JPWO2019142760A1 - Hyaluronidase activity inhibitor - Google Patents

Abstract

An object of the present invention is to provide a hyaluronidase inhibitor that can be used in a wide range of applications. The present invention is a hyaluronidase activity inhibitor containing β-1,3-1,6-glucan in which a part of the hydroxy group is carboxymethylated. This hyaluronidase activity inhibitor is particularly beneficial for cosmetic compositions.

Description

The present invention relates to an additive for inhibiting the activity of hyaluronidase, a cosmetic composition containing the additive, a method for suppressing the decomposition of hyaluronic acid, a method for producing the additive, and carboxymethylated β-1,3-. Regarding 1,6-glucan.

Hyaluronic acid is a type of acidic mucopolysaccharide having a structure in which glucuronic acid and N-acetylglucosamine are alternately linked by β-glycosidic bonds, and is widely distributed in connective tissue together with chondroitin sulfate and the like. In the skin, it is abundant in the intercellular spaces and plays an important role in maintaining the elasticity, moisturizing property, and flexibility of the skin. It is known that this hyaluronic acid is hydrolyzed by β (1 → 4) bond in hyaluronic acid by hyaluronidase. Hyaluronidase is abundant in inflammatory cells (white blood cells, etc.), and is often extremely high in the inflamed area, and is said to decompose hyaluronic acid, which is a component of cells, to enhance inflammation ( Patent Document 1). Further, it is known that in an aqueous solution containing hyaluronic acids, the molecular weight of hyaluronic acids decreases due to decomposition over time due to mixed hyaluronidase and the like, and the viscosity decreases. As a result, the physical properties and functions are different from those immediately after production. There is a problem that the feeling of use is deteriorated or the feeling of use is deteriorated.

By inhibiting the activity of hyaluronidase, effects such as suppression of inflammation can be expected, and also effects of preventing decomposition of hyaluronic acid and keeping the skin in a good condition can be expected. Further, various inhibitors of hyaluronidase activity have been studied because the stability of cosmetics and the like can be enhanced.

For example, glycyrrhizic acid, sodium cromoglycate, baicalin, indomethacin, aspirin and the like have been confirmed to have high hyaluronidase activity inhibitory effects, and these are currently used as anti-inflammatory agents. However, glycyrrhizic acid and baicalin have restrictions on their uses and concentrations, and sodium cromoglycate requires strict precautions for pregnant women (Patent Document 2).

On the other hand, as compounds having hyaluronidase inhibitory activity extracted from natural products, tea polyphenols extracted from tea used for drinking (Patent Document 3), chimpi, kijitsu and chinpi used as crude drugs or foods and drinks An organic solvent extract of Rakanka (Patent Document 4), a specific seaweed extract (Patent Document 5), etc. have been found, but their safety has not been sufficiently confirmed and their actions and effects are insufficient. In addition, it has been pointed out that it is difficult to stably mix the drug with the preparation while maintaining the activity.

JP 2001-010964 JP-A-2007-161632 Japanese Unexamined Patent Publication No. 6-9391 Japanese Unexamined Patent Publication No. 6-80576 Japanese Unexamined Patent Publication No. 9-67266

Therefore, an object of the present invention is to provide a hyaluronidase inhibitor that can be used in a wide range of applications.

The present inventors have conducted various studies to solve the above problems, and found that β-1,3-1,6-glucan, which does not have hyaluronidase inhibitory activity, is subjected to specific derivatization to obtain strong hyaluronidase inhibitory activity. It was found that it had, and that this effect was higher than when other β-glucans were similarly derivatized.
The present invention has been completed based on the above findings.

That is, the present invention is a hyaluronidase activity inhibitor containing β-1,3-1,6-glucan in which a part of the hydroxy group is carboxymethylated.
Further, the present invention is a cosmetic composition containing the hyaluronidase activity inhibitor.
Further, the present invention is a method for suppressing the decomposition of hyaluronic acids, which comprises applying the cosmetic composition to the skin.

The present invention is a method for producing a hyaluronidase activity inhibitor, which comprises carboxylmethylating a part of the hydroxy group of β-1,3-1,6-glucan represented by the following general formula (1). is there.

(In the formula, d represents at least 20 numbers and e represents at least 1 number. However, the total number of d and e is β-1,3- represented by the general formula (1). The mass average molecular weight of 1,6-glucan is 3000 to 5 million.)

Further, in the present invention, the hydrogen atom of a part of the hydroxy group of β-1,3-1,6-glucan composed of the units represented by the following general formulas (a) and (b) is the general formula (c). It is a carboxymethylated β-1,3-1,6-glucan substituted with a group represented by.
However, in the units represented by the general formulas (a) and (b) located at the ends, a hydroxy group is bonded to the carbon at the 1-position, or the hydrogen atom of the hydroxy group is represented by the general formula (c). It has a structure substituted with a group, and hydrogen is bonded to the oxygen atom bonded to the carbon at the 3-position, or a group represented by the general formula (c) is bonded.

-CH ₂ COOX (c)
(In the formula, X represents a hydrogen atom, an alkali metal or an alkaline earth metal.)

According to the present invention, a hyaluronidase inhibitor that can be used in a wide range of applications can be obtained.

Hyaluronidase inhibitory activity on (1) glycyrrhizin, (2) to (4) carboxylated β-glucan of the present invention, (5) β-1,3-1,6-glucan, (6) carboxymethyl cellulose and (7) pullulan. It is a figure which showed.

The hyaluronidase activity inhibitor of the present invention contains β-1,3-1,6-glucan in which a part of the hydroxy group is carboxymethylated as an active ingredient.

First, β-1,3-1,6-glucan will be described.
β-1,3-1,6-glucan refers to a β-glucan in which glucose is linked by β-1,3-glycosidic bond and β-1,6-glycosidic bond, and (1) the main chain is β-. 1,3-Glycosidic bond with branch of β-1,6-glycosidic bond, (2) Main chain consisting of β-1,3-glycosidic bond and β-1,6-glycosidic bond Etc. are known. As the β-1,3-1,6-glucan used in the present invention, those having a bond such as β-1,4-glycosidic bond may be used, but β-1,3-glycosidic bond is used. The content of glucosidic bonds other than the bonds and β-1,6-glycosidic bonds must be 10 mol% or less of the total of β-1,3-glycosidic bonds and β-1,6-glycosidic bonds.

As the β-1,3-1,6-glucan, any β-1,3-1,6-glucan can be used, but the solubility is good and carboxymethylation is performed efficiently. Therefore, β-1,3-1,6-glucan represented by the following general formula (1) is preferable:

In the above general formula (1), d represents at least 20 numbers, and e represents at least 1 number. However, the total number of d and e is preferably a number in which the mass average molecular weight of β-1,3-1,6-glucan represented by the general formula (1) is 3000 to 5 million, and is 7,000. ~ 1,000,000 is more preferable, and 10,000 to 500,000 is most preferable.

In the present invention, the mass average molecular weight of β-1,3-1,6-glucan is the pullulan equivalent when gel permeation chromatography (also referred to as GPC) analysis is performed using water as a solvent. Mass average molecular weight. The "mass average molecular weight" may also be referred to as a "weight average molecular weight".

The method for measuring the mass average molecular weight is not particularly limited, but as an example, a calibration curve (holding time on the x-axis) using a pullulan having a known molecular weight (concentration is arbitrary) and a differential refractometer is used. The y-axis is the molecular weight). Next, it is common to measure a sample (concentration is arbitrary) and calculate the relative molecular weight (molecular weight in terms of pullulan) from the holding time using the calibration curve.

However, pullulan and β-1,3-1,6-glucan have different molecular sizes even if they have the same molecular weight (same number of glucose units) due to the difference in structure, so only relative values can be obtained by gel permeation chromatography, which is a molecular sieve. However, it is possible to calculate the intrinsic molecular weight close to the absolute value by correcting it. Examples of the correction include a method of measuring the concentration of a sample and measuring and calculating three points of differential pressure viscosity, differential refractometer, and light scattering. Specifically, first, a pullulan standard solution having a known concentration, viscosity, and refractive index is used to determine the device constant k.

Next, the original body whose concentration of β-1,3-1,6-glucan was measured by the phenol-sulfuric acid method is precisely measured, and an aqueous solution having a known concentration is prepared and used as a sample. Then, the molecular weight is calculated from the values measured by the differential pressure viscosity detector, the differential refractometer detector, and the light scattering detector.

In the above general formula (1), the value (e / d) of the ratio of e to d is preferably 0.2 to 1 in that the effect of the present invention is more clearly exhibited, and is preferably 0.5 to 1. It is more preferably 0.95, and most preferably 0.6 to 0.9. The unit having the number of repetitions d and the unit having the number of repetitions e may be randomly connected or may be connected in a block shape.

β-1,3-1,6-glucan is extracted from known methods such as yeast, lactic acid bacteria, natto bacteria, acetic acid bacteria, aspergillus, algae such as chlorella and spirulina, and cell walls and products of filamentous fungi. Can be obtained by doing. The method for extracting β-1,3-1,6-glucan is not particularly limited, and a known method may be used.

Among these, β-1,3-1,6-glucan, which has a high moisturizing effect on the skin, can be extracted from black yeast (Aureobasidium pullulans). Further, since β-1,3-1,6-glucan having better water solubility can be obtained from the black yeast culture solution, it can be particularly preferably used in the present invention, and further, the black of deposit number FERM BP-8391 The yeast culture solution is more preferable because it contains β-1,3-1,6-glucan at a higher solid content purity (concentration in the solid content). In addition, β-1,3-1,6-glucan is commercially available. For example, the trade name "BBG" manufactured by Oriental Yeast Co., Ltd. is β-1,3-1,6-glucan derived from baker's yeast. And can be used in the present invention.

The details of the deposit number FERM BP-8391 are explained in International Publication No. 2004/001053 (WO2004 / 001053), and the deposit number is deposited at the Patent Organism Depositary Center of the National Institute of Advanced Industrial Science and Technology. .. The details that identify the deposit are described below.

(1) Depositary Institution Name: National Institute of Advanced Industrial Science and Technology (Currently: National Institute of Advanced Industrial Science and Technology) Patent Biological Deposit Center (Current Depositary Institution Name: Incorporated Administrative Agency Product Evaluation Technology Infrastructure Organization Patent Biological Deposit Center) )
(2) Contact: 1-1-1, Higashi, Tsukuba-shi, Ibaraki, Japan 305-8566 Central 6th
(Current contact information :: 〒292-0818 Kisarazu City, Chiba Prefecture 2-5-8 Kazusakamatari Room 120 Phone number 0438-20-5910)
(3) Contract number: FERM BP-8391
(4) Display for identification: Aureobasidium pullulans ADK-34
(5) Original deposit date: July 11, 2002 (6) Transfer date to deposit based on the Budapest Convention: June 2, 2003

The case of concentrating the extracted β-1,3-1,6-glucan is not particularly limited as long as it is a method for removing water or pulverizing, for example, spray drying, freeze drying, vacuum drying. , Heat drying, extraction with a solvent or a supercritical fluid, precipitation recovery, freeze-thawing, etc., and these can be appropriately combined.

