JP6553341B2 - Composition for external use - Google Patents

Description

  The present invention relates to an external use composition containing a high concentration of hyaluronic acid. More specifically, the present invention, while containing a high concentration of hyaluronic acid, suppresses stickiness and easily spreads at the time of application without impairing the heavy coating feeling and moisturizing feeling inherent to hyaluronic acid, and the excellent use The present invention relates to an external composition that can provide a feeling.

  Hyaluronic acid and salts thereof can be widely used in the field of compositions for external use such as cosmetics because they can impart moisturizing feeling and heavy application feeling to the skin. Moreover, in recent years, the demand for functional improvement of the composition for external use is increasing more and more, by containing hyaluronic acid and its salt at a high concentration, the moisturizing feeling and heavy coating feeling by hyaluronic acid are made more effective. There is a need for external compositions that can be applied.

  On the other hand, hyaluronic acid and its salts have disadvantages such as stickiness and ease of spreading upon application. In particular, such a drawback becomes prominent when a high concentration of hyaluronic acid is added to the external composition. Heretofore, various studies have been made on formulations for solving the disadvantages of such hyaluronic acid and its salts. For example, Patent Document 1 reports that, by blending a gum and a specific quaternary ammonium salt with hyaluronic acid, it is possible to suppress stickiness and improve the feeling of use. Further, in Patent Document 2, it is also possible to suppress stickiness and improve the feeling of use by using hyaluronic acid in combination with 1,2-pentanediol, polyglycerin and / or polyoxypropylene diglyceryl ether. It has been reported.

  However, the techniques of Patent Documents 1 and 2 have a disadvantage that the heavy coating feeling and moisturizing feeling originally provided for hyaluronic acid and its salt are impaired. Therefore, even if high concentration hyaluronic acid is blended by the conventional formulation, it is possible to suppress stickiness and improve ease of application at the time of application without impairing the heavy coating feeling and moisturizing feeling originally provided by hyaluronic acid and its salts. It was not possible to have a feeling of use that satisfied consumer demand.

  In addition, hyaluronic acid and salts thereof have poor solubility in water and tend to become lumpy (lumpy) when dissolved in water, and therefore, when preparing an external composition containing high concentration of hyaluronic acid, hyaluronic acid Dissolving takes a long time, and there is a problem that the manufacturing cost increases. Therefore, the development of a composition for external use containing a high concentration of hyaluronic acid and / or a salt thereof requires establishment of a technique for improving the solubility of hyaluronic acid and / or a salt thereof to shorten the dissolution time.

JP-A-9-95432 JP 2000-344656 A

  The object of the present invention is to reduce the stickiness and to apply the external composition containing high concentration of hyaluronic acid and / or a salt thereof without impairing the heavy coating feeling and the moisturizing feeling inherent to hyaluronic acid and / or a salt thereof. It is an object of the present invention to provide a formulation technology that makes it easy to stretch at times and provides excellent feeling of use. Another object of the present invention is to provide a technique for improving the solubility of hyaluronic acid and / or its salt and dissolving hyaluronic acid and / or its salt in water in a short time.

  As a result of intensive studies to solve the above-mentioned problems, the present inventor has prepared a hyaluronic acid oligosaccharide and / or a composition for external use containing hyaluronic acid and / or a salt thereof at a high concentration (0.05% by weight or more). By blending the salt, it is possible to suppress stickiness while maintaining the heavy coating feeling and moisturizing feeling inherent to hyaluronic acid and / or the salt thereof, to be easily stretched at the time of coating, and to have an excellent feeling of use I found out.

  Furthermore, the present inventor improves the solubility of hyaluronic acid and / or salt thereof in a short time by adding hyaluronic acid oligosaccharide and / or salt thereof together with hyaluronic acid and / or salt thereof to water. It has been found that it is possible to dissolve hyaluronic acid and / or its salt in water.

The present invention has been completed by further investigation based on these findings. That is, the present invention provides the invention of the aspects listed below.
Item 1. An external use composition comprising (A) 0.05% by weight or more of hyaluronic acid and / or a salt thereof, and (B) hyaluronic acid oligosaccharide and / or a salt thereof.
Item 2. The composition for external use according to item 1, wherein the component (A) is contained in an equal amount or more of the component (B) in a weight ratio.
Item 3. The composition for external use according to item 1 or 2, wherein the component (B) is contained in an amount of 0.0001 to 1.5% by weight.
Item 4. The composition for external use according to any one of Items 1 to 3, wherein the component (B) is unsaturated hyaluronic acid oligosaccharide and / or a salt thereof.
Item 5. The composition for external use according to any one of Items 1 to 4, which is a cosmetic.
Item 6. (B) A method for dissolving hyaluronic acid and / or a salt thereof, which comprises dissolving (A) hyaluronic acid and / or a salt thereof in water in the presence of a hyaluronic acid oligosaccharide and / or a salt thereof.

  According to the present invention, in a composition for external use containing hyaluronic acid and / or a salt thereof at a high concentration (0.05% by weight or more), the heavy coating feeling and moisturizing feeling inherent to hyaluronic acid and / or a salt thereof are maintained. However, stickiness can be suppressed, and it can be easily stretched during application. Therefore, according to the present invention, it is possible to provide an external composition having both high functionality and good usability.

  In addition, according to the present invention, the solubility of hyaluronic acid and / or its salt in water can be improved, so that an external composition containing a high concentration of hyaluronic acid and / or its salt is produced. Even in this case, hyaluronic acid and / or a salt thereof can be dissolved in water in a short time, and lead time can be shortened and manufacturing cost can be reduced.

