JPWO2016121611A1 - Water-soluble hyaluronic acid gel and method for producing the same - Google Patents

Abstract

Provided is a water-soluble hyaluronic acid gel in which a water-soluble crystalline sugar is present in a dissolved state. Hyaluronic acid, a water-soluble crystalline sugar, water, and a water-soluble hyaluronic acid gel containing an acid different from hyaluronic acid, wherein the water content is used to prepare a saturated aqueous solution of the water-soluble crystalline sugar. A water-soluble hyaluronic acid gel that is 50% by mass or more of the required amount.

Description

  The present invention relates to a water-soluble hyaluronic acid gel and a method for producing the same.

  In recent years, hyaluronic acid, which is excellent in biocompatibility and has many effective actions including a moisturizing action, has attracted attention in the beauty field, the medical field, the food field, and the like. Hyaluronic acid is a linear high-molecular polysaccharide in which β-D-N-acetylglucosamine and β-D-glucuronic acid are alternately bound, and is distributed in the connective tissue of mammals. 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.

  Conventionally, gel compositions containing a polymer material have been used in the beauty field, the medical field, the food field, and the like. In particular, 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. For this reason, the use of 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. Furthermore, in such a gel composition, 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.

  For example, 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 of hyaluronic acid. Has been. Furthermore, 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.

  However, as disclosed in Patent Documents 1 to 3, in many of the hyaluronic acid gels in which hyaluronic acid is used alone as a gel-forming component, hyaluronic acid is chemically modified. There is a problem that the characteristic as a natural material is lost.

  In addition, for example, in 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. Has disclosed a method for producing a hyaluronic acid gel, characterized by forming a hyaluronic acid gel. However, since the hyaluronic acid gel obtained in Patent Document 4 is hardly soluble in water, it is difficult for hyaluronic acid to dissolve in water. For this reason, 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.

  For example, 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. However, 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. In the beauty field, the medical field, and the like, there is an advantage that the gel composition is easily applied to the skin by forming a sheet. However, 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.

  Furthermore, Patent Document 6 discloses a hyaluronic acid gel containing 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.

Japanese National Patent Publication No. 11-509256 JP-A-8-143604 International Publication No. 2006-051950 Pamphlet International Publication No. 01/57093 Pamphlet JP-A-5-58881 JP 2014-24828 A

  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. As a result, in the water-soluble hyaluronic acid gel containing hyaluronic acid, water-soluble crystalline sugar, water, and an acid different from hyaluronic acid, the water content can be adjusted to prepare a saturated aqueous solution of water-soluble crystalline sugar. By setting the required amount to 50% by mass or more, even when hyaluronic acid is contained alone as a gel-forming component (that is, when it does not substantially contain other gel-forming components), hyaluronic acid is gelled. It has been found that 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. Further, such 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.

That is, this invention provides the invention of the aspect hung up below.
Item 1. 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.
Item 3. Item 3. 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 a sheet form.
Item 6. 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. Cosmetics 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. A medical device composition using the water-soluble hyaluronic acid gel according to any one of Items 1 to 5.
Item 11. The 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. The method for producing a water-soluble hyaluronic acid gel according to Item 11 or 12, further comprising a step of adding water after evaporating water contained in the gel-forming aqueous solution.
Item 14. The 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. The 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. The 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.

  According to the present invention, there is provided 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. In the water-soluble hyaluronic acid gel of the present invention, hyaluronic acid is not chemically modified, and natural materials can be used. Furthermore, according to this invention, 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. Hereinafter, 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. As will be described later, 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. Can be produced by adjusting the content of water in the water to 50% by mass or more of the amount required for the preparation of a saturated aqueous solution of a water-soluble crystalline sugar. As will be described later, the water content may be adjusted by, for example, a method of evaporating water from the gel forming aqueous solution.

  In the water-soluble hyaluronic acid gel of the present invention, hyaluronic acid is included as a gel-forming component. In the water-soluble hyaluronic acid gel of the present invention, 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. Other 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, carboxymethyl cellulose Na, hydroxypropyl cellulose, polyvinyl alcohol, carboxyvinyl polymer, starch / acrylate graft copolymer, methyl vinyl ether / maleic anhydride copolymer, and the like. . However, when other gel-forming components are included, from the viewpoint of utilizing the characteristics of the water-soluble hyaluronic acid gel of the present invention, 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. When not blended, the amount is preferably not more than the amount at which no gel is formed. For example, the content of the other gel-forming component varies depending on the type of the other gelling component, but is 5% by mass or less, preferably 2.5% by mass or less, more preferably in the water-soluble hyaluronic acid gel of the present invention. Is 1% by mass or less, more preferably 0.5% by mass or less, and still more preferably 0.1% by mass or less.