Next, β-1,3-1,6-glucan in which a part of the hydroxy group is carboxymethylated will be described.
Β-1,3-1,6-glucan in which a part of the hydroxy group is carboxymethylated (hereinafter, may be referred to as "carboxymethylated β-glucan" or "CM glucan" in the present specification) is the above-mentioned β-. It can be obtained by carboxymethylating the hydroxy group of 1,3-1,6-glucan. Carboxymethylation can be carried out using known methods, specifically, for example, β-1,3-1,6-glucan is dissolved or dispersed in a suitable solvent, and alkali metal hydroxide or hydroxide is used. This can be done by reacting with monohalogenated acetic acid and / or a metal salt thereof in the presence of an alkaline earth metal.

In the present invention, the carboxymethylated β-glucan may also include a metal salt that can be easily converted to a carboxymethylated β-glucan by pH, specifically, an alkali metal salt or an alkaline earth metal salt. Examples of the alkali metal include sodium and potassium, and examples of the alkaline earth metal include calcium, magnesium and barium. As the metal salt, a sodium salt is preferable.

The specific conditions for performing the above-mentioned carboxymethylation are not particularly limited, but are as follows, for example.
In the carbokimethylation reaction, a base such as sodium hydroxide enhances the nucleophilicity of the hydroxyl group of β-1,3-1,6-glucan, and an etherification reagent such as monohalogenated acetic acid substitutes the hydroxyl group for an electrophilic substitution. It is a reaction. As specific conditions, for example, when obtaining carboxymethylated β-1,3-1,6-glucan having a degree of substitution of 0.3 to 0.9, β-1,3-1,6-glucan is formed. The amount of sodium hydroxide per 1 mol of glucose unit is 0.5 to 1.1 mol (in the present specification, this is referred to as "1 to 1.5 equivalents with respect to glucose unit"), and sodium monohalide acetate. A method of reacting 0.5 to 3 mol can be mentioned. At this time, since about 30 mol% of sodium monohalogenated acetate contributes to carboxymethylation, the amount of sodium monohalogenated acetate may be adjusted according to the desired degree of substitution.

Examples of the solvent include a mixed solvent of water, a lower alcohol and ketones, and examples of the lower alcohol include methanol, ethanol, N-propyl alcohol, isopropyl alcohol, N-butanol, isobutanol, tertiary butanol and the like alone, or Two or more kinds of mixed media can be preferably used. Further, as the ketones, a single medium such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, cyclohexanone, or a mixed medium of two or more kinds can be preferably used. More preferably, it is a mixed solvent of water and a lower alcohol, and the mixing ratio of the lower alcohol is preferably 60 to 95% by mass.
Examples of the alkali metal hydroxide or alkaline earth metal hydroxide include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like.

Specific examples of the monohalogenated acetic acid and the monohalogenated metal salt include monochloroacetic acid, sodium monochloroacetate, potassium monochloroacetate, sodium monobromoacetate, and potassium monobromoacetate. These monohalogenated acetic acid and its metal salt can be used alone or in combination of two or more.

The reaction temperature for carboxymethylation is usually 0 to 150 ° C, preferably in the range of 30 to 100 ° C. After completion of the reaction, the alkali can be neutralized with an acid, if necessary. As the acid, an inorganic acid such as sulfuric acid, hydrochloric acid or phosphoric acid, or an organic acid such as acetic acid can be used. Further, the next reaction may be carried out without neutralization on the way. The carboxymethylated β-1,3-1,6-glucan thus obtained is separated by filtration or the like, if necessary, or washed with hot water, hydrous isopropyl alcohol, hydrous acetone solvent or the like. It is also possible to remove unreacted carboxymethylating agents and salts produced by side by neutralization or the like before use.

In the hyaluronidase activity inhibitor of the present invention, any β-1,3-1,6-glucan can be used as the β-glucan for carboxymethylation, but since it has good solubility, it is described below. A carboxymethylated β-glucan composed of the general formulas (a) and (b) and having a hydrogen atom of a part of the hydroxy group represented by the general formula (c) is preferable.

-CH ₂ COOX (c)
(In the formula, X represents a hydrogen atom, an alkali metal or an alkaline earth metal.)

Examples of the alkali metal of the general formula (c) include sodium and potassium, and examples of the alkaline earth metal include calcium, magnesium and barium. It is preferable that X is a hydrogen atom or sodium.

The degree of substitution of the carboxymethylated β-glucan is preferably 0.05 to 2, more preferably 0.1 to 1, and even more preferably 0.3 to 0.9. The degree of substitution is expressed as the ratio of carboxymethyl groups introduced per glucose unit. For example, when the degree of substitution is 0.5, an average of 0.5 carboxymethyl groups are introduced per glucose unit. In the case of β-1,3-1,6-glucan, the maximum value of the carboxymethyl group introduced per glucose unit is approximately 3, and the minimum value is 0. For example, the unit of the general formula (a) has three hydroxyl groups, and the unit of the general formula (b) has two glucose units and six hydroxyl groups, so that the maximum is for one glucose unit. It is possible to introduce three carboxymethyl groups. Further, since there may be a glucose unit in which no carboxymethyl group is introduced, the value of the carboxymethyl group introduced is 0 in that case.

In the present invention, if the degree of substitution is smaller than 0.1, the effect of the present invention may not be obtained, and if it is larger than 2, the effect of the present invention corresponding to the value cannot be expected, and the carboxymethylated β-glucan Manufacturing conditions may become strict.

As a method for measuring the degree of substitution, for example, it can be obtained by the following method.
First, about 0.5 g of carboxymethylated β-glucan is precisely weighed and heated at 550 ° C. for 6 hours in a muffle furnace. Subsequently, 250 ml of water and 35 ml of 0.1 M sulfuric acid are added to the white solid of the residue, and the mixture is boiled for 30 minutes. After cooling, phenolphthalein is added, neutralized titration is performed using a 0.1 M potassium hydroxide aqueous solution, and the calculation is performed by the following formula:
A = (af-bf1) / sample (g)
Substitution = 162 x A / (10,000-80A)
However, A: ml of 0.05 mol / l sulfuric acid consumed by the bound alkali in 1 g of sample.
a: 0.05 mol / l Sulfuric acid used ml, f: 0.05 mol / l Sulfuric acid titer b: 0.1 mol / l Potassium hydroxide titrated ml, f1: 0.1 mol / l Hydroxide Potassium hydroxide titration

The hyaluronidase activity inhibitor of the present invention preferably contains the above carboxymethylated β-glucan as a solid content in an amount of 0.1% by mass or more, preferably 0.5% by mass or more, based on the total amount of the hyaluronidase activity inhibitor. Is preferable, and it is more preferable to contain 0.7% by mass or more. If it is less than 0.1% by weight, the amount of hyaluronidase activity inhibitor required to obtain an effective effect may be too large.

The hyaluronidase activity inhibitor of the present invention contains various compounding ingredients that can be usually used in cosmetics depending on the purpose of use, such as various surfactants, various enzymes, drugs, preservatives, isotonic agents, buffers, stabilizers, and chelates. Agents, solubilizers, pH adjusters, fragrances, solvents and the like can be used alone or in combination of two or more as appropriate within the range of normal usage amounts.

Next, the cosmetic composition of the present invention will be described.
The cosmetic composition of the present invention contains the above hyaluronidase activity inhibitor.
The content of the hyaluronidase activity inhibitor contained in the cosmetic composition of the present invention is 0.0001 to 1% by mass based on the total amount of the cosmetic composition as carboxymethylated β-glucan which is an active ingredient of the hyaluronidase activity inhibitor. , Preferably 0.0005 to 0.5% by mass, more preferably 0.001 to 0.3% by mass, still more preferably 0.005 to 0.1% by mass, and most preferably 0.01 to 0.1% by mass. %.
If the concentration of carboxymethylated β-glucan is less than 0.0001% by mass, the effect of the present invention cannot be obtained, and if it is more than 1% by mass, the effect as a hyaluronidase activity inhibitor commensurate with the amount of addition cannot be expected. It may also affect the usability of the composition.

The cosmetic composition of the present invention preferably contains hyaluronic acids because decomposition can be suitably suppressed even when hyaluronic acids are contained. The content of hyaluronic acids in the cosmetic composition is not particularly limited, but is 0.01 to 10% by mass, more preferably 0.1 to 8% by mass, and further preferably 0.5 to 5% by mass. is there.

Examples of the hyaluronic acids include hyaluronic acid, hyaluronic acid derivatives, and salts thereof. Examples of the hyaluronic acid derivative include acetylated hyaluronic acid, hydroxypropyltrimonium hyaluronate, hyaluronic acid sulfate, stearyl hyaluronate, and methacryl hyaluronate oxide. The salt of hyaluronic acid or hyaluronic acid derivative may be any salt that is acceptable for cosmetics, external preparations for skin, foods or pharmaceuticals, and particularly preferable examples include sodium salt, potassium salt, magnesium salt and calcium salt. Can be mentioned.

The cosmetic composition of the present invention is preferably an aqueous cosmetic. Aqueous cosmetics are cosmetics in which the continuous phase is an aqueous phase, and have an emulsified form of oil-in-water type or water-in-water type.
The proportion of the aqueous phase is preferably 50 to 99.5% by mass, more preferably 60 to 99% by mass, and most preferably 70 to 95% by mass based on the cosmetic composition. If the aqueous phase is less than 50% by mass, the effect of the hyaluronidase activity inhibitor of the present invention may not function sufficiently.

In addition to water, the aqueous phase contains components derived from the hyaluronidase activity inhibitor of the present invention and water-soluble components among any components described below, but the proportion of water in the aqueous phase is 20% by mass or more. Is more preferable, 50% by mass or more is more preferable, and 70% by mass or more is most preferable. If the proportion of water in the aqueous phase is less than 20% by mass, the effect of the hyaluronidase activity inhibitor of the present invention may not function sufficiently.
In addition to the water to be added, the water to be added includes water derived from the hyaluronidase activity inhibitor and water contained in any component described later.

The proportion of the oil phase is preferably 0.5 to 50% by mass, more preferably 1 to 40% by mass, and most preferably 5 to 30% by mass with respect to the total amount of the cosmetic composition.

Further, the cosmetic composition of the present invention preferably has a viscosity at 25 ° C. of 500 mPa · s or less, more preferably 400 mPa · s or less, still more preferably 300 mPa · s or less, as measured by a cone plate type rotational viscometer. Most preferably, it is 200 mPa · s or less. The rotation speed when measured with a rotational viscometer can be appropriately set between 1 and 100 rpm depending on the apparatus and viscosity. For example, when a TV-20 (cone plate type rotational viscometer) manufactured by Toki Sangyo Co., Ltd. is used, measurement is performed at a rotation speed of 5 rpm at 20 to 600 mPa · s.

