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WO2016121611A1 - Gel d'acide hyaluronique hydrosoluble et son procédé de production - Google Patents

Gel d'acide hyaluronique hydrosoluble et son procédé de production Download PDF

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Publication number
WO2016121611A1
WO2016121611A1 PCT/JP2016/051670 JP2016051670W WO2016121611A1 WO 2016121611 A1 WO2016121611 A1 WO 2016121611A1 JP 2016051670 W JP2016051670 W JP 2016051670W WO 2016121611 A1 WO2016121611 A1 WO 2016121611A1
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Prior art keywords
water
hyaluronic acid
soluble
gel
aqueous solution
Prior art date
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Ceased
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PCT/JP2016/051670
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English (en)
Japanese (ja)
Inventor
邦夫 米戸
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RITAPHARMA Co Ltd
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RITAPHARMA Co Ltd
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Priority to JP2016571980A priority Critical patent/JP6519930B2/ja
Publication of WO2016121611A1 publication Critical patent/WO2016121611A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/58—Adhesives

Definitions

  • the present invention relates to a water-soluble hyaluronic acid gel and a method for producing the same.
  • Hyaluronic acid which is excellent in biocompatibility and shows many effective actions including moisturizing action, has attracted attention in the beauty field, medical field, food field and the like.
  • Hyaluronic acid is a linear high-molecular polysaccharide in which ⁇ -DN-acetylglucosamine and ⁇ -D-glucuronic acid are alternately bound, and is distributed in mammalian connective tissue. It is also known to exist in the streptococcal capsule.
  • Commercially available hyaluronic acid is generally prepared by isolation and extraction from a chicken crown, umbilical cord or the like, or a fermentation method using a microorganism such as Streptococcus.
  • gel compositions containing a polymer material have been used in the beauty field, the medical field, the food field, and the like.
  • gel compositions used in the beauty field, the medical field, the food field, and the like are required to be excellent in safety and biocompatibility because they are applied to the human body.
  • hyaluronic acid which is a natural material and excellent in safety and biocompatibility, as a polymer material contained in such a gel composition has been studied.
  • hyaluronic acid is used without using conventionally used gel-forming components such as polyacrylic acid or a salt thereof, xanthan gum, glucomannan, guar gum, locust bean, agar, carrageenan, polyvinyl alcohol and the like. Attempts have been made to develop hyaluronic acid gels that contain gel alone as a gel-forming component.
  • Patent Document 1 discloses a method for preparing a gel composition using crosslinked hyaluronic acid.
  • Patent Document 2 discloses a gel of a photocrosslinkable hyaluronic acid derivative characterized in that 0.0005 to 0.05 photodimerizable crosslinking groups are introduced on average per disaccharide unit constituting hyaluronic acid.
  • Patent Document 3 discloses a method for producing a crosslinked hyaluronic acid gel characterized by stirring and mixing a mixture containing hyaluronic acid 10 W / V% or more, a crosslinking agent, and water under acid or alkaline conditions. It is disclosed.
  • Patent Documents 1 to 3 in many of the hyaluronic acid gels in which hyaluronic acid is used alone as a gel-forming component, chemically modified hyaluronic acid is used. There is a problem that the characteristic as a natural material is lost.
  • Patent Document 4 hyaluronic acid, water having a hyaluronic acid concentration of 5% by mass or more, and a carboxyl group of hyaluronic acid and an equimolar or more acid component are allowed to coexist and the coexistence state is maintained.
  • the hyaluronic acid gel obtained in Patent Document 4 is hardly soluble in water, it is difficult for hyaluronic acid to dissolve in water.
  • the poorly water-soluble hyaluronic acid gel as disclosed in Patent Document 4 is less effective in moisturizing and firming the skin with hyaluronic acid when applied to the skin. Not suitable for use.
  • the hyaluronic acid gel disclosed in Patent Document 4 is obtained by allowing hyaluronic acid, an acid, and water to stand at low temperatures for at least several days, and it takes a long time to produce the hyaluronic acid gel. There is also a problem.
  • Patent Document 5 discloses that a hyaluronic acid gel can be obtained by bringing a hyaluronic acid solution into contact with a water-soluble organic solvent such as methanol, ethanol, isopropanol, and acetone at pH 2.0 to 3.8. Is disclosed.
  • a water-soluble organic solvent such as methanol, ethanol, isopropanol, and acetone at pH 2.0 to 3.8.
  • the method of Patent Document 5 has a problem that it is difficult to use in the beauty field, the medical field, the food field, etc., because these water-soluble organic solvents are contained in a large amount in the hyaluronic acid gel.
  • the hyaluronic acid gel disclosed in Patent Document 5 has a problem that it is difficult to form a sheet by a simple method such as a casting method.
  • Patent Document 6 discloses a hyaluronic acid gel comprising hyaluronic acid, polyvalent carboxylic acid or oxycarboxylic acid, and polyhydric alcohol as constituent components.
  • the hyaluronic acid gel described in Patent Document 6 has an advantage that hyaluronic acid that is not chemically modified can be used, and it is not necessary to use a large amount of an organic solvent.
  • the main object of the present invention is to provide a water-soluble hyaluronic acid gel containing a water-soluble crystalline sugar in a dissolved state. Furthermore, the present invention also aims to provide a method for producing the water-soluble hyaluronic acid gel, a cosmetic, a medical device composition, a food composition, or a pharmaceutical composition using the water-soluble hyaluronic acid gel. .
  • the present inventor has intensively studied to solve the above problems.
  • the water content can be adjusted to prepare a saturated aqueous solution of water-soluble crystalline sugar.
  • a water-soluble hyaluronic acid gel functions as a forming component and a water-soluble crystalline sugar can be present in a dissolved state in the water-soluble hyaluronic acid gel.
  • a water-soluble hyaluronic acid gel is prepared by mixing an acid different from hyaluronic acid, water-soluble crystalline sugar, water, and hyaluronic acid to prepare an aqueous solution for gel formation. It has also been found that it can be easily produced by setting it to 50% by mass or more of the amount necessary for the preparation of a saturated aqueous solution of crystalline sugar. The present invention has been completed by further studies based on these findings.
  • a water-soluble hyaluronic acid gel comprising hyaluronic acid, water-soluble crystalline sugar, water, and an acid different from hyaluronic acid, A water-soluble hyaluronic acid gel, wherein the water content is 50% by mass or more of the amount required for preparing the saturated aqueous solution of the water-soluble crystalline sugar.
  • Item 2. Item 2. The water-soluble hyaluronic acid gel according to item 1, wherein the content of the water-soluble crystalline sugar is 0.05 parts by mass or more with respect to 1 part by mass of the hyaluronic acid.
  • the water-soluble hyaluronic acid gel according to Item 1 or 2 wherein the pH of the aqueous solution measured by the following measurement method is in the range of 1.9 to 5.2. (Measurement method of pH) Among the components contained in the water-soluble hyaluronic acid gel in an amount containing 1 g of hyaluronic acid, an aqueous solution was prepared by dissolving all ionic components except water in water to 200 mL, and the pH of the obtained aqueous solution Measure. Item 4. Item 4. The water-soluble hyaluronic acid gel according to any one of Items 1 to 3, wherein the water content is 400 parts by mass or less with respect to 1 part by mass of the hyaluronic acid. Item 5.
