is no knowledge about the action of niacinamide having an inhibitory effect on the activity of hyaluronidase and further having an anti-inflammatory effect.

Prior Art Documents

Patent Documents

[0005] [Patent Document 1] Japanese Patent Application Publication No. 8-104617 [Patent Document 2] Japanese Patent Application Publication No. 9-194383 [Patent Document 3] Japanese Patent Publication No. 2022-124931 [Overview of the project] [Problems that the invention aims to solve]

[0006] Under these circumstances, providing technology to suppress the degradation of hyaluronic acid, which plays a vital role in living organisms, remains an ongoing technological challenge.

[0007] Therefore, the object of the present invention is to provide an agent for inhibiting the activity of hyaluronidase, an enzyme that hydrolyzes hyaluronic acid, i.e., a hyaluronidase inhibitor. [Means for solving the problem]

[0008] As a result of diligent research, the inventors have found that niacinamide inhibits the activity of hyaluronidase and can solve the above-mentioned problems. This invention is based on this finding.

[0009] In other words, the present invention provides the following invention. [1] A hyaluronidase inhibitor containing niacinamide. [2] A hyaluronidase inhibitor comprising niacinamide, as described in [1]. [3] A hyaluronidase inhibitor according to [1] or [2], further comprising a mucopolysaccharide. [4] The hyaluronidase inhibitor according to [3], wherein the mucopolysaccharide is a heparin-like substance. [5] The hyaluronidase inhibitor according to any one of [1] to [4], wherein the niacinamide content is 0.05 to 30% by mass relative to the total mass of the hyaluronidase inhibitor. [6] The hyaluronidase inhibitor according to any one of [1] to [5], wherein the content of the mucopolysaccharide is 0.0001 to 1% by mass relative to the total mass of the hyaluronidase inhibitor. [7] A hyaluronidase inhibitor according to any one of [3] to [6], wherein the ratio of the amount of niacinamide to the amount of mucopolysaccharide is 1 / 20 to 300,000. [8] A hyaluronidase inhibitor used to inhibit the degradation of hyaluronic acid, as described in any of [1] to [7]. [9] A hyaluronidase inhibitor used to suppress inflammation, as described in any of [1] to [8].

[10] A hyaluronidase inhibitor described in any of [1] to [9], which is a cosmetic or topical skin preparation. [Effects of the Invention]

[0010] According to the present invention, it is possible to provide a novel agent that inhibits the activity of hyaluronidase. [Modes for carrying out the invention]

[0011] [Hyaluronidase inhibitors] According to one aspect of the present invention, an agent that inhibits the activity of hyaluronidase (hereinafter also simply referred to as "hyaluronidase inhibitor" or "the hyaluronidase inhibitor of the present invention") is provided. The hyaluronidase inhibitor of the present invention contains niacinamide (also referred to as "nicotinamide").

[0012] Niacinamide Conventionally, niacinamide has been known to be used as an active ingredient in the treatment of acne vulgaris (so-called pimples) and as an active ingredient in cosmetic treatments such as skin whitening and wrinkle improvement. However, it was not known that niacinamide inhibits the activity of hyaluronidase, nor was it known that it could be used to suppress the degradation of hyaluronic acid or to suppress inflammation. This invention is the first to discover the previously unknown inhibition of hyaluronidase activity by niacinamide, and the hyaluronidase inhibitor of this invention exerts an inhibitory effect on the activity of hyaluronidase by containing niacinamide.

[0013] The niacinamide content in the hyaluronidase inhibitor of the present invention is not particularly limited as long as the effects of the present invention are achieved, but is preferably 0.05 to 30% by mass, more preferably 0.1 to 20% by mass, and even more preferably 0.5 to 10% by mass, relative to the total mass of the hyaluronidase inhibitor. By setting the niacinamide content in the hyaluronidase inhibitor to 0.05% by mass or more, a sufficient inhibitory effect on the activity of hyaluronidase can be achieved. On the other hand, by setting the niacinamide content in the hyaluronidase inhibitor to 30% by mass or less, the feel and stability of the hyaluronidase inhibitor can be improved.

[0014] In the hyaluronidase inhibitor of the present invention, there are no particular limitations on whether or not components other than niacinamide are included; it may or may not contain components other than niacinamide. Therefore, in one embodiment, the hyaluronidase inhibitor of the present invention consists of niacinamide.

[0015] Mucopolysaccharides In one embodiment, the hyaluronidase inhibitor of the present invention further contains mucopolysaccharides. As used herein, mucopolysaccharides include not only mucopolysaccharides themselves but also salts, esters, etc. of mucopolysaccharides. Mucopolysaccharides may be used alone or in combination of two or more. By containing niacinamide and mucopolysaccharides in combination, the hyaluronidase inhibitor of the present invention can synergistically inhibit the activity of hyaluronidase as compared with the case where the hyaluronidase inhibitor does not contain mucopolysaccharides.

[0016] The mucopolysaccharide preferably contains glycosaminoglycan. Glycosaminoglycan is a polysaccharide in which two sugar units are repeatedly linked without branching, and has a structure in which one of the two sugars is an amino sugar and the other is uronic acid or galactose. The amino sugar may or may not be sulfated.

[0017] The amino sugar constituting the glycosaminoglycan is not particularly limited, and examples thereof include glucosamine, galactosamine, etc. Also, the uronic acid constituting the glycosaminoglycan is not particularly limited, and examples thereof include glucuronic acid, iduronic acid, etc.