The cosmetic composition of the present invention preferably contains β-1,3-1,6-glucan in addition to the hyaluronidase activity inhibitor, because it can provide a cosmetic composition having an excellent texture. In particular, when hyaluronic acids are used in combination, it is more preferable because the stickiness caused by hyaluronic acids can be suitably improved.

The cosmetic composition of the present invention can contain any component that can be usually used in cosmetics in addition to the above hyaluronidase activity inhibitor, hyaluronic acids, and β-1,3-1,6-glucan. For example, surfactants, chelating agents, low molecular weight polyols, plant-derived extracts, animal-derived extracts, microbial-derived extracts, zinc compounds, thickeners, oils, pigments, pigments, antibacterial agents, moisturizers, pH adjusters, antioxidants. Examples include agents, UV absorbers, moisturizing ingredients, enzymes, fragrances and the like.

Examples of the surfactant include anionic surfactants, nonionic surfactants, cationic surfactants and amphoteric surfactants. Examples of the anionic surfactant include higher fatty acid salt, higher alcohol sulfate ester salt, sulfated olefin salt, higher alkyl sulfonate, α-olefin sulfonate, sulfated fatty acid salt, sulfonated fatty acid salt, and phosphoric acid ester. Salts, fatty acid ester sulfates, glyceride sulfates, fatty acid ester sulfonates, α-sulfo fatty acid methyl ester salts, polyoxyalkylene alkyl ether sulfates, polyoxyalkylene alkylphenyl ether sulfates, polyoxy Alkylene alkyl ether carboxylate, acylated peptide, fatty acid alkanolamide or sulfate ester salt of its alkylene oxide adduct, sulfosuccinate, alkylbenzene sulfonate, alkylnaphthalene sulfonate, alkylbenzoimidazole sulfonate, polyoxyalkylene Sulfosuccinate, salt of N-acyl-N-methyltaurine, N-acylglutamic acid or its salt, acyloxyethane sulfonate, alkoxyethane sulfonate, N-acyl-β-alanine or its salt, N-acyl- Examples thereof include N-carboxyethyl taurine or a salt thereof, N-acyl-N-carboxymethylglycine or a salt thereof, an acyl lactate, an N-acylsulfosin salt, and an alkyl or alkenylaminocarboxymethyl sulfate.

Examples of the nonionic surfactant include polyoxyalkylene alkyl ether, polyoxyalkylene alkenyl ether, and polyoxyethylene polyoxypropylene alkyl ether (the addition form of ethylene oxide and propylene oxide may be either random or block. ), Polyethylene glycol propylene oxide adduct, Polypropylene glycol ethylene oxide adduct, glycerin fatty acid ester or ethylene oxide adduct thereof, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, alkyl polyglucoside, fatty acid monoethanolamide or ethylene oxide addition thereof. Things, fatty acids-N-methylmonoethanolamide or ethylene oxide adducts thereof, fatty acid diethanolamides or ethylene oxide adducts thereof, sucrose fatty acid esters, alkyl (poly) glycerin ethers, polyglycerin fatty acid esters, polyethylene glycol fatty acid esters, fatty acids Examples thereof include methyl ester ethoxylate and N-long chain alkyldimethylamine oxide.

Examples of the cationic surfactant include an alkyl (alkenyl) trimethylammonium salt, a dialkyl (alkenyl) dimethylammonium salt, an alkyl (alkenyl) quaternary ammonium salt, and a mono or dialkyl (alkenyl) containing an ether group or an ester group or an amide group. ) Quaternary ammonium salt, alkyl (alkenyl) pyridinium salt, alkyl (alkenyl) dimethylbenzylammonium salt, alkyl (alkenyl) isoquinolinium salt, dialkyl (alkenyl) morpholinium salt, polyoxyethylene alkyl (alkenyl) amine, alkyl (alkenyl) amine Examples thereof include salts, polyamine fatty acid derivatives, amyl alcohol fatty acid derivatives, benzalconium chloride, and benzethonium chloride.
Examples of the amphoteric tenside agent include carboxybetaine, sulfobetaine, phosphobetaine, amide amino acid, imidazolinium betaine-based surfactant and the like.

The above-mentioned surfactant may contain one kind or two or more kinds mentioned above. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.01 to 80% by mass, more preferably 0.05 to 60% by mass, based on the total amount of the cosmetic composition.

Examples of the chelating agent include amino polycarboxylic acid chelating agents, aromatic or aliphatic carboxylic acid chelating agents, amino acid chelating agents, ether polycarboxylic acid chelating agents, phosphonic acid chelating agents, and phosphoric acid chelating agents. Examples thereof include hydroxycarboxylic acid chelating agents, high molecular weight electrolyte (including oligomeric electrolyte) chelating agents, dimethyl glyoxime, ascorbic acid, thioglycolic acid, phytic acid, glyoxylic acid, and glyoxal acid. Each of these chelating agents may be in the form of a free acid or in the form of a salt such as a sodium salt, a potassium salt or an ammonium salt. In addition, they may be in the form of their hydrolyzable ester derivatives.

Examples of the aminopolycarboxylic acid-based chelating agent include ethylenediaminetetraacetic acid, ethylenediaminediacetic acid, cyclohexanediaminetetraacetic acid, nitrilotriacetic acid, iminodiacetic acid, N- (2-hydroxyethyl) iminodiacetic acid, diethylenetriaminepentaacetic acid, and N- (2). -Hydroxyethyl) ethylenediaminetriacetic acid, glycol etherdiaminetetraacetic acid, glutamate diacetic acid, aspartate diacetic acid and salts thereof.

Examples of aromatic or aliphatic carboxylic acid-based chelating agents include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, sebacic acid, azelaic acid, itaconic acid, aconitic acid, pyruvate, and salicylic acid. Examples thereof include acetylsalicylic acid, hydroxybenzoic acid, aminobenzoic acid (including anthranylic acid), phthalic acid, fumaric acid, trimellitic acid, oxalic acid, hexahydrophthalic acid and salts thereof, methyl esters and ethyl esters.

Examples of the amino acid-based chelating agent include glycine, serine, alanine, lysine, cystine, cysteine, ethionine, tyrosine, methionine and salts and derivatives thereof.
Examples of the phosphonic acid-based chelating agent include iminodimethylphosphonic acid, alkyldiphosphonic acid, 1-hydroxyethane-1,1-diphosphonic acid and salts thereof.
Examples of the phosphoric acid-based chelating agent include orthophosphoric acid, pyrophosphoric acid, triphosphoric acid and polyphosphoric acid.

Examples of the hydroxycarboxylic acid-based chelating agent include malic acid, citric acid, glycolic acid, gluconic acid, heptonic acid, tartrate acid, lactic acid and salts thereof.
Examples of the polymer electrolyte (including oligomeric electrolyte) chelating agent include an acrylic acid polymer, a maleic anhydride polymer, an α-hydroxyacrylic acid polymer, an itaconic acid polymer, and two types of constituent monomers of these polymers. Examples thereof include copolymers and epoxy succinic acid polymers composed of the above.

Among these chelating agents, ethylenediaminetetraacetic acid, ethylenediaminediacetic acid, nitrilotriacetic acid, iminodiacetic acid, N- (2-hydroxyethyl) iminodiacetic acid, aspartate diacetic acid, and succinic acid are highly safe and have a large chelating effect. Acids, salicylic acid, oxalic acid, lactic acid, fumaric acid, citric acid, tartaric acid, 1-hydroxyethane-1,1-diphosphonic acid and salts thereof are preferred.

As the chelating agent, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.01 to 30% by mass, more preferably 0.05 to 20% by mass, based on the total amount of the cosmetic composition.

The low molecular weight polyol is a polyol having a molecular weight of 50 to 1000, preferably a molecular weight of 50 to 500, and for example, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, 1,3. -Propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 2-methyl-1,2-propanediol, 2-methyl-1,3 − Propanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,5-pentanediol, 2,3-pentanediol, 2,4-pentanediol, 2-methyl- 1,2-butanediol, 2-methyl-2,3-butanediol, 2-methyl-1,4-butanediol, 3-methyl-1,2-butanediol, 3-methyl-1,3-butanediol, 2-Ethyl-1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 1,2-hexanediol, 1,5-hexanediol, 1,6-hexanediol, 2,5-hexane Diol, 3,3-hexanediol, 2-methyl-1,3-pentanediol, 2-methyl-1,5-pentanediol, 2-methyl-2,4-pentanediol, 3-methyl-1,5- Pentandiol, 3-methyl-2,3-pentanediol, 3-methyl-2,4-pentanediol, 4-methyl-1,2-pentanediol, 2-ethyl-2-methyl-1,3-propanediol , 2,2-Dimethyl-1,3-butanediol, 2,3-dimethyl-1,2-butanediol, 1,2-heptanediol, 1,7-heptanediol, 3,4-heptanediol, 2- Propyl-2-methyl-1,3-propanediol, 2-isopropyl-2-methyl-1,3-propanediol, 1,2-octanediol, 1,8-octanediol, 3,6-octanediol, 2 -Ethyl-1,3-hexanediol, 2-sec-butyl-2-butyl-1,3-propanediol, 2,2-dimethyl-1,3-hexanediol, 2,5-dimethyl-2,5- Hexanediol, 2,2,4-trimethyl-1,3-pentanediol, 1,2-nonanediol, 1,3-nonanediol, 1,9-nonanediol, 3,6-octanediol , 2-Ethyl-2- (2-methyl) propyl-1,3-propanediol, 2,2,4-trimethyl-1,6-hexanediol, 2,4,4-trimethyl-1,6-hexanediol , 2-Butyl-2-ethyl-1,3-propanediol, 2,4-diethyl-1,5-pentanediol, 2-methyl-1,8-octanediol, 1,2-decanediol, 1,10 -Decandiol, 5,6-decanediol, 3,6-dimethyl-3,6-octanediol, 3,7-dimethyl-1,6-octanediol, 3,7-dimethyl-1,7-octanediol, 1,2-undecanediol, 1,4-undecanediol, 1,11-undecanediol, 6-ethyl-3-methyl-1,6-octanediol, 1,2-dodecanediol, 1,10-dodecanediol, 1,12-Dodecanediol, 2,4-diethyl-1,5-octanediol, 2,8,8-trimethyl-2,7-nonanediol, 1,2-tetradecanediol, 1,14-tetradecanediol, 7 , 8-Tetradecanediol, 1,2-pentadecanediol, 1,2-hexadecandiol, 1,16-hexadecandiol, 1,17-heptadecanediol, 1,2-octadecandiol, 1,12-octadecandiol, 1, , 2-Eicosandiol, 1,2-docosanediol, 1,2-tetracosanediol and other saturated diols or condensates thereof;

