WO2018043532A1 - Method for producing water-insoluble powder dispersion, water-insoluble powder dispersion, and film-like moulded body - Google Patents

Method for producing water-insoluble powder dispersion, water-insoluble powder dispersion, and film-like moulded body Download PDF

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WO2018043532A1
WO2018043532A1 PCT/JP2017/031078 JP2017031078W WO2018043532A1 WO 2018043532 A1 WO2018043532 A1 WO 2018043532A1 JP 2017031078 W JP2017031078 W JP 2017031078W WO 2018043532 A1 WO2018043532 A1 WO 2018043532A1
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water
insoluble powder
powder dispersion
insoluble
film
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PCT/JP2017/031078
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French (fr)
Japanese (ja)
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康幸 礒野
泰晴 野一色
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大日精化工業株式会社
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    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B13/00—Preparation of cellulose ether-esters

Definitions

  • the present invention relates to a method for producing a water-insoluble powder dispersion, a water-insoluble powder dispersion, a film-shaped product, an adhesion-preventing film, a liquid adhesion-preventing material, and a medical / beauty material.
  • Polyanionic polysaccharides such as hyaluronic acid and alginic acid are known to exhibit moderate viscosity, tackiness, moisture retention, and biocompatibility. For this reason, these polyanionic polysaccharides and salts thereof are widely used as raw materials for medical materials, food materials, cosmetic materials and the like.
  • hyaluronic acid is used in various applications such as foods, cosmetics, and pharmaceuticals because of its excellent physical properties such as water retention and high safety and biocompatibility.
  • hyaluronic acid is used as a raw material for joint lubricants and anti-adhesion materials.
  • sodium hyaluronate as a raw material has high water solubility, it is necessary to perform some insolubilization treatment depending on the application.
  • Patent Document 1 describes a method for producing a water-insoluble derivative of a polyanionic polysaccharide such as hyaluronic acid or carboxymethylcellulose by a crosslinking reaction using carbodiimide.
  • Patent Documents 2 and 3 describe a method for water insolubilizing polyanionic polysaccharides such as hyaluronic acid and carboxyalkyl cellulose by ionic bonding using a polyvalent cation. Furthermore, Patent Document 4 describes a method for obtaining a water-insolubilized film by ion-exchanging carboxymethyl cellulose using a metal salt.
  • Patent Document 5 describes a method in which an aqueous sodium hyaluronate solution is cooled to ⁇ 20 ° C. under acidic conditions to form intramolecular crosslinks and thereby insolubilize in water.
  • Patent Document 6 describes that acetylation is performed by reacting powdered hyaluronic acid and acetic anhydride in the presence of concentrated sulfuric acid.
  • Patent Document 7 describes a method of producing hyaluronic acid gel using an acidic liquid containing alcohol, and Patent Document 8 treats a raw material molded body made of sodium hyaluronate with acetic anhydride. The method of water insolubilization is described.
  • Patent Document 1 uses a cross-linking agent, it is often difficult to apply when considering the safety of uses such as pharmaceuticals given to the human body.
  • Patent Documents 2 to 4 do not describe any degree of water insolubility of the obtained film or the like.
  • Patent Document 5 Furthermore, in the method described in Patent Document 5, it is necessary to adjust the pH of the sodium hyaluronate aqueous solution to about 1.2, and the viscosity increases remarkably, so that handling such as molding is difficult. In addition, since freeze-drying over a long period of time, there is also a problem in terms of power cost required for cooling. Furthermore, when the sodium hyaluronate aqueous solution is placed under acidic conditions, the viscosity increases rapidly, so that molding becomes difficult and uses may be limited. In Patent Document 5, the intramolecular cross-linked structure is confirmed, but the degree of insolubilization is not mentioned.