[0018] Specific glycosaminoglycans include, for example, hyaluronic acid (amino acid: D-glucosamine, uronic acid: D-glucuronic acid), chondroitin 4-sulfate (chondroitin sulfate A, amino acid: D-galactosamine, uronic acid: D-glucuronic acid), chondroitin 6-sulfate (chondroitin sulfates C and D, amino acid: D-galactosamine, uronic acid: D-glucuronic acid), dermatan sulfate (chondroitin sulfate B, amino acid: D-galactosamine, uronic acid: L-iduronic acid), chondroitin 4,6-disulfate (chondroitin sulfate E, amino acid: D-galactosamine, uronic acid: D-glucuronic acid), keratan sulfate (amino acids: D-glucosamine, D-galactose), heparan sulfate (amino acid: D-glucosamine, uronic acid: L-iduronic acid, D-glucuronic acid), and heparin (amino acid: D-glucosamine, uronic acid: L-iduronic acid, D-glucuronic acid), and the like.

[0019] In a preferred embodiment, the mucopolysaccharide is preferably a polysulfated mucopolysaccharide, particularly preferably a glycosaminoglycan in which the amino sugar is sulfated, a so-called "heparin-like substance".

[0020] Heparin-like substances refer to a general term for polysulfated mucopolysaccharides such as chondroitin polysulfate, and each monosaccharide molecule constituting the mucopolysaccharide preferably has an average of 0.5 to 5 sulfate groups, more preferably an average of 0.6 to 3 sulfate groups. More specifically, heparin-like substances include heparin, chondroitin sulfate D (consisting of a repeating structure of acetylgalactosamine 6-sulfate and glucuronic acid 2-sulfate), and chondroitin sulfate E (consisting of a repeating structure of acetylgalactosamine 4,6-disulfate and glucuronic acid), which are called chondroitin polysulfates. Heparin-like substances can be obtained by sulfated mucopolysaccharides, or by extraction and purification using an aqueous carrier from the internal organs, including the bronchi, of animals such as cattle and pigs, and then sulfated as necessary. Furthermore, since heparin-like substances have been developed and are commercially available as pharmaceutical and cosmetic raw materials, such commercially available products can also be used. In the present invention, heparin-like substances listed in the Japanese Pharmacopoeia Standards for Non-Pharmacopoeia Drugs are preferably used.

[0021] The salts of mucopolysaccharides are not particularly limited as long as they are pharmaceutically or physiologically acceptable, and examples include salts with organic bases (e.g., organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt, etc.) and salts with inorganic bases (e.g., alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as zinc salt and aluminum salt, ammonium salt, etc.).

[0022] If the hyaluronidase inhibitor of the present invention contains a salt of a mucopolysaccharide, the salt of the mucopolysaccharide may be included as the mucopolysaccharide salt itself, or it may be a salt formed in the hyaluronidase inhibitor as a result of separately combining the mucopolysaccharide with an organic or inorganic base.

[0023] The mucopolysaccharide content in the hyaluronidase inhibitor of the present invention is not particularly limited as long as the effects of the present invention are achieved, but is preferably 0.0001 to 1% by mass, more preferably 0.001 to 0.5% by mass, and even more preferably 0.005 to 0.1% by mass, relative to the total mass of the hyaluronidase inhibitor. By setting the mucopolysaccharide content in the hyaluronidase inhibitor to 0.0001% by mass or more, the hyaluronidase inhibitory effect can be more synergistically improved. On the other hand, by setting the mucopolysaccharide content in the hyaluronidase inhibitor to 1% by mass or less, the feel and stability of the hyaluronidase inhibitor can be improved.

[0024] The ratio of the amount of niacinamide to the amount of mucopolysaccharides in the hyaluronidase inhibitor of the present invention (amount of niacinamide / amount of mucopolysaccharides) is not particularly limited as long as the effects of the present invention are achieved, but is preferably 0.05 to 300,000, more preferably 0.2 to 20,000, even more preferably 5 to 2,000, and particularly preferably 50 to 2,000. By setting the ratio of the amount of niacinamide to the amount of mucopolysaccharides in the hyaluronidase inhibitor to 0.05 to 300,000, the hyaluronidase inhibitory effect can be more synergistically improved.

[0025] Other ingredients In addition to the niacinamide and mucopolysaccharides described above, the hyaluronidase inhibitor of the present invention may further contain, as necessary, other components such as antioxidants, mineral and synthetic oils, ester oils, animal and vegetable oils, waxes, fatty acids, alcohols, silicone oils, surfactants, chelating agents, abrasives, thickeners, wetting agents, emulsifiers, excipients, solubilizers, foaming agents, lubricants, polymer compounds, animal and plant extracts, amino acids, sweeteners, fragrances, cooling agents, solvents, anti-inflammatory agents, preservatives, UV inhibitors, metal ion sequestering agents, antioxidants, pigments, pH adjusters, colorants, flavoring components, antiperspirant components, functional components, etc. These other components may be used individually or in combination of two or more. These other components are commonly used in formulations of pharmaceutical compositions, food compositions, cosmetic compositions, skin compositions, oral compositions, etc., and can be appropriately selected within a range that does not impair the effects of the present invention, and can be incorporated into the hyaluronidase inhibitor in appropriate amounts. Other ingredients may be used individually or in combination of two or more.