  In the present invention, “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. In this invention, 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. As the hyaluronic acid, one having a single molecular weight may be used, or plural kinds of molecular weights may be mixed and used. In the present invention, “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. Moreover, high mechanical strength means the intensity | strength of the grade which a sheet | seat does not fracture | rupture, for example, even if it picks up and lifts the sheet-like water-soluble hyaluronic acid gel of thickness about 2 mm with a finger. In addition, 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., or those prepared by fermentation using microorganisms such as Streptococcus can be preferably used. In the present invention, 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.

  Specific examples of chemically modified hyaluronic acid 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.

  In the water-soluble hyaluronic acid gel of the present invention, 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. In addition, when 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 a crystalline sugar as a sugar alone or as a hydrate. Crystalline sugars ranging from monosaccharide, disaccharide to decasaccharide are used. Can be used. Specific examples of the water-soluble crystalline sugar include glucose, fructose, xylitol, sorbitol, trehalose, lactose, maltose, sucrose, raffinose, oligosaccharide (fructo-oligosaccharide, galacto-oligosaccharide, mannan-oligosaccharide, whey oligosaccharide, etc.), Examples include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. One type of water-soluble crystalline sugar may be used alone, or two or more types may be used in combination.

  In the present invention, 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. Preferably it is about 0.1-400 mass parts with respect to 1 mass part of hyaluronic acid, More preferably, about 1-200 mass parts is mentioned. In addition, when multiple types of water-soluble crystalline sugar are contained in water-soluble hyaluronic acid gel, 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. Examples of 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. Examples of 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; glycolic acid, citric acid, lactic acid, pyruvic acid, malic acid, tartaric acid, salicylic acid and other oxycarboxylic acids; glucono-δ-lactone, lactopionic acid and other polyhydroxy acids; glutamic acid, aspartic acid and other acidic amino acids; (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 Examples include acids, salicylic acid, ethyl ascorbate, ascorbic acid glucoside, glucono-δ-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 still more preferably about 2.9 to 4.6. It is preferable to adjust so that.

(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.

  When the pH is measured by dissolving the water-soluble hyaluronic acid gel in water as it is, it is difficult to measure the pH suitable for the present invention depending on the type and amount of the nonionic component contained in the water-soluble hyaluronic acid gel. Therefore, it is desirable to measure the pH of the aqueous solution prepared by the measurement method as described above. For example, when water-soluble hyaluronic acid gel contains a large amount of non-ionic sugar, etc., gelation of hyaluronic acid or crystalline sugar exists in dissolved state in water-soluble hyaluronic acid gel It is difficult to accurately measure the desired pH. For this reason, in this invention, the method of melt | dissolving only the ionic component except water among the components mix | blended with a hyaluronic acid gel in water, and measuring the pH of the obtained aqueous solution is used.

  In addition, 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 the preparation of 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. In the present invention, 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. For example, 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. Therefore, 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. Is possible. When the water-soluble hyaluronic acid gel of the present invention contains a plurality of types of water-soluble crystalline sugars, 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. In the water-soluble hyaluronic acid gel, the crystalline sugar can be present in a dissolved state. However, depending on the type of water-soluble crystalline sugar, 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. It may be possible for the crystalline sugar to be present in a dissolved state in the water-soluble hyaluronic acid gel while functioning as a component. However, in the present invention, by setting 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). When the water-soluble hyaluronic acid gel of the present invention contains a water-soluble organic solvent, 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. 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. In addition, 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. Further, for example, when the molecular weight of hyaluronic acid in the water-soluble hyaluronic acid gel is increased, 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. Furthermore, for example, 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. There is.

  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 μm, 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 depending on 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.

  For example, when 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 for example, about 0.01 to 10 mm, preferably about 0.05 to 5 mm. For example, when the water-soluble hyaluronic acid gel 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.

  Since 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 skin and the like in the beauty field, the medical field, and the like. 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.

  When the water-soluble hyaluronic acid gel of the present invention is 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. 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. Moreover, 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.

  Specific examples of the whitening component include vitamin C or a derivative thereof, 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, lipid (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.