  • Patent Document 6 does not describe any degree of water insolubility of the obtained acetylated product of hyaluronic acid. Furthermore, since the hyaluronic acid gel obtained by the method described in Patent Document 7 contains a large amount of moisture, it is difficult to lift. For this reason, it is difficult to insolubilize while maintaining the shape of the molded body. According to the method described in Patent Document 8, it is not possible to produce a water-insoluble molded article useful as a medical material such as an anti-adhesion material, in which characteristics such as hyaluronic acid as a raw material are maintained. It was. However, the actual situation is that only a molded body having a limited shape such as a film shape and a manufacturing method thereof have been studied in detail.
  • the present invention has been made in view of such problems of the prior art, and the object of the present invention is to retain the original characteristics of the polyanionic polysaccharide as a raw material and to perform chemical crosslinking at the time of production.
  • An object of the present invention is to provide a method for producing a water-insoluble powder dispersion that is highly safe because it does not require the use of an agent and is useful as a base material for medical and cosmetic materials that can be placed in the affected area evenly.
  • the subject of the present invention is a water-insoluble powder dispersion produced by the above-described method, and a film-like molded product, an adhesion-preventing film, a liquid adhesion-preventing material, and a medical / beauty product obtained by using the same. To provide materials.
  • the following method for producing a water-insoluble powder dispersion is provided.
  • the following film-shaped molded article, adhesion preventing film, liquid adhesion preventing material, and medical / beauty material are provided.
  • [6] A film-like molded body obtained by drying the water-insoluble powder dispersion according to [5].
  • [8] A liquid adhesion preventing material containing the water-insoluble powder dispersion according to [5] above and a polyhydric alcohol.
  • a medical / beauty material based on the water-insoluble powder dispersion described in [5].
  • the medical / beauty material according to [9] which is a spray, an ointment, or a coating solution.
  • a medical / beauty material comprising the film-like molded product according to [6] as a base material.
  • the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and since there is no need to use a chemical cross-linking agent during production, the medical treatment is highly safe and can be placed in the affected area evenly.
  • a method for producing a water-insoluble powder dispersion useful as a base material for cosmetics and cosmetics can be provided.
  • a water-insoluble powder dispersion produced by the production method described above, and a film-like molded article, an adhesion-preventing film, a liquid adhesion-preventing material, and a medical / beauty material obtained using the same are obtained. Can be provided.
  • FIG. 6 is a view showing a state of a film-like molded body (film) manufactured in Example 5.
  • FIG. It is a figure which shows the state of the net-like dried material obtained in the comparative example 1.
  • the “average particle diameter” means “median diameter (50% particle diameter (D50) based on volume distribution)”.
  • a raw material powder comprising a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride, and the raw material powder is insolubilized in water to obtain a water-insoluble powder.
  • a step water insolubilization step
  • the raw material powder used in the water insolubilization step is formed of a water-soluble salt of a polyanionic polysaccharide.
  • the polyanionic polysaccharide is a polysaccharide having one or more negatively charged anionic groups such as a carboxy group and a sulfonic acid group in its molecular structure.
  • the water-soluble salt of the polyanionic polysaccharide is a salt in which at least a part of the anionic group in the polyanionic polysaccharide forms a salt.
  • the anionic group in the polyanionic polysaccharide may be introduced into the polysaccharide molecule.
  • polyanionic polysaccharide examples include carboxyalkyl cellulose such as carboxymethyl cellulose and carboxyethyl cellulose, carboxymethyl starch, carboxymethyl amylose, chondroitin sulfate (including chondroitin-4-sulfate and chondroitin-6-sulfate), hyaluronic acid, Examples include heparin, heparin sulfate, heparan sulfate, alginic acid, pectin, carrageenan, dermatan sulfate, and dermatan-6-sulfate. These polyanionic polysaccharides can be used singly or in combination of two or more.
  • water-soluble salts of polyanionic polysaccharides include inorganic salts, ammonium salts, and organic amine salts.
  • specific examples of the inorganic salt include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium salts; metal salts such as zinc and iron.
  • the raw material powder can be prepared, for example, by pulverizing a water-soluble salt of a dried polyanionic polysaccharide.
  • the process liquid used in order to process raw material powder contains an acid anhydride.