[0026] Examples of antioxidants include vitamin E and its derivatives (e.g., tocopherols and their derivatives such as dl-α(β,γ)-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol nicotinate, dl-α-tocopherol linoleate, dl-α-tocopherol succinate, ubiquinones, etc.), vitamin A and its derivatives (e.g., retinols and their derivatives such as retinyl palmitate and retinol acetate, retinals and their derivatives such as dehydroretinal, etc.), carotenoids (e.g., carotene, lycopene, astaxanthin, etc.), vitamin B and its derivatives (e.g., thiamine hydrochloride, thiamine sulfate, riboflavin, riboflavin acetate, pyridoxine hydrochloride, pyridoxine dioctanoate). Examples include flavin adenine dinucleotide, cyanocobalamin, folic acids, nicotinic acids such as benzyl nicotinate, choline, etc., vitamin C and its derivatives (e.g., L-ascorbate alkyl esters such as L-ascorbyl dipalmitate and L-ascorbyl tetraisopalmitate, L-ascorbate phosphate, L-ascorbate sulfate, etc.), vitamin D and its derivatives (e.g., ergocalciferol, cholecalciferol, dihydroxystanal, etc.), rutin and its derivatives, thiotaurine, taurine, hydroquinone and its derivatives, histidine, catechin and its derivatives, glabridin, glabrene, liquiritin, isoliquiritin, and licorice extracts containing these.

[0027] Examples of mineral and synthetic oils include liquid paraffin, liquid isoparaffin, petrolatum, paraffin, ceresin, microstarin wax, α-olefin oligomer, polyethylene, polybutene, and synthetic squalane.

[0028] Examples of ester oils include glyceryl tricaprylate, glyceryl tri-2-ethylhexanoate, isononyl isononanoate, ethylene glycol dioctanoate, caprylic / capric triglyceride, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, butyl stearate, ethyl oleate, ethyl linoleate, isopropyl linoleate, cetyl caprylate, decyl myristate, hexyl laurate, myristyl myristate, cetyl myristate, cetyl palmitate, and stearate. Lyl, oleyl oleate, decyl oleate, cetyl ricinoleate, isostearyl laurate, isotridecyl myristate, isotridecyl isononanoate, isocetyl myristate, isostearyl myristate, 2-octyldodecyl myristate, octyl palmitate, isocetyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, 2-octyldodecyl oleate, 2-octyldodecyl ricinoleate, ethyl isostearate, isopropyl isostearate, cetyl octanoate, cetyl octanoate Stearyl ester, stearyl octanoate, hexyl isostearate, ethylene glycol dioleate, propylene glycol dicaprate, di(caprylic / capric acid)propylene glycol, propylene glycol dioleate, neopentyl glycol dicaprate, cetyl 2-ethylhexanoate, neopentyl glycol di-2-ethylhexanoate, glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate Pentaerythritol tetra-2-ethylhexanoate, pentaerythritol tetramyristate, pentaerythritol tetraisostearate, 2-octyldodecyl neopentanoate, isocetyl octanoate, isostearyl octanoate, 2-hexyldecyl neodecanoate, 2-octyldodecyl neodecanoate, octyl isopalmitate, isocetyl isostearate, isostearyl isostearate, 2-octyldodecyl isostearate, lauryl lactate, myristyl lactate, cetyl lactate, 2-octyldodecyl lactate, triethyl citrate,Examples include acetyltriethyl citrate, acetyltributyl citrate, tri-2-ethylhexyl citrate, triisocetyl citrate, tri-2-octyldodecyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, dioctyl succinate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, dibutyloctyl sebacate, cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, hexyldecyl dimethyloctanoate, diethyl phthalate, dibutyl phthalate, and dialkyl carbonate.

[0029] Examples of animal and vegetable oils include squalane, olive oil, camellia oil, wheat germ oil, jojoba oil, avocado oil, carrot oil, shea butter, liquid shea butter, palm oil, palm kernel oil, hydrogenated oil, horse oil, lanolins, egg yolk oil, clove oil, rosehip oil, lavender oil, peppermint oil, spearmint oil, rosemary oil, macadamia nut oil, apricot kernel oil, safflower oil, safflower oil (2), sunflower oil, sunflower oil (2), meadowfoam oil, almond oil, perilla oil, sesame oil, borage oil, and cocoa oil. Examples include fats, rice bran oil, rice germ oil, fennel oil, orange oil, chamomile oil, cucumber oil, kukui nut oil, soybean oil, tea tree oil, corn oil, rapeseed oil, peach kernel oil, castor oil, cottonseed oil, peanut oil, turtle oil, mink oil, argania spinosa kernel oil, crambe abyssinica seed oil, almond oil, peach kernel oil, grapeseed oil, emu oil, mink oil, hemp seed oil, linseed oil, camellia oil, Japanese wax, coconut oil, evening primrose oil, pistachio seed oil, mango butter, etc.

[0030] Examples of waxes include jojoba oil, beeswax, carnauba wax, rice bran wax, whale wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, candelilla wax, montan wax, shellac, and orange roughy oil.

[0031] Examples of fatty acids include natural fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, isostearic acid, behenic acid, linoleic acid, linolenic acid, docosahexaenoic acid, eicosapentaenoic acid, 12-hydroxystearic acid, undecylenic acid, and lanolinic acid, as well as synthetic fatty acids such as isononanoic acid, caproic acid, 2-ethylbutanoic acid, isopentanoic acid, 2-methylpentanoic acid, and isopentanoic acid.

[0032] Examples of alcohols include ethanol, isopropanol, butyl alcohol, benzyl alcohol, lauryl alcohol, myristyl alcohol, cetanol, cetostearyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, hexyldecanol, behenyl alcohol, octyldodecanol, lanolin alcohol, cholesterol, phytosterol, 2-hexyldecanol, 2-octyldodecanol, batyl alcohol, and others.

[0033] Examples of silicone oils include methylpolysiloxane, methylphenylpolysiloxane, silicone resins, methylhydrogenpolysiloxane, methylcyclopolysiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexasiloxane, cyclic silicone resins, octamethyltrisiloxane, tetradecamethylhexasiloxane, highly polymerized methylpolysiloxane, trimethylsiloxysilicic acid, poly(oxyethylene / oxypropylene)methylpolysiloxane copolymer, poly(oxyethylene / oxypropylene) / butylene / methylpolysiloxane copolymer, polyoxyethylene / methylpolysiloxate copolymer, polyoxypropylene / methylpolysiloxane copolymer, dimethylsiloxane / methylcetyloxysiloxane copolymer, and dimethylsiloxane / methylstearoxysiloxane copolymer.