2-Buten-1,4-diol, 3-butene-1,2-diol, 2-methylene-1,3-propanediol, 2-butin-1,4-diol, 5-hexene-1,2-diol , 3-Methyl-2-pentene-1,5-diol, 3-methylenepentane-1,5-diol, 1,5-hexadien-3,4-diol, 7-octene-1,2-diol, 2, 5-Diol-3-hexene-2,5-diol, 9-decene-1,2-diol, 2,6-dimethyl-7-octene-2,6-diol, 3,7-dimethyl-7-octene- 1,6-diol, 13-tetradecene-1,2-diol, 12-hydroxy-9-octadesenol, 2-pentin-1,4-diol, 3-hexine-2,5-diol, 4-methyl-2- Pentin-1,4-diol, 3-heptin-2,5-diol, 4-methyl-2-pentin-1,4-diol, 3,4-dimethyl-1-pentin-3,4-diol, 2, 5-Diol-3-hexin-2,5-diol, 5-decine-4,7-diol, 2,6-dimethyl-7-octin-2,6-diol, 3,6-dimethyl-4-octin- 3,6-diol, 2,3,6,7-tetramethyl-4-octin-3,6-diol, 2,4,7,9-tetramethyl-5-decine-4,7-diol, 2, 5,8,11-Tetramethyl-6-dodecin-5,8-diol, 1,1,4,4-tetraisopropyl-4-octin-3,6-diol, 5,10-diethyl-7-tetradecin- Unsaturated diols such as 6,9-diol;

1,2-Cyclopentanediol, 1,3-cyclopentanediol, 1,2-cyclohexanediol, 1,3-cyclohexanediol, 1,4-cyclohexanediol, 1,2-cycloheptanediol, 2,3-norbornane Diol, 2,5-norbornandiol, 2,7-norbornandiol, 1,2-cyclooctanediol, 1,4-cyclooctanediol, 1,2-cyclodecanediol, 5-cyclooctene-1,2-diol , 1,5-decalindiol, limonene glycol, 1,2-terpenediol, 4,4'-bicyclohexanediol, 1,2-cyclododecanediol and other alicyclic diols;

Glycerin, 1,2,3-butanetriol, 1,2,4-butanetriol, 2-methyl-1,2,3-propanetriol, 1,2,3-pentanetriol, 1,2,4-pentanetriol , 1,3,5-pentantriol, 2,3,4-pentantriol, 2-methyl-2,3,4-butanetriol, trimethylolethane, 2,3,4-hexanetriol, 2-ethyl-1 , 2,3-Butantriol, Trimethylol Propane, 4-propyl-3,4,5-Heptanetriol, 2,4-Dimethyl-2,3,4-Pentantriol, Triethanolamine, Triisopropanolamine, etc. 3 Triol;

Ellisritol, pentaerythritol, 1,2,3,4-pentatetrol, 2,3,4,5-hexatetrol, 1,2,4,5-pentantetrol, 1,3,4,5-hexane Tetrol, diglycerin, sorbitan, N, N, N', N'-tetrakis (2-hydroxypropyl) ethylenediamine, N, N, N', N'-tetrakis (hydroxyethyl) ethylenediamine and other tetrahydric alcohols;

Pentahydric alcohols such as adonitol, arabitol, xylitol and triglycerin; hexahydric alcohols such as dipentaerythritol, sorbitol, mannitol, iditol, inositol, darsitol, tarose and allose;

1-Methyl glyceryl ether, 2-Methyl glyceryl ether, 1-ethyl glyceryl ether, 2-ethyl glyceryl ether, 1-propyl glyceryl ether, 2-propyl glyceryl ether, 1-isopropyl glyceryl ether, 2-isopropyl glyceryl ether, 1- Butyl glyceryl ether, 2-butyl glyceryl ether, 1-isobutyl glyceryl ether, 2-isobutyl glyceryl ether, 1-pentyl glyceryl ether, 2-pentyl glyceryl ether, 1-hexyl glyceryl ether, 2-hexyl glyceryl ether, 1-heptyl glyceryl Ether, 2-Heptylglyceryl ether, 1-octylglyceryl ether, 2-octylglyceryl ether, 1- (2-ethylhexyl) glyceryl ether, 2- (2-ethylhexyl) glyceryl ether, 1-nonylglyceryl ether, 2-nonylglyceryl Ether, 1-decyl glyceryl ether, 2-decyl glyceryl ether, 1-undecyl glyceryl ether, 2-undecyl glyceryl ether, 1-dodecyl glyceryl ether, 2-dodecyl glyceryl ether, 1-tridecyl glyceryl ether, 2-tri Decyl glyceryl ether, 1-tetradecyl glyceryl ether, 2-tetradecyl glyceryl ether, 1-hexadecyl glyceryl ether, 2-hexadecyl glyceryl ether, 1-octadecyl glyceryl ether, 2-octadecyl glyceryl ether, 1-branched octadecyl glyceryl Ether, 2-branched octadecyl glyceryl ether, 1-eicosyl glyceryl ether, 2-eicosyl glyceryl ether, 1-allyl glyceryl ether, 2-allyl glyceryl ether, 1-undecenyl glyceryl ether, 2-undecenyl glyceryl Glycerin monoethers such as ether, 1-oleyl glyceryl ether, 2-oleyl glyceryl ether, 1-phenyl glyceryl ether, 2-phenyl glyceryl ether;

N-substituted diethanolamines such as N-methyldiethanolamine, N-ethyldiethanolamine, N-propyldiethanolamine, N-isopropyldiethanolamine, N-butyldiethanolamine, N-cyclohexyldiethanolamine, N- (2-ethylhexyl) diethanolamine;
N-Methyldiisopropanolamine, N-ethyldiisopropanolamine, N-propyldiisopropanolamine, N-isopropyldiisopropanolamine, N-butyldiisopropanolamine, N-cyclohexyldiisopropanolamine, N- (2-ethylhexyl) di N-substituted diisopropanolamines such as isopropanolamine;

3-Dimethylamino-1,2-propanediol, 3-diethylamino-1,2-propanediol, 3-dipropylamino-1,2-propanediol, 3-diisopropylamino-1,2-propanediol, 3- Examples thereof include N, N-di-substituted-3-amino-1,2-propanediols such as dibutylamino-1,2-propanediol.

Among these low molecular weight polyols, propylene glycol, dipropylene glycol, tripropylene glycol, 1,2-butanediol, 1,3-butanediol, 2,3-butanediol, 1,2-pentanediol, 3-methyl -1,3 butanediol, 1,2-hexanediol, 1,2-heptanediol, 1,2-octanediol, 2-ethyl-1,3-hexanediol, 1,2-nonanediol, 2-butyl- 2-Ethyl-1,3-propanediol, 1,2-decanediol, 1,10-decanediol, glycerin, triethanolamine, triisopropanolamine, erythritol, diglycerin, sorbitan, N, N, N', N '-Tetrax (2-hydroxypropyl) ethylenediamine, N, N, N', N'-Tetrax (hydroxyethyl) ethylenediol, sorbitol, 1-methylglyceryl ether, 1-ethylglyceryl ether, 1-propyl glyceryl ether, 1- Butyl glyceryl ether, 1-octyl glyceryl ether, 1- (2-ethylhexyl) glyceryl ether, 1-decyl glyceryl ether, 1-allyl glyceryl ether are preferred, propylene glycol, dipropylene glycol, tripropylene glycol, 1,3-butane. Diol, 3-methyl-1,3 butanediol, 1,2-octanediol, glycerin, triethanolamine, diglycerin, sorbitan, N, N, N', N'-tetrakis (2-hydroxypropyl) ethylenediamine, sorbitol , 1-allyl glyceryl ether is more preferable, and propylene glycol, dipropylene glycol, 1,3-butanediol, 3-methyl-1,3-butanediol, glycerin, sorbitol, and 1-allyl glyceryl ether are further preferable.

The low molecular weight polyol may be a mixture of one or more of the above. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.01 to 90% by mass, more preferably 0.05 to 70% by mass, based on the total amount of the cosmetic composition. Some low molecular weight polyols have a moisturizing effect.

The plant-derived extract is the whole plant, algae, or fungus, or a specific part such as flowers, leaves, stems, fruits, bark, roots, seeds, and resin, as it is, or by pressing, drying, crushing, or fermenting. It is obtained by extracting with a solvent at room temperature or heating, and is soluble in water, ethanol, propylene glycol or fats and oils. Alternatively, the extract may be diluted, concentrated, or dried. Further, the essential oil may be obtained by using a steam distillation method, an extraction method, a chromatography method or the like.

As the extraction solvent for the plant-derived extract, those usually used for extracting natural components, for example, water; alcohols such as methanol, ethanol, propanol and butanol; polyvalents such as ethylene glycol, propylene glycol, butylene glycol and glycerin. Alcohols; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; ethers such as tetrahydrofuran, diethyl ether and polyethylene glycol; halogenated hydrocarbons such as dichloroethane and chloroform; petroleum ethers, n-hexane, Examples thereof include aliphatic hydrocarbons such as cyclohexane; aromatic hydrocarbons such as toluene; pyridines; sodium chloride solution and the like, and water, ethanol, propylene glycol and butylene glycol are particularly preferable.

