JP4993890B2 - Topical skin preparation - Google Patents

Description

  The present invention relates to an external preparation for skin containing acetyl hyaluronic acid or a salt thereof and hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less and capable of stabilizing the preparation.

Hyaluronic acid is a mucopolysaccharide composed of glucuronic acid and N-acetylglucosamine. It is a substance that exists in the dermis in large quantities as a bonding substance that fills cells and fibers in vivo, and is also found in the epidermis. Since it has high water retention and viscoelasticity (Non-patent Document 1: fragrance journal No. 2, 30 (1990)), it is widely used as a moisturizing agent and the like for skin external preparations. In addition, high molecular hyaluronic acid with a molecular weight of 1 million or more by the intrinsic viscosity method, low molecular hyaluronic acid with a molecular weight of 100,000 or less, polyhydric alcohol, and edetate may suppress the decrease in the viscosity of the preparation and have excellent sensory characteristics. Known (Patent Document 1: Registration 2666210).
Furthermore, it is known that acetyl hyaluronic acid can exhibit excellent skin softening effects while improving the drawbacks of hyaluronic acid such as high spinnability (Patent Document 2: Registered 3554444). There is no report on coloring (especially under heating conditions) for acids.
On the other hand, low molecular weight hyaluronic acid having a molecular weight of 10,000 or less by GPC analysis enhances angiogenesis (Patent Document 3: Japanese Patent Laid-Open No. 11-292758), cell death inhibitor, cell disorder inhibitor, and cell / tissue A protective agent (Patent Document 4: International Publication No. 2002/004471 pamphlet) is known, but the effect on coloring of acetyl hyaluronic acid is not known.
Thus, since the coloring of acetyl hyaluronic acid has not been studied at all, improvement is demanded.

  This invention makes it a subject to provide the skin external preparation which contains acetyl hyaluronic acid or its salt, and can suppress coloring.

  As a result of diligent research to solve the above problems, the present inventors have used hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less in combination with an external skin preparation containing acetylhyaluronic acid or a salt thereof. They found that coloring of the external preparation for skin was suppressed.

That is, this invention is a skin external preparation shown to the following (1)-(4).
(1) An external preparation for skin containing acetyl hyaluronic acid or a salt thereof, and hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less.
(2) The skin external preparation according to (1), further comprising one or more selected from the group consisting of polyhydric alcohols, glycol ethers, water-soluble thickeners, and chelating agents.
(3) Further, it contains one or more selected from the group consisting of a whitening component, an anti-inflammatory component, an antibacterial component, a cell activation component, an antioxidant component, an anti-aging component and a moisturizing component (1) or (2) The external preparation for skin described in (2).
Moreover, this invention also includes the coloring suppression method of the skin external preparation shown to the following (4).
(4) A method for suppressing the coloring of acetyl hyaluronic acid or a salt thereof with hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less.
In the present specification, “%” means “% by weight” unless otherwise specified.

  In this invention, coloring of the skin external preparation containing acetyl hyaluronic acid or its salt can be suppressed by containing hyaluronic acid or its salt with an average molecular weight of 250,000 or less. For this reason, the effect | action of acetyl hyaluronic acid or its salt can be effectively exhibited over a long period of time according to the compounding quantity.

BEST MODE FOR CARRYING OUT THE INVENTION

  The present invention is an external preparation for skin containing acetyl hyaluronic acid or a salt thereof and hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less.

In the external preparation for skin of the present invention, acetyl hyaluronic acid is acetylated hyaluronic acid, and preferably acetylated hydroxyl group of hyaluronic acid. Hyaluronic acid has four hydroxyl groups per structural unit (disaccharide), and the acetyl hyaluronic acid preferably has 2 to 4 substitutions of acetyl groups.
In addition, a pharmaceutically and physiologically acceptable salt of acetyl hyaluronic acid can also be used for the external preparation for skin of the present invention. Examples of such salts include alkali metal salts such as sodium and potassium, magnesium and calcium, and the like. Alkali earth metal salts such as ammonium salts, alkanolamine salts such as ammonium salts and monoethanolamine, and the like, preferably alkali metal salts such as sodium salts.