  • Item 5 The water-soluble hyaluronic acid gel according to any one of Items 1 to 4, which is in the form of a sheet.
  • Item 6. A water-soluble hyaluronic acid gel sheet, wherein the water-soluble hyaluronic acid gel according to any one of items 1 to 5 is formed on a support.
  • Item 7. Item 6. A cosmetic using the water-soluble hyaluronic acid gel according to any one of Items 1 to 5.
  • Item 8. Item 6. A food composition using the water-soluble hyaluronic acid gel according to any one of Items 1 to 5.
  • Item 9. Item 6. A pharmaceutical composition using the water-soluble hyaluronic acid gel according to any one of Items 1 to 5.
  • Item 10. Item 6.
  • Item 11. Item 6. A method for producing a water-soluble hyaluronic acid gel according to any one of Items 1 to 5, A method for producing a water-soluble hyaluronic acid gel, comprising preparing a gel-forming aqueous solution by mixing hyaluronic acid, water-soluble crystalline sugar, water, and an acid different from hyaluronic acid.
  • Item 12. Item 12. The method for producing a water-soluble hyaluronic acid gel according to Item 11, further comprising a step of evaporating water contained in the aqueous solution for gel formation.
  • Item 13. Item 13.
  • Item 14. Item 6. A method for producing a water-soluble hyaluronic acid gel according to any one of Items 1 to 5, Preparing a hyaluronic acid aqueous solution by mixing hyaluronic acid, a water-soluble crystalline sugar, and water; Adding an acid different from hyaluronic acid to the aqueous hyaluronic acid solution; A method for producing a water-soluble hyaluronic acid gel.
  • Item 15. Item 6.
  • a method for producing a water-soluble hyaluronic acid gel according to any one of Items 1 to 5, Preparing a hyaluronic acid aqueous solution by mixing hyaluronic acid, a water-soluble crystalline sugar, and water; Drying the hyaluronic acid aqueous solution; Adding an acid different from hyaluronic acid to the dried aqueous hyaluronic acid solution; A method for producing a water-soluble hyaluronic acid gel. Item 16. Item 6.
  • a method for producing a water-soluble hyaluronic acid gel according to any one of Items 1 to 5, A step of preparing an aqueous solution by mixing water-soluble crystalline sugar, an acid different from hyaluronic acid, and water; A method for producing a water-soluble hyaluronic acid gel, comprising the step of adding and dissolving hyaluronic acid in the aqueous solution.
  • a water-soluble hyaluronic acid gel in which water-soluble crystalline sugar is present in a dissolved state even when hyaluronic acid is contained alone as a gel-forming component. Can do.
  • hyaluronic acid is not chemically modified, and natural materials can be used.
  • the manufacturing method of the said water-soluble hyaluronic acid gel, the cosmetics using the said water-soluble hyaluronic acid gel, the composition for medical devices, the food composition, or the pharmaceutical composition can be provided. .
  • the water-soluble hyaluronic acid gel of the present invention is a water-soluble hyaluronic acid gel containing hyaluronic acid, a water-soluble crystalline sugar, water, and an acid different from hyaluronic acid, and the water content is a water-soluble crystal. It is characterized by being 50% by mass or more of the amount necessary for the preparation of a saturated aqueous solution of a natural sugar.
  • the water-soluble hyaluronic acid gel of the present invention, the method for producing the water-soluble hyaluronic acid gel, cosmetics using the water-soluble hyaluronic acid gel, compositions for medical devices, food compositions, or pharmaceutical compositions (external use, Oral) will be described in detail.
  • the water-soluble hyaluronic acid gel of the present invention contains hyaluronic acid, water-soluble crystalline sugar, water, and an acid different from hyaluronic acid.
  • the water-soluble hyaluronic acid gel of the present invention is prepared by preparing an aqueous solution for gel formation containing, for example, hyaluronic acid, water-soluble crystalline sugar, water, and an acid different from hyaluronic acid.
  • the water content may be adjusted by, for example, a method of evaporating water from the gel forming aqueous solution.
  • hyaluronic acid is included as a gel-forming component.
  • hyaluronic acid is contained alone as a gel-forming component, and other gel-forming components may not be substantially contained.
  • the water-soluble hyaluronic acid gel of the present invention may contain other gel forming components in addition to hyaluronic acid, as long as the effects of the present invention are not inhibited.
  • gel-forming components are not particularly limited, for example, polyacrylic acid or a salt thereof, xanthan gum, gellan gum, glucomannan, guar gum, locust bean gum, agar, gelatin, pectin, casein, gum arabic, carrageenan, agarose, Known gel-forming components such as alginic acid, propylene glycol alginate, carboxymethylcellulose Na, hydroxypropylcellulose, polyvinyl alcohol, carboxyvinyl polymer, starch / acrylate graft copolymer, methyl vinyl ether / maleic anhydride copolymer, etc. .
  • the content of the other gel-forming components is the hyaluronic acid in the composition of the water-soluble hyaluronic acid gel of the present invention.
  • the amount is preferably not more than the amount at which no gel is formed.
  • the content of other gel-forming components varies depending on the type of other gelling components, but in the water-soluble hyaluronic acid gel of the present invention, it is 5% by mass or less, preferably 2.5% by mass or less, more preferably Is 1% by mass or less, more preferably 0.5% by mass or less, and still more preferably 0.1% by mass or less.
  • hyaluronic acid is used in a concept including hyaluronic acid and a salt thereof. Therefore, “hyaluronic acid and a salt thereof” may be simply referred to as “hyaluronic acid”.
  • the salt of hyaluronic acid is not particularly limited, and examples thereof include sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate and the like.
  • hyaluronic acid and its salt may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the molecular weight of hyaluronic acid is not particularly limited as long as it can form a gel even when hyaluronic acid is used alone, but water-soluble hyaluronic acid is present in the dissolved state while water-soluble crystalline sugar is present in a dissolved state. From the viewpoint of providing the acid gel with appropriate elasticity, high mechanical strength, and shape maintenance, it is preferably about 5.0 ⁇ 10 4 to 5.0 ⁇ 10 6 daltons, more preferably 1.0 ⁇ 10 5. About 2.3 ⁇ 10 6 daltons.
  • the hyaluronic acid one having a single molecular weight may be used, or plural kinds of molecular weights may be mixed and used.
  • “moderate elasticity” means, for example, a characteristic that when a water-soluble hyaluronic acid gel is pressed with a finger, it repels moderately and does not pull when it is pulled and broken.
  • high mechanical strength means the intensity
  • the form maintaining property refers to the property that, when a water-soluble hyaluronic acid gel is allowed to stand, unlike a high-viscosity solution, the shape when it is left standing is maintained.
  • the origin of hyaluronic acid is not particularly limited, and, for example, those isolated and extracted from chicken crowns, umbilical cords, etc., and those prepared by fermentation using microorganisms such as Streptococcus can be preferably used.
  • a commercially available product can be used as the hyaluronic acid. Since the water-soluble hyaluronic acid gel of the present invention does not need to be chemically modified as hyaluronic acid, it is excellent in biocompatibility and can exhibit the characteristics of natural hyaluronic acid. That is, in the water-soluble hyaluronic acid gel of the present invention, only hyaluronic acid that is not substantially chemically modified may be used as hyaluronic acid.