Plants that can be used as plant-derived extracts include, for example, arch choke, almond, eye, Eisenhardia polystakia, eyebright, anoryuzetsuran, aomoji, acacia concinna, acacia senegal, acacia senegal gum, acacia declins, alfalfa, etc. Akaharnile, Akayaziou, Agi, Agrimonia eupatoria, Akebii, Asagaokakarakusa, Azami, Ashi, Ashitaba, Ajugatsuru Kestonica, Azuki, Asunaro, Asparagus, Asparasas linearis, Acerola, Asenyaku, Asenyakunoki, Atlas Gace Sleiocarps, Avenastrigosa, Avocado, Ama, Amacha, Jiaogulan, Amadokoro, Amamo, Amiris balsamifera, American Psychic, American Sansho, American Showma, American Carrot, Amomu Aromachikum, Arakashi, Arcana, Arctium Majus , Arctium minus, Arnica, Arnica camisonis, Alpinia officinalum, Alfalfa (also known as alfalfa), Aloebella, Anzanju, Anzu, Angelica, Antilis brunellaria, Amperopsis grosedentata, Ammaroku, Ikarisou, Izayoibara, Itadori, Italian Itosugi, Strawberry, Ichijiku, Ichiyakuso, Ginkgo, Itlan, Carob, Ibukitranoo, Imosemiru, Irakusa, Iran Iran, Iris, Iris Parida, Iwabenkei, Iwamitsuba, Ingenmame, Fennel, Witania Somnifera, Ukon Utsubogusa, Udo, Umikuroumedoki, Ume, Uyaku, Uralkan elephant, Uri, Urbarakutsuka, Urumsudavidiana, Uncariatomentosa, Unshuumikan, Agetsu, Eirantai, Edelweiss, Ezokogi, Ezosnake strawberry, Ezomisohagi Ebine, Everyco, Elm,
Elemi, Enju, Peony, Eastern Red Cedar, Passionflower, Passionflower, Ouren, Oazami, Pipsissewa, Oezodenda, Passionflower, Orchisma Clata, Orchis Maskula, Orchid, Oak (also known as European Oak), Okra, Obana Oobanakakaonoki, Oobana salsbury, Oobeni mikan, Omitengu palm, Ominotokeisou, Omugi, All spice, Okazeri, Okra, Oshiroibana, Otaneninjin, Otogirisou, Onigeshi, Onisalvia, Onihamadaikon, Onitana Karashi, Dutch peony, Olive, Origanum Herakleochikum, Orthosihon stamineus, Ormenis multicauris, Orange, Orobankerapum,

Gardenia Tahitensis, Carnation, Kaya Senegalensis, Cacao, Kakyok, Cassia, Cashew Nut, Cascara Sagrada, Cassia Itarica, Kappa Fikas Alvarez, Cattleya, Canadian Comfrey, Canary Tree, Caninabara, Kanokosou, Kabaanatake, Cub, Gama (蒲), Camiture (also known as chamomile), Kamimebouki, Kayupte, Karakusakeman, Karasumugi, Karasumugiwara, Karatouki, Galana, Garikabara, Califlower, Karin, Karuna (also known as Gyoryumodoki), Garsina Cambodia, Karot, Kawarayomogi Comfrey, Arugula, Comfrey, Kiwi, Comfrey, Comfrey, Kigeria Africana, Kidachi Aloe, Kidachihakka, Kinanoki, Kinoa, Kihada (also known as Oubaku), Kibanasuzushiro, Kibananohauchiwamame, Kibi, Gymnema, Kimokuren Caraway, Cucumber (also known as Cucumber), Kyoou, Gyoryu, Gyoryubai, Kiraya, Kiri, Ginbaika (also known as Suikazura), Gua, Guava, Quinceseed, Quercus Alba, Kukuinoki, Kuco, Kusanoou, Kuzu, Kusunoki, Kudano , Kumakokemomo, Kumazasa, Verbena, Kumanogiku, Cumin, Crameria Triandra, Clara, Granberry, Chrismum Marichimum, Grindia lobsta, Clintonia borealis, Carbassaw, Walnut, Grapefruit, Clematis, Black mustard, Black mustard, Gentiana lutea Black mustard, verbena, cumin, keketo, kei (also known as cinnamon), comfrey, comfrey, cape aloe, keshi, gekabijin, bay laurel, getto, chemiyamakouzorina, gentiana, gentiana prostrata, gennoshouko, kemponashi, kouki, kouki , Kobo, Kohone, Coffee tree, Koganebana, Kokusina indica, Kokutan, Cocrearia officinalis, Kokemomo, Coco palm, Gosho strawberry, Kosho, Koshiro no Sendangusa, Kochinir cactus, Kochosekoku, Kochoran, Konara, Kohakobe Koranoki, Coriander, Coleus, Coleus barbatus, Gorenshi, Koroha, Conzlango, Comfrey (also known as Comfrey), Cuminnamon Cransom,

Jasmine Asa, Saishin, Cyperus Escrentus, Cypress, Rowan, South Rare Involcrata, Sakishima Buttonzuru, Sakura, Sakura Bakanboku, Pomegranate, Sato Kaede, Satoukibi, Sato Matsu, Southern Ka, Sassa Frasunoki, Saffron, Sabonsou, Sarasouju , Sanguinaria canadensis, hawthorn, sanshikisumire, sanshichininjin, sanshuyu, sansho, sanpens, theatea medularis, cyanotis arakunoidea, shea butterflies, shiozakisou, shishinburiumirio, cystrose (also known as lovedanum), cistus Monsperiensis, Sistus sladaniferus, Perilla, Sicilian, Rowan, Shibamugi, Gypterix odorata, Siberian fir, Simulva, Shimisifugadafrika, Shimotsukesou, Potato, Shakuyaku, Jasmine, Janohige, Janomeerika, Shuksha, Juzuda Sukkonkasumisou, Junipels Mexicana, Junsai, Ginger, Cardamom (also known as Cardamom), Shobu, Shouyoudaiou, Shirakaba, Silane, Rogarashi, Shirobanindosokei, Shirobanarupin, Shirobanawata, Shinkonakarisaya, Synsepalm Durushim Simplocos lasemosa, sweet acacia, watermelon, watermelon, scabiosa albensis, sugina, scutellaria galeri crater, stevia, strobe pine, spiny bamboo, spirulina platensis, spirulina maxima, suberihiyu, spertocomgi, sminomizakura, smilax aristro Chiaehoria, Akane, Akane, Akamatsu, Isonoki, Arakusa, Oobako, Otogirisou, Otogirisou, Otogirisou, Seiyo Pumpkin, Seiyo Karin, Seiyo Kawaraninjin, Seiyo Kizuta, Seiyo Gurumi, Seiyo Gomanohagusa, Seiyo Sakura Rowan, Japanese white yanagi, Japanese dandelion, Japanese medlar, Japanese medlar, Japanese medlar, Japanese pear, Japanese medlar, Rowan, Japanese medlar, Japanese medlar, Japanese medlar, Japanese medlar, Japanese medlar, Japanese medlar, Japanese medlar, Japanese medlar, Japanese medlar, Japanese medlar Rowan, Crataegus, Rowan, Rowan Rigi, Buckwheat Strawberry, Ceylon Nikkei, Sage, Secropia Obtusifolia, Sequoia Osgi, Cecil Oak, Sedum Purpreum, Mallow, Senega, Geranium, Celsidium Floridam, Celeus Grandiflorus, Celery, Senkyu, Sentifolia Rose, Centipedakunningamy, Senninkoku, Inula japonica, Senburi, Soujutsu, Souhakuhi, Sou Palmetto, Sokei, Buckwheat, Soranumuricocarpum,

Daii corn, radish, daisant chiku, soybean, taiso, daidai, taitsuriougi, thyme, taiwan hinoki, takasaburo, tachijakousou, tachibana, tabnoki, tabebuia aberanedae, tamasaki tsuzurafuji, damask rose, onion, damiana, tarragon Phila, chigaya, cha (brown), chabotokeiso, tuberose, chowji, calendula, corn, chili atmentosa, tsukushimenamomitsubaki, tsubokusa, tsurugumi, tsurudokudami, tsurureishi, tea tree, dioscorea compositor, dioscorea birosa, Dioscorea Mexicana, Teuchigurumi, Tecoma Clearis, Tetsuzainoki, Duke, Duboisia Reikardoch, Terminaria, Tencha, German Ayame, German Touhi, Tougashi, Togarashi, Touki, Tokinsenka, Tounin, Tounezumimochi, Touhi, Corn Silk, corn, toxa, calendula, calendula, toshishi (also known as mamedaoshi), tosho, tomato, trigonella foenum, tormentilla, trolley aoimodoki,

Nagabagishigishi, Nagiikada, Nas, Nazuna, Natamame, Natsushirogiku, Natsubodaijue, Natsume, Natsumeyashi, Nankyosou, Nanbanai, Nanbankafuji, Nioisumire, Nioitenjikuaoi, Nioihiba, Nigayomogi, Nikuzuku , Ninfaea Alba, Nenashikazura, Neubara, Nouzenharen, Nojisumire, Novara, Noborogiku,

Pineapple, Hibiscus, High Pine, Baobab, Bakuhosia Citriodora, Bakumondou, Bakopamonniera, Hagoromogusa, Hass, Parsley, Pachori, Hazelnut, Baccaris Genisteroides, Passiflora Arata, Hatomugi, Banana, Hanahacka, Honeysack Tahitensis, Hanesenna, Papaya, Pafio Pedirum Maudiae, Havelrea Rodopensis, Hamanas, Hamamelis, Hayatouri, Rose, Parsley, Harienju, Harpagofitum, Palmarosa, Barosmabetsurina, Banukon, Pansy, Bambaramame, Beat, Hiira , Bisnagabella, Bitter Almond, Bitter Orange, Hydrastis canadensis, Hinagiku, Hinageshi, Binan Kazura, Pinus Heda, Hinoki, Hibamata, Hihiragigiku, Hipophaeram Neudes, Sunflower, Himekouji, Himekora, Himetsuru Nichini Byakudan, chick lentil, lentil, fin harrisou, below aoi, pyrocarps pennachihorius, biwa, binrou, fafia panicrata, fusenkazura, pruneria mirifica, ferula galvanifurua, fukitanpopo, bukuryo, fusazakisuisen, fusagi Spicatus, Petit Glen, Petit Copetalum Orakoides, Bussouge, Butcher Bloom, Pterocarpus Marspium, Grapes, Futomomo, Beech, Zanthoxylum armacesis, Fuyubodaiju, Fuyumusina Tsukusatake, Fragaria tyroensis, Brazilian nut tree, French kai Gansho, French Lavender, Plantago Afra, Plantago Obata, Plantagopsilium, Primula Sikimensis, Prunes, Prunus Africana, Prunus Serotina, Plumeria, Plectrantus Barbatas, Brecia Hiacintina, Propolis, Bay, Hayflower, Hazelnut , Pecan, Bechibel, Hechima, Pennyroyal Mint, Beninoki, Benibana, Benibana Assembly, Pepo Pumpkin, Hera Obako, Pelargonium Capitatum, Helichrysum Arenalium, Helichrysum Angustihorium, Helichrysum Italicum, Belgamot, Perthol , Peruvian balsam, bergamot, velberis aquihorium, veronica ophicinalis, henna, hazelnut, summer lilac, boshuboku , Bowshunka, Impatiens, Adiantum capillus, Spinach, Hawkweed, Magnolia obovata, Hokubeifuurosou, Bocoa prouasensis, Boswellia serata, Hosobasenna, Hosobabarengiku, Bodaiju, Button, Hop, Poterium officinale, Jojoba, Polygonatumuru Ponkan,

Macademia, Magnolia Officinalis, Magnolia Bionji, Magwa, Magnojakushi, Masaki, Madake, Matsu, Matsurika, Matecha, Madonna Lily, Mayorana, Maria Azami, Marpigia Grabra, Quince, Maronnier, Mango, Mangosteen, Mangosteen, Mangosteen Red pine, Manjugiku, Mandarin orange, Mandrake, Mishima Psycho, Mizuhakka, Mizulemon, Michiyanagi, Mitsugashiwa, Mitracapas scavenger, Mimosa tenuiflora, Milciaria dubia, Milla (also known as Motsuyakuju), Milotamnus flaberifolia, Milobaran Murasaki, Murasakikibu, Murasaki Senburi, Murasaki Barengiku, Murayakoenji, Mebouki, Evening Primrose, Melia Azajirakuta, Melissa (also known as Kousuihakka), Merirot, Melosria, Melon, Menta Albensis, Moukoyomogi, Mourera Furubia Evening primrose, peach, peach tamana,