The weight average molecular weight of acetyl hyaluronic acid or a salt thereof is not particularly limited, but is preferably about 1 to 1 million in terms of hyaluronic acid.
Acetyl hyaluronic acid or a salt thereof used in the external preparation for skin of the present invention can be prepared by a known method, for example, a method in which powdered hyaluronic acid is suspended in acetic anhydride solvent and further reacted with concentrated sulfuric acid, cosmetics, etc. , A commercially available product of acetyl hyaluronic acid or a salt thereof, which is usually used for an external preparation for skin, can be used.

  In the external preparation for skin of the present invention, the blending amount of acetyl hyaluronic acid or a salt thereof is 0.0001 to 10% by weight with respect to the total weight of the external preparation for skin as a total amount of acetyl hyaluronic acid or a salt thereof. It can select suitably according to the use of an external preparation. In view of the effect of the present invention, the content is preferably 0.0002 to 6% by weight, particularly preferably 0.0005 to 5% by weight.

In the external preparation for skin of the present invention, the hyaluronic acid having an average molecular weight of 250,000 or less refers to hyaluronic acid having a number average molecular weight of 250,000 or less by size exclusion chromatography. The number average molecular weight is corrected by limiting viscosity. The measurement conditions for size exclusion chromatography are defined as follows.
Column ... TSKgel GMPWXL 7.8mm × 30cm
Column temperature… Constant temperature around 40 ℃ Detector… Differential refractometer Mobile phase… 0.2mol / L NaCl
Flow rate ... 0.3mL / min
Injection volume ... 100μL

  In the external preparation for skin of the present invention, as the hyaluronic acid having an average molecular weight of 250,000 or less, a pharmaceutically and physiologically acceptable salt can be used. Examples of such a salt include alkali metal salts such as sodium and potassium. , Alkaline earth metal salts such as magnesium and calcium, ammonium salts, alkanolamine salts such as monoethanolamine, and the like, preferably alkali metal salts such as sodium salts.

  In the skin external preparation of the present invention, the average molecular weight of hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less is not particularly limited as long as it is 250,000 or less, but is usually 1,000 to 200,000, preferably 2,000. 100,000 to more preferably 3,000 to 50,000. In particular, those having a molecular weight of 10,000 or less are also called hyaluronic acid oligosaccharides or oligohyaluronic acid.

  Hyaluronic acid having an average molecular weight of 250,000 or less used in the external preparation for skin of the present invention is partially decomposed by a known method, for example, enzymatic (hyaluronidase, chondroitinase, etc.) or acid hydrolytic (DMSO, hydrochloric acid, etc.) Products manufactured by fractionating low molecular weight hyaluronic acid with various average molecular weights by elution with gel filtration column or ion exchange column using sodium chloride solution or acetic acid buffer solution with linear concentration gradient as needed, cosmetics For example, commercially available products of hyaluronic acid having an average molecular weight of 250,000 or less, which are usually used for topical skin preparations, can be used.

  In the external preparation for skin of the present invention, the blending amount of hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less is 0.0001 to 10% with respect to the total weight of the external preparation for skin as the total amount of hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less. It can be selected as appropriate according to the use of the external preparation for skin within such a range. In view of the effect of the present invention, the content is preferably 0.0002 to 6% by weight, particularly preferably 0.0005 to 5% by weight.

  In the external preparation for skin of the present invention, for the purpose of enhancing or supplementing the effects of the present invention, a polyhydric alcohol, a glycol ether, a water-soluble thickener, and a chelating agent may be added in combination of one or more. it can. Each of these components is not particularly limited as long as it is conventionally used as a component of a skin external preparation in the pharmaceutical, quasi-drug, or cosmetic field, and used in the future. Can be used.

  Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, isoprene glycol, 1,2-pentylene glycol, 1,2-hexylene glycol, octylene glycol, glycerin, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, tripropylene glycol, diglycerin, polyethylene glycol, etc. are preferable, preferably propylene glycol, 1,3 -Butylene glycol, glycerin, dipropylene glycol, diglycerin, polyethylene glycol.