  • the water-soluble hyaluronic acid gel of the present invention may further contain chemically modified hyaluronic acid as long as the effects of the present invention are not inhibited.
  • chemically modified hyaluronic acid examples include hydroxypropyltrimonium hyaluronate, hydrolyzed alkyl hyaluronate (C12-13) glyceryl, propylene glycol hyaluronate, sodium acetylated hyaluronate, and the like. Chemically modified hyaluronic acid may be used alone or in combination of two or more.
  • the content of hyaluronic acid is not particularly limited as long as the gel can be formed, but the water-soluble hyaluronic acid gel is present in a dissolved state while the water-soluble crystalline sugar is present in a dissolved state. From the viewpoint of providing appropriate elasticity, high mechanical strength, and shape maintainability, for example, about 0.2 to 50% by mass, preferably about 0.3 to 35% by mass, and more preferably 0.7 to 10% by mass. %. When the content of hyaluronic acid in the water-soluble hyaluronic acid gel is less than 0.2% by mass, the gel may not be formed from an aqueous solution for gel formation described below.
  • the content of hyaluronic acid in the water-soluble hyaluronic acid gel exceeds 50% by mass, the water-soluble hyaluronic acid gel becomes too hard, and a cosmetic, food, pharmaceutical composition, or medical device composition described later, etc. It may be difficult to use as.
  • the water-soluble crystalline sugar is not particularly limited as long as it is water-soluble and is crystalline sugar as a sugar alone or as a hydrate. Crystalline sugars ranging from monosaccharide, disaccharide to decasaccharide are included. Can be used.
  • water-soluble crystalline sugars include glucose, fructose, xylitol, sorbitol, trehalose, lactose, maltose, sucrose, raffinose, oligosaccharides (fructo-oligosaccharides, galactooligosaccharides, mannan-oligosaccharides, whey oligosaccharides, etc.) Examples include ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
  • One type of water-soluble crystalline sugar may be used alone, or two or more types may be used in combination.
  • the content of the water-soluble crystalline sugar contained in the water-soluble hyaluronic acid gel is not particularly limited, and examples thereof include 0.05 parts by mass or more with respect to 1 part by mass of hyaluronic acid. From the viewpoint of providing the water-soluble hyaluronic acid gel with appropriate elasticity, high mechanical strength, and shape maintaining property while suitably presenting the water-soluble crystalline sugar in a dissolved state in the water-soluble hyaluronic acid gel.
  • the amount is preferably about 0.1 to 400 parts by weight, more preferably about 1 to 200 parts by weight with respect to 1 part by weight of hyaluronic acid.
  • these content means the total amount of all the water-soluble crystalline sugars.
  • the acid different from hyaluronic acid is not particularly limited as long as it is acidic when mixed with water, and either an inorganic acid or an organic acid can be used.
  • the inorganic acid include phosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, and carbonic acid, and preferably phosphoric acid, hydrochloric acid, and sulfuric acid.
  • organic acids include monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and lipoic acid; dicarboxylic acids such as succinic acid, phthalic acid, fumaric acid, oxalic acid, malonic acid, and glutaric acid.
  • Acids such as glycolic acid, citric acid, lactic acid, pyruvic acid, malic acid, tartaric acid and salicylic acid; polyhydroxy acids such as glucono- ⁇ -lactone and lactopionic acid; acidic amino acids such as glutamic acid and aspartic acid; (Registered trademark, methyl carboxymethylphenylaminocarboxypropylphosphonate) and the like; ascorbic acid such as ascorbic acid, ethyl ascorbate, ascorbic acid glucoside or derivatives thereof, preferably phosphoric acid, ascorbic acid, citric acid, Glycolic acid, lactic acid, malic acid, tartar
  • acids salicylic acid, ethyl ascorbate, ascorbic acid glucoside, glucono- ⁇ -lactone, and lactopionic acid.
  • An acid may be used individually by 1 type and may be used in combination of 2 or more type.
  • the content of the acid is not particularly limited, but from the viewpoint of providing the water-soluble hyaluronic acid gel with appropriate elasticity, high mechanical strength, and shape maintaining property while presenting the water-soluble crystalline sugar in a dissolved state.
  • the pH of the aqueous solution measured by the following measurement method is preferably in the range of about 1.9 to 5.2, more preferably about 2.4 to 4.9, and even more preferably about 2.9 to 4.6. It is preferable to adjust so that.
  • hyaluronic acid even when the pH of the aqueous solution is about the same as the pH when an acid different from hyaluronic acid is not included (for example, the pH exceeds 5.2), depending on the type of water-soluble crystalline sugar, It may be possible for hyaluronic acid to function as a gel-forming component. However, in the present invention, by setting the pH to a predetermined value of preferably 5.2 or lower, hyaluronic acid is made to function as a gel-forming component in common when various water-soluble crystalline sugars are used. Has the technical advantage of being able to.
  • the water-soluble hyaluronic acid gel of the present invention contains 50% by mass or more of water necessary for preparing the saturated aqueous solution of the water-soluble crystalline sugar described above. In the present invention, this enables the crystalline sugar to be present in a dissolved state in the water-soluble hyaluronic acid gel while hyaluronic acid functions as a gel-forming component.
  • the saturated aqueous solution of water-soluble crystalline sugar means that only water-soluble crystalline sugar is distilled water up to the upper limit at a predetermined temperature (temperature at which water-soluble hyaluronic acid gel exists) at 1 atm. It is a dissolved aqueous solution.
  • the content of water in the water-soluble hyaluronic acid gel is based on a saturated aqueous solution when the water-soluble hyaluronic acid gel is present at 1 atm and room temperature (for example, 20 ° C.). it can. That is, in the present invention, for example, 50% by mass or more of water required for the preparation of the above-mentioned saturated aqueous solution of water-soluble crystalline sugar under the conditions of 1 atm and room temperature (for example, 20 ° C.) is included.
  • the crystalline sugar is allowed to exist in a dissolved state in the water-soluble hyaluronic acid gel for at least 48 hours under storage conditions at room temperature (for example, 20 ° C.) while the hyaluronic acid functions as a gel-forming component.
  • the saturated aqueous solution means an aqueous solution in which all water-soluble crystalline sugars are dissolved in water.
  • the water-soluble hyaluronic acid gel of the present invention contains 50% by mass or more of water necessary for the preparation of the saturated aqueous solution of the above-mentioned water-soluble crystalline sugar, whereby hyaluronic acid is converted into a gel-forming component.
  • the crystalline sugar can be present in a dissolved state.
  • hyaluronic acid may form a gel even when the water content is less than 50% by mass of the amount required for preparing a saturated aqueous solution of water-soluble crystalline sugar.
  • the crystalline sugar may be present in a dissolved state in the water-soluble hyaluronic acid gel while functioning as a component.
  • the amount of water in the water-soluble hyaluronic acid gel to a predetermined value of 50% by mass or more, it is common to use various water-soluble crystalline sugars. It has the technical advantage that the crystalline sugar can be present in a dissolved state in the hyaluronic acid gel.
  • the content of water contained in the water-soluble hyaluronic acid gel of the present invention is not particularly limited as long as it is 50% by mass or more of the amount necessary for preparing a saturated aqueous solution of crystalline sugar, but hyaluronic acid 1 Preferably it is 400 mass parts or less with respect to a mass part, More preferably, it is 300 mass parts or less, More preferably, 200 mass parts or less is mentioned.