Yakumosou, Yagurumagiku, Yashabushi, Yachiyanagi, Yanagihakka, Yanagiran, Yamagwa, Yamazakura, Yamanoimo, Yamayomogi, Yugao, Eucalyptus, Eupatorium Ayapana, Eupatorium rebauzianumbertoni, Yukinoshita, Yuzu, Yuzu , Yuri, Youshutsurukinbai, Yoshuhozuki, Yoshuyamagobo, European Akinokirinsou, European Kistrawberry, European Guri, European Black Yamanarashi, European Shirakaba, European Beech, European Mannengusa, European Fir, Yomogi, Yomogigiku, Litchi (also known as lychee) , Lima bean, lime, limegi, lilac, radiata pine, latania, lychee, lanunculus ficaria, lavandura hybrida, rafuma, lavender, lalix europaea, larea divaricata, larea mexicana, rambutan, lychee, lychee Lithosea glutinosa, Ryugan, Lirios maobataki, apple, louisbos, lupinus bucarnosus, rubusbiloss, rumpuyan, borage, rurichensou, respedeza, resedalteora, lettuce, redama, redam pulse tore, lebanon sugi, levis Nare, Lemon, Lemongrass, Litchi, Rosewood, Rosemary, Lowbush Blueberry, Roman chamomile, Laurel (also known as laurel), Logwood, Robsta coffee tree, Wild thyme, Wasabi, Wasabi daikon, Wasabi tree, Watasugigiku, Watafuji Utsugi, Wal Plants such as terrier indica and lychee;

Ascofilm Nodosum, Aname, Oukimo, Okinawamozuku, Gigarchina Stellata, Kugermaniera Girata, Sargassum Filipendura, Sargassum Fushiform, Sargassum Mutikam, Sfaceraria Scoparia, Durbilea Antartica, Padina Pavonica Himantaria elongata, fucas seratsus, pervecia canaliculata, macrocystis pirifera, mitsushikonbu, laminaria ochlorosquid, laminaria crowstoni, laminaria digitata, laminaria hiperbolea, wakame, asparagopsis armata, igis, squid , Catamen Kirinsai, Geridium Curtilagineum, Saimi, Shimatengusa, Darus, Chinorimo, Tochaka, Porphyridium cruentum, Marubachishimakuronori, Lithosamnium Coralioides, Anaaosa, Chlorella emersoni, Chlorella pyrenoidosa, Dunariella salina , Duna Liera Badawill, Hira Aonori, Spirulina Platensis, Spirulina Maxima, Haslea Ostrearia, Deleceria sanguinea, Pikea Lobusta, Pruurocrisis Cartere, Hematococcus bulbiaris, Orchid Algae, Condor Scrisps, Coral, Sea Whip, Red Algae such as algae;

Examples include lichens and hyphae such as Ebernia full fracea, Oakmoss, Usnia barbata, Cynomorium cocci, Kabaanatake, Shiitake, Ningyotake, Himematsutake, Fuyumusinatsukusatake, Kabaanatake, Choreimaitake, and winter worm summer grass.

The plant-derived extract may contain one or more of the above. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.0001 to 5% by mass, more preferably 0.001 to 1% by mass, based on the total amount of the cosmetic composition.

Examples of animal-derived extracts include cow placenta extract, cow apical ligament (elastin) extract, cow blood (hematin) extract, cow / pig stomach (mucopolysaccharide) extract, cow / pig skin (collagen) extract, and the like. Examples include chicken crown extract, bee royal milk (royal jelly), silk (fibroin, sericin) extract, and milk (whey, sugar protein, lactoferrin) extract.

The animal-derived extract may contain one or more of the above. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.0001 to 5% by mass, more preferably 0.001 to 1% by mass, based on the total amount of the cosmetic composition.

Examples of the microbial-derived extract include bacterial metabolites, bacterial extract extracts, metabolites such as mold or mushroom, actinomycete metabolites, extracts such as mold or mushroom, actinomycete extract, natto fungus metabolite, and natto extract. , Rice fermented extract, rice bran (red bran, white bran) fermented extract, Euglena extract or its decomposition product or its water-soluble derivative, lactic acid fermented product of raw milk or defatted milk powder, trehalose or its derivative and the like.

The above-mentioned one or more kinds of microbial-derived extracts may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.0001 to 5% by mass, more preferably 0.001 to 1% by mass, based on the total amount of the cosmetic composition.

Examples of zinc compounds include zinc acetate, zinc laurate, zinc myristate, zinc palmitate, zinc ricinoleate, zinc undesylene, zinc aspartate, zinc acetylmethionine, zinc gluconate, zinc citrate, and polypyrrolidone carboxylic acid. Organic acid zinc salts such as zinc and zinc picolinate; zinc sulfonates such as zinc p-phenol sulfonate, zinc phosphate esters such as zinc ascorbyl phosphate, sodium cetyl phosphate, and DNA zinc; zinc complexes such as zinc pyrithione. Zinc-bearing zeolite such as (silver / zinc / ammonium) zeolite, silicic acid (ammonium / silver / zinc / aluminum); aluminum hydroxide such as aluminum oxide / zinc, aluminum oxide / zinc / cerium, aluminum oxide / zinc / iron Inorganic zinc salts such as zinc sulfate, zinc sulfide, zinc chloride, zinc bromide, zinc nitrate, zinc ammonium chloride, zinc aluminum sulfate, potassium zinc sulfate, zinc iodide, basic zinc carbonate, etc.; / Carbonate) (Mg / Al / Zinc), zinc oxide and the like. Among these, a compound that easily dissolves in water to form zinc ions is preferable, the solubility in 100 g of water at 20 ° C. is preferably 5 g or more, and the solubility is more preferably 10 g or more. Examples of such zinc compounds include zinc sulfate, zinc chloride, zinc gluconate, zinc bromide, zinc nitrate, zinc ammonium chloride, zinc aluminum sulfate, potassium zinc sulfate, zinc iodide and the like.

As the zinc compound, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.001 to 10% by mass, more preferably 0.01 to 3% by mass, based on the total amount of the cosmetic composition.

Examples of the thickener include dimethyldiallyl ammonium chloride / acrylamide copolymer, acrylamide / acrylic acid / dimethyldialylammonium chloride copolymer, cellulose or a derivative thereof, keratin and collagen or a derivative thereof, calcium alginate, purulan, agar. , Gelatin, tamarind seed polysaccharide, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, arabic gum, crystalline cellulose, arabinogalactan, karaya gum, tragacanth gum, alginic acid, albumin, casein, curdran, β-1,3 Examples thereof include β-glucan other than -1,6-glucan, β-glucan derivative, gellan gum, dextran, α-glucose and α-glucose derivative.

As the thickener, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.01 to 20% by mass, more preferably 0.05 to 10% by mass, based on the total amount of the cosmetic composition.

Examples of the oil agent include volatile and non-volatile oil agents and solvents and resins usually used in cosmetic compositions, which may be liquids, pastes or solids at room temperature, but liquids having excellent handling are preferable. Examples of the oil agent include higher alcohols such as cetyl alcohol, isostearyl alcohol, lauryl alcohol, hexadecyl alcohol, and octyldodecanol; lauric acid, undecylenic acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, 12 -Higher fatty acids such as hydroxystearic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, isostearic acid, 12-hydroxystearic acid, lanolin fatty acids; myristyl myristate, hexyl laurate, oleic acid Decyl, isopropyl myristate, hexyldecyl dimethyloctanoate, glycerin monostearate, diethyl phthalate, ethylene glycol monostearate, octyl oxystearate, diisopropyl adipate, cetyl octanate, isononyl isononanoate, isopropyl palmitate, stearic acid Stearyl, isotridecyl myristate, 2-ethylhexyl palmitate, octyldodecyl ricinolate, fatty acid cholesteryl / lanosteryl with 10-30 carbon atoms, cetyl lactate, lanolin acetate, ethylene glycol di-2-ethylhexanoate, pentaerythritol Estares such as fatty acid ester, dipentaerythritol fatty acid ester, cetyl caprate, glyceryl tricaprylate, diisostearyl malate, dioctyl succinate, and cetyl 2-ethylhexanoate; hydrocarbons such as liquid paraffin, vaseline, squalane; Rows such as lanolin, reduced lanolin, carnauba wax; fats and oils such as mink oil, cacao butter, palm oil, palm kernel oil, camellia oil, sesame oil, castor oil, olive oil; dimethylpolysiloxane, methylhydrozinepolysiloxane, methylphenylpolysiloxane , Polyether-modified organopolysiloxane, Fluoroalkyl-polyoxyalkylene co-modified organopolysiloxane, Alkyl-modified organopolysiloxane, Terminal-modified organopolysiloxane, Fluorine-modified organopolysiloxane, Amodimethicone, Amino-modified organopolysiloxane, Silicone gel, Acrylic Silicone compounds such as silicone, trimethylsiloxysilicate, silicone RTV rubber; fluorine compounds such as perfluoropolyether, fluoride pitch, fluorocarbon, fluoroalcohol; polybutene, polyisobutene, hydrogenated polyi Polyolefins such as sobutene, ethylene / α-olefin / co-oligomer, or olefin oligomers; hydrocarbons such as mineral oil, light liquid isoparaffin, petrolatum, and squalane can be mentioned.

The oil agent may contain one or more of the above. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.1 to 90% by mass, more preferably 0.5 to 70% by mass, based on the total amount of the cosmetic composition.

Examples of the dye include dyes such as Red No. 201, Yellow No. 4, Blue No. 1 and Black No. 401, and rake dyes such as Yellow No. 4 Al Lake and Yellow No. 203 Ba Lake.

Examples of the pigment include white pigments such as titanium oxide, extender pigments such as silica, talc, mica, sericite and kaolin, and pearl pigments such as mica titanium. The shape of these pigments (spherical, rod-shaped, needle-shaped, plate-shaped, indefinite-shaped, fluff-shaped, spindle-shaped, etc.) is not particularly limited. These pigments have conventionally known surface treatments such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, silane coupling agent treatment, titanium coupling agent treatment, oil agent treatment, N-acylated lysine treatment, and polyacrylic. The surface may be treated in advance by acid treatment, metal soap treatment, amino acid treatment, inorganic compound treatment, plasma treatment, mechanochemical treatment or the like.

As the pigment and / or the pigment, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.1 to 90% by mass, more preferably 0.5 to 70% by mass, based on the total amount of the cosmetic composition.