  Moreover, you may mix | blend a polyhydric alcohol with the water-soluble hyaluronic acid gel of this 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, polyethylene glycol 400, Triethylene glycol 600,1,3- propanediol, 1,2-pentanediol, 1,2-hexanediol and the like. Among these, glycerin and butanediol are particularly preferable. A polyhydric alcohol may be used individually by 1 type, and may be used in combination of 2 or more type.

  Since 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. When 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. When used as a pack agent, 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. In addition, when 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.

  Moreover, since the water-soluble hyaluronic acid gel of the present invention has water solubility, the hyaluronic acid is likely to be dissolved in water. 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.

  Furthermore, since 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 in medical devices for protecting wound sites and pressure ulcer sites. For example, 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. Moreover, when using for such a use, healing promotion components, such as epidermal growth factor, and an antimicrobial component can also be mix | blended in water-soluble hyaluronic acid gel.

  The water-soluble hyaluronic acid gel of the present invention may be used on a support. 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 like for the purpose of holding the gel on the skin.

  The water-soluble hyaluronic acid gel of the present invention can be used alone as a product as it is. In addition, 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. For example, the gel may be fixed and used.

  In addition, as described above, 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.

  When using the water-soluble hyaluronic acid gel of this invention as a food composition, the well-known component mix | blended with a food composition can further be mix | blended. Examples of such components include sweeteners, fragrances, colorants, acidulants, antioxidants, emulsifiers, preservatives, stabilizers, and the like. Moreover, when using the water-soluble hyaluronic acid gel of this invention as an oral pharmaceutical composition, the well-known component mix | blended with an oral pharmaceutical composition can further be mix | blended. Examples of such components include medicinal ingredients, fragrances, colorants, acidulants, antioxidants, emulsifiers, preservatives, stabilizers, and the like. In a food composition or an oral pharmaceutical composition, these components may be used alone or in combination of two or more.

  Since 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.

  When the 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. For example, 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. For example, 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. In the method for producing the water-soluble hyaluronic acid gel of the present invention, the mixing order of each component is not particularly limited. Moreover, the mixing method of each component is not particularly limited, and may be stirred using, for example, a stirrer.

  In 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. By setting such a pH, 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. With respect to 1 part by mass of hyaluronic acid, for example, about 20 to 1000 parts by mass, preferably about 40 to 400 parts by mass can be mentioned. 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.

  In the method for producing a water-soluble hyaluronic acid gel of the present invention, 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. Therefore, for example, 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. Moreover, 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. For example, 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. Examples thereof include a method and a method of heating and drying a gel-forming aqueous solution on a hot plate. For example, when the water-soluble hyaluronic acid gel of the present invention is formed into a sheet, 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.

  For example, when the water-soluble hyaluronic acid gel of the present invention is formed into a sheet having a thickness of about 0.01 to 10 mm, the temperature at which at least a part of water is evaporated from the gel-forming aqueous solution is not particularly limited, but is large. In atmospheric pressure, about 20-110 degreeC is mentioned. Further, the time for evaporating is not particularly limited, but may be about 0.05 to 48 hours in such a temperature range.

  In addition, 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.

  In the method for producing a water-soluble hyaluronic acid gel of the present invention, water may be added after preparing a water-soluble hyaluronic acid gel having a low water content. For example, after evaporating water contained in the gel-forming aqueous solution, a step of adding water can be performed. In particular, 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. In 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.

  In the method for producing the water-soluble hyaluronic acid gel of the present invention, 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. According to these addition methods, 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. Even when this production method is adopted, the amount of acid different from hyaluronic acid, water-soluble crystalline sugar, water, and hyaluronic acid can be the same as described above. In the case of using a heat labile acid or a volatile acid, the gel production process does not include a drying process, and thus the amount of acid in the gel can be suitably controlled. Moreover, also when the said various components are included in a gel, 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. In addition, when an appropriate amount of water is required, such as an emulsion or nanoemulsion, moisture can be suitably controlled in the gel. Furthermore, 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.

  Further, as another method for producing the water-soluble hyaluronic acid gel of the present invention, 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. In the case of using a heat labile acid or a volatile acid, the amount of acid in the gel can be suitably controlled by adding the acid after the drying step. In addition, when the above-mentioned various components are included in the gel, 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. Furthermore, water may be added in the step of adding the acid. Producing a water-soluble hyaluronic acid gel in which the amount of acid and the amount of water are suitably controlled by once evaporating most of the water contained in the aqueous solution of hyaluronic acid and then adding water together with the acid. Can do.