  • the acid anhydride include acetic anhydride, propionic anhydride, succinic anhydride, butyric anhydride, phthalic anhydride, and maleic anhydride. Of these, acetic anhydride and propionic anhydride are preferable. These acid anhydrides can be used singly or in combination of two or more.
  • the concentration of the acid anhydride in the treatment liquid is usually 0.1 to 50% by mass, preferably 5 to 30% by mass, and more preferably 15 to 25% by mass.
  • concentration of the acid anhydride is less than 0.1% by mass, the degree of water insolubilization of the obtained water-insoluble powder tends to be insufficient, or it takes a long time for water insolubilization.
  • concentration of the acid anhydride exceeds 50% by mass, the effect tends to reach its peak.
  • the treatment liquid preferably contains water in such a range that the raw material powder composed of the water-soluble salt of the polyanionic polysaccharide is not dissolved.
  • the content of water in the treatment liquid is preferably 0.01 to 50% by mass, and more preferably 5 to 25% by mass. If the content of water in the treatment liquid is less than 0.01% by mass, water insolubilization may be insufficient with a solvent other than methanol. Further, when the content of water in the treatment liquid is more than 50% by mass, the raw material powder may be easily dissolved.
  • the raw material powder is treated with a treatment liquid containing an acid anhydride.
  • a treatment liquid containing an acid anhydride By treating the raw material powder with the treatment liquid, the raw material powder is insolubilized while maintaining its shape, and a water-insoluble powder is formed.
  • the method for treating the raw material powder with the treatment liquid is not particularly limited, but it is preferable to treat the treatment liquid so that the treatment liquid contacts the entire raw material powder and penetrates into the raw material powder.
  • Specific treatment methods include a method of immersing the raw material powder in the treatment liquid and applying or spraying (spraying) the treatment liquid onto the raw material powder.
  • the raw material powder is dispersed in a poor solvent of a water-soluble salt of a polyanionic polysaccharide.
  • the treatment liquid is added, and the raw material powder dispersed in the poor solvent may be brought into contact with the treatment liquid.
  • the poor solvent methanol, ethanol, propanol, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, or the like can be used. Of these, methanol, ethanol, and dimethyl sulfoxide are preferable. These poor solvents can be used alone or in combination of two or more.
  • R 1 represents the main chain of the polyanionic polysaccharide
  • R 2 represents the main chain of the alcohol.
  • the water-insoluble powder obtained by the above process retains the original characteristics of the polyanionic polysaccharide as a raw material and is highly safe.
  • the water-insoluble powder obtained in the water insolubilization step is pulverized by a pulverization method such as wet pulverization or dry pulverization, and dispersed in an aqueous solvent.
  • a pulverization method such as wet pulverization or dry pulverization
  • the water-insoluble powder dispersion of the present invention can be obtained.
  • the water-insoluble powder obtained in the water insolubilization step is pulverized to an average particle size of 80 ⁇ m or less, preferably 20 ⁇ m or less, and dispersed in an aqueous solvent.
  • the dispersibility of the water-insoluble powder in the obtained water-insoluble powder dispersion is improved, and an anti-settling effect is obtained. Expected to get. Further, by pulverizing the water-insoluble powder so as to have a predetermined particle size, it is possible to obtain a water-insoluble powder dispersion capable of producing a film-shaped molded article useful as a medical / beauty material. In addition, even if the water-insoluble powder obtained in the water insolubilization step is dispersed in an aqueous solvent without pulverization, a dispersion can be obtained. However, even if a dispersion prepared without pulverizing water-insoluble powder is used, it is difficult to form a film-shaped molded article useful as a medical / beauty material.
  • the water-insoluble powder dispersion of the present invention produced by the above production method is useful, for example, as a base material for medical and cosmetic materials. That is, when the water-insoluble powder dispersion of the present invention is used, a liquid or paste-like medical / beauty material can be obtained. Such a liquid or paste-like medical / beauty material can be used as a spray, an ointment, or a coating solution. Further, if the water-insoluble powder dispersion of the present invention is dried, a solid (film or sheet) medical / beauty material can be obtained.