Examples of the antibacterial agent include paraben-based antibacterial agents such as methylparaben and ethylparaben; imidazole-based antibacterial agents such as thiabendazole and methylpriventol 2-benzimidazolylcarbamate; and carvanilide-based antibacterial agents such as trichlorocarbanilide and cloflucarban. Thiazol-based antibacterial agents such as benzothiazole; Triazine-based antibacterial agents such as debuconazole and cabinone; Biguanide-based antibacterial agents such as chlorhexidine hydrochloride and polyhexamethylene biguanide.

The antibacterial agent may be one or more of the above-mentioned ones, but when these antibacterial agents are used in combination, they should be used carefully in consideration of irritation to the human body. The blending amount is preferably 0.01 to 10% by mass, more preferably 0.03 to 3% by mass, based on the total amount of the cosmetic composition.

Examples of the pH adjuster include potassium carbonate, sodium hydrogen carbonate, ammonium hydrogen carbonate and the like.

As the pH adjuster, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.001 to 10% by mass, more preferably 0.01 to 5% by mass, based on the total amount of the cosmetic composition.

Examples of the antioxidant include tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, phytic acid and the like.
As the antioxidant, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.001 to 10% by mass, more preferably 0.01 to 5% by mass, based on the total amount of the cosmetic composition.

Examples of the ultraviolet absorber include salicylic acids such as homomentyl salicylate, octyl salicylate, and triethanolamine salicylate; paraaminobenzoic acid, ethyldihydroxypropyl paraaminobenzoic acid, glyceryl paraaminobenzoic acid, octyldimethylparaaminobenzoic acid, and paradimethylaminobenzoic acid. PABAs such as amyl, 2-ethylhexyl paradimethylaminobenzoate; 4- (2-β-glucopyranosyloxy) propoxy-2-hydroxybenzophenone, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone disulfonate, 2-hydroxy -4-methoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its trihydrate, sodium hydroxymethoxybenzophenone sulfonate, 2-hydroxy-4-methoxybenzophenone-5-sulfate, 2,2'-dihydroxy-4-methoxybenzophenone, 2 , 4-Dihydroxybenzophenone, 2,2'4,4'-tetrahydroxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2-hydroxy-4-N-octoxybenzophenone and other benzophenones; 2-Ethylhexyl paramethoxycinerate (also known as octyl paramethoxycinerate), mono-2-ethylhexanate glyceryl diparamethoxycinerate, methyl 2,5-diisopropylsilicate, 2,4,6- Tris [4- (2-ethylhexyloxycarbonyl) anilino] -1,3,5-triazine, methylbis trimethoxycinerate (trimethylsiloxy) silylisopentyl, isopropyl diisopropylsilicate benzoate paramethoxycinerate Mixtures, silicic acids such as p-methoxyhydrosilicate diethanolamine salt; 2-phenyl-benzimidazole-5-sulfate, 4-isopropyldibenzoylmethane, 4-tert-butyl-4'-methoxydibenzoylmethane, etc. Benzophenone methane-based; 2-cyano-, 3-diphenylprop-2-enoic acid 2-ethylhexyl ester (also known as octocrylene), dimethoxybenzilidendioxoimidazolidine propionate 2-ethylhexyl, 1- (3,4-) Dimethoxyphenyl) -4,4-dimethyl-1,3-pentandione, synoxate, methyl-O-aminobenzophenone, 2-ethylhexyl-2-cyano-3,3-diphenylactary , 3- (4-Methylbenzylidene) camphor, octylriazone, 4- (3,4-dimethoxyphenylmethylene) -2,5-dioxo-1-imidazolidinepropionate 2-ethylhexyl, high molecular weight derivatives of these, And silane derivatives.

As the ultraviolet absorber, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.01 to 10% by mass, more preferably 0.1 to 1% by mass, based on the total amount of the cosmetic composition.

Moisturizing ingredients include, for example, deoxyribonucleic acid, mucopolysaccharide, chondroitin sulfate, collagen, elastin, chitin, chitosan, hydrolyzed eggshell membrane, polyoxyethylene methyl glucoside, polyoxypropylene methyl glucoside, sodium lactate, urea, pyrrolidone carboxylic acid. Examples thereof include sodium, betaine, whey, ceramide, cholesterol, amino acids, fatty acids, phospholipids (including polymers) and the like.

As the moisturizing ingredient, one or more of the above may be blended. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.001 to 30% by mass, more preferably 0.01 to 20% by mass, based on the total amount of the cosmetic composition.

Examples of the enzyme include acylcoenzyme A desaturase, aminopeptidase, amyloglucosidase, oxidoreductase, catalase, glucose oxidase, superoxide dismutase, soybean peroxidase, dextran-immobilized protease, transglutaminase, protease, hesperidinase, lactoperoxidase, lipase and the like. Can be mentioned.

The enzyme may contain one or more of the above. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.001 to 10% by mass, more preferably 0.01 to 5% by mass, based on the total amount of the cosmetic composition.

Fragrances are added to impart aroma, scent, or to mask unpleasant odors in cosmetic compositions. The fragrance generally blended in the cosmetic composition is not particularly limited, and the flowers, seeds, leaves, roots, etc. of various plants including various extracts exemplified in the above-mentioned physiologically active ingredients and the like are not particularly limited. Fragrances extracted from, fragrances extracted from seaweeds, fragrances extracted from animal parts or secretions (eg, musk, musk), fragrances derived from microbial cultures, fragrances artificially synthesized (eg, menthol, Musk, acetate, vanilla) are exemplified.

The fragrance may be a mixture of one or more of the above. The blending amount is not particularly limited and varies depending on the type of cosmetic composition, but is preferably 0.001 to 10% by mass, more preferably 0.01 to 3% by mass, based on the total amount of the cosmetic composition.

Specific uses of the cosmetic composition of the present invention include, for example, hair care cosmetics such as shampoo, rinse-integrated shampoo, hair rinse, hair conditioner, hair mist, hair lotion; pigment wash, face wash cream, face wash foam, cleansing cream. , Cleansing foam, hand soap, body soap, body lotion, sunscreen, lotion, milky lotion, beauty liquid, face cream, hand cream, cold cream, face pack, antiperspirant, shaving soap, shaving foam, shaving lotion, Skin care cosmetics such as after-shave lotion and after-sun lotion are mentioned, and among them, body lotion, sunscreen lotion, lotion, milky lotion, and beauty liquid are particularly preferable.

Next, a method for producing the cosmetic composition of the present invention will be described.
The cosmetic composition of the present invention can be produced according to a conventional method as long as the hyaluronidase inhibitor is contained in the aqueous phase.

Finally, carboxymethylated β-1,3-1,6-glucan, which has good hyaluronidase inhibitory activity and can be particularly suitably used for cosmetic compositions, will be described.
The carboxymethylated β-1,3-1,6-glucan of the present invention can be obtained by carboxymethylating the hydroxy group of the above β-1,3-1,6-glucan. Carboxymethylation can be performed using known methods. Specifically, for example, the above β-1,3-1,6-glucan is dissolved or dispersed in an appropriate solvent, and in the presence of an alkali metal hydroxide or an alkaline earth metal hydroxide, acetic acid monohalogenated and / Or it can be done by reacting with its metal salt.

Examples of the solvent include a mixed solvent of water, a lower alcohol and ketones, and examples of the lower alcohol include methanol, ethanol, N-propyl alcohol, isopropyl alcohol, N-butanol, isobutanol, tertiary butanol and the like alone, or Two or more kinds of mixed media can be preferably used. Further, as the ketones, a single medium such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, cyclohexanone, or a mixed medium of two or more kinds can be preferably used. More preferably, it is a mixed solvent of water and a lower alcohol, and the mixing ratio of the lower alcohol is preferably 60 to 95% by mass.

Examples of the alkali metal hydroxide or alkaline earth metal hydroxide include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and the like.

Specific examples of the monohalogenated acetic acid and the monohalogenated metal salt include monochloroacetic acid, sodium monochloroacetate, potassium monochloroacetate, sodium monobromoacetate, and potassium monobromoacetate. These monohalogenated acetic acid and its metal salt can be used alone or in combination of two or more.

The reaction temperature for carboxymethylation is usually 0 to 150 ° C, preferably in the range of 30 to 100 ° C. After completion of the reaction, the alkali can be neutralized with an acid, if necessary. As the acid, an inorganic acid such as sulfuric acid, hydrochloric acid or phosphoric acid, or an organic acid such as acetic acid can be used. Further, the next reaction may be carried out without neutralization on the way. The carboxymethylated β-1,3-1,6-glucan thus obtained is separated by filtration or the like, if necessary, or washed with hot water, hydrous isopropyl alcohol, hydrous acetone solvent or the like. It is also possible to remove unreacted carboxymethylating agents and salts produced by side by neutralization or the like before use.

Any β-1,3-1,6-glucan can be used as the carboxymethylated β-glucan of the present invention, but since it has good solubility and can be efficiently carboxymethylated, it is described below. Β-1,3-1,6-glucan represented by the general formula (1) is preferable:

(In the formula, d represents at least 20 numbers and e represents at least 1 number. However, the total number of d and e is β-1,3- represented by the general formula (1). The mass average molecular weight of 1,6-glucan is 3000 to 5 million.)

The carboxymethylated β-glucan of the present invention is composed of the following general formulas (a) and (b), and a carboxymethylated β-glucan in which a hydrogen atom of a part of the hydroxy group is represented by the general formula (c) is preferable.

-CH ₂ COOX (c)
(In the formula, X represents a hydrogen atom, an alkali metal or an alkaline earth metal.)

Examples of the alkali metal of the general formula (c) include sodium and potassium, and examples of the alkaline earth metal include calcium, magnesium and barium. It is preferable that X is a hydrogen atom or sodium.

In the above general formulas (1) to (3), the ratio of the number of repeating units of b to the number of repeating units of a is preferably 0.2 to 1 in that the effect of the present invention is more clearly exhibited. , 0.5 to 0.95, more preferably 0.6 to 0.9. The unit a and the unit b may be randomly connected or may be connected in a block shape.
Further, as the side chain, the side chain bonded to the 6-position is preferably a monosaccharide or a disaccharide, and more preferably a monosaccharide.

The degree of substitution of the carboxymethylated β-glucan is preferably 0.05 to 2, more preferably 0.1 to 1, and even more preferably 0.3 to 0.9. The degree of substitution is expressed as the ratio of carboxymethyl groups introduced per glucose unit. For example, when the degree of substitution is 0.5, an average of 0.5 carboxymethyl groups are introduced per glucose unit. In the case of β-1,3-1,6-glucan, the maximum value of the carboxymethyl group introduced per glucose unit is approximately 3, and the minimum value is 0. For example, the unit of the general formula (a) has three hydroxyl groups, and the unit of the general formula (b) has two glucose units and six hydroxyl groups, so that the maximum is for one glucose unit. It is possible to introduce three carboxymethyl groups. Further, since there may be a glucose unit in which no carboxymethyl group is introduced, the value of the carboxymethyl group introduced is 0 in that case.