  Furthermore, 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.

  Furthermore, in the method for producing the 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.

  When the 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. You may manufacture a block-shaped water-soluble hyaluronic acid gel by immersing in the solution to contain.

  In these water-soluble hyaluronic acid gel production methods, 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.

  Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples. However, the present invention is not limited to the examples. The reagents used in the following examples and comparative examples are as follows. Moreover, the unit of the composition in each table | surface is a mass part.

<Reagent>
Hyaluronic acid (1.2 million): Sodium hyaluronate, trade name “Hyaluronic sun HA-LQ” (product notation: molecular weight 85-1.6 million; average molecular weight 1.2 million) hyaluronic acid (2.3 million): sodium hyaluronate, Product name “HYALURONSAN HA-LQSH” (product display: molecular weight 1.6 million to 2.9 million, average molecular weight 2.3 million)
Hyaluronic acid (100,000): sodium hyaluronate, trade name “Hyaluronic acid FCH-SU” manufactured by Kikkoman Biochemifa Co., Ltd. (product display: average molecular weight 50,000 to 110,000)
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.
γ-cyclodextrin: γ-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-δ-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.

[Examples 1 to 8 and Comparative Example 1]
Hyaluronic acid (sodium hyaluronate), phosphoric acid, and distilled water (for pH measurement) are mixed using a propeller-type rotary stirrer so that the blending ratio (parts by mass) shown in Table 2 is obtained. A 200 mL hyaluronic acid aqueous solution for pH measurement containing 1 g of acid was obtained. The pH of the obtained hyaluronic acid aqueous 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.

  Separately, hyaluronic acid (sodium hyaluronate), sugar (glucose), and distilled water (for preparation of hyaluronic acid aqueous solution) were mixed with a propeller-type rotary stirrer so that the mixing ratio (parts by mass) shown in Table 2 was obtained. And mixed to prepare an aqueous solution of hyaluronic acid. Next, 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 weight of this high-viscosity hyaluronic acid solution was measured to calculate the amount of water contained, and the amount of water in the gel shown in Table 2 (here, the amount of water necessary for the preparation of a saturated aqueous solution of glucose at 25 ° C. 50% by weight) of distilled water and phosphoric acid are uniformly mixed, uniformly applied to the surface of this high-viscosity hyaluronic acid solution, stored at room temperature for 12 hours, and a water-soluble hyaluronic acid gel sheet having a thickness of about 2 mm. Got. In Comparative Example 1, sheets were obtained in the same manner as in Examples 1 to 8, except that phosphoric acid was not mixed. However, in Comparative Example 1, a gel was not obtained even when distilled water was added, and a high-viscosity solution was obtained that was pulled when the sheet was pulled with a finger.

  Next, 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.

<Property evaluation of hyaluronic acid gel sheet>
The properties of the hyaluronic acid gel sheets obtained in Examples 1 to 8 and the sheet-like high viscosity liquid obtained in Comparative Example 1 were evaluated according to the following criteria. The results are shown in Table 2.
1: colorless and transparent gel having moderate elasticity and high shape maintainability 2: colorless and transparent gel soft and slightly high shape maintainability 3: colorless and transparent, fairly soft and somewhat low shape maintainability Gel 4: having a clear and colorless, high viscosity liquid 5: hard sheet on which sugar crystals are precipitated

  From the results shown in Table 2, in Examples 1 to 8 using hyaluronic acid, sugar (glucose), an acid different from hyaluronic acid, and water, a water-soluble hyaluronic acid gel sheet in which glucose crystals are not precipitated is obtained. It became clear. In the preparation process of the water-soluble hyaluronic acid gel sheet, the pH of the aqueous hyaluronic acid solution obtained by mixing hyaluronic acid, an acid different from hyaluronic acid, and distilled water according to the pH measurement method described above is 1.9 to 4.6. When it is set in the range, it has become clear that it can be particularly suitably applied to skin and the like as a cosmetic, pharmaceutical composition, or medical device composition from the viewpoint of elasticity and shape maintenance. On the other hand, in the case of Comparative Example 1 in which an acid different from hyaluronic acid was not used, a gel was not obtained, and a high-viscosity liquid was obtained that was pulled when the sheet was pulled with a finger.