  • Liquid or paste-like medical / beauty materials can be used as, for example, joint function improving agents or cosmetic materials for subcutaneous injection.
  • the water-insoluble powder remains in the affected area.
  • the water-insoluble powder has a more uniform and appropriate range as compared with the case where the water-insoluble powder is injected or applied to the affected area by a method such as spraying. Can be detained.
  • the water-insoluble powder gradually changes into a water-soluble salt by the neutralizing action in the body and is absorbed and metabolized. For this reason, if a medical or cosmetic material in the form of liquid or paste is used, a sustained release system that gradually maintains the effect over a long period of time at the treatment site (affected site) is realized.
  • the film-shaped molded product of the present invention can be produced.
  • the film-like molded product thus obtained is useful as an adhesion-preventing film or a base material for medical / beauty materials.
  • the water-insoluble powder can be placed in a more uniform and appropriate range as compared with the case where the water-insoluble powder is disposed on the affected part by a method such as spraying.
  • the anti-adhesion membrane of the present invention is obtained by holding a polyhydric alcohol in the above-mentioned film-like molded product. Moreover, the liquid adhesion preventing material of the present invention contains the water-insoluble powder dispersion described above and a polyhydric alcohol.
  • polyhydric alcohol examples include ethylene glycol, diethylene glycol, polyethylene glycol, methyl glycerol, polyoxyethylene glycoside, maltitol, mannitol, xylitol, sorbitol, reduced starch syrup, dipropylene glycol, butylene glycol, valine, propylene glycol, Examples thereof include glycerin (glycerol), polyglycerin, and glycerin fatty acid ester. Of these, polyhydric alcohols used in the medical field and food field such as glycerin, xylitol, sorbitol, and low molecular weight polyethylene glycol are preferably used.
  • polyhydric alcohols can be obtained from the market and used as they are.
  • glycerin, sorbitol, etc. it is desirable to use those suitable for the Japanese Pharmacopoeia. Glycerin is particularly preferable because it is a material that is safe enough to be used as an intravenous injection.
  • Examples of the method for retaining the polyhydric alcohol in the film-shaped molded body include a method of casting a water-insoluble powder dispersion added with polyhydric alcohol on a tray and then drying. By such a method or the like, an adhesion preventing film in which a polyhydric alcohol is held on the film-shaped molded body can be obtained.
  • the thickness of the adhesion-preventing film of the present invention is not particularly limited, but is preferably 20 to 200 ⁇ m, more preferably 60 to 120 ⁇ m. By setting the thickness within the above range, it is possible to reduce the burden on the living body when indwelling in the body and to more effectively exhibit the adhesion preventing effect.
  • the liquid adhesion preventing material can be obtained by adding a polyhydric alcohol to the water-insoluble powder dispersion described above.
  • Example 1 ⁇ Production of water-insoluble powder dispersion> (Example 1) 1.0 g of sodium hyaluronate (molecular weight 1,500,000 Da) powder (average particle size: 150 ⁇ m) was dispersed in 80 mL of a 75% aqueous ethanol solution. After heating to 50 ° C. with stirring, 20 mL of acetic anhydride was added and the mixture was further heated and stirred for 1 hour. The precipitate recovered by centrifugation was washed with ethanol and water and then dried. Furthermore, dry pulverization was performed to obtain a water-insoluble powder having an average particle size of 80 ⁇ m. 0.5 g of the obtained water-insoluble powder was placed in 50 mL of water and dispersed uniformly using a homogenizer to obtain a water-insoluble powder dispersion.
  • Example 2 1.0 g of sodium hyaluronate (molecular weight: 800,000 Da) powder (average particle size: 150 ⁇ m) was dispersed in 100 mL of 75% ethanol aqueous solution. After heating to 50 ° C. with stirring, 20 mL of acetic anhydride was added and the mixture was further heated and stirred for 1 hour. The precipitate collected by filtration through a filter having a pore size of 10 ⁇ m was washed with ethanol and water, dried and pulverized to obtain a water-insoluble powder.