  Examples of the glycol ether include ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol. Examples include monopropyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether. Diethylene glycol monoethyl ether and diethylene glycol monobutyl ether are preferred.

  These polyhydric alcohols or glycol ethers can be used alone or in combination of two or more. The total amount of polyhydric alcohol and glycol ether is 0.01 to 70% by weight, preferably 0.1 to It may be 60% by weight, particularly preferably 1 to 50% by weight, but is not particularly limited as long as the effects of the present invention are exhibited.

Examples of the water-soluble thickener include carboxyvinyl polymer, sodium polyacrylate, polyethylene glycol, acrylic acid / alkyl methacrylate copolymer, polyoxyethylene polyoxypropylene block copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether. , Methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cationized cellulose, sodium alginate, propylene glycol alginate, guar gum, locust bean gum, carrageenan, xanthan gum, dextran, bentonite, etc. Is carboxyvinyl polymer, acrylic Acid-methacrylic acid alkyl copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methylcellulose.
These water-soluble thickeners can be used alone or in combination of two or more, and the ratio of the water-soluble thickener is usually based on the total amount of the water-soluble thickener as the total amount of the water-soluble thickener. 0.0003 to 20% by weight, preferably 0.01 to 10% by weight, particularly preferably 0.05 to 5% by weight.

Examples of chelating agents include ethylenediaminetetraacetic acid (edetic acid), ethylenediaminetetraacetate (sodium salt (sodium edetate: Japanese Pharmacopeia, EDTA-2Na, etc.), potassium salt, etc.), phytic acid, gluconic acid, polyphosphoric acid , Metaphosphoric acid and the like, and edetic acid, sodium edetate, potassium edetate, and phytic acid are preferable.
These chelating agents can be used singly or in combination of two or more. The proportion of the chelating agent blended in the external preparation for skin of the present invention is usually 0.0003 to 20% by weight as the total amount of chelating agent with respect to the entire external preparation for skin. Yes, preferably 0.01 to 10% by weight, particularly preferably 0.05 to 5% by weight.

  The skin external preparation of the present invention is added with other useful effects such as whitening ingredients, anti-inflammatory ingredients, antibacterial ingredients, cell activation ingredients, antioxidant ingredients, acne improving ingredients, anti-aging ingredients, and biological components such as collagen. Various components such as a synthesis promoting component, a blood circulation promoting component, a moisturizing component, an anti-aging component and the like can be used alone or in combination of two or more. Preferably, the whitening component, anti-inflammatory component, antibacterial component, cell activation component, antioxidant component, anti-aging component or moisturizing component is used. Each of these components is not particularly limited as long as it is conventionally used as a component of a skin external preparation in the pharmaceutical, quasi-drug, or cosmetic field, and used in the future. Can be used.

  For example, whitening ingredients include quinones such as hydroquinone and arbutin; ellagic acid; phytic acid; lucinol; chamomile ET; α-hydroxy acids such as glycolic acid, citric acid, malic acid, tartaric acid, and lactic acid; ascorbic acid, tetraiso Examples include vitamin C such as ascorbyl palmitate, ascorbyl stearate, ascorbyl palmitate, and L-ascorbyl magnesium phosphate, and derivatives thereof. Of these, preferred are hydroquinone, arbutin, ellagic acid, glycolic acid, malic acid, lactic acid, ascorbic acid, and ascorbyl tetraisopalmitate. These whitening components may be used alone or in combination of two or more.

  In the case of using the above-described whitening component, the ratio to be blended in the external preparation for skin of the present invention is not particularly limited as long as the effects of the present invention are exhibited, and may be appropriately selected and used in consideration of the feeling of use and effects on the skin. However, it is usually 0.0003 to 20% by weight, preferably 0.01 to 10% by weight, particularly preferably 0.05 to 5% by weight, based on the whole external preparation for skin.