[Examples 9 to 18]
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 hyaluronic acid aqueous solution was measured using TwinpH (B-212) manufactured by Horiba, Ltd. The results are shown in Table 3.

  Separately, hyaluronic acid (sodium hyaluronate), sugar (glucose), and distilled water (for preparation of hyaluronic acid aqueous solution) were mixed with a propeller-type rotary stirrer so that the mixing ratio (parts by mass) shown in Table 3 was obtained. And mixed to prepare an aqueous solution of hyaluronic acid. 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. for 24 hours, and most of the distilled water is evaporated to obtain a high-viscosity hyaluronic acid solution. Got. By measuring the weight of the high-viscosity hyaluronic acid solution and calculating the amount of water to be contained, respectively, distilled water and phosphoric acid in an amount corresponding to the amount of water in the gel shown in Table 3 were uniformly mixed. 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. Next, the water-soluble hyaluronic acid gel sheets obtained in Examples 9 to 18 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. It was.

<Evaluation of properties of water-soluble hyaluronic acid gel sheet>
The properties of the water-soluble hyaluronic acid gel sheets obtained in Examples 9 to 18 were evaluated according to the following criteria. The results are shown in Table 3.
A: It is a colorless and transparent gel, has high shape maintainability, moderate elasticity, and sufficient mechanical strength. The gel does not break when lifted by hand.
B: A colorless and transparent gel that has moderate elasticity, but is inferior to A in shape maintenance and mechanical strength, but does not break even when the gel is lifted by hand.
C: A colorless and transparent gel having moderate elasticity but weak in shape maintenance and inferior in mechanical strength to B, but does not break even when the gel is lifted by hand.
D: Hard sheet on which sugar crystals are deposited

  From the results shown in Table 3, even when sugar (glucose) is blended in the range of 5 to 400 parts by mass with respect to 1 part by mass of hyaluronic acid, the amount of 50 necessary for the preparation of a saturated aqueous solution of sugar is obtained. It has been clarified that a water-soluble hyaluronic acid gel sheet containing crystalline sugar in a dissolved state can be obtained by containing water in an amount of not less than mass%.

[Examples 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. In Comparative Example 2, sheets were obtained in the same manner as in Examples 19 to 25 except that the moisture content in the gel was substantially 0 part by mass. Next, in the same manner as in Examples 9 to 18, the properties of the water-soluble hyaluronic acid gel sheets obtained in Examples 19 to 25 and Reference Example 1 were evaluated. Moreover, it carried out similarly to Examples 9-18, the hyaluronic acid aqueous solution for pH measurement obtained in Examples 19-25, Reference Example 1, and Comparative Example 2 was prepared, and pH of the said aqueous solution was measured. These results are shown in Table 4.

  Next, the water-soluble hyaluronic acid gel sheets obtained in Examples 19 to 25 and Reference Example 1 were stored for 48 hours under the condition of 20 ° C., and the gels were observed. Was not observed.

  From the results shown in Table 4, good mechanical properties in the range of 50% by mass or more of the amount of water necessary for the preparation of a saturated aqueous solution of glucose at 25 ° C. and 400 parts by mass or less with respect to 1 part by mass of hyaluronic acid. It turns out that the water-soluble hyaluronic acid gel which has intensity | strength is obtained. In addition, as shown in Reference Example 1, when glucose is used as the sugar, 20 ° C. may be used even when only 20% by mass of water necessary for preparation of a saturated aqueous solution of glucose is contained at 25 ° C. Below, a water-soluble hyaluronic acid gel sheet containing crystalline sugar in a dissolved state was obtained. On the other hand, in Comparative Example 2 in which moisture was not substantially contained in the gel, when stored for 48 hours under the condition of 20 ° C., glucose crystals were precipitated to form a hard sheet.

[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 for 48 hours under the condition of 20 ° C., and the gels were observed, but all were colorless and transparent gels, and no glucose crystals were observed.

  From the results shown in Table 5, an aqueous solution containing the same amount of each component as glucose, phosphoric acid, and distilled water in a preset gel was prepared, and hyaluronic acid was added to this aqueous solution to prepare a gel. Even in the same manner as in Example 21, Example 23, and Example 25, it can be seen that a good water-soluble hyaluronic acid gel in which glucose crystals are not precipitated can be obtained.