[0034] Examples of surfactants include lauryl sulfate, sodium α-olefin sulfonate, sodium dodecylbenzenesulfonate, sodium lauryl sulfoacetate, sodium N-lauroyl sarcosinate, N-acyl glutamate, sucrose fatty acid ester, alkyl sulfate, polyoxyethylene alkyl sulfate, tetradecene sulfonate, polyoxyethylene alkyl sulfosuccinate, lauroyl sarcosinate, alkylmethyl-β-alanine salt, polyoxyethylene alkyl ether phosphate, fatty acid soap, N-acyl glutamate, lauric acid diethanolamide, coconut oil fatty acid diethanolamide, alkyldimethylamine oxide, alkylmethyl taurate, alkylaminoprocyonate, polyoxyethylene alkyl ether carboxylate, alkyl phosphate, alkyl glucoside, polyether-modified silicone, alkyltrimethylammonium chloride, alkyltrimethylammonium bromide, amidoamine, and dialkyldimethyl ammonium chloride. Examples include ammonium dimethyl acetate betaine, alkylamidopropyl betaine, alkylcarboxymethyl hydroxyethylimidazolinium betaine, lecithin (e.g., lecithin derived from soybeans and egg yolks) and its derivatives, propylene glycol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers, alkyl glycosides, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, alkyldimethylamine oxide, lauryl ethanolamide, sodium cocoyl sarcosinate, sodium N-lauroyl methyl taurate solution, polyethylene glycol fatty acid esters, polyoxyethylene alkyl ethers, polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene alkyl nonylphenyl ethers, and polyoxyethylene alkyl ether phosphates and phosphates.

[0035] Examples of chelating agents include pyrophosphate or its salts, polyphosphate or its salts, metaphosphate or its salts, phytic acid or its salts, hydroxyethanediphosphonic acid or its salts, aminotrimethylenephosphonic acid or its salts, ethylenediaminetetramethylenephosphonic acid or its salts, phosphonobutanetricarboxylic acid or its salts, EDTA or its salts, nitrilotriacetic acid (NTA) or its salts, hydroxyethyliminodiacetic acid (HIDA) or its salts, tetrasodium 3-hydroxy-2,2'-iminodisuccinate (HIDS) or its salts, diethylenetriaminepentaacetic acid (DPTA) or its salts, hydroxyethyl Examples of chelating agents include ethylenediaminetriacetic acid (HEDTA) or its salts, dihydroxyethylglycine (DHEG) or its salts, L-glutamic acid diacetic acid (GLDA) or its salts, methylglycine diacetic acid (MGDA), aspartic acid or its salts, glutamic acid or its salts, citric acid or its salts, malic acid or its salts, tartaric acid or its salts, gluconic acid or its salts, lactic acid or its salts, mandelic acid or its salts, glycolic acid or its salts or its salts, oxalic acid or its salts, maleic acid or its salts, malonic acid or its salts, succinic acid or its salts, pantothenic acid or its salts, phthalic acid or its salts, fumaric acid or its salts, etc. The chelating agent may be used alone or in combination of two or more types. The content of the chelating agent is, for example, 0 to 30% by mass of the total mass of the instantaneous sterilization composition of the present invention.

[0036] Examples of abrasives include calcium carbonate, calcium phosphate, discalcium phosphate, calcium pyrophosphate, insoluble calcium metaphosphate, hydrated silicic acid, anhydrous silicic acid, titanium dioxide, amorphous silica, crystalline silica, aluminosilicate, aluminum oxide, aluminum hydroxide, and resins.

[0037] Examples of thickening agents include cellulose derivatives such as carrageenan, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; alkali metal alginates such as sodium alginate; gums such as propylene glycol alginate, xanthan gum, tragacanth gum, and gum arabic; synthetic thickening agents such as polyvinyl alcohol, sodium polyacrylate, and polyvinylpyrrolidone; and inorganic thickening agents such as silica gel, aluminum silica gel, and bee gum.

[0038] Examples of humectants include glycerin, diglycerin, polyglycerin, 1,3-butylene glycol, polyethylene glycol, 1,2-pentanediol, 1,3-hexanediol, propylene glycol, dipropylene glycol, isopropylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, maltitol, reduced starch syrup, lactitol, palatinite, erythritol, sorbitol, mannitol, xylitol, xylose, trehalose, glycosyltrehalose, glucose, glucose, lactose, mannose, maltose, fructose, inositol, pentaerythritol, maltotriose, starch-derived sugars, starch-derived sugar-reduced alcohols, ethylene oxide, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, propylene oxide, water-soluble proteoglycans, collagen, ceramides, and the like.

[0039] Examples of emulsifiers include polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, sodium stearoyl lactylate, soybean phospholipids, and alkyltrimethylammonium chloride.

[0040] Examples of excipients include sucrose, lactose, starch, glucose, crystalline cellulose, mannitol, sorbitol, xylitol, erythritol, palatinitol, palatinose, maltitol, trehalose, lactitol, lactulose, reduced starch sugar, reduced isomaltoligosaccharide, coupling sugar, gum base, gum arabic, gelatin, cetyl methylcellulose, light anhydrous silicic acid, magnesium aluminate, calcium aluminometasilicate, sodium bicarbonate, calcium phosphate, and the like.

[0041] Examples of solubilizing agents include esters, polyethylene glycol derivatives, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid esters, and sulfated fatty alcohols.