  • the water-soluble hyaluronic acid gel of the present invention may contain a water-soluble organic solvent (excluding a polyhydric alcohol described later).
  • a water-soluble organic solvent excluding a polyhydric alcohol described later.
  • the content thereof is 10% by mass or less, preferably 5% by mass or less, more preferably 2% by mass or less.
  • the water-soluble organic solvent is not particularly limited, and examples thereof include ethanol, methanol, isopropanol, and acetone.
  • a water-soluble organic solvent may be used individually by 1 type, and may be used in combination of 2 or more types. As described later, the water-soluble hyaluronic acid gel of the present invention is suitably used in the beauty field, the medical field, and the food field.
  • the water-soluble hyaluronic acid gel of the present invention does not substantially contain a water-soluble organic solvent.
  • a water-soluble organic solvent when a water-soluble organic solvent is used, the viscosity of an aqueous solution for gel formation described later tends to increase, and it may be difficult to spread the aqueous solution for gel formation thinly on a substrate or the like. For this reason, when a water-soluble organic solvent is used, it may be difficult to form a water-soluble hyaluronic acid gel into a sheet by a simple method such as a casting method. Also from such a viewpoint, it is preferable that the water-soluble hyaluronic acid gel of the present invention does not substantially contain a water-soluble organic solvent.
  • the elasticity, mechanical strength, shape maintainability, etc. of the water-soluble hyaluronic acid gel of the present invention include the content of each component in the water-soluble hyaluronic acid gel, the molecular weight of the hyaluronic acid, or the pH of the aqueous solution in the aforementioned pH measurement method. It can be adjusted by setting the range to a predetermined range. For example, when the content of hyaluronic acid in the water-soluble hyaluronic acid gel is increased (the ratio is increased), the water-soluble hyaluronic acid gel becomes harder and the elasticity, mechanical strength, and shape maintenance of the water-soluble hyaluronic acid gel are improved. Tend to be higher.
  • the water-soluble hyaluronic acid gel becomes hard, and the elasticity, mechanical strength, and shape maintainability of the water-soluble hyaluronic acid gel tend to increase.
  • the pH in the above-mentioned range of pH 1.9 to 5.2, when the pH is lowered, the water-soluble hyaluronic acid gel becomes harder, and the elasticity, mechanical strength, and shape maintainability of the water-soluble hyaluronic acid gel tend to increase.
  • the water-soluble hyaluronic acid gel of the present invention is water-soluble.
  • the water solubility of the water-soluble hyaluronic acid gel of the present invention means that a water-soluble hyaluronic acid gel having a thickness of 100 ⁇ m, a length of 4 cm, and a width of 4 cm is placed in 100 mL of a pH 7.4 phosphate buffer at 37 ° C. When it stirs at 120 rpm using a stirrer, it means that it dissolves completely within 4 hours.
  • the shape of the water-soluble hyaluronic acid gel of the present invention is not particularly limited and can be appropriately set according to the application.
  • Examples of the shape of the water-soluble hyaluronic acid gel of the present invention include a sheet shape, a granular shape, and a lump shape.
  • the water-soluble hyaluronic acid gel is in the form of a sheet (water-soluble hyaluronic acid gel sheet), as described later, for example, the water-soluble hyaluronic acid gel of the present invention is applied to the skin, oral cavity, etc. It can be suitably used as a composition or a composition for medical devices. Further, the sheet-like water-soluble hyaluronic acid gel may be used as a food composition such as an oral hygiene improving film or an oral pharmaceutical composition such as an oral sustained release film.
  • the thickness of the water-soluble hyaluronic acid gel sheet is not particularly limited, and may be, for example, about 0.01 to 10 mm, preferably about 0.05 to 5 mm.
  • the water-soluble hyaluronic acid gel when it is in the form of a lump, it can be suitably used as a cosmetic composition for massaging the face and body. It can also be suitably used as a food composition such as a jelly drink or an oral pharmaceutical composition such as a swallowing assistance drink. When the water-soluble hyaluronic acid gel is granular, it can be suitably used as a food composition such as gummy or an oral pharmaceutical composition.
  • the water-soluble hyaluronic acid gel of the present invention contains hyaluronic acid having a moisturizing action and the like, it can be applied to the skin and the like in the beauty field and the medical field. Moreover, since it can also be comprised only with components which can be used for food and medicine, such as hyaluronic acid and water-soluble crystalline sugar, it can be suitably applied to the oral cavity. That is, the water-soluble hyaluronic acid gel of the present invention can be suitably used as a cosmetic, a food composition, a pharmaceutical composition, or a medical device composition.
  • the water-soluble hyaluronic acid gel of the present invention When used as a cosmetic, a pharmaceutical composition, or a medical device composition, a known component that is blended in the cosmetic, quasi-drug, pharmaceutical, or medical device is further blended. be able to.
  • a known component that is blended in the cosmetic, quasi-drug, pharmaceutical, or medical device is further blended.
  • examples of such components include whitening ingredients, anti-aging ingredients, oil ingredients, various vitamins and derivatives thereof, various animal and plant extracts, anti-inflammatory agents, antioxidants, pigments, fragrances (aromatic ingredients), preservatives, honey, and the like. Is mentioned.
  • the fat-soluble component when adding a fat-soluble component to the water-soluble hyaluronic acid gel of the present invention, the fat-soluble component can also be added in the form of liposome, emulsion, nanoemulsion or the like. These components may be used alone or in combination of two or more.
  • whitening ingredients include vitamin C or its derivatives, astaxanthin and the like.
  • Specific examples of the anti-aging component include Narusgene (registered trademark, methyl carboxymethylphenylaminocarboxypropylphosphonate), pyrroloquinoline quinone, LR2412 (registered trademark, sodium tetrahydrojasmonate), Green Peel (registered trademark, vegetable essential oil). ) And the like.
  • Specific examples of the oil component include squalane, jojoba oil, olive oil and the like.
  • the water-soluble hyaluronic acid gel of the present invention includes collagen, porphyrin, proteoglycan, acetylglucosamine, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, lipida (registered trademark, 2-methacryloyloxyethyl phosphorylcholine homopolymer or copolymer),
  • a water-soluble polymer such as low molecular weight hyaluronic acid having a molecular weight of 10,000 or less or a salt thereof may be blended.
  • One type of water-soluble polymer may be used alone, or two or more types may be used in combination.
  • a polyhydric alcohol may be added to the water-soluble hyaluronic acid gel of the present invention.
  • the polyhydric alcohol is not particularly limited as long as it is in a liquid state at 1 atm and room temperature (for example, 25 ° C.), but preferably glycerins such as glycerin and diglycerin; propylene glycols such as propylene glycol and dipropylene glycol 1,3-propanediol, butanediol (1,3-butanediol, 1,4-butanediol, etc.), 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol; ethylene glycol , Ethylene glycols such as diethylene glycol, triethylene glycol, polyethylene glycol and the like, more preferably glycerin, diglycerin, propylene glycol, 1,3-butanediol, polyethylene glycol 200
  • the water-soluble hyaluronic acid gel of the present invention can be imparted with appropriate elasticity, appropriate mechanical strength, and appropriate shape maintenance, the water-soluble hyaluronic acid gel of the present invention is used as it is as a pack agent. You can also.