[Examples 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 ratio (parts by mass) shown in Table 6 was 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. Moreover, it carried out similarly to Examples 1-8, and prepared the hyaluronic acid aqueous solution for pH measurement obtained in Examples 29-32, and measured the pH of the said aqueous solution. These results are shown in Table 6. Next, the gel sheets obtained in Examples 29 to 32 were stored for 48 hours under the condition of 20 ° C., and the gels were observed, but all were colorless and transparent gels, and no glucose crystals were observed.

  From the results shown in Table 6, it can be seen that a water-soluble hyaluronic acid gel can be suitably produced even when hyaluronic acid having an average molecular weight of 100,000 or 1.2 million is used.

[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 having carried out, it carried out similarly to Examples 1-8, and obtained the water-soluble hyaluronic acid gel sheet. Next, in the same manner as in Examples 1 to 8, the properties of the water-soluble hyaluronic acid gel sheets obtained in Examples 33 to 40 were evaluated. Moreover, it carried out similarly to Examples 1-8, and measured the pH of the hyaluronic acid aqueous solution for pH measurement obtained in Examples 33-40. These results are shown in Table 7. Next, the gel sheets obtained in Examples 33 to 40 were stored for 48 hours under the condition of 20 ° C., and the gel was observed, but all were colorless and transparent gels, and no glucose crystals were observed.

  From the results shown in Table 7, it is preferable to use various acids other than phosphoric acid (sulfuric acid, citric acid, lactic acid, tartaric acid, gluconolactone, lactopionic acid, vitamin C, aspartic acid) as the acid. It can be seen that an acid gel is obtained.

[Examples 41 to 57, Reference Examples 2 to 6, Comparative Examples 3 and 4]
Instead of glucose, using various sugars (fructose, xylitol, sorbitol, trehalose, maltose, lactose, sucrose, γ-cyclodextrin), the hyaluronic acid (part by mass) can be obtained as shown in Table 8 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. Next, this hyaluronic acid aqueous solution is placed in a plastic petri dish (diameter 9 cm) so as to have 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. Got. By measuring the weight of the high-viscosity hyaluronic acid solution and calculating the amount of water contained therein, 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. 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. In Comparative Examples 3 and 4, sheets were obtained in the same manner as in Examples 41 to 57 except that the water content in the gel was substantially 0 part by mass. Next, the properties of the hyaluronic acid gel sheets obtained in Examples 41 to 57, Reference Examples 2 to 6, and Comparative Examples 3 and 4 were evaluated in the same manner as in Examples 1 to 8. Moreover, it carried out similarly to Examples 1-8, and measured the pH of the hyaluronic acid aqueous solution for pH measurement obtained in Examples 41-57, Reference Examples 2-6, and Comparative Examples 3 and 4. These results are shown in Table 8. Next, the gel sheets obtained in Examples 41 to 57 and Reference Examples 2 to 6 were stored for 48 hours under the condition of 20 ° C., and the gels were observed. Not observed. On the other hand, in Comparative Example 3 and Comparative Example 4 in which moisture was not substantially contained in the gel, when stored for 48 hours under the condition of 20 ° C., the respective sugar crystals were precipitated to form a hard sheet.

  From the results shown in Table 8, a water-soluble hyaluronic acid gel is suitably obtained by using various sugars other than glucose (fructose, xylitol, sorbitol, trehalose, maltose, lactose, sucrose, γ-cyclodextrin). You can see that In addition, as shown in Reference Examples 2 to 5, in xylitol and sorbitol, even when an acid different from hyaluronic acid is not included, hyaluronic acid functions as a gel-forming component and a good water-soluble hyaluronic acid gel sheet is obtained. It became clear that it was obtained. In addition, as shown in Reference Examples 3, 5, and 6, 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. Thus, it was revealed that a water-soluble hyaluronic acid gel sheet containing crystalline sugar in a dissolved state can be obtained.

<Solubility test of hyaluronic acid gel>
A hyaluronic acid gel sheet (4 cm × 4 cm) obtained in the same manner as in Example 1, Example 7, Example 12, Example 34, and Example 35 except that the thickness of the hyaluronic acid gel sheet was about 100 μm. The solution was placed in 100 mL of a phosphate buffer solution having a pH of 7.4 and stirred at 37 ° C. with a stirring bar at 120 rpm for 4 hours. As a result, all the hyaluronic acid gel sheets were completely dissolved, and it was confirmed that the hyaluronic acid gel sheets were water-soluble.