[0042] Examples of foaming agents include sodium lauryl sulfate, sodium lauroyl sarcosinate, sodium alkyl sulfosuccinate, sodium coconut oil fatty acid monoglycerin sulfonate, sodium α-olefin sulfonate, N-acyl amino acid salts such as N-acyl glutamate, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, maltitol fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, fatty acid diethanolamide, polyoxyethylene sorbitan monostearate, polyoxyethylene hydrogenated castor oil, and polyoxyethylene fatty acid esters.

[0043] Examples of lubricants include magnesium stearate, sucrose fatty acid esters, talc, and hydrogenated oils.

[0044] Examples of polymer compounds include sodium alginate, carrageenan, agar, ferceleran, guar gum, quince seed, konjac mannan, tamarind gum, tara gum, dextrin, starch, locust bean gum, gum arabic, guatti gum, karaya gum, tragacanth gum, arabinogalactan, pectin, quince, wheat protein, soy protein, albumin, casein, gelatin, chitosan, hyaluronic acid, curdlan, xanthan gum, gellan gum, cyclodextrin, dextran, pullulan, crystalline cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cationized cellulose, cationized guar gum, hydroxypropylated guar gum, carboxyvinyl polymer, polyacrylamide, sodium polyacrylate, high polymer polyethylene glycol, polyvinyl alcohol, and polyvinylpyrrolidone.

[0045] Examples of plant and animal extracts include placenta extract, hydrolyzed keratin, hydrolyzed silk, yeast extract, aloe extract, comfrey extract, peony extract, perilla extract, sage extract, swertia japonica extract, witch hazel water, Isodon japonicus extract, hop extract, horse chestnut extract, peach leaf extract, saxifrage extract, lemon balm extract, mugwort extract, rosemary extract, and rice bran fermentation extract.

[0046] Examples of amino acids include L-alanine, L-arginine, L-aspartic acid, L-glutamine, L-asparagine, L-cysteine, L-serine, L-tyrosine, L-proline, pyrrolidone carboxylate, glycine, valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, cystine, hydroxyproline, hydroxylysine, ornithine, histidine, γ-aminobutyric acid, and ε-aminocaproic acid.

[0047] Examples of sweeteners include palatinite, aspartame, sodium saccharin, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, glycyrrhizin, perillarumin, thaumatin, aspartylphenylalanyl methyl ester, ρ-methoxycinnamic aldehyde, sucralose, xylitol, and stevia.

[0048] Examples of fragrances include blended fragrances such as strawberry, apple, banana, pineapple, grape, mango, butter, milk, fruit mix, and tropical fruit flavors, as well as terpenoid essential oils and phenylpropanoid essential oils.

[0049] Examples of cooling agents include N-ethyl-p-menthane-3-carboxamide, ethyl-3-(p-menthane-carboxamide)acetate, and N-(4-cyanomethylphenyl)-p-menthanecarboxamide.

[0050] Examples of solvents include organic solvents such as ethanol, propyl alcohol, and isopropyl alcohol, as well as purified water and tap water.

[0051] Examples of anti-inflammatory agents include glycyrrhizic acid, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, glycyrrhetinic acid, stearyl glycyrrhetinate, guaiazulene, sodium guaiazulene sulfonate, allantoin, ε-aminocaproic acid, and tranexamic acid.

[0052] Examples of preservatives include methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, phenoxyethanol, bisabolol, hinokitiol, parahydroxybenzoic acid esters, benzoic acid, sodium benzoate, salicylic acid, sodium salicylate, sorbic acid, potassium sorbate, undecylenic acid, pionin, l-menthol, d-camphor, isopropylmethylphenol, benzethonium chloride, alkyldiaminoethylglycine hydrochloride, and ethylhexylglycerin.

[0053] Examples of UV-blocking agents include para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para-aminobenzoate, 2-ethylhexyl para-dimethylaminobenzoate, oxybenzone, dihydroxybenzophenone, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone sulfonate, sodium hydroxymethoxybenzophenone sulfonate, octyl salicylate, 4-tert-butyl-4'-methoxydibenzoylmethane, ferulic acid, titanium dioxide, fine particle titanium dioxide, zinc oxide, and fine particle zinc oxide.

[0054] Examples of metal ion chelating agents include EDTA, EDTA salts, trisodium ethylenediaminehydroxyethyl triacetate, diethylenetriaminepentaacetic acid, pentasodium diethylenetriaminepentaacetic acid, ethylenediaminetetrakis(2-hydroxyisopropyl) dioleate, hydroxyethanediphosphonic acid, tetrasodium hydroxyethanediphosphonic acid, and phytic acid.

[0055] Examples of antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, erythorbic acid, propyl gallate, and d-δ-tocopherol.

[0056] Examples of pigments include azo pigments and phthalocyanine pigments, and lake-formed pigments are also used. Examples of pigments include organic pigment powders such as Red 201, Red 202, Red 205, Red 226, Red 228, Orange 203, Orange 204, Blue 404, and Yellow 401, as well as zirconium, barium, and aluminum lakes such as Red 3, Red 104, Red 106, Orange 205, Yellow 4, Yellow 5, Green 3, and Blue 1. Examples of inorganic pigments include anhydrous silicic acid, magnesium silicate, talc, kaolin, bentonite, mica, titanium mica, bismuth oxychloride, zirconium oxide, magnesium oxide, zinc oxide, titanium dioxide, calcium carbonate, magnesium carbonate, yellow iron oxide, red iron oxide, black iron oxide, ultramarine, chromium oxide, chromium hydroxide, carbon black, calamine, cerium oxide, barium sulfate iron oxide, and Prussian blue.