In the present invention, if the degree of substitution is smaller than 0.1, the effect of the present invention may not be obtained, and if it is larger than 2, the effect of the present invention corresponding to the value cannot be expected, and the carboxymethylated β-glucan Manufacturing conditions may become strict.

Hereinafter, the present invention will be specifically described with reference to Examples. In the following examples and the like, "%" is a "mass standard" unless otherwise specified.

Preparation of hyaluronidase activity inhibitor [Preparation Example 1]
Black yeast (deposit number FERM BP-8391) was cultured in potato dextrose agar slope medium to prepare a preserved strain, inoculated into a 500 ml Erlenmeyer flask containing 100 ml of YM liquid medium (manufactured by Diffco), and at 28 ° C. Pre-cultured for 3 days. This culture broth was transferred to a 30 liter fermenter containing 15 liters of Czapeak's medium (manufactured by Diffco) and cultured at 28 ° C. for 3 days. The culture solution was sterilized by heating at 90 ° C. for 30 minutes, and then the cells were removed by centrifugation to obtain a culture supernatant. The β-1,3-1,6-glucan contained in this culture supernatant is a compound having a ratio of e to d of 0.85 and a mass average molecular weight of 300,000 in the general formula (1). It was. The precipitate formed by adding to the obtained culture supernatant to an ethanol concentration of 70% was dried and pulverized to obtain β-1,3-1,6-glucan (purity: 90%).

Subsequently, 660 g of isopropyl alcohol, 85 g of a 4.1 M aqueous sodium hydroxide solution, and 40.0 g of the above β-1,3-1,6-glucan were mixed in a 1 L volume four-necked flask. After raising the temperature to 60 ° C., 60 g of monochloroacetate was added, and the mixture was reacted at 60 ° C. for 1 hour while refluxing. After decanting the supernatant of the reaction mixture, the residue was washed with 220 g of 73 mass% ethanol. Subsequently, the residue was dissolved in 1.5 L of water, adjusted to pH 7.2 with hydrochloric acid, filtered, and then 3 L of isopropyl alcohol was added to the filtrate for reprecipitation. The precipitate was dissolved in 1.5 L of water and dialyzed, and then the solvent was distilled off with an evaporator to obtain 58.0 g of carboxymethylated β-glucan. (Replacement degree 0.79)

[Preparation Example 2]
660 g of isopropyl alcohol, 12 g of a 10.5 M aqueous sodium hydroxide solution, and 40.0 g of the above β-1,3-1,6-glucan were mixed in a 1 L four-necked flask. After raising the temperature to 60 ° C., 60 g of monochloroacetate was added, and the mixture was reacted at 60 ° C. for 0.5 hours while refluxing. After decanting the supernatant of the reaction mixture, the residue was washed with 220 g of 73 mass% ethanol. Subsequently, the residue was dissolved in 1.5 L of water, adjusted to pH 7.1 with hydrochloric acid, filtered, and then 3.6 L of isopropyl alcohol was added to the filtrate for reprecipitation. The precipitate was dissolved in 1.5 L of water and dialyzed, and then the solvent was distilled off with an evaporator to obtain 42.0 g of carboxymethylated β-glucan. (Replacement degree 0.13)

[Preparation Example 3]
In a 1 L four-necked flask, 660 g of isopropyl alcohol, 85 g of 4.1 M sodium hydroxide aqueous solution, β-1,3-1,6-glucan derived from baker's yeast (manufactured by Oriental Yeast Co., Ltd .: trade name " BBG ") 40 g was mixed.
After raising the temperature to 60 ° C., 60 g of monochloroacetic acid was added, and the mixture was reacted at 60 ° C. for 1 hour while refluxing. After decanting the supernatant of the reaction solution, the residue was washed with 220 g of 73 mass% ethanol. Subsequently, the residue was dissolved in 1.5 L of water, adjusted to pH 7.2 with hydrochloric acid, filtered, and then 3 L of isopropyl alcohol was added to the filtrate for reprecipitation. After dialysis was performed by dissolving the precipitate in 1.5 L of water, the solvent was distilled off with an evaporator to obtain 51.0 g of carboxymethylated β-glucan (degree of substitution 0.75).

<Measurement of replacement degree>
A known method used for carboxymethylated cellulose or the like was used for measuring the degree of substitution.
First, about 0.5 g of carboxymethylated β-glucan is precisely weighed and heated at 550 ° C. for 6 hours in a muffle furnace. Subsequently, 250 ml of water and 35 ml of 0.1 M sulfuric acid are added to the white solid of the residue, and the mixture is boiled for 30 minutes. After cooling, phenolphthalein is added, neutralized titration is performed using a 0.1 M potassium hydroxide aqueous solution, and the calculation is performed by the following formula:
A = (af-bf1) / sample (g)
Substitution = 162 x A / (10,000-80A)
However, A: ml of 0.05 mol / l sulfuric acid consumed by the bound alkali in 1 g of sample.
a: 0.05 mol / l Sulfuric acid used ml, f: 0.05 mol / l Sulfuric acid titer b: 0.1 mol / l Potassium hydroxide titrated ml, f1: 0.1 mol / l Hydroxide Potassium hydroxide titration

<Evaluation of hyaluronidase inhibitory activity>
The hyaluronidase inhibitory activity of the obtained hyaluronidase inhibitor of the present invention, glycyrrhizin, β-1,3-1,6-glucan, carboxymethyl cellulose, and pullulan as comparative samples was measured. Glycyrrhizin is a raw material for pharmaceutical products and is used as an anti-inflammatory agent, and is known to have hyaluronidase inhibitory activity.

First, 200 μl of the evaluation sample was added to 100 μl of an enzyme solution of hyaluronidase, and the mixture was incubated at 37 ° C. for 20 minutes. Next, 200 μl of a hyaluronidase activator was added to this solution and incubated at 37 ° C. for 20 minutes, and then 500 μl of a substrate solution was added and further reacted at 37 ° C. for 40 minutes. Then, in order to inactivate hyaluronidase, 200 μl of a 0.4 M NaOH aqueous solution was added and ice-cooled, and then 200 μl of a boric acid solution was added and boiled at 100 ° C. for 3 minutes. After cooling with ice, 6 ml of p-DAB solution was added, and the mixture was incubated at 37 ° C. for 20 minutes, and then the absorbance at 585 nm was measured.

The reagents used in the above evaluation are as follows.
Enzyme solution: Hyaluronidase Type-IV-S (cow-derived, Sigma) adjusted to 400 NFU / ml with 0.1 M Buffer acetate (pH 4) Solution activator: Compound 48/80 (Sigma) Solution adjusted with Buffer to 0.1 mg / ml Substrate solution: Solution of potassium hyaluronate (derived from chicken, Wako Junyakusha) adjusted with Buffer to 0.4 mg / ml Boric acid solution: 0. 8M aqueous solution (pH = 9.1)
p-DAB solution: A solution obtained by diluting a concentrated p-DAB solution 10 times with acetic acid immediately before use. Concentrated p-DAB solution: p-DAB 10 g + 10N hydrochloric acid 12.5 ml + acetic acid 87.5 ml
* P-DAB: 4-Dimethylaminobenzaldehyde (Sigma)

The evaluation sample was prepared by adding a powder sample to 0.1 M Buffer acetate (pH 4.1) so that the active ingredient was 100 μg / ml and dissolving at room temperature.
The inhibition rate was calculated using the following formula.
Inhibition rate (%) = [(AB)-(CD)] / (AB) x 100
A: Absorbance of control solution B: Absorbance of control solution blank C: Absorbance of sample solution D: Absorbance of sample solution blank

The results are shown in FIG. The specific inhibition rates are as follows.
(1) Glycyrrhizin: Inhibition rate 96.8%
(2) Carboxymethylated β-glucan (Preparation Example 1: Mass average molecular weight = 420,000, degree of substitution = 0.79): Inhibition rate 95.5%
(3) Carboxymethylated β-glucan (Preparation Example 2: Mass average molecular weight = 320,000, degree of substitution = 0.13): Inhibition rate 73.1%
(4) Carboxymethylated β-glucan (Preparation Example 3: Mass average molecular weight = 520,000, degree of substitution = 0.75): Inhibition rate 65.3%
(5) β-1,3-1,6-glucan: Inhibition rate -5.4%
(6) Carboxymethyl cellulose (degree of substitution = 0.6): inhibition rate 61.1%
(7) Pullulan: Inhibition rate 6.9%

Below, a specific formulation example of a cosmetic composition containing the hyaluronidase activity inhibitor (carboxymethylated glucan) of the present invention is shown.

This application is based on Japanese Patent Application No. 2018-4754 (Filing date: January 16, 2018) filed in Japan, the entire contents of which are incorporated herein by reference.

Claims (9)

A hyaluronidase activity inhibitor containing β-1,3-1,6-glucan in which a part of the hydroxy group is carboxymethylated. The hydrogen atom of a part of the hydroxy group of β-1,3-1,6-glucan consisting of the units represented by the following general formulas (a) and (b) is a group represented by the general formula (c). The hyaluronidase activity inhibitor according to claim 1, which has been substituted.

-CH ₂ COOX (c)
(In the formula, X represents a hydrogen atom, an alkali metal or an alkaline earth metal.) The hyaluronidase activity inhibitor according to claim 1 or 2, wherein the degree of carboxymethyl substitution per glucose unit is 0.05 to 2. A cosmetic composition containing the hyaluronidase activity inhibitor according to any one of claims 1 to 3. A method for suppressing the decomposition of hyaluronic acids, which comprises applying the cosmetic composition according to claim 4 to the skin. A method for producing a hyaluronidase activity inhibitor, which comprises carboxymethylating a part of the hydroxy group of β-1,3-1,6-glucan represented by the general formula (1).

(In the formula, d represents at least 20 numbers and e represents at least 1 number. However, the total number of d and e is β-1,3- represented by the general formula (1). The mass average molecular weight of 1,6-glucan is 3000 to 5 million.) The method for producing a hyaluronidase activity inhibitor according to claim 6, wherein the degree of carboxymethyl substitution per glucose unit is 0.05 to 2. The hydrogen atom of a part of the hydroxy group of β-1,3-1,6-glucan consisting of the units represented by the following general formulas (a) and (b) is a group represented by the general formula (c). Substituted carboxymethylated β-1,3-1,6-glucan.

-CH ₂ COOX (c)
(In the formula, X represents a hydrogen atom, an alkali metal or an alkaline earth metal.) The carboxymethylated β-1,3-1,6-glucan according to claim 8, wherein the degree of carboxymethyl substitution per glucose unit is 0.05 to 2.

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