1. Composition for External Use The composition for external use of the present invention is characterized by containing (A) 0.05% by weight or more of hyaluronic acid and / or a salt thereof, and (B) hyaluronic acid oligosaccharide and / or a salt thereof. . Hereinafter, the external composition of the present invention will be described in detail.

(A) Hyaluronic acid and / or salt thereof The composition for external use of the present invention has hyaluronic acid (so-called high molecular hyaluronic acid) and / or a salt thereof ((A) to provide a heavy coating feeling and moisturizing feeling. It may be described as an ingredient).

  Hyaluronic acid is a polysaccharide containing as a repeating unit a disaccharide in which the carbon atom at position 1 of glucuronic acid and the carbon atom at position 3 of N-acetylglucosamine are linked by a glycosidic bond.

  The hyaluronic acid salt used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, alkali metal salts such as sodium salts and potassium salts; alkaline earth salts such as calcium salts and magnesium salts; Metal salts; amine salts such as tri (n-butyl) amine salts, triethylamine salts, pyridine salts, amino acid salts, and the like. Among these salts of hyaluronic acid, preferred are alkali metal salts, more preferably sodium salts. These hyaluronic acid salts may be used alone or in combination of two or more.

  The average molecular weight of the hyaluronic acid and / or the salt thereof used in the present invention is not particularly limited, and may be, for example, 500,000 or more, preferably 500,000 to 3,000,000. In particular, the average molecular weight of hyaluronic acid is preferably 800,000 to 2,500,000, more preferably 1,000,000, from the viewpoint of more effectively improving the heavy coating feeling, moisturizing feeling, ease of stretching, and tackiness suppressing action. Up to 2.5 million. In the present invention, the average molecular weight of hyaluronic acid and / or a salt thereof is a weight average molecular weight determined by gel permeation chromatography (GPC) using pullulan as a standard substance.

  The origin of the hyaluronic acid and / or salt thereof used in the present invention is not particularly limited, and may be naturally derived from a biological tissue such as chicken crown, umbilical cord, skin, joint fluid, or enzyme. It may be produced by reaction, chemical synthesis, microorganism culture or the like.

  Hyaluronic acid and / or a salt thereof are commercially available, and in the present invention, commercially available products may be used. Specifically, as a commercial product of hyaluronic acid and / or a salt thereof, the trade name "hyaluronic acid HA-LQH" (average molecular weight 120 to 220,000; Kewpie Corporation), the trade name "hyaluronic acid HA-LQ" (average molecular weight Kewpie Co., Ltd.), trade name “Hyaluronic acid FCH-200” (average molecular weight: 180 to 2.2 million; Kikkoman Biochemifa Co., Ltd.), trade name “hyaluronic acid FCH-150” (average molecular weight: 140 to 1.8 million Kikkoman Biochemifa Co., Ltd., trade name "hyaluronic acid FCH-120" (average molecular weight 100 to 1.4 million; Kikkoman Biochemifa Co., Ltd.), trade name "biohyaluronate sodium HA9" (average molecular weight 800 to 1.2 million; stock Company Shiseido), trade name "Bio hyaluronic acid Nato" Umm HA12 "(average molecular weight of 110 to 1,600,000; Shiseido Co., Ltd.), trade name" sodium bio hyaluronic acid HA20 "(average molecular weight of 190 to 2,700,000; Shiseido Co., Ltd.), and the like.

  In the composition for external use of the present invention, either one of hyaluronic acid or a salt thereof may be used alone as the component (A), or these may be used in combination.

  In the composition for external use of the present invention, the concentration of the component (A) is set to 0.05% by weight or more. Thus, by setting the component (A) to a high concentration of 0.05% by weight or more, it is possible to effectively exert a heavy coating feeling and moisturizing feeling peculiar to hyaluronic acid and / or a salt thereof. Become. Moreover, in the prior art, when the component (A) is contained at such a high concentration, stickiness may occur or it may be difficult to stretch at the time of application. However, in the composition for external use of the present invention, hyaluronic acid oligosaccharides and By including the salt thereof, stickiness is suppressed, and it becomes easy to spread at the time of application, and the feeling in use can be improved. From the viewpoint of more effectively improving the heavy coating feeling, moisturizing feeling, ease of stretching, and stickiness-inhibiting action, the concentration of component (A) is preferably 0.05 to 2% by weight, more preferably 0. .05-1 weight% is mentioned.

(B) Hyaluronic Acid Oligosaccharide and / or its Salt The composition for external use according to the present invention contains, together with the aforementioned component (A), hyaluronic acid oligosaccharide and / or its salt (sometimes referred to as component (B)). To do. By using the hyaluronic acid oligosaccharide and / or the salt thereof, even when the component (A) is contained at a high concentration of 0.05% by weight or more, the heavy coating feeling and moisturizing feeling that the component (A) originally has While maintaining, stickiness is suppressed, and further, it becomes easy to extend at the time of application, and it becomes possible to provide the composition for external use with excellent usability. In addition, by using hyaluronic acid oligosaccharide and / or a salt thereof, it becomes possible to improve the solubility of the component (A) in water and shorten the time required to dissolve the component (A).

  The hyaluronic acid oligosaccharide is an oligosaccharide containing as a repeating unit a disaccharide in which a carbon atom at position 1 of glucuronic acid and a carbon atom at position 3 of N-acetylglucosamine are linked by a glycosidic bond, and the repeating unit is one or more .