[0057] Examples of pH adjusting agents include hydrochloric acid, phosphoric acid, pyrophosphate, polyphosphate, metaphosphate, pantothenic acid, malic acid, lactic acid, tartaric acid, glycerophosphate, acetic acid, nitric acid, silicic acid, citric acid, and chemically possible salts thereof, as well as sodium hydroxide, potassium hydroxide, and the like.

[0058] Examples of coloring agents include pigments such as Blue No. 1, Green No. 3, Yellow No. 4, and Red No. 105, as well as titanium dioxide, zinc oxide, and ultramarine.

[0059] Examples of flavoring ingredients include tea extract, tea distillate, and monosodium glutamate.

[0060] Examples of antiperspirant ingredients include zinc paraphenolsulfonate, aluminum chloride, aluminum chlorohydrate, and alum.

[0061] Examples of functional ingredients include glycyrrhizic acid and its salts, glycyrrhetinic acid, pyridoxine hydrochloride, ε-aminocaproic acid, allantoin, sodium chloride, ascorbic acid and its salts, ascorbic acid derivatives, tocopherol acetate, zeolite, sodium fluoride, sodium monofluorophosphate, stannous fluoride, polyethylene glycol, potassium nitrate, azulene sulfonic acid and its salts, aluminum lactate, ascorbic acid and its salts, and tranexamic acid.

[0062] In addition to the components mentioned above, other components may include humectants, antibacterial agents, anti-inflammatory agents, fluoride, vitamins, and herbal extracts. These pharmacoactive ingredients are commonly used in formulations of pharmaceutical compositions, food compositions, cosmetic compositions, skin compositions, oral compositions, etc., and can be appropriately selected within a range that does not impair the effects of the present invention, and can be incorporated into hyaluronidase inhibitors in appropriate amounts. Other components may be used individually or in combination of two or more.

[0063] Examples of moisturizers include natural extracts such as amino acids and their salts, pyrrolidone carboxylic acid, mucin, sodium lactate, urea, panthenol, aloe extract, rosemary extract, thyme extract, and tea extract (tea distillate extract), as well as so-called extracellular matrix components such as collagen and elastin.

[0064] Examples of antibacterial agents include cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, decalinium chloride, chlorhexidine hydrochloride, sodium chlorhexidine gluconate, bisabolol chlorhexidine, lactoferrin, parabens, and butylparabens.

[0065] Examples of anti-inflammatory agents include lysozyme chloride, ε-aminocaproic acid, aluminum hydroxyl allantoin, glycyrrhetinic acid, glycyrrhizinates, guaiazulene sulfonic acid, and dl-α-tocopherol acetate.

[0066] Examples of fluorides include sodium fluoride, potassium fluoride, sodium monofluorophosphate, and stannous fluoride.

[0067] Examples of vitamin supplements include vitamin A compounds such as retinoic acid and beta-carotene, pantothenic acid and its salts, vitamin B compounds such as niacin and biotin, vitamin C compounds such as ascorbic acid and its salts and derivatives, vitamin E compounds such as alpha-tocopherol, and folic acid.

[0068] Examples of herbal extracts include chamomile extract, valerian extract, jujube extract, hop extract, ramender extract, linden extract, quince extract, honeysuckle extract, bamboo grass extract, elm extract, clove extract, ginseng extract, sage extract, and soapberry extract.

[0069] The hyaluronidase inhibitor of the present invention can suppress the degradation of hyaluronic acid. Therefore, the hyaluronidase inhibitor of the present invention can be suitably used to suppress phenomena caused by a decrease in hyaluronic acid (for example, a decrease in the skin's moisturizing ability, a decrease in the skin's firmness, a decrease in the skin's flexibility, a decrease in joint lubrication, etc.). Furthermore, the hyaluronidase inhibitor of the present invention can be suitably used to suppress inflammation.

[0070] In one embodiment, the hyaluronidase inhibitor of the present invention is applied to the skin surface of a living organism. Furthermore, the hyaluronidase inhibitor of the present invention exerts a hyaluronidase inhibitory effect not only on the skin surface but also on other parts of the body, such as the oral cavity, mucous membranes, hair, and joints. Moreover, as described above, since the hyaluronidase inhibitor of the present invention can be applied to the skin and other parts of the body, it can also be used as a cosmetic, pharmaceutical composition (e.g., a topical skin preparation), or oral composition having a hyaluronidase inhibitory effect.

[0071] The form of the hyaluronidase inhibitor of the present invention is not particularly limited as long as the effects of the present invention are achieved, and examples include antiperspirants, antiperspirants for underarm odor, deodorants, deodorants, topical skin preparations, acne prevention agents, hand sanitizers, hand soaps, skin cleansers, scrubs, body shampoos, body soaps, facial cleansing foams, makeup removers, soaps, hair cosmetics, hair shampoos, hair rinses, hair conditioners, hair treatments (including leave-in types), hair styling agents, anti-dandruff agents, toothpastes, gel toothpastes, liquid toothpastes, mouthwashes, oral moisturizers, and the like.

[0072] The dosage form of the hyaluronidase inhibitor of the present invention is not particularly limited as long as the effects of the present invention are achieved, and may be solid or liquid. For example, it can be in the form of ointments, pastes, pastes (mud ointments), gels, liquids, sprays, gums, tablets, etc.

[0073] [Methods to suppress the breakdown of hyaluronic acid] According to another aspect of the present invention, a method for suppressing the degradation of hyaluronic acid in a target area is provided (hereinafter also simply referred to as "the hyaluronic acid degradation suppression method of the present invention"). The hyaluronic acid degradation suppression method of the present invention includes applying the hyaluronidase inhibitor of the present invention to a target area such as the skin, thereby suppressing the degradation of hyaluronic acid present in the target area. The amount of the hyaluronidase inhibitor of the present invention applied is per 1 cm of the target area. 2 For example, the amount per serving can be 0.01 to 2 g, preferably 0.05 to 1.5 g, and more preferably 0.1 to 1 g.