  • the water-soluble hyaluronic acid gel of the present invention is used as a pack agent, the water-soluble hyaluronic acid gel of the present invention is preferably in the form of a sheet.
  • the water-soluble hyaluronic acid gel sheet of the present invention is directly applied to the skin and held for a certain period of time, thereby providing the skin with a moisturizing effect by hyaluronic acid.
  • the water-soluble hyaluronic acid gel of the present invention contains known ingredients blended in the cosmetics, quasi drugs, pharmaceuticals, and medical devices as described above, the water-soluble hyaluronic acid gel sheet of the present invention is directly applied to the skin. By pasting, these components can be absorbed percutaneously.
  • the water-soluble hyaluronic acid gel of the present invention has water solubility, hyaluronic acid is likely to dissolve into moisture. For this reason, the water-soluble hyaluronic acid gel of the present invention has a high effect of moisturizing and firming the skin with hyaluronic acid when applied to the skin, and is suitable for use in the beauty field. For example, after applying the water-soluble hyaluronic acid gel sheet of the present invention to the skin, the skin is massaged while being gradually dissolved by applying water to the sheet, thereby further enhancing the moisturizing effect of hyaluronic acid dissolved in water. be able to.
  • the water-soluble hyaluronic acid gel of the present invention is excellent in safety and biocompatibility and has high water absorption / water retention, it is suitable for use as a medical device for protecting wound sites and pressure ulcer sites.
  • the water-soluble hyaluronic acid gel of the present invention is excellent in safety and biocompatibility, and has high water absorption / water retention, so that it can be suitably used as a pad for emergency bandages or a covering protective material for pressure ulcers. it can.
  • healing promotion components such as epidermal growth factor, and an antimicrobial component can also be mix
  • the water-soluble hyaluronic acid gel of the present invention may be used on a support.
  • a water-soluble hyaluronic acid gel sheet By forming a water-soluble hyaluronic acid gel on a support, a water-soluble hyaluronic acid gel sheet can be suitably formed.
  • the support is not particularly limited, and examples thereof include non-woven fabrics, woven fabrics, woven fabrics, paper, polymer films (polyethylene terephthalate, polyolefins such as polyethylene, vinyl chloride, polyurethane films, etc.), and more preferably, From the viewpoint of the adhesive strength between the water-soluble hyaluronic acid gel and the support, a laminate film made of a nonwoven fabric / polymer film, a nonwoven fabric and the like can be mentioned. Further, the water-soluble hyaluronic acid gel on the support may be fixed with an adhesive tape, a hydrogel tape, a supporter, a bandage, a mask, an eye mask or the
  • the water-soluble hyaluronic acid gel of the present invention can be used alone as a product as it is.
  • the product can be a product in which the gel is integrated with an adhesive tape or a support, or a water-soluble hyaluronic acid gel is used as the product, and the adhesive tape, hydrogel tape, supporter, bandage, mask, eye mask.
  • the gel may be fixed and used.
  • the water-soluble hyaluronic acid gel of the present invention can be composed only of components that can be used for food or medicine, such as hyaluronic acid and water-soluble crystalline sugar. It can also be suitably used as a food composition, an oral pharmaceutical composition and the like.
  • a known component to be blended in the food composition can be further blended.
  • such components include sweeteners, fragrances, colorants, acidulants, antioxidants, emulsifiers, preservatives, stabilizers, and the like.
  • blended with an oral pharmaceutical composition can further be mix
  • such components include medicinal ingredients, fragrances, colorants, acidulants, antioxidants, emulsifiers, preservatives, stabilizers, and the like.
  • these components may be used alone or in combination of two or more.
  • the food composition or oral pharmaceutical composition using the water-soluble hyaluronic acid gel of the present invention contains hyaluronic acid, by ingesting the food composition or oral pharmaceutical composition, for example, the skin The effect of increasing the moisture content and enhancing the skin moisturizing effect can be expected. Furthermore, when the food composition or oral pharmaceutical composition contains known components as described above, the effects of these components can be exhibited. In addition, by using cyclodextrin as a sugar, a bitterness masking effect and sustained release effect due to the action of encapsulating the hydrophobic component of cyclodextrin can be expected. Further, by using xylitol as a sugar, an effect of inhibiting caries caused by bacteria in the oral cavity of xylitol can be expected.
  • water-soluble hyaluronic acid gel of the present invention is used as a food composition or an oral pharmaceutical composition
  • these forms are not particularly limited.
  • a sheet shape such as an oral hygiene improvement film, a granular shape such as a gummi, and a swallowing It can be a lump like an auxiliary beverage / jelly beverage.
  • the method for producing the water-soluble hyaluronic acid gel of the present invention is not particularly limited.
  • the gel-forming aqueous solution is prepared by mixing the above-mentioned hyaluronic acid, water-soluble crystalline sugar, water, and an acid different from hyaluronic acid.
  • Examples of the method include a step of preparing.
  • the mixing order of each component is not particularly limited.
  • the mixing method of each component is not particularly limited, and may be stirred using, for example, a stirrer.
  • the method for producing the water-soluble hyaluronic acid gel of the present invention it is preferable to set the blending amount of each component so that the pH of the aqueous solution prepared by the above-described pH measurement method has the above-mentioned value.
  • the water-soluble hyaluronic acid gel has appropriate elasticity, high mechanical strength, and shape maintenance while the water-soluble crystalline sugar is present in a dissolved state in the water-soluble hyaluronic acid gel. It becomes possible to impart sex.
  • the amount of water in the gel-forming aqueous solution is not particularly limited as long as the amount of water contained in the water-soluble hyaluronic acid gel is equal to or greater than the amount necessary for the preparation of a saturated aqueous solution of crystalline sugar. For example, about 20 to 1000 parts by mass, preferably about 40 to 400 parts by mass, per 1 part by mass of hyaluronic acid. If the amount of water in the gel-forming aqueous solution is too small, the viscosity of the gel-forming aqueous solution becomes too high, and hyaluronic acid, water-soluble crystalline sugar, water, and an acid different from hyaluronic acid are uniformly distributed in water. It may be difficult to mix. Moreover, when there is too much quantity of water, in order to gelatinize the aqueous solution for gel formation, it will be necessary to remove a lot of water at a next process.
  • the water contained in the aqueous gel-forming solution is used for the purpose of gelling the gel-forming aqueous solution and enhancing the elasticity of the water-soluble hyaluronic acid gel. You may further provide the process of evaporating at least one part.
  • the elasticity of the water-soluble hyaluronic acid gel of the present invention is appropriately set depending on the application.
  • the water-soluble hyaluronic acid gel of the present invention when using the water-soluble hyaluronic acid gel of the present invention very softly, by appropriately adjusting the proportion of each component of the gel-forming aqueous solution, the pH of the aqueous solution in the pH measurement method described above,
  • the water-soluble hyaluronic acid gel of the present invention can be used as it is without evaporating water from the gel-forming aqueous solution.
  • the elasticity, mechanical strength, and shape maintenance property of water-soluble hyaluronic acid gel can also be improved by evaporating a part of water from the gel-forming aqueous solution.
  • the method for evaporating water from the gel-forming aqueous solution is not particularly limited.
  • the gel-forming aqueous solution is heated and dried with a dryer such as a thermostatic bath, or the gel-forming aqueous solution is heated and dried by applying hot air.