  The salt of the hyaluronic acid oligosaccharide used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, alkali metal salts such as sodium salt and potassium salt; calcium salt and magnesium salt Examples include alkaline earth metal salts; amine salts such as tri (n-butyl) amine salts, triethylamine salts, pyridine salts, amino acid salts, and the like. Among the salts of these hyaluronic acid oligosaccharides, preferred are alkali metal salts, more preferably sodium salts. These hyaluronic acid salts may be used alone or in combination of two or more.

  The number of constituent monosaccharides of hyaluronic acid oligosaccharide and / or a salt thereof is not particularly limited, and examples thereof include about 2 to 16 saccharides. The number of constituent monosaccharides of hyaluronic acid oligosaccharide and / or a salt thereof is preferably 2 to 12 from the viewpoint of more effectively improving heavy coating feeling, moisturizing feeling, ease of stretching, and suppression of stickiness. And more preferably 2 to 10 sugars, particularly preferably 2 to 8 sugars.

  As the hyaluronic acid oligosaccharide and / or salt thereof used in the present invention, either a saturated type or an unsaturated type may be used alone, or a saturated type and an unsaturated type may be used in combination. From the viewpoint of more effectively improving the heavy coating feeling, moisturizing feeling, easiness of stretching, and stickiness suppression, unsaturated hyaluronic acid oligosaccharides and / or salts thereof are preferable. In the present invention, the saturated hyaluronic acid oligosaccharide and / or a salt thereof is a hyaluronic acid oligosaccharide and / or a salt thereof in which the pyranose skeleton of all constituent monosaccharides is formed by a single bond. The unsaturated hyaluronic acid oligosaccharide and / or salt thereof is hyaluronic acid oligosaccharide and / or salt thereof in which a double bond is contained in the pyranose skeleton of at least one constituent monosaccharide. As the unsaturated hyaluronic acid oligosaccharide and / or salt thereof, specifically, the hydroxyl group bonded to the 4-position carbon atom of glucuronic acid located at the non-reducing end is removed, and the 4-position carbon atom is removed. There are hyaluronic acid oligosaccharides and / or salts thereof in which the carbon atom at position 5 is bonded by a double bond.

  Hyaluronic acid oligosaccharides and / or salts thereof can be produced by hydrolyzing hyaluronic acid, and can also be produced by enzymatic reaction, chemical synthesis, microbial culture, and the like. Examples of the method for producing hyaluronic acid oligosaccharide and / or a salt thereof by hydrolyzing hyaluronic acid include known methods such as an enzymatic decomposition method, an alkali decomposition method, a heat treatment method, and an ultrasonic treatment method. Specifically, the enzymatic degradation method includes a method of degrading hyaluronic acid with a hyaluronic acid hydrolase such as hyaluronic acid degrading enzyme (hyaluronidase (derived from testicles), hyaluronidase (derived from Streptomyces), hyaluronidase SD, etc.). . Specific examples of the alkali decomposition method include a method of adding a base such as 1N sodium hydroxide to an aqueous solution containing hyaluronic acid and heating it for several hours to lower the molecular weight. Furthermore, as a method for producing by microbial culture, for example, in an aqueous solution of hyaluronic acid and / or a salt thereof, a microorganism having a resolution of hyaluronic acid and / or a salt thereof (for example, Streptomyces, Streptococcus, Peptococcus, Arthrobacter, Proteus, The method of culture | cultivating Flavobacterium etc. is mentioned.

  Hyaluronic acid oligosaccharides and / or salts thereof are commercially available. In the present invention, commercially available products may be used. As a commercial product of hyaluronic acid oligosaccharide and / or a salt thereof, specifically, as a saturated hyaluronic acid oligosaccharide and / or a salt thereof, the trade name “hyaluronic acid oligosaccharide hexasaccharide” (Carbohydrate Co., Ltd.) Scientific Research Laboratories), trade name "Hyaluronic Acid Oligosaccharide Octasaccharide" (Glucose Science Laboratories, Inc.), trade name "Hyaluronic Acid Oligosaccharide 10 Sugar" (Glucose Science Laboratories, Inc.) Oligosaccharide 12 sugars (Glycochemical Research Institute, Inc.), trade name "Hyaluronic Acid Oligosaccharide" (mixture of disaccharides and tetrasaccharides, manufactured by AdipoGen), trade name "Hyaluronic Acid Oligosaccharide" (mixture of 4 to 8 sugars , AdipoGen), trade name "Hyaluronic Acid Oligosacchar de (<1.5 kDa) (a mixture of disaccharides and tetrasaccharides, manufactured by AdipoGen), trade name “micro hyaluronic acid FCH” (a mixture of 12 to 14 saccharides, manufactured by Kikkoman Biochemifa), and the like. Further, as the unsaturated hyaluronic acid oligosaccharide and / or a salt thereof, specifically, the trade name “Hyaluronic Acid Oligosaccharide, dp2” (manufactured by Iduron Ltd), the trade name “Hyaluronic Acid Oligosaccharide, dp4” (IduronLt) ), Trade name “Hyaluronic Acid Oligosaccharide, dp6” (manufactured by Iduron Ltd), trade name “Hyaluronic Acid Oligosaccharide, dp8” (Iduron) Ltd.), trade name “Hyaluronic Acid Oligosaccharide, dp10” (manufactured by Iduron Ltd), trade name “Hyaluronic Acid Oligosaccharide, dp12” (manufactured by Iduronic Ltd), trade name “Hyaluronidac14” Name “Hyaluronic Acid Oligosaccharide, dp 18” (manufactured by Iduron Ltd.), trade name “Hyaluronic Acid Oligosaccharide, dp 20” (manufactured by Iduron Ltd), and the like.

  In the composition for external use of the present invention, as the component (B), either one of hyaluronic acid oligosaccharide or a salt thereof may be used alone, or these may be used in combination.