<Moisturizing effect evaluation by sticking test of water-soluble hyaluronic acid gel sheet>
The water-soluble hyaluronic acid gel sheet of Example 48 (2 cm × 2 cm) was attached to the right forearm of 4 volunteers for 1 hour. Thereafter, about 10 mL of purified water was added little by little on the gel and dissolved while massaged for about 3 minutes, then washed with purified water and allowed to dry naturally. The moisture retention state of the skin of the left forearm portion of the same volunteer who was treated with this water-soluble hyaluronic acid gel sheet and the untreated left forearm portion was observed.

  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.

<Evaluation of oral administration of water-soluble hyaluronic acid gel sheet>
[Examples 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 under the condition of 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 to 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) so as to have 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. Got. By measuring the weight of the high-viscosity hyaluronic acid solution and calculating the amount of water contained therein, 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. Next, 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. Moreover, it carried out similarly to Examples 1-8, and measured the pH of the hyaluronic acid aqueous solution for pH measurement obtained in Examples 60-65. These results are shown in Table 10. Next, the gel sheets obtained in Examples 60 to 65 were stored for 48 hours under the condition of 20 ° C., and the gels were observed, but all were colorless and transparent gels, and no xylitol crystals were observed.

[Examples 66 to 70]
Using xylitol instead of glucose in Examples 9-18, 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) so as to have 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. Got. By measuring the weight of the high-viscosity hyaluronic acid solution and calculating the amount of water contained therein, distilled water and phosphoric acid in an amount corresponding to the amount of water in the gel shown in Table 11 were mixed uniformly, respectively. 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. Next, in the same manner as in Examples 9 to 18, the properties of the hyaluronic acid gel sheets obtained in Examples 66 to 70 were evaluated. Moreover, it carried out similarly to Examples 9-18, and measured the pH of the hyaluronic acid aqueous solution for pH measurement obtained in Examples 66-70. 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) so as to have 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. Got. By measuring the weight of the high-viscosity hyaluronic acid solution and calculating the amount of water to be contained, respectively, distilled water and phosphoric acid in an amount corresponding to the amount of water in the gel shown in Table 12 were mixed uniformly, 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. Next, in the same manner as in Examples 1 to 8, the properties of the hyaluronic acid gel sheets obtained in Examples 71 and 72 and Reference Examples 7 and 8 were evaluated. Moreover, it carried out similarly to Examples 1-8, and measured the pH of the hyaluronic acid aqueous solution for pH measurement obtained in Examples 71 and 72 and Reference Examples 7 and 8. These results are shown in Table 12. Next, the gel sheets obtained in Examples 71 and 72 and Reference Examples 7 and 8 were stored at 20 ° C. for 48 hours, and the gels were observed. Both were colorless and transparent gels, and crystals of xylitol or sorbitol. Was not observed.

<Storage test at low temperature>
The gel sheets obtained in 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. As a result, 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. On the other hand, 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.

Claims (16)

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.   The water-soluble hyaluronic acid gel according to claim 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 claim 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.   The water-soluble hyaluronic acid gel according to any one of claims 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.   The water-soluble hyaluronic acid gel according to any one of claims 1 to 4, which is in a sheet form.   A water-soluble hyaluronic acid gel sheet, wherein the water-soluble hyaluronic acid gel according to any one of claims 1 to 5 is formed on a support.   Cosmetics using the water-soluble hyaluronic acid gel according to any one of claims 1 to 5.   The food composition using the water-soluble hyaluronic acid gel in any one of Claims 1-5.   The pharmaceutical composition using the water-soluble hyaluronic acid gel in any one of Claims 1-5.   The composition for medical devices using the water-soluble hyaluronic acid gel in any one of Claims 1-5. It is a manufacturing method of the water-soluble hyaluronic acid gel in any one of Claims 1-5,
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.   The method for producing a water-soluble hyaluronic acid gel according to claim 11, further comprising a step of evaporating water contained in the aqueous solution for gel formation.   The method for producing a water-soluble hyaluronic acid gel according to claim 11 or 12, further comprising a step of adding water after evaporating water contained in the aqueous solution for gel formation. It is a manufacturing method of the water-soluble hyaluronic acid gel in any one of Claims 1-5,
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. It is a manufacturing method of the water-soluble hyaluronic acid gel in any one of Claims 1-5,
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. It is a manufacturing method of the water-soluble hyaluronic acid gel in any one of Claims 1-5,
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.