  • a dryer such as a thermostatic bath
  • examples thereof include a method and a method of heating and drying a gel-forming aqueous solution on a hot plate.
  • the gel-forming aqueous solution spread to a uniform thickness on a substrate such as a polyethylene terephthalate film is heated and dried (casting method).
  • a water-soluble hyaluronic acid gel sheet can be easily produced.
  • the temperature for evaporating at least a part of the water from the gel-forming aqueous solution is not particularly limited. About 20 to 110 ° C. in atmospheric pressure. Further, the time for evaporating is not particularly limited, but may be about 0.05 to 48 hours within such a temperature range.
  • a water-soluble hyaluronic acid gel sheet can also be obtained by placing an aqueous gel-forming solution in a container such as a tray or vat so that the gel has a predetermined thickness and drying it in a dryer such as a thermostatic bath (batch method). It can be manufactured easily. That is, by putting a gel-forming aqueous solution in a container and evaporating water, for example, a water-soluble hyaluronic acid gel sheet formed in the container can be used as it is as a final product. Processing steps such as cutting can be omitted.
  • water may be added after preparing a water-soluble hyaluronic acid gel having a low water content.
  • a step of adding water can be performed after evaporating water contained in the gel-forming aqueous solution.
  • the water content was suitably controlled by performing a step of adding water after once forming a water-soluble hyaluronic acid gel with a low water content by evaporating most of the water contained in the gel-forming aqueous solution.
  • a water-soluble hyaluronic acid gel can be produced.
  • the step of adding water the above various components can be easily added. When a thermally unstable component or a volatile component is included in the gel, the amount of the component in the gel can be suitably controlled by adding it together with water after the drying step.
  • the content of the water-soluble crystalline sugar, water, and the acid different from hyaluronic acid in the gel-forming aqueous solution is the above when the water-soluble hyaluronic acid gel is used. What is necessary is just to set so that it may become content of.
  • Other methods for producing the water-soluble hyaluronic acid gel of the present invention include, for example, a step of preparing a hyaluronic acid aqueous solution in which the above hyaluronic acid, a water-soluble crystalline sugar, and water are mixed, and the hyaluronic acid aqueous solution. And a step of adding an acid different from hyaluronic acid.
  • a method for adding an acid different from hyaluronic acid is not particularly limited. For example, a method of spraying and applying a solution containing the acid over a hyaluronic acid aqueous solution can be employed.
  • an acid can be uniformly added to the hyaluronic acid aqueous solution spread in a sheet form, which is suitable for obtaining a sheet-like water-soluble hyaluronic acid gel.
  • the amount of acid different from hyaluronic acid, water-soluble crystalline sugar, water, and hyaluronic acid can be the same as described above.
  • the gel production process does not include a drying process, and thus the amount of acid in the gel can be suitably controlled.
  • the component amount in a gel can be suitably controlled by adding a heat unstable component and a volatile component in the process of adding the said acid.
  • a heat unstable component and a volatile component in the process of adding the said acid.
  • an appropriate amount of water such as an emulsion or nanoemulsion
  • moisture can be suitably controlled in the gel.
  • water may be added in the step of adding the acid. Since the gel production process does not include a drying process, a water-soluble hyaluronic acid gel in which the amount of acid and the amount of water are suitably controlled can be produced.
  • a step of preparing a hyaluronic acid aqueous solution by mixing hyaluronic acid, a water-soluble crystalline sugar and water, and drying the hyaluronic acid aqueous solution examples include a method comprising a step and a step of adding an acid different from hyaluronic acid to the dried hyaluronic acid aqueous solution.
  • the amount of acid in the gel can be suitably controlled by adding the acid after the drying step.
  • the amount of components in the gel is suitably controlled by adding thermally unstable components and volatile components in the step of adding the acid after the drying step. can do.
  • water may be added in the step of adding the acid.
  • another method for producing the water-soluble hyaluronic acid gel of the present invention includes a step of preparing an aqueous solution by mixing a water-soluble crystalline sugar, an acid different from hyaluronic acid, and water, and adding hyaluronic acid to the aqueous solution.
  • a method for producing a water-soluble hyaluronic acid gel comprising a step of adding and dissolving.
  • water-soluble hyaluronic acid gel of the present invention for example, when the above-mentioned known ingredients blended in cosmetics, foods, quasi drugs, pharmaceuticals, and medical devices are further blended, water-soluble hyaluronic acid These components may be added after the gel is prepared.
  • water-soluble hyaluronic acid gel of the present invention is produced as a lump, for example, an aqueous solution of hyaluronic acid in which the above hyaluronic acid, water-soluble crystalline sugar, and water are mixed with an acid different from hyaluronic acid.
  • the content of hyaluronic acid, water-soluble crystalline sugar, and water in the aqueous hyaluronic acid solution and the content of an acid different from the added hyaluronic acid are: What is necessary is just to set so that it may become said content when it is set as an acid gel.
  • Hyaluronic acid (1.2 million): Sodium hyaluronate, trade name “Hyaluronic sun HA-LQ” manufactured by Kewpie Co., Ltd. (product notation: molecular weight 85 to 1.6 million; average molecular weight 1.2 million) hyaluronic acid (2.3 million): sodium hyaluronate, Product name "HYALURONSAN HA-LQSH” manufactured by Kewpie Co., Ltd.
  • Glucose D (+)-glucose (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Fructose D (-)-fructose (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Xylitol Xylitol (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Sorbitol D (+)-sorbitol (first grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Trehalose Trehalose dihydrate (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Maltose D (+)-maltose monohydrate (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Lactose Lactose monohydrate (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Sucrose Sucrose (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • ⁇ -cyclodextrin ⁇ -cyclodextrin (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Phosphoric acid phosphoric acid (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Sulfuric acid Sulfuric acid (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Vitamin C L (+)-ascorbic acid (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Citric acid Citric acid monohydrate (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Lactic acid DL-lactic acid (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Tartaric acid D (-)-tartaric acid (first grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Gluconolactone Glucono- ⁇ -lactone manufactured by Wako Pure Chemical Industries, Ltd.
  • Lactopionic acid Lactopionic acid (first grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Aspartic acid DL-aspartic acid (special grade) manufactured by Wako Pure Chemical Industries, Ltd.
  • Hyaluronic acid sodium hyaluronate
  • phosphoric acid sodium hyaluronate
  • distilled water for pH measurement
  • Table 2 A 200 mL hyaluronic acid aqueous solution for pH measurement containing 1 g of acid was obtained.
  • the pH of the obtained aqueous hyaluronic acid solution was measured using TwinpH (B-212) manufactured by Horiba, Ltd. The results are shown in Table 2.
  • the saturated solubility of various sugars in 100 g of water at 20 ° C. or 25 ° C. under 1 atm is as shown in Table 1.
  • the saturation solubility of various sugars in 100 g of water at 25 ° C. is larger than the saturation solubility at 20 ° C. That is, when the amount of sugar is fixed, the amount of water necessary for preparing a saturated aqueous solution of sugar at 25 ° C. is less than the amount of water required for preparing a saturated aqueous solution of sugar at 20 ° C.
  • hyaluronic acid sodium hyaluronate
  • sugar sugar
  • distilled water for preparation of hyaluronic acid aqueous solution
  • a propeller-type rotary stirrer so that the mixing ratio (parts by mass) shown in Table 2 was obtained.