  The concentration of the component (B) in the composition for external use of the present invention is not particularly limited, and, for example, 0.0001 to 1.5% by weight can be mentioned. The concentration of the component (B) is preferably 0.0001 to 1% by weight, more preferably 0.1 to 1% by weight, from the viewpoint of more effectively improving heavy coating feeling, moisturizing feeling, ease of stretching, and suppression of stickiness. There may be mentioned 0,025 to 1% by weight, particularly preferably 0.001 to 1% by weight.

  Further, in the composition for external use of the present invention, the ratio of the component (A) to the component (B) is not particularly limited, but it is more effective to prevent heavy coating feeling, moisturizing feeling, stretchability, and stickiness suppression. From the viewpoint of improvement, the component (B) is preferably 0.1 parts by weight or more, more preferably 0.1 to 300 parts by weight, per 100 parts by weight of the component (A). The component (A) is not less than the same amount as the component (B), that is, 100 parts by weight or less of the component (B) per 100 parts by weight of the component (A), preferably 0.1 to 100 parts by weight, When 0.1 to 80 parts by weight, particularly preferably 0.1 to 50 parts by weight is satisfied, the solubility of the component (A) tends to be further improved, and the remarkably excellent heavy It becomes possible to provide a feeling of application and a feeling of moisture.

(C) Low-molecular-weight hyaluronic acid and / or a salt thereof The composition for external use of the present invention comprises, in addition to the components (A) and (B), a low-molecular-weight hyaluronic acid and / or a salt thereof ((C) component May be included). By blending such a low molecular weight hyaluronic acid and / or salt thereof, it is possible to more effectively improve the heavy coating feeling, moisturizing feeling, and easiness of extension, especially the heavy coating feeling. .

  The salt of the low molecular weight hyaluronic acid used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples thereof include alkali metal salts such as sodium salt and potassium salt; calcium salt and magnesium salt, etc. Examples include alkaline earth metal salts; amine salts such as tri (n-butyl) amine salts, triethylamine salts, pyridine salts, amino acid salts, and the like. Among these salts of low molecular weight hyaluronic acid, preferred are alkali metal salts, more preferably sodium salts. These low molecular hyaluronic acid salts may be used alone or in combination of two or more.

  The average molecular weight of the low molecular weight hyaluronic acid and / or the salt thereof to be used in the present invention may be usually about 8,000 to 120,000, and preferably 50,000 to 120,000. In the present invention, the average molecular weight of the low molecular weight hyaluronic acid and / or a salt thereof is a weight average molecular weight obtained by using gel pull chromatography (GPC) method using pullulan as a standard substance.

  Low molecular hyaluronic acid and / or a salt thereof can be produced by hydrolyzing hyaluronic acid, and can also be produced by enzymatic reaction, chemical synthesis, microbial culture, or the like.

  Low molecular weight hyaluronic acid and / or salts thereof are commercially available, and in the present invention, commercially available ones may be used. Specifically, as a commercial product of low molecular weight hyaluronic acid and / or a salt thereof, specifically, trade name "hyalooligo" (average molecular weight 10,000 or less, Kewpie Corporation), trade name "hyaluronic acid FCH-SU" (average molecular weight 5 ~ 110,000, Kikkoman Biochemifa Co., Ltd., trade name "hyaluronic acid (L)" (average molecular weight 50,000 or less, FAP Japan Co., Ltd.), trade name "hyaluronic acid (SL)" (average molecular weight 10,000 or less, stock Company FAP Japan) etc.

  In the composition for external use of the present invention, either low molecular weight hyaluronic acid or a salt thereof may be used alone as the component (C), or these may be used in combination.

  In the composition for external use of the present invention, the concentration of the low molecular weight hyaluronic acid and / or the salt thereof is not particularly limited, and, for example, 0.001 to 3% by weight can be mentioned. From the viewpoint of more effectively improving the heavy coating feeling, moisturizing feeling, and easiness of extension, particularly the thick coating feeling, the concentration of the low-molecular hyaluronic acid and / or salt thereof is preferably 0.002 to 2. % By weight, more preferably 0.002 to 1% by weight.

  Further, in the composition for external use of the present invention, the ratio of hyaluronic acid and / or a salt thereof to low molecular weight hyaluronic acid and / or a salt thereof is not particularly limited, but heavy coating feeling, moisturizing feeling, and ease of stretching In particular, from the viewpoint of more effectively improving the dense coating feeling, the total amount of low molecular weight hyaluronic acid and / or its salt is preferably 0.1 per 100 parts by weight of the total amount of hyaluronic acid and / or its salt. The amount is preferably 300 to 300 parts by weight, more preferably 0.2 to 200 parts by weight, still more preferably 0.5 to 150 parts by weight, and particularly preferably 1 to 100 parts by weight.

Composition for external use of the water present invention, water used as a base is prepared in the desired dosage form. In the composition for external use of the present invention, the concentration of water may be appropriately set according to the type of the composition for external use, etc., but for example 20 to 99.9% by weight, preferably 30 to 99.9% by weight More preferably, 35-99.9 weight% is mentioned.

Other Components The composition for external use of the present invention may contain, in addition to the components described above, functional components exhibiting physiologically useful functionality, as necessary. Such functional components are not particularly limited as long as they can be added to cosmetics and external medicines, but, for example, water-soluble vitamins, oil-soluble vitamins, enzymes, peptides, amino acids , Hormones, various cytokines, various animal and plant extracts, steroids, moisturizers, whitening agents, crude drugs, antihistamines, astringents, cell activators, keratin softeners, local anesthetics, anti-inflammatory agents, antioxidants, antibacterial agents, Antipruritic agents, skin protectants, blood circulation enhancers, sterols and the like can be mentioned.