  • Example 3 5.0 g of the water-insoluble powder obtained in Example 2 was placed in 100 mL of a 0.5% glycerin aqueous solution, and the water-insoluble powder was finely pulverized to a mean particle size of 20 ⁇ m using a wet pulverizer, and dispersed uniformly. An insoluble powder dispersion (a spray) was obtained. The obtained propellant was put in a sprayer and sprayed onto a gelatin sheet. The gelatin sheet sprayed with the propellant is shown on the left side of FIG. In addition, the gelatin sheet which has not sprayed the spray agent is shown on the right of FIG. As shown in FIG. 1, a water-insoluble powder (hyaluronic acid powder) could be uniformly coated on a gelatin sheet.
  • a water-insoluble powder honeyuronic acid powder
  • Example 4 25.0 g of the water-insoluble powder obtained in Example 2 was placed in 100 mL of a 0.5% glycerin aqueous solution, and the water-insoluble powder was finely pulverized to a mean particle size of 20 ⁇ m using a wet pulverizer, and dispersed uniformly. An insoluble powder dispersion (paste) was obtained. When the obtained paste was spread on the skin, a water-insoluble powder (hyaluronic acid powder) could be uniformly applied on the skin.
  • a water-insoluble powder hyaluronic acid powder
  • Example 5 ⁇ Manufacture of film-like molded product (film)> (Example 5) After adding 0.2 g of glycerin to 100 g of the water-insoluble powder dispersion obtained in Example 2 and stirring, it was poured into a stainless tray having a length of 12 cm and a width of 10 cm and dried in a constant temperature bath at 20 ° C. As a result, a film-like molded body (film) having a thickness of about 80 ⁇ m containing hyaluronic acid powder as shown in FIG. 2 was obtained.
  • Example 6 ⁇ Manufacture of anti-adhesion membrane> (Example 6)
  • the film obtained in Example 5 was sealed in a sterilization bag, and the sterilization bag was sterilized with ethylene oxide gas to obtain an adhesion prevention film.
  • the water-insoluble powder dispersion of the present invention can be suitably used, for example, as a base material for medical / beauty materials.

Abstract

Provided is a method for producing a water-insoluble powder dispersion which maintains the inherent properties of a polyanionic polysaccharide used as a starting material thereof, exhibits high safety due to not needing a chemical crosslinking agent to be used during the production thereof, and is useful as a base material for medical and cosmetic materials or the like which can indwell evenly in an affected site. The method for producing the water-insoluble powder dispersion is provided with: a step in which a starting material powder comprising a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid including an acid anhydride, to make the starting material powder water-insoluble and obtain a water-insoluble powder; and a step in which the water-insoluble powder is ground to an average particle size of 80 µm or lower, and dispersed in an aqueous solvent to obtain the water-insoluble powder dispersion.

Description

水不溶性粉末分散液の製造方法、水不溶性粉末分散液、及び膜状成形体Method for producing water-insoluble powder dispersion, water-insoluble powder dispersion, and film-shaped molded body
　本発明は、水不溶性粉末分散液の製造方法、水不溶性粉末分散液、膜状成形体、癒着防止膜、液状癒着防止材、及び医療用・美容材料に関する。 The present invention relates to a method for producing a water-insoluble powder dispersion, a water-insoluble powder dispersion, a film-shaped product, an adhesion-preventing film, a liquid adhesion-preventing material, and a medical / beauty material.
　ヒアルロン酸やアルギン酸等のポリアニオン性多糖類は、適度な粘性、粘着性、保湿性、及び生体適合性を示すことが知られている。このため、これらのポリアニオン性多糖類及びその塩は、医療用材料、食品用材料、及び化粧品用材料等の原材料として幅広く用いられている。 Polyanionic polysaccharides such as hyaluronic acid and alginic acid are known to exhibit moderate viscosity, tackiness, moisture retention, and biocompatibility. For this reason, these polyanionic polysaccharides and salts thereof are widely used as raw materials for medical materials, food materials, cosmetic materials and the like.