  • aqueous solution of hyaluronic acid was prepared.
  • this aqueous solution is placed in a plastic petri dish (diameter 9 cm) to a uniform thickness and stored at 70 ° C. for 24 hours to evaporate most of the distilled water to obtain a high-viscosity hyaluronic acid solution. It was.
  • the gel sheets obtained in Examples 1 to 8 were stored at 20 ° C. for 48 hours, and the gels were observed, but all were colorless and transparent gels, and no glucose crystals were observed.
  • Hyaluronic acid sodium hyaluronate
  • phosphoric acid phosphoric acid
  • distilled water for pH measurement
  • Example 3 Hyaluronic acid (sodium hyaluronate), phosphoric acid, and distilled water (for pH measurement) were mixed using a propeller-type rotary stirrer so that the blending ratio (parts by mass) shown in Table 3 was obtained.
  • a 200 mL hyaluronic acid aqueous solution for pH measurement containing 1 g of acid was obtained.
  • the pH of the obtained aqueous hyaluronic acid solution was measured using TwinpH (B-212) manufactured by Horiba, Ltd. The results are shown in Table 3.
  • hyaluronic acid sodium hyaluronate
  • sugar sugar
  • distilled water for preparation of hyaluronic acid aqueous solution
  • Example 19 to 25 Reference Example 1, Comparative Example 2
  • the water-soluble hyaluronic acid gel sheets of Examples 19 to 25 and Reference Example 1 were used in the same manner as Examples 9 to 18 except that the water content in the gel was the ratio (parts by mass) shown in Table 4. Obtained.
  • Comparative Example 2 sheets were obtained in the same manner as in Examples 19 to 25 except that the water content in the gel was substantially 0 part by mass.
  • the properties of the water-soluble hyaluronic acid gel sheets obtained in Examples 19 to 25 and Reference Example 1 were evaluated in the same manner as in Examples 9 to 18.
  • Examples 26 to 28 A mixed solution of glucose, distilled water (the amount of water in the gel), and phosphoric acid solution was prepared so as to achieve the blending ratio (parts by mass) shown in Table 5, and placed in a plastic petri dish (diameter 9 cm). Hyaluronic acid was added to this aqueous solution, stirred with a spatula, and stored at room temperature for 48 hours to obtain a water-soluble hyaluronic acid gel sheet having a thickness of about 2 mm. Next, the properties of the water-soluble hyaluronic acid gel sheets obtained in Examples 26 to 28 were evaluated in the same manner as in Examples 9 to 18. The results are shown in Table 5. Next, the gel sheets obtained in Examples 26 to 28 were stored at 20 ° C. for 48 hours, and the gels were observed. All were colorless and transparent gels, and no glucose crystals were observed.
  • Example 29 to 32 Examples 1 to 8 except that hyaluronic acid (molecular weight: 100,000 and 1,200,000) was used instead of hyaluronic acid (molecular weight: 2.3 million) and the mixing ratios (parts by mass) shown in Table 6 were obtained. Similarly, a water-soluble hyaluronic acid gel sheet was obtained. Next, the properties of the water-soluble hyaluronic acid gel sheets obtained in Examples 29 to 32 were evaluated in the same manner as in Examples 1 to 8. Further, in the same manner as in Examples 1 to 8, the pH measurement hyaluronic acid aqueous solution obtained in Examples 29 to 32 was prepared, and the pH of the aqueous solution was measured. These results are shown in Table 6. Next, the gel sheets obtained in Examples 29 to 32 were stored at 20 ° C. for 48 hours, and the gels were observed. All were colorless and transparent gels, and no glucose crystals were observed.
  • Examples 33 to 40 In place of phosphoric acid, various acids (sulfuric acid, citric acid, lactic acid, tartaric acid, gluconolactone, lactopionic acid, vitamin C, aspartic acid) were used and mixed so as to have the blending ratio (parts by mass) shown in Table 7. Except that, water-soluble hyaluronic acid gel sheets were obtained in the same manner as in Examples 1-8. Next, the properties of the water-soluble hyaluronic acid gel sheets obtained in Examples 33 to 40 were evaluated in the same manner as in Examples 1 to 8. Further, the pH of the hyaluronic acid aqueous solution for pH measurement obtained in Examples 33 to 40 was measured in the same manner as in Examples 1 to 8. These results are shown in Table 7. Next, the gel sheets obtained in Examples 33 to 40 were stored at 20 ° C. for 48 hours, and the gels were observed. All were colorless and transparent gels, and no glucose crystals were observed.
  • Examples 41 to 57, Reference Examples 2 to 6, Comparative Examples 3 and 4 Using various sugars (fructose, xylitol, sorbitol, trehalose, maltose, lactose, sucrose, ⁇ -cyclodextrin) instead of glucose, hyaluronic acid Sodium hyaluronate), sugar, and distilled water (for preparing a hyaluronic acid aqueous solution) were mixed using a propeller-type rotary stirrer to prepare a hyaluronic acid aqueous solution.
  • sugars fructose, xylitol, sorbitol, trehalose, maltose, lactose, sucrose, ⁇ -cyclodextrin
  • sugar, and distilled water for preparing a hyaluronic acid aqueous solution
  • distilled water for preparing a hyaluronic acid aqueous solution
  • this hyaluronic acid aqueous solution is placed in a plastic petri dish (diameter 9 cm) to a uniform thickness and stored at 70 ° C. for 6 to 24 hours, and distilled water is evaporated to obtain a high-viscosity hyaluronic acid solution.
  • distilled water is evaporated to obtain a high-viscosity hyaluronic acid solution.
  • each of the high-viscosity hyaluronic acid solution was uniformly mixed with distilled water and phosphoric acid in an amount corresponding to the amount of water in the gel described in Table 8.
  • a water-soluble hyaluronic acid gel is preferably obtained by using various sugars other than glucose (fructose, xylitol, sorbitol, trehalose, maltose, lactose, sucrose, ⁇ -cyclodextrin).
  • xylitol, sorbitol, or a combination of glucose and fructose contains 20% by mass of water necessary for preparation of a saturated aqueous solution of sugar.
  • xylitol, sorbitol, or a combination of glucose and fructose contains 20% by mass of water necessary for preparation of a saturated aqueous solution of sugar.
  • Example 48 As a result, in all four volunteers, by treating the water-soluble hyaluronic acid gel sheet obtained in Example 48, a clear skin moist feeling was confirmed as compared with the case of no treatment. Moreover, since the water-soluble hyaluronic acid gel sheet has appropriate elasticity and excellent shape maintenance, it is easy to handle and does not cause problems such as skin irritation.
  • Example 58 to 59 A mixed solution of xylitol, water in the gel (distilled water), and citric acid was prepared so as to have a blending ratio (parts by mass) shown in Table 9, and placed in a plastic petri dish (diameter 9 cm). Hyaluronic acid was added to this aqueous solution, stirred with a spatula, and stored at room temperature for 48 hours to obtain a water-soluble hyaluronic acid gel sheet having a thickness of about 5 mm. Next, the properties of the hyaluronic acid gel sheets obtained in Examples 58 to 59 were evaluated in the same manner as in Examples 9 to 18. The results are shown in Table 9. Next, the gel sheets obtained in Examples 58 to 59 were stored for 48 hours at 20 ° C., and the gels were observed. All were colorless and transparent gels, and no xylitol crystals were observed.