  In addition to the components described above, the external composition of the present invention may further contain other bases and additives in order to prepare a desired dosage form. Such bases and additives are not particularly limited as long as they can be incorporated into cosmetics and external medicines, etc., but, for example, oily components, lower alcohols, surfactants, preservatives, thickeners , Perfumes, pigments, buffers, pH adjusters and the like.

  As the oil component, regardless of the origin of animal oil, vegetable oil, synthetic oil, etc., and properties of solid oil, semi-solid oil, liquid oil, volatile oil, etc., for example, hydrocarbons, fats and oils, higher alcohols, wax And hydrogenated oils, ester oils, fatty acids, fluorine-based oils, lanolin derivatives, oily gelling agents, oil-soluble ultraviolet light absorbers, and the like. Specific examples of oil components include hydrocarbons such as liquid paraffin, squalane, petrolatum, polyisobutylene, polybutene, paraffin wax, ceresin wax, microcrystalline wax, and fisher trops wax; olive oil, castor oil, jojoba oil, mink Oils and fats such as macadamian nut oil; waxes such as beeswax, carnauba wax, candelilla wax, gay wax, moclaw and montan wax; cetyl 2-ethylhexanoate, isotridecyl isostearate, isopropyl myristate, isopropyl palmitate Octyldodecyl myristate, cetyl trioctanoate, glyceryl tri-2-ethylhexanoate, polyglyceryl diisostearate, diglyceryl triisostearate, glyce tribehenate , Rosin acid pentaerythritol ester, neopentyl glycol dioctanoate, diisostearyl malate, cholesterol fatty acid ester, N-lauroyl-L-glutamate di (cholesteryl, behenyl, octyldodecyl), esters of macadamian nut fatty acid phytosteryl, etc. Fatty acids such as stearic acid, lauric acid, myristic acid, behenic acid, isostearic acid, oleic acid; higher alcohols such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, behenyl alcohol; perfluoropolyethers, perfluorodecane, Fluorine-based oil agents such as perfluorooctane; lanolin derivatives such as lanolin, lanolin acetate, lanolin fatty acid isopropyl and lanolin alcohol; dextrin fatty acid S Oily gelling agents such as sucrose fatty acid ester, starch fatty acid ester, 12-hydroxystearic acid, aluminum stearate, calcium stearate; ethyl paraaminobenzoate, 2-ethylhexyl paramethoxycinnamate, 4-tert-butyl -4'-methoxydibenzoylmethane, octyltriazone, bisethylhexyloxyphenol methoxyphenyltriazine, hexyl diethylaminohydroxybenzoyl benzoate, methylenebisbenzotriazolyltetramethylbutylphenol, oxybenzone, etc. It is done. These oily components may be used alone or in combination of two or more.

  Examples of lower alcohols include lower monohydric alcohols such as ethanol and isopropanol; polyhydric alcohols such as propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol, glycerin, diglycerin and polyglycerin; -Pentanediol and the like. These lower alcohols may be used alone or in combination of two or more.

  As surfactant, nonionic surfactant, anionic surfactant, cationic surfactant, amphoteric surfactant etc. are mentioned.

  Specific examples of the nonionic surfactant include sorbitan fatty acid esters (for example, sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate). Sorbitan trioleate, diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate); glycerin polyglycerin fatty acids (eg mono cottonseed oil fatty acid glycerin, monoerucic acid glycerin, sesquioleate glycerin, mono Glyceryl stearate, α, α′-oleic acid pyroglutamate glycerin, monostearate glycerin malate, etc.); propylene glycol fatty acid esters (eg, Propylene glycol nostearate); hardened castor oil derivative; glycerin alkyl ether, POE-sorbitan fatty acid esters (for example, POE-sorbitan monooleate, POE-sorbitan monostearate, POE-sorbitan monooleate, POE-sorbitan tetraole) POE sorbite fatty acid esters (eg, POE-sorbite monolaurate, POE-sorbite monooleate, POE-sorbite pentaoleate, POE-sorbite monostearate, etc.); POE-glycerin fatty acid esters (eg, POE-glycerin monostearate, POE-glycerin monoisostearate, POE-glyceryl triisostearate etc. POE-monooleate etc.); POE-fatty acid ester (For example, POE-distearate, POE-monodiolate, ethylene glycol distearate, etc.); POE-alkyl ethers (for example, POE-lauryl ether, POE-oleyl ether, POE-stearyl ether, POE-behenyl ether, POE- 2-octyldodecyl ether, POE-cholestanol ether etc.); Pluronic types (eg, Pluronic etc.); POE • POP-alkyl ethers (eg, POE • POP-cetyl ether, POE • POP-2-decyl tetradecyl) Ether, POE.POP-monobutyl ether, POE.POP-hydrogenated lanolin, POE.POP-glycerin ether, etc .; tetra POE. Tetra POP-ethylene diamine condensates (eg, tetronyl) POE-castor oil hardened castor oil derivatives (for example, POE-castor oil, POE-hardened castor oil, POE-hardened castor oil monoisostearate, POE-hardened castor oil triisostearate, POE-hardened castor oil) Monopyroglutamic acid monoisostearic acid diester, POE-hardened castor oil maleic acid, etc.); alkanolamide (for example, coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, fatty acid isopropanolamide, etc.); sucrose fatty acid ester; alkylethoxydimethylamine Oxides; trioleyl phosphate and the like.