  Examples of the anti-inflammatory component include allantoin, calamine, glycyrrhizic acid or derivatives thereof, glycyrrhetinic acid or derivatives thereof, zinc oxide, guaiazulene, pyridoxine hydrochloride, menthol, camphor, turpentine oil, indomethacin, salicylic acid or derivatives thereof. Preferred are allantoin, glycyrrhizic acid or derivatives thereof, glycyrrhetinic acid or derivatives thereof, guaiazulene, menthol, indomethacin, and salicylic acid.

  When using the above-mentioned anti-inflammatory component, the ratio to be blended in the external preparation for skin of the present invention is not particularly limited as long as the effects of the present invention are exhibited, and should be appropriately selected in consideration of the feeling of use and effects on the skin. However, it is usually 0.0003 to 10% by weight, preferably 0.01 to 5% by weight, based on the whole external preparation for skin.

  Antibacterial ingredients include ethanol, benzethonium chloride, cetylpyridinium chloride, cresol, acrinol, isopropylmethylphenol, triclocarban, triclosan, salicylic acid, chlorhexidine, chlorhexidine gluconate, benzalkonium chloride, paraben, phenoxyethanol, 1,2-pentanediol , Popidone iodine, potassium iodide, iodine, photosensitive element 101, photosensitive element 201 and the like. Preferably, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, triclocarban, triclosan, chlorhexidine gluconate, benzalkonium chloride, paraben, phenoxyethanol, 1,2-pentanediol, Photosensitizer 101, Photosensitizer 201 It is done. More preferred are benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, benzalkonium chloride, chlorhexidine gluconate, phenoxyethanol, and 1,2-pentanediol.

  When the antibacterial component is used, it is not particularly limited as long as the effect of the present invention is achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. It is 0.0003-10 weight%, More preferably, it is 0.01-5 weight%.

  Cell activation components include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid: retinoids (retinol, retinoic acid, retinal, α-tocopheryl retinoate, δ-tocopheryl retinoate, etc.), thiamine, riboflavin, Vitamins such as pyridoxine hydrochloride and pantothenic acids: tannins, flavonoids, saponins, allantoin, photosensitizer 301 and the like. Preferred are amino acids such as γ-aminobutyric acid and ε-aminocaproic acid: vitamins such as retinol, α-tocopheryl retinoate, δ-tocopheryl retinoate and pantothenic acids.

  When using the above-mentioned cell activation component, it is not particularly limited as long as the effect of the present invention is achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin, but with respect to the entire external preparation for skin. The amount is usually 0.0003 to 10% by weight, more preferably 0.01 to 5% by weight.

  Antioxidant components include tocopherol, tocopherol acetate, butylhydroxyanisole, dibutylhydroxytoluene, sodium bisulfite, erythorbic acid and its salts, flavonoids, glutathione, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase, thioredoxin, Examples include taurine, thiotaurine, and hypotaurine. Tocopherol, tocopherol acetate, butylhydroxyanisole, dibutylhydroxytoluene, and flavonoid are preferable.

  When an antioxidant component is used, it is not particularly limited as long as the effects of the present invention are exhibited, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. It is 0.00001-10 weight%, Preferably it is 0.0001-5 weight%, More preferably, it is 0.001-5 weight%.

  Examples of anti-aging components include kinetin, pangamic acid, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone. Preferably, it is kinetin.

  When using the anti-aging component, it is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. Usually, it is 0.0003-10 weight%, More preferably, it is 0.01-5 weight%.

  As moisturizing ingredients, amino acids such as alanine, serine, leucine, isoleucine, threonine, glycine, proline, hydroxyproline, glucosamine, theanine and derivatives thereof; peptides such as collagen, collagen peptide, gelatin; sugar alcohols such as sorbitol; lecithin, Examples include phospholipids such as hydrogenated lecithin; mucopolysaccharides such as heparin and chondroitin; NMF-derived components such as sodium pyrrolidonecarboxylate and urea, and polyglutamic acid. Preferred are alanine, serine, glycine, proline, hydroxyproline, glucosamine, theanine, collagen, collagen peptide, glycerin, 1,3-butylene glycol, hydrogenated lecithin, heparin, chondroitin, sodium pyrrolidonecarboxylate, polyglutamic acid. .