  • the obtained water-soluble hyaluronic acid gel sheet of Example 58 was cut into about 2 cm ⁇ 2 cm and sampled by two volunteers. As a result, both two volunteers chewed while feeling an elastic texture like gummy, and the gel dissolved in the oral cavity over time.
  • the obtained water-soluble hyaluronic acid gel sheet of Example 59 was cut into about 2 cm ⁇ 2 cm and sampled by two volunteers. As a result, both volunteers felt a soft, moderately elastic texture similar to that of an oral nutritional supplement jelly and swallowed the throat as it was.
  • Examples 60 to 65 Using xylitol instead of glucose in Examples 1 to 8, hyaluronic acid (sodium hyaluronate), xylitol, and distilled water (preparation of aqueous hyaluronic acid solution) so as to achieve the blending ratio (parts by mass) shown in Table 10 Were mixed using a propeller-type rotary stirrer to prepare a hyaluronic acid aqueous solution. Next, this hyaluronic acid aqueous solution is placed in a plastic petri dish (diameter 9 cm) to a uniform thickness and stored at 70 ° C.
  • each of the high-viscosity hyaluronic acid solutions was uniformly mixed with distilled water and phosphoric acid in an amount corresponding to the amount of water in the gel shown in Table 10. It was uniformly coated on the surface of the viscous hyaluronic acid solution and stored at room temperature for 12 hours to obtain a water-soluble hyaluronic acid gel sheet having a thickness of about 2 mm.
  • the properties of the hyaluronic acid gel sheets obtained in Examples 60 to 65 were evaluated in the same manner as in Examples 1 to 8. Further, in the same manner as in Examples 1 to 8, the pH of the aqueous hyaluronic acid solution for pH measurement obtained in Examples 60 to 65 was measured. These results are shown in Table 10. Next, the gel sheets obtained in Examples 60 to 65 were stored at 20 ° C. for 48 hours, and the gels were observed. All were colorless and transparent gels, and no xylitol crystals were observed.
  • Examples 66 to 70 Using xylitol instead of glucose in Examples 9 to 18, hyaluronic acid (sodium hyaluronate), xylitol, and distilled water (preparation of aqueous hyaluronic acid solution) so as to achieve the blending ratio (parts by mass) shown in Table 11 Were mixed using a propeller-type rotary stirrer to prepare a hyaluronic acid aqueous solution. Next, this hyaluronic acid aqueous solution is placed in a plastic petri dish (diameter 9 cm) to a uniform thickness and stored at 70 ° C.
  • Example 66 to 70 pH of the hyaluronic acid aqueous solution for pH measurement obtained in Examples 66 to 70 was measured in the same manner as in Examples 9 to 18. These results are shown in Table 11. Next, the gel sheets obtained in Examples 66 to 70 were stored at 20 ° C. for 48 hours, and the gels were observed. All were colorless and transparent gels, and no xylitol crystals were observed.
  • Examples 71 and 72, Reference Examples 7 and 8 As in Examples 41 to 57, using xylitol or sorbitol, hyaluronic acid (sodium hyaluronate), xylitol or sorbitol, and distilled water (hyaluronic acid) so as to achieve the blending ratio (parts by mass) shown in Table 12 Aqueous solution) was mixed using a propeller-type rotary stirrer to prepare a hyaluronic acid aqueous solution. Next, this hyaluronic acid aqueous solution is placed in a plastic petri dish (diameter 9 cm) to a uniform thickness and stored at 70 ° C.
  • hyaluronic acid sodium hyaluronate
  • xylitol or sorbitol xylitol or sorbitol
  • distilled water hyaluronic acid
  • Example 43, Example 44, Example 45, Example 46, Example 71, Example 72, Reference Example 7 and Reference Example 8 were stored for 48 hours at 5 ° C., respectively. The gel was observed.
  • the water-soluble hyaluronic acid gels of Example 43, Example 44, Reference Example 7 and Reference Example 8 were colorless and transparent gels, and no xylitol solid was observed in the gels.
  • the water-soluble hyaluronic acid gels of Example 45, Example 46, Example 71, and Example 72 were hard sheets on which sorbitol crystals were precipitated.

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Abstract

La présente invention concerne un gel d'acide hyaluronique hydrosoluble dans lequel du sucre cristallin hydrosoluble est présent dans un état dissous. Le gel d'acide hyaluronique hydrosoluble contient de l'acide hyaluronique, du sucre cristallin hydrosoluble, de l'eau, et un acide autre que l'acide hyaluronique. La teneur en eau du gel d'acide hyaluronique hydrosoluble représente 50 % en masse ou plus de la quantité nécessaire pour préparer une solution aqueuse saturée du sucre cristallin hydrosoluble.
PCT/JP2016/051670 2015-01-29 2016-01-21 Gel d'acide hyaluronique hydrosoluble et son procédé de production Ceased WO2016121611A1 (fr)

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JP2019037608A (ja) * 2017-08-28 2019-03-14 大日精化工業株式会社 柔軟性成形体の製造方法及び柔軟性成形体
JP2020531499A (ja) * 2017-08-21 2020-11-05 ジボダン エス エー 有機化合物におけるまたは関する改善
WO2020262381A1 (fr) * 2019-06-26 2020-12-30 株式会社リタファーマ Gel soluble dans l'eau d'acide hyaluronique et procédé de production associé
JP2025107169A (ja) * 2024-01-05 2025-07-17 プサン ナショナル ユニバーシティ インダストリー－ユニバーシティ コーポレーション ファウンデーション 光開始剤、それを含むバイオインク及びハイドロゲルの製造方法

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BR112021024266A2 (pt) * 2019-06-14 2022-01-11 Procter & Gamble Composições para tratamento bucal sem enxágue
CN114040742A (zh) 2019-06-14 2022-02-11 宝洁公司 免洗型口腔护理组合物
JP2022538521A (ja) 2019-06-14 2022-09-05 ザ プロクター アンド ギャンブル カンパニー 洗い流さない口腔ケア組成物
WO2020248239A1 (fr) * 2019-06-14 2020-12-17 The Procter & Gamble Company Compositions de soins bucco-dentaires sans rinçage

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WO2009084234A1 (fr) * 2007-12-27 2009-07-09 Kao Corporation Préparation de feuille devant être appliquée sur le corps humain
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JP2020531499A (ja) * 2017-08-21 2020-11-05 ジボダン エス エー 有機化合物におけるまたは関する改善
JP7186767B2 (ja) 2017-08-21 2022-12-09 ジボダン エス エー 有機化合物におけるまたは関する改善
JP2019037608A (ja) * 2017-08-28 2019-03-14 大日精化工業株式会社 柔軟性成形体の製造方法及び柔軟性成形体
WO2020262381A1 (fr) * 2019-06-26 2020-12-30 株式会社リタファーマ Gel soluble dans l'eau d'acide hyaluronique et procédé de production associé
JP6836820B1 (ja) * 2019-06-26 2021-03-03 株式会社リタファーマ 水溶性ヒアルロン酸ゲル及びその製造方法
JP2025107169A (ja) * 2024-01-05 2025-07-17 プサン ナショナル ユニバーシティ インダストリー－ユニバーシティ コーポレーション ファウンデーション 光開始剤、それを含むバイオインク及びハイドロゲルの製造方法

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