  Specific examples of the anionic surfactant include fatty acid soaps (eg, sodium laurate, sodium palmitate, etc.); higher alkyl sulfates (eg, sodium lauryl sulfate, potassium lauryl sulfate, etc.); alkyl ether sulfates Salts (eg, POE-lauryl sulfate triethanolamine, POE-sodium lauryl sulfate, etc.); N-acyl sarcosic acids (eg, lauroyl sarcosine sodium etc.); higher fatty acid amido sulfonates (eg, N-myristoyl-N-methyl) Sodium taurine, coconut oil fatty acid methyl taurine sodium, lauryl methyl taurine sodium etc .; sulfosuccinates (eg sodium di-2-ethylhexyl sulfosuccinate, monolauroyl monoethanolamide polyoxy) Sodium ethylene sulfosuccinate, lauryl polypropylene glycol sodium sulfosuccinate etc .; alkyl benzene sulfonate (eg, sodium linear dodecyl benzene sulfonate, triethanolamine linear dodecyl benzene sulfonate, linear dodecyl benzene sulfonic acid, etc.), higher fatty acid ester sulfate ester Salts (eg, hardened coconut oil fatty acid glycerin sodium sulfate etc.); N-acyl glutamates (eg N-lauroylglutamic acid monosodium, N-stearoylglutamic acid disodium, N-myristoyl-L-glutamic acid monosodium etc); POE- Alkyl ether carboxylic acid; POE-alkyl allyl ether carboxylate; α-olefin sulfonate; lauroyl monoethanolamine Sodium dosuccinate; N-palmitoyl aspartic acid ditriethanolamine etc. are mentioned.

  Specific examples of the cationic surfactant include alkyl trimethyl ammonium salts (for example, stearyl trimethyl ammonium chloride, lauryl trimethyl ammonium chloride and the like); alkyl pyridinium salts (for example, cetyl pyridinium chloride and the like); distearyl dimethyl ammonium dialkyl chloride Dimethyl ammonium salt; poly (N, N'-dimethyl-3,5-methylene piperidinium chloride); alkyl quaternary ammonium salt; alkyl dimethyl benzyl ammonium salt; alkyl isoquinolinium salt; Benzalkonium; benzethonium chloride and the like.

  Examples of amphoteric surfactants include imidazoline-based amphoteric surfactants (eg, 2-undecyl-N, N, N- (hydroxyethylcarboxymethyl) -2-imidazoline sodium, 2-cocoyl-2-imidazolinium hydroxide). Side-1-carboxyethyloxy disodium salt and the like); betaine surfactants (eg, 2-heptadecyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, amidoamine type amphoteric surfactant, lauryl dimethylamino acetic acid And betaines, alkyl betaines, amido betaines, sulfobetaines etc.

  These surfactants may be used alone or in combination of two or more.

  Examples of the preservative include p-hydroxybenzoic acid ester, phenoxyethanol, benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, benzyl alcohol, chlorobutanol, sorbic acid and salts thereof, chlorhexidine gluconate and the like. These preservatives may be used alone or in combination of two or more.

  Examples of the thickener include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, guar gum, locust bean gum, carrageenan, xanthan gum, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, acrylic Examples thereof include alkyl methacrylate acid copolymer, polyethylene glycol, bentonite, alginic acid, macrogol, sodium chondroitin sulfate, carboxyethyl cellulose and the like. These thickeners may be used alone or in combination of two or more.

Production method The composition for external use according to the present invention is desired by mixing the components (A) and (B) with the component (C) added as needed, other functional components, a base, additives, etc. It can obtain by preparing to the formulation form.

  Further, since the component (A) is improved in solubility in water by the component (B), in the production of the composition for external use of the present invention, when the component (A) is dissolved in water, the component (B) Preferably coexist. As a method of coexisting component (B) when dissolving component (A) in water, for example, a method of simultaneously adding components (A) and (B) to water; adding component (A) to water, A method of adding the component (B) until the component (A) dissolves; a method of adding the component (A) after the component (B) is added to water.

Dosage Form and Formulation Form The composition for external use of the present invention may be in any form such as liquid, solid, cream, or gel. Among these dosage forms, the liquid external composition is suitable as a dosage form of the external composition of the present invention because it can easily realize effects such as a heavy coating feeling, moisturizing feeling, easiness of stretching, and stickiness suppression. is there.

  The composition for external use of the present invention is used in the form of a preparation for external preparations for skin such as cosmetics and external medicines. The formulation form of the composition for external use according to the present invention is not particularly limited, but, for example, cosmetics such as cream, lotion, cosmetic solution, milk, gel, lipstick and foundation; liquid agent (lotion agent, spray agent, aerosol agent, And emulsions for external use), foams, ointments, creams, gels, patches and the like. Among these formulation forms, from the viewpoint of making it easy to realize effects such as heavy application feeling, moisturizing feeling, ease of stretching, and suppression of stickiness, cosmetics, preferably cosmetic liquids, cosmetic liquids and emulsions, are preferred. Can be mentioned.

2. Method for Dissolving Hyaluronic Acid and / or Salt Thereof As described above, hyaluronic acid oligosaccharides and / or salts thereof have the effect of improving the solubility of hyaluronic acid and / or salts in water. Therefore, the present invention is further characterized by dissolving hyaluronic acid and / or a salt thereof (component (A)) in water in the presence of hyaluronic acid oligosaccharide and / or a salt thereof (component (B)). A method for dissolving hyaluronic acid and / or a salt thereof is provided.

  In the dissolution method of the present invention, the type of the component (A), the type of the component (B) and the like to be used are as described in the above-mentioned "1. Composition for external use".