  When a moisturizing component is used, it is not particularly limited as long as the effects of the present invention are achieved, and can be appropriately selected and used in consideration of the feeling of use and effects on the skin. -10% by weight, preferably 0.5-5% by weight, more preferably 0.5-5% by weight.

  The external preparation for skin of the present invention may further contain a surfactant, a solubilizing component, fats and oils, sugars, or a percutaneous absorption promoting component in addition to the above components.

  Examples of the surfactant include POE-branched alkyl ethers such as polyoxyethylene (hereinafter referred to as POE) -octyldodecyl alcohol and POE-2-decyltetradecyl alcohol; POE-oleyl alcohol ether and POE-cetyl alcohol ether. POE-alkyl ethers such as sorbitan monooleate, sorbitan monoisostearate and sorbitan monolaurate, etc .; POE-sorbitan monooleate, POE-sorbitan monoisostearate, POE-sorbitan monolaurate, etc. Glycerol fatty acid esters such as glycerol monooleate, glycerol monostearate, and glycerol monomyristate; POE-glycerol monooleate, POE-glycerol monostearate, and POE-G POE-glycerin fatty acid ester such as serine monomyristate; POE-dihydrocholesterol ester, POE-hardened castor oil, and POE-hardened castor oil fatty acid ester such as POE-hardened castor oil isostearate; POE-octylphenyl ether, etc. POE-alkyl aryl ether; glycerin alkyl ether such as monoisostearyl glyceryl ether and monomyristyl glyceryl ether; POE-glycerin alkyl ether such as POE-monostearyl glyceryl ether and POE-monomyristyl glyceryl ether; diglyceryl monostearate, deca Various nonionic surfactants such as polyglycerin fatty acid esters such as glyceryl decastearate, decaglyceryl decaisostearate, and diglyceryl diisostearate: or lecithin Hydrogenated lecithin, saponin, sodium surfactin can be exemplified cholesterol, a surfactant of natural origin, such as bile acids. These surfactants may be used alone or in any combination of two or more.

  When a surfactant is used, the blending ratio in the external preparation for skin of the present invention is not particularly limited as long as it does not affect the skin and mucous membranes and does not interfere with the effects of the present invention. It can be appropriately selected and used in such a range that it is contained in the agent at a ratio of 0.01 to 30% by weight. From the viewpoint of the stability of the active ingredient in the external preparation for skin of the present invention and the feeling of use on the skin, the range is preferably 0.1 to 20% by weight, more preferably 0.1 to 10% by weight.

  The fats and oils are not particularly limited as long as they are used as components of external preparations in the field of pharmaceuticals, quasi drugs and cosmetics. For example, synthetic fats and oils such as medium chain fatty acid triglycerides; soybean oil, rice oil, rapeseed oil, cottonseed oil, sesame oil, safflower oil, castor oil, olive oil, cacao oil, coconut oil, sunflower oil, palm oil, flax oil, perilla oil, shea Vegetable oils such as oil, monkey oil, palm oil, tree wax, jojoba oil, grape seed oil, and avocado oil; animal oils such as mink oil, egg yolk oil, beef tallow, milk fat, and pork fat; beeswax, whale wax, lanolin Waxes such as carnauba wax and candelilla wax; hydrocarbons such as liquid paraffin, squalene, squalane, microcrystalline wax, ceresin wax, paraffin wax, petrolatum; lauric acid, myristic acid, stearic acid, oleic acid, isostearic acid, Natural and synthetic fatty acids such as behenic acid; cetanol, stearyl alcohol, hexylde Nord, octyldecanol, natural and synthetic higher alcohols such as lauryl alcohol; isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, octyldodecyl oleate, esters and ethers such as cholesterol oleate; silicone oil, and the like. These fats and oils may be used alone or in any combination of two or more.

  When these oils and fats are used, the blending ratio in the external preparation for skin of the present invention is not particularly limited as long as it does not affect the skin and mucous membranes and does not interfere with the effects of the present invention. Although it can be appropriately selected and used within the range of 0.01 to 70% by weight contained in the external preparation for skin, it is possible to use the active ingredient in the external preparation for skin according to the present invention in terms of stability and feeling of use on the skin. Therefore, the range of 0.1 to 60% by weight, more preferably 0.1 to 50% by weight can be mentioned.