　なかでもヒアルロン酸は、保水性などの特徴的な物性に優れているとともに、安全性及び生体適合性が高いことから、食品、化粧品、及び医薬品等の様々な用途に利用されている。例えば医療分野では、ヒアルロン酸は関節潤滑剤や癒着防止材の原料などに利用されている。但し、原料となるヒアルロン酸ナトリウムは水溶性が高いため、用途によっては何らかの不溶化処理を施す必要がある。 Of these, hyaluronic acid is used in various applications such as foods, cosmetics, and pharmaceuticals because of its excellent physical properties such as water retention and high safety and biocompatibility. For example, in the medical field, hyaluronic acid is used as a raw material for joint lubricants and anti-adhesion materials. However, since sodium hyaluronate as a raw material has high water solubility, it is necessary to perform some insolubilization treatment depending on the application.
　これまで、カルボキシ基を利用した架橋反応によりヒアルロン酸ナトリウムを水不溶化させる方法について種々検討されている。例えば、特許文献１には、カルボジイミドを用いた架橋反応により、ヒアルロン酸やカルボキシメチルセルロース等のポリアニオン性多糖類の非水溶性誘導体を製造する方法が記載されている。 Until now, various methods for insolubilizing sodium hyaluronate by a crosslinking reaction utilizing a carboxy group have been studied. For example, Patent Document 1 describes a method for producing a water-insoluble derivative of a polyanionic polysaccharide such as hyaluronic acid or carboxymethylcellulose by a crosslinking reaction using carbodiimide.
　また、特許文献２及び３には、多価カチオンを用いてイオン結合させることにより、ヒアルロン酸やカルボキシアルキルセルロース等のポリアニオン性多糖類を水不溶化させる方法が記載されている。さらに、特許文献４には、金属塩を用いてカルボキシメチルセルロースをイオン交換し、水不溶化フィルムを得る方法が記載されている。 Patent Documents 2 and 3 describe a method for water insolubilizing polyanionic polysaccharides such as hyaluronic acid and carboxyalkyl cellulose by ionic bonding using a polyvalent cation. Furthermore, Patent Document 4 describes a method for obtaining a water-insolubilized film by ion-exchanging carboxymethyl cellulose using a metal salt.
　そして、特許文献５には、ヒアルロン酸ナトリウム水溶液を酸性条件下で－２０℃に冷却し、分子内架橋を形成させて水不溶化する方法が記載されている。また、特許文献６には、粉末状ヒアルロン酸と無水酢酸とを濃硫酸の存在下で反応させてアセチル化することが記載されている。さらに、特許文献７には、アルコールを含む酸性の液を用いてヒアルロン酸ゲルを製造する方法が記載されており、特許文献８には、ヒアルロン酸ナトリウムからなる原料成形体を無水酢酸で処理して水不溶化する方法が記載されている。 Patent Document 5 describes a method in which an aqueous sodium hyaluronate solution is cooled to −20 ° C. under acidic conditions to form intramolecular crosslinks and thereby insolubilize in water. Patent Document 6 describes that acetylation is performed by reacting powdered hyaluronic acid and acetic anhydride in the presence of concentrated sulfuric acid. Further, Patent Document 7 describes a method of producing hyaluronic acid gel using an acidic liquid containing alcohol, and Patent Document 8 treats a raw material molded body made of sodium hyaluronate with acetic anhydride. The method of water insolubilization is described.
特表２００３－５１８１６７号公報JP 2003-518167 A 特開平５－１２４９６８号公報JP-A-5-124968 特開２００８－１３５１０号公報JP 2008-13510 A 特開平６－１２８３９５号公報JP-A-6-128395 特開２００３－２５２９０５号公報JP 2003-252905 A 特開平８－５３５０１号公報JP-A-8-53501 特開平５－５８８８１号公報Japanese Patent Laid-Open No. 5-58881 国際公開第２０１５／０２９８９２号International Publication No. 2015/029892
　しかしながら、特許文献１に記載の方法では架橋剤を用いるため、医薬品等の人体に付与される用途等の安全性を考慮する場合には適用が困難な場合が多い。また、特許文献２～４には、得られたフィルム等の水不溶性の程度については一切記載されていない。 However, since the method described in Patent Document 1 uses a cross-linking agent, it is often difficult to apply when considering the safety of uses such as pharmaceuticals given to the human body. Patent Documents 2 to 4 do not describe any degree of water insolubility of the obtained film or the like.