[0074] [Methods to suppress inflammation] According to yet another aspect of the present invention, a method for suppressing inflammation in a subject (hereinafter also simply referred to as "the inflammation suppression method of the present invention") is provided. The inflammation suppression method of the present invention can be carried out, for example, by the same procedure as the hyaluronic acid degradation suppression method of the present invention described above. [Examples]

[0075] The present invention will be described more specifically below based on examples, but the present invention is not limited to these examples. In Tables 1 and 2 below, the values ​​for each component represent the mass percentage relative to the total mass of the hyaluronidase inhibitor.

[0076] [Preparation of hyaluronidase inhibitors] Samples for Examples 1-14 and Comparative Examples 1-4 were prepared by adding and mixing each component shown in Tables 1 and 2 in the amounts indicated in each table to 0.1 M acetate buffer (pH 4.0). Heparin-like substances were used as the mucopolysaccharides.

[0077] [Table 1]

[0078] [Table 2]

[0079] [Evaluation of hyaluronidase inhibitory activity] Each sample from the examples and comparative examples was added to a 400 units / mL hyaluronidase (Type IV-S, 750-3000 units / mg, Sigma-Adrich) solution (0.1M acetate buffer, pH 4.0) and incubated at 37°C for 20 minutes. Next, a 0.1M acetate buffer (pH 4.0) containing enzyme activation solution (0.1 mg / mL Compound 48 / 80, Sigma-Adrich), 2.5 nM calcium chloride, and 0.15 M sodium chloride was added and incubated at 37°C for a further 20 minutes. Next, a 0.4 mg / mL sodium hyaluronate (Fujifilm Wako Pure Chemical Industries, Ltd.) solution (0.1M acetate buffer, pH 4.0) was added and incubated at 37°C for a further 40 minutes. Finally, a 0.4M sodium hydroxide solution and a 0.8M boric acid solution (pH 9.1) were added to stop the enzymatic reaction, and the mixture was heated in a boiling water bath for 3 minutes. After cooling to room temperature, the p-dimethylaminobenzaldehyde reagent (a solution prepared by dissolving p-dimethylaminobenzaldehyde in a mixture of acetic acid and 10M hydrochloric acid in a 7:1 ratio, and then diluting it 10-fold with acetic acid before use) was added, and the mixture was incubated at 37°C for 20 minutes. After returning to room temperature, 1 mL of the colored solution was transferred to a 48-well plate, and the absorbance at a wavelength of 585 nm was measured using a plate reader. Note that 585 nm is the absorbance wavelength of the compound formed by the binding of p-dimethylaminobenzaldehyde and the decomposition product of sodium hyaluronate by hyaluronidase, and its absorbance is used as an indicator of hyaluronidase activity. Based on the absorbance at 585 nm for each sample in the examples and comparative examples, the percentages (activity rates) are shown in Tables 1 and 2, with the hyaluronidase activity based on the absorbance of Comparative Example 1 (a sample containing neither niacinamide nor mucopolysaccharides) set to 100.

[0080] As shown in Table 1, each sample from Examples 1 to 6, which contains niacinamide alone, exhibits lower activity and superior hyaluronidase inhibitory activity compared to the sample from Comparative Example 1, which does not contain niacinamide or mucopolysaccharides. Furthermore, Example 7, which contains niacinamide (0.5% by mass) and mucopolysaccharides (0.005% by mass), exhibits synergistically lower activity compared to Comparative Example 2, which contains mucopolysaccharides (0.005% by mass) alone, and Example 1, which contains niacinamide (0.5% by mass) alone, indicating particularly superior hyaluronidase inhibitory activity (possessing synergistic hyaluronidase inhibitory activity). Similarly, Example 13, which contains niacinamide (0.25% by mass) and mucopolysaccharides (0.005% by mass), shows a synergistically lower activity rate compared to Comparative Example 2, which contains mucopolysaccharides (0.005% by mass) alone, and Example 2, which contains niacinamide (0.25% by mass) alone, indicating that it is particularly excellent in hyaluronidase inhibitory activity (having synergistic hyaluronidase inhibitory activity). Similarly, Example 14, which contains niacinamide (0.2% by mass) and mucopolysaccharides (0.007% by mass), shows a synergistically lower activity rate compared to Comparative Example 4, which contains mucopolysaccharides (0.007% by mass) alone, and Example 3, which contains niacinamide (0.2% by mass) alone, indicating that it is particularly excellent in hyaluronidase inhibitory activity (having synergistic hyaluronidase inhibitory activity). Furthermore, Example 7 (0.5% by mass of niacinamide, 0.005% by mass of mucopolysaccharides) exhibited superior hyaluronidase inhibitory activity compared to Example 4 (1% by mass of niacinamide), which contained twice the amount of niacinamide as in Example 7, and Comparative Example 3 (0.01% by mass of mucopolysaccharides), which contained twice the amount of mucopolysaccharides as in Example 7. This indicates that combining niacinamide and mucopolysaccharides is more effective in improving hyaluronidase inhibitory activity than containing twice the amount of each individually.

[0081] [Example prescription] The following are examples of formulations of the hyaluronidase inhibitor of the present invention, prepared by mixing the components described herein. The units of the amounts of each component are in mass%, where the total amount of the hyaluronidase inhibitor is 100% by mass.