  The saccharide is not particularly limited as long as it is used as a component of an external preparation in the pharmaceutical, quasi-drug or cosmetic field. For example, monosaccharides (for example, glucose, galactose, mannose, ribose, arabinose, xylose, deoxyribose, fructose, ribulose, lyxose, etc.), disaccharides (for example, sucrose, trehalose, lactose, maltose, cellobiose, etc.), oligosaccharides ( For example, lactulose, raffinose, pullulan, etc.), high molecular sugars [for example, chondroitin sulfate, dermatan, heparan, heparin, keratan or salts thereof (for example, chondroitin sulfate sodium, dermatan sulfate, heparan sulfate, keratan sulfate, etc. Physiologically acceptable salts, etc.)], and sugar alcohols (eg, mannitol, xylitol, erythritol, pentaerythritol, maltitol, sorbitol, polydextro) Scan, etc.) other, xylose, inositol, dextrin and derivatives thereof, honey, brown sugar extract, and the like. These saccharides may be used alone or in any combination of two or more.

  The external preparation for skin of the present invention includes pharmaceuticals, quasi-drugs or cosmetics as necessary within a quantitative and qualitative range that does not impair quality such as appearance stability and viscosity and does not impair the effects of the present invention. Various ingredients commonly used in the field as components of external preparations, for example, amino acids, irritation reducers, thickeners, preservatives, UV protection agents, colorants, dispersants, pH adjusters, fragrances and the like are blended. be able to. These components may be used alone or in combination of two or more.

  The external preparation for skin of the present invention comprises the above acetyl hyaluronic acid or a salt thereof, a hyaluronic acid having an average molecular weight of 250,000 or less or a salt thereof, and, if necessary, each component, and if necessary, other solvents and usual By blending the base of the external preparation used, various desired forms such as paste, mousse, gel, liquid, emulsion, cream, sheet (substrate support), aerosol, spray, etc. Can be prepared in form. These can be produced by conventional methods in the art. Among these, gel, liquid, emulsion, cream, aerosol, and spray are preferable, and liquid, emulsion, and cream are particularly preferable.

  The external preparation for skin of the present invention is usually required to have a liquidity of pH 1 to 8, but from the viewpoint of the stability of the preparation, mild irritation to the skin and mucous membranes, and good usability of skin use, it is preferably pH 2 to 2. 7, more preferably an acidic region of pH 2-6.

  Skin external preparations of the present invention include, for example, makeup cosmetics such as foundations, lipsticks, mascaras, eye shadows, eye liners, eyebrows and beauty nails; basic cosmetics such as emulsions, creams, lotions, oils and packs; Cleansing agents such as skin and cleansing, body cleansing agents; odor control agents, athlete's foot treatment agents, antipruritic agents, wound healing agents, wiping agents, detergents, anti-inflammatory analgesics, acne treatment agents, anti-inflammatory agents, antiseptics, whitening agents In addition, various external compositions belonging to the field of cosmetics, external medicines or quasi-drugs such as UV protection agents can be obtained. From the viewpoint of the effect on the skin, the present invention is preferably a basic cosmetic, a cleansing agent or a whitening agent used in products applied to the outer skin such as an external preparation for skin (preparation for outer skin). Particularly preferred.

The present invention also includes a method for suppressing coloration of acetyl hyaluronic acid or a salt thereof. In the method of the present invention, suppression of coloring of acetyl hyaluronic acid or a salt thereof can be achieved by using hyaluronic acid or a salt thereof having an average molecular weight of 250,000 or less in combination.
In the method of the present invention, acetyl hyaluronic acid or a salt thereof, hyaluronic acid having an average molecular weight of 250,000 or less or a salt thereof, and their contents are the same as those used in the above-mentioned external preparation for skin. Furthermore, the product obtained by this method can be used in known or commonly used dosages and dosages by dividing it once to several times per day according to the application.

  Hereinafter, the present invention will be described in more detail based on examples and test examples, but the present invention is not limited to these examples.