　さらに、特許文献５に記載の方法では、ヒアルロン酸ナトリウム水溶液のｐＨを１．２程度に調整する必要があるとともに、粘度が著しく上昇するため、成形等の取扱いが困難である。また、長期間にわたって凍結乾燥するため、冷却に要する電力コストの面においても課題があった。さらに、ヒアルロン酸ナトリウム水溶液を酸性条件下におくと粘度が急激に上昇するため、成形が困難になり、用途が限定される場合がある。なお、特許文献５においては、分子内の架橋構造を確認しているが、不溶化の程度については言及していない。 Furthermore, in the method described in Patent Document 5, it is necessary to adjust the pH of the sodium hyaluronate aqueous solution to about 1.2, and the viscosity increases remarkably, so that handling such as molding is difficult. In addition, since freeze-drying over a long period of time, there is also a problem in terms of power cost required for cooling. Furthermore, when the sodium hyaluronate aqueous solution is placed under acidic conditions, the viscosity increases rapidly, so that molding becomes difficult and uses may be limited. In Patent Document 5, the intramolecular cross-linked structure is confirmed, but the degree of insolubilization is not mentioned.
　また、特許文献６には、得られたヒアルロン酸のアセチル化物の水不溶性の程度については一切記載されていない。さらに、特許文献７に記載の方法で得られるヒアルロン酸ゲルは多量の水分を含むため、持ち上げることも難しい。このため、成形体の形状を維持したまま不溶化することは困難である。なお、特許文献８に記載の方法によれば、原料であるヒアルロン酸等の特性が維持された、癒着防止材などの医療用材料として有用な水不溶性の成形体を製造することが可能ではあった。しかし、膜状等の限られた形状の成形体及びその製造方法についてしか詳細に検討されていないのが実情である。 Patent Document 6 does not describe any degree of water insolubility of the obtained acetylated product of hyaluronic acid. Furthermore, since the hyaluronic acid gel obtained by the method described in Patent Document 7 contains a large amount of moisture, it is difficult to lift. For this reason, it is difficult to insolubilize while maintaining the shape of the molded body. According to the method described in Patent Document 8, it is not possible to produce a water-insoluble molded article useful as a medical material such as an anti-adhesion material, in which characteristics such as hyaluronic acid as a raw material are maintained. It was. However, the actual situation is that only a molded body having a limited shape such as a film shape and a manufacturing method thereof have been studied in detail.
　本発明は、このような従来技術の有する問題点に鑑みてなされたものであり、その課題とするところは、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、製造時に化学架橋剤を用いる必要がないため安全性が高く、患部に均等に留置させることが可能な医療用・美容材料等の基材として有用な水不溶性粉末分散液の製造方法を提供することにある。また、本発明の課題とするところは、上記の方法によって製造される水不溶性粉末分散液、並びにそれを用いて得られる膜状成形体、癒着防止膜、液状癒着防止材、及び医療用・美容材料を提供することにある。 The present invention has been made in view of such problems of the prior art, and the object of the present invention is to retain the original characteristics of the polyanionic polysaccharide as a raw material and to perform chemical crosslinking at the time of production. An object of the present invention is to provide a method for producing a water-insoluble powder dispersion that is highly safe because it does not require the use of an agent and is useful as a base material for medical and cosmetic materials that can be placed in the affected area evenly. Further, the subject of the present invention is a water-insoluble powder dispersion produced by the above-described method, and a film-like molded product, an adhesion-preventing film, a liquid adhesion-preventing material, and a medical / beauty product obtained by using the same. To provide materials.