  In the dissolution method of the present invention, the final concentration of the component (A) to be dissolved in water is not particularly limited, and for example, 0.01% by weight or more, preferably 0.03 to 2% by weight can be mentioned. In particular, when the final concentration of component (A) is set to a high concentration of 0.05% by weight or more, the amount of addition of hyaluronic acid and / or its salt increases, so that the conventional technique causes a large amount of lumps during dissolution. And the dissolution time is prolonged. In contrast, the dissolution method of the present invention can improve the solubility of the component (A) and shorten the dissolution time even when dissolving such a high concentration of the component (A). . In view of the effects of the present invention, the final concentration of the component (A) to be dissolved in water is preferably 0.05% by weight or more, more preferably 0.05 to 2% by weight, particularly preferably 0.05 Up to 1% by weight.

  In the dissolution method of the present invention, the amount of component (B) used is not particularly limited, but the final concentration of component (B) in water is, for example, 0.0001 to 1.5% by weight, preferably The amount is 0.0001 to 1% by weight, more preferably 0.00025 to 1% by weight, and particularly preferably 0.001 to 1% by weight.

  In the dissolution method of the present invention, the ratio of the component (A) and the component (B) is not particularly limited. For example, the component (B) is preferably 0.1 part by weight or more per 100 parts by weight of the component (A). Is from 0.1 to 300 parts by weight, and from the viewpoint of further improving the solubility of the component (A), more preferably 0.1 to 100 parts by weight, more preferably 0.1 to 80 parts by weight, in particular Preferably, 0.1 to 50 parts by weight can be mentioned.

  In the dissolution method of the present invention, as a technique for dissolving the component (A) in water in the presence of the component (B), specifically, a method of simultaneously adding the components (A) and (B) to water; (A) component is added to this, and (B) component is added until (A) component melt | dissolves; The method of adding (A) component after adding (B) component to water is mentioned.

  The dissolution method of the present invention can be used in the dissolution step of the component (A) when producing a product or raw material in which the component (A) is dissolved in water in all fields such as cosmetics, pharmaceuticals, and foods. In particular, the step of dissolving the component (A) at the time of production of an external composition such as cosmetics and external medicines, especially the dissolution of the component (A) at the time of production of the external composition shown in the column of “1. It is suitably used in the process.

  In the dissolution method of the present invention, the water for dissolving the component (A) may contain components other than the component (B). For example, if the dissolution method of the present invention is used in the step of dissolving the component (A) at the time of producing the external composition shown in the column of “1. External composition”, water for dissolving the component (A) The component (C) described in the section “1. Composition for external use”, other functional components, a base, additives and the like may be contained in the above.

  EXAMPLES The present invention will be more specifically described below by way of Examples, but the present invention is not limited thereto.

Production Example: Method for Producing “Unsaturated Hyaluronic Acid Oligosaccharide” In the following examples and comparative examples, “unsaturated hyaluronic acid oligosaccharide” was produced according to the method described in JP-A-2008-35858. I used something. Specifically, in a 1% by weight aqueous solution of sodium hyaluronate, Arthrobacter atrocyaneus JU-01 (Arthrobacter atrocyaneus JU-01) strain (National Institute of Technology and Evaluation, Patent Microbiology Depositary Center, Accession Number: NITE) P-245) was statically cultured at 25 ° C. for 120 hours. Thereafter, the strain was removed with a 0.22 μm membrane filter and lyophilized to obtain an unsaturated hyaluronic acid oligosaccharide. The obtained hyaluronic acid oligosaccharide is a disaccharide (the number of constituent monosaccharides is 2), the hydroxyl group bonded to the 4-position carbon atom of glucuronic acid located at the non-reducing end is removed, and the 4-position carbon is removed It had a structure in which the atom and the carbon atom at the 5-position were bonded by a double bond.

Test Example 1: Evaluation of solubility of hyaluronic acid in water A predetermined amount of purified water at room temperature was added to a 200 mL container to which a predetermined amount of hyaluronic acid and unsaturated hyaluronic acid oligosaccharide shown in Table 1 were added (container The total amount of the content was 100 g) and stirring was started at room temperature with a propeller stirrer at a speed of 500 rpm. The time (dissolution time) from the start of stirring until hyaluronic acid was completely removed and hyaluronic acid was completely dissolved was measured.

  The obtained results are shown in Table 1. From this result, it was confirmed that by dissolving hyaluronic acid in water in the presence of hyaluronic acid oligosaccharide, the time required for dissolving hyaluronic acid can be significantly shortened. In addition, it was found that the dissolution time can be shortened by making the content of sodium hyaluronate equal to or more than the same amount of unsaturated hyaluronic acid oligosaccharide.

Test Example 2: Evaluation of hyaluronic acid composition Hyaluronic acid compositions having the compositions shown in Tables 2 and 3 were prepared. Specifically, a hyaluronic acid composition in which hyaluronic acid is completely dissolved is manufactured by adding a predetermined amount of other components simultaneously to water at room temperature and stirring at a speed of 500 rpm with a propeller stirrer at room temperature. did. In the production of the hyaluronic acid composition, the solubility of hyaluronic acid was evaluated by the following method.
Hyaluronic acid solubility Stirring of hyaluronic acid from the start of stirring until hyaluronic acid was completely dissolved and hyaluronic acid was completely dissolved (dissolution time) was measured, and the solubility of hyaluronic acid was evaluated according to the following criteria.
<Criteria for solubility of hyaluronic acid>
○: Dissolution time is less than 50 minutes.
X: Dissolution time is 50 minutes or more.