Production of sodium hyaluronate with an average molecular weight of 250,000 or less
Sodium hyaluronate having a molecular weight of 1 million was hydrolyzed by heating under reflux under acidic conditions, desalted with Sephadex G-10 (Pharmacia, φ3 × 124), and then lyophilized. For the lyophilized product, the number average molecular weight was calculated using the size exclusion chromatography method under the following measurement conditions.
Detector ... Differential refractometer Column ... TSKgel GMPWXL 7.8mm × 30cm
Column temperature… Constant temperature around 40 ℃ Mobile phase… 0.2mol / L NaCl
Flow rate ... 0.3mL / min
Injection volume ... 100μL
Of the obtained sodium hyaluronate, sodium hyaluronate having a number average molecular weight (after correction by intrinsic viscosity) by size exclusion chromatography of 200,000, 50,000 and 4,000 was subjected to the following tests and preparations.

Test Example 1 Stabilization evaluation of acetyl hyaluronic acid
According to the formulations (% by weight) described in Tables 1 and 2, acetyl hyaluronic acid, hyaluronic acid having various average molecular weights of 250,000 or less, and water were mixed and dissolved to prepare a test solution. All test solutions immediately after preparation were colorless and transparent. This was measured using a spectrophotometer CM-3500d (manufactured by MINOLTA) using the L * a * b color system of the International Commission on Illumination (CIE). Similarly, a test solution stored for 24 hours and 4 days in a constant temperature bath at 60 ° C. was measured, and ΔE was calculated based on the test solution immediately after preparation. Moreover, the color of the test liquid was determined visually.
The results are shown in Tables 1 and 2.

  In all of Examples 1 to 3 of the present invention, the value of ΔE was small after 24 hours, and it was confirmed that it was slightly colored by visual observation, and the color was slightly yellow even after 4 days. On the other hand, in Comparative Example 1 not containing sodium hyaluronate having an average molecular weight of 250,000 or less, the value of ΔE exceeded 1 after 24 hours and was colored pale yellow and reached brown after 4 days. In addition, sodium hyaluronate having an average molecular weight of 4,000 in Comparative Example 2 was colored to the same extent after 24 hours and after 4 days.

From Comparative Examples 1 and 3 and Example 4, it was found that even if the amount of the low molecular weight sodium hyaluronate was considerably reduced, there was a coloring suppression effect. Furthermore, from Reference Example 1 and Comparative Example 4 , the effect of suppressing coloration was confirmed by blending a small amount of sodium hyaluronate having a higher average molecular weight. On the other hand, in Comparative Example 6, hyaluronic acid having a large molecular weight was used, but it was found that coloring was further enhanced. Further, even in the case of a low molecular weight sodium hyaluronate having an average molecular weight of 50,000, it was possible to suppress the coloration to a slightly yellow color by adding 1%.
Thus, it was found that the external preparation for skin of the present invention has an unexpected effect that the coloration of acetylhyaluronic acid by heat can be suppressed and stabilized by hyaluronic acid having an average molecular weight of 250,000 or less.

  The formulation examples are given below.

Claims (4)

A skin external preparation containing acetyl hyaluronic acid or a salt thereof, and hyaluronic acid or a salt thereof having an average molecular weight of 4,000 or less . Furthermore, the skin external preparation of Claim 1 containing 1 type, or 2 or more types selected from the group which consists of a polyhydric alcohol, glycol ether, a water-soluble thickener, and a chelating agent. Furthermore, whitening ingredients, anti-inflammatory ingredients, antibacterial ingredients, cell activation ingredients, antioxidant ingredients, acne improving ingredients, anti-aging ingredients, biocomponent synthesis promoting ingredients, blood circulation promoting ingredients, moisturizing ingredients, surfactants, solubilizing ingredients, The skin external preparation of Claim 1 or 2 containing 1 type, or 2 or more types selected from the group which consists of fats and oils, saccharides, and a percutaneous absorption promotion component. A method for suppressing the coloring of acetyl hyaluronic acid or a salt thereof by hyaluronic acid or a salt thereof having an average molecular weight of 4,000 or less .