[0082] <Example prescription 1: Lotion> Niacinamide 3 Heparin-like substance 0.1 Dipotassium glycyrrhizinate 0.05 Glycerin 10 1,3-Butylene glycol 10 Phenoxyethanol 1 Purified water remainder Total 100% by mass

[0083] <Example prescription 2: All-in-one gel> Niacinamide 10 Heparin-like substance 0.1 Dipotassium glycyrrhizinate 0.1 Glycerin 15 1,3-Butylene glycol 10 Dipropylene glycol 5 1,2-Pentanediol 1 Glycosyltrehalose 5 Rice bran oil 5 Squalane 1 Glycerin fatty acid ester 0.5 Polyoxyethylene hydrogenated castor oil 0.5 Vitamin E 0.1 Carboxyvinyl polymer 0.5 Acrylic acid / alkyl methacrylate polymer 0.5 Potassium hydroxide 0.1 Xanthan gum 0.1 Phenoxyethanol 1 Ethylhexylglycerin 0.5 Purified water remainder Total 100% by mass

[0084] <Example prescription 3: Serum> Niacinamide 10 Heparin-like substance 0.05 Dipotassium glycyrrhizinate 0.05 Glycerin 10 1,3-Butylene glycol 10 Propanediol 5 Dipropylene glycol 1 1,2-Pentanediol 1 Polyethylene glycol 1 Polyoxyethylene sorbitan fatty acid ester 0.5 Carboxyvinyl polymer 0.5 Potassium hydroxide 0.1 Hydroxypropyl methylcellulose 0.1 Phenoxyethanol 1 Ethylhexylglycerin 0.5 Purified water remainder Total 100% by mass

[0085] <Prescription Example 4: Emulsion> Niacinamide 5 Heparin-like substance 0.1 Dipotassium glycyrrhizinate 0.05 Glycerin 10 1,3-Butylene glycol 5 Dipropylene glycol 5 Cetyl 2-ethylhexanoate 5 Shea butter 1 Squalane 3 Cetanol 1 Behenyl alcohol 0.5 Glycerin fatty acid ester 2 Vitamin E 0.1 Carboxyvinyl polymer 0.5 Acrylic acid / alkyl methacrylate polymer 0.5 Potassium hydroxide 0.1 Phenoxyethanol 1 Ethylhexylglycerin 0.5 Purified water remainder Total 100% by mass

[0086] <Prescription Example 4: Cream> Niacinamide 3 Heparin-like substance 0.05 Dipotassium glycyrrhizinate 0.05 Glycerin 2 1,3-Butylene glycol 5 1,2-Pentanediol 1 Pentaerythritol Tetraisostearate 2 Cetanol 1 Behenyl alcohol 0.5 Beeswax 3 Methylpolysiloxane 3 Squalane 5 Glycerin fatty acid ester 2 Carboxyvinyl polymer 0.5 Potassium hydroxide 0.1 Hydroxyethylcellulose 0.5 Phenoxyethanol 1 Ethylhexylglycerin 0.5 Purified water remainder Total 100% by mass

[0087] <Example prescription 5: Hand cream> Niacinamide 10 Heparin-like substance 0.1 Dipotassium glycyrrhizinate 0.05 1,3-Butylene glycol 5 1,2-Pentanediol 1 Tri(caprylic / capric acid) glyceryl 3 Liquid paraffin 7 Behenyl alcohol 5 Beeswax 3 α-Olefin Oligomer 3 Sorbitan fatty acid ester 2 Carboxyvinyl polymer 0.5 Potassium hydroxide 0.1 Xanthan gum 0.1 Phenoxyethanol 1 Ethylhexylglycerin 0.5 Purified water remainder Total 100% by mass

[0088] <Prescription Example 6: Balm> Niacinamide 3 Heparin-like substance 0.05 Dipotassium glycyrrhizinate 0.05 Glycerin 15 1,3-Butylene glycol 5 1,2-Pentanediol 1 Tri(caprylic / capric acid) glyceryl 3 Liquid paraffin 7 Wax 9 Stearyl alcohol 10 Behenyl alcohol 5 Beeswax 3 Sorbitan fatty acid ester 2 Carboxyvinyl polymer 0.5 Potassium hydroxide 0.1 Xanthan gum 0.1 Phenoxyethanol 1 Ethylhexylglycerin 0.5 Purified water remainder Total 100% by mass

[0089] <Formulation Example 7: Sheet Mask Impregnation Solution> Niacinamide 5 Heparin-like substance 0.1 Glycerin 10 1,3-Butylene glycol 10 Dipropylene glycol 10 1,2-Pentanediol 1 Glycosyltrehalose 5 Polyoxyethylene hydrogenated castor oil 1 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.05 Hydroxyethylcellulose 0.1 Phenoxyethanol 1 Ethylhexylglycerin 0.5 Purified water remainder Total 100% by mass

Claims

1. A hyaluronidase inhibitor containing niacinamide.

2. A hyaluronidase inhibitor according to claim 1, comprising niacinamide.

3. The hyaluronidase inhibitor according to claim 1, further comprising mucopolysaccharides.

4. The hyaluronidase inhibitor according to claim 3, wherein the mucopolysaccharide is a heparin-like substance.

5. The hyaluronidase inhibitor according to claim 1, wherein the niacinamide content is 0.05 to 30% by mass relative to the total mass of the hyaluronidase inhibitor.

6. The hyaluronidase inhibitor according to claim 3, wherein the content of the mucopolysaccharide is 0.0001 to 1% by mass relative to the total mass of the hyaluronidase inhibitor.

7. The hyaluronidase inhibitor according to claim 3, wherein the ratio of the amount of niacinamide to the amount of mucopolysaccharide is 0.05 to 300,000.

8. A hyaluronidase inhibitor according to claim 1 or 2, used to inhibit the degradation of hyaluronic acid.

9. A hyaluronidase inhibitor according to claim 1 or 2, used for suppressing inflammation.

10. A hyaluronidase inhibitor according to claim 1 or 2, which is a cosmetic or topical skin preparation.

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