In addition, each evaluation hyaluronic acid composition of about 0.5 is applied to the face by 10 evaluation monitors, and the feeling of use (the ease of stretching, the feeling of applying, the feeling of stickiness not feeling) and the feeling of using after application (moisturizing feeling) ) Was evaluated. The evaluation was conducted by conducting a questionnaire based on Visual Analogue Scale (hereinafter referred to as VAS) which is scored between 1 and 10 based on the criteria shown below. The questionnaire results were averaged, and the evaluation results were summarized by rounding off the first decimal place.
<Ease of extension>
1 point: Difficult to extend at the time of application 10 points: Easy to extend at the time of application <Applying feeling>
1 point: There is no heavy application feeling at the time of application 10 points: There is a heavy application feeling at the time of application <no stickiness>
1 point: Sticky during application 10 points: Not sticky during application <Moisturizing feeling>
1 point: 15 seconds after application no feeling of moistness 10 points: 15 seconds after application feeling of moist

  The obtained results are shown in Tables 2 and 3. In the case of containing 0.05% by weight or more of hyaluronic acid alone (Comparative Examples 1 and 2), although good coating feeling and moisturizing feeling were observed, the solubility of hyaluronic acid is poor, and further, it is difficult to stretch at the time of application I felt stickiness and I did not get a sufficient feeling of use. Moreover, when hyaluronic acid was less than 0.05% by weight (Comparative Examples 3 and 4), although the solubility of hyaluronic acid was good, the feeling of application and moisturizing were maintained regardless of the presence or absence of hyaluronic acid oligosaccharides. It was insufficient. Furthermore, even when containing low molecular weight hyaluronic acid, N-acetyl D-glucosamine, or lactose together with 0.5 wt% or more of hyaluronic acid, the solubility of hyaluronic acid is poor, and further, the ease of application and stickiness There was no improvement in point either.

  On the other hand, when hyaluronic acid oligosaccharides are contained together with 0.05% by weight or more of hyaluronic acid (Examples 6 to 18), the solubility of hyaluronic acid is good, and it is easy to extend during application. It was good in all points of the application feeling, the non-stickiness and the moisturizing feeling. In particular, when unsaturated hyaluronic acid oligosaccharide was used as the hyaluronic acid oligosaccharide (Examples 8 to 18), the ease of coating and the absence of stickiness were further improved.

Test Example 3: Evaluation of lotion containing hyaluronic acid A lotion having the composition shown in Table 4 was prepared. Specifically, first, a predetermined amount of the components shown in Table 4 (I) was mixed to prepare a mixed solution (I). A predetermined amount of the components shown in (II) of Table 4 was mixed to prepare a mixed solution (II). Next, the liquid mixture (I) was added to the liquid mixture (II) and stirred to prepare a lotion (hyaluronic acid final concentration 0.05% by weight).

  The obtained lotion was evaluated in the same manner as in Test Example 1 with respect to the feeling during use (ease of stretching, feeling of application, no stickiness) and feeling after use (moisturizing feeling).

  The obtained results are shown in Table 4. From this result, it is difficult to stretch at the time of application, and the stickiness is felt, and the feeling of use is not satisfactory in the lotion (Comparative Examples 10 and 11) containing 0.05% by weight of hyaluronic acid and containing no hyaluronic acid oligosaccharide It was. On the other hand, in the lotion containing hyaluronic acid 0.05% by weight and hyaluronic acid oligosaccharides (Examples 19 and 20), it is easy to stretch at the time of application, a feeling of application, no stickiness, and a moisturizing feeling. Good in all respects.

Formulation Examples 1-20
Lotions having the compositions shown in Table 5 and Table 6 were prepared. Specifically, first, a predetermined amount of the components shown in Tables 5 and 6 (A) was mixed to prepare a mixed solution (A). Separately, a predetermined amount of the components shown in Tables 5 and 6 (B) was mixed to prepare a mixed solution (B). Next, the liquid mixture (A) was added to the liquid mixture (B) and stirred to produce a lotion. All the obtained lotions were good in all points of the ease of application at the time of application, a feeling of application, no stickiness, and a feeling of moisture.

  In these formulation examples, sodium hyaluronate uses the trade name "Hyaluronic acid HA-LQH" (average molecular weight 120 to 220,000; Kewpie Corporation), and low molecular weight hyaluronic acid has the trade name "Hyaluronic acid FCH- SU (with a molecular weight of 5 to 110,000) (manufactured by Kikkoman Biochemifa Co., Ltd.) was used. Moreover, in these formulation examples, each saturation type hyaluronic acid oligosaccharide used any commercial item. Furthermore, in these formulation examples, each unsaturated type hyaluronic acid oligosaccharide has a hydroxyl group bonded to the 4-position carbon atom of glucuronic acid located at the non-reducing end removed, and the 4-position carbon atom and 5 The carbon atoms at the positions have a structure in which they are bonded by a double bond, and commercial products were used for all of them.

Claims (5)

  An external composition containing (A) 0.05% by weight or more of hyaluronic acid and / or a salt thereof, and (B) unsaturated hyaluronic acid oligosaccharide and / or a salt thereof. The composition for external use according to claim 1 , wherein the component (B) is contained in an amount of 0.1 to 80 parts by weight per 100 parts by weight of the component (A) .   The external composition according to claim 1 or 2, wherein the component (B) is contained in an amount of 0.0001 to 1.5% by weight.   The composition for external use according to any one of claims 1 to 3, which is a cosmetic. (B) Dissolution of hyaluronic acid and / or a salt thereof, characterized in that (A) hyaluronic acid and / or a salt thereof are dissolved in water in the presence of unsaturated hyaluronic acid oligosaccharide and / or a salt thereof How to save time.