　すなわち、本発明によれば、以下に示す水不溶性粉末分散液の製造方法が提供される。
　［１］ポリアニオン性多糖類の水溶性塩からなる原料粉末を、酸無水物を含む処理液で処理し、前記原料粉末を水不溶化させて水不溶性粉末を得る工程と、前記水不溶性粉末を平均粒子径８０μｍ以下に粉砕し、水系溶媒中に分散させて水不溶性粉末分散液を得る工程と、を有する水不溶性粉末分散液の製造方法。
　［２］前記ポリアニオン性多糖類が、ヒアルロン酸、カルボキシメチルセルロース、及びアルギン酸からなる群より選択される少なくとも一種である前記［１］に記載の水不溶性粉末分散液の製造方法。
　［３］前記酸無水物が、無水酢酸及び無水プロピオン酸の少なくともいずれかである前記［１］又は［２］に記載の水不溶性粉末分散液の製造方法。
　［４］前記水不溶性粉末を湿式粉砕する前記［１］～［３］のいずれかに記載の水不溶性粉末分散液の製造方法。 That is, according to the present invention, the following method for producing a water-insoluble powder dispersion is provided.
[1] A step of treating a raw material powder composed of a water-soluble salt of a polyanionic polysaccharide with a treatment solution containing an acid anhydride, insolubilizing the raw material powder to obtain a water-insoluble powder, and averaging the water-insoluble powder. And a step of pulverizing to a particle size of 80 μm or less and dispersing in an aqueous solvent to obtain a water-insoluble powder dispersion.
[2] The method for producing a water-insoluble powder dispersion according to [1], wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxymethylcellulose, and alginic acid.
[3] The method for producing a water-insoluble powder dispersion according to [1] or [2], wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.
[4] The method for producing a water-insoluble powder dispersion according to any one of [1] to [3], wherein the water-insoluble powder is wet-pulverized.
　また、本発明によれば、以下に示す水不溶性粉末分散液が提供される。
　［５］前記［１］～［４］のいずれかに記載の水不溶性粉末分散液の製造方法により製造された水不溶性粉末分散液。 Moreover, according to this invention, the water-insoluble powder dispersion shown below is provided.
[5] A water-insoluble powder dispersion produced by the method for producing a water-insoluble powder dispersion according to any one of [1] to [4].
　さらに、本発明によれば、以下に示す膜状成形体、癒着防止膜、液状癒着防止材、及び医療用・美容材料が提供される。
　［６］前記［５］に記載の水不溶性粉末分散液を乾燥させて得られる膜状成形体。
　［７］前記［６］に記載の膜状成形体に多価アルコールが保持されてなる癒着防止膜。
　［８］前記［５］に記載の水不溶性粉末分散液と、多価アルコールとを含有する液状癒着防止材。
　［９］前記［５］に記載の水不溶性粉末分散液を基材とする医療用・美容材料。
　［１０］噴霧剤、軟膏、又は塗布液である前記［９］に記載の医療用・美容材料。
　［１１］前記［６］に記載の膜状成形体を基材とする医療用・美容材料。 Furthermore, according to the present invention, the following film-shaped molded article, adhesion preventing film, liquid adhesion preventing material, and medical / beauty material are provided.
[6] A film-like molded body obtained by drying the water-insoluble powder dispersion according to [5].
[7] An adhesion-preventing film obtained by holding a polyhydric alcohol on the film-shaped molded product according to [6].
[8] A liquid adhesion preventing material containing the water-insoluble powder dispersion according to [5] above and a polyhydric alcohol.
[9] A medical / beauty material based on the water-insoluble powder dispersion described in [5].
[10] The medical / beauty material according to [9], which is a spray, an ointment, or a coating solution.
[11] A medical / beauty material comprising the film-like molded product according to [6] as a base material.
　本発明によれば、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、製造時に化学架橋剤を用いる必要がないため安全性が高く、患部に均等に留置させることが可能な医療用・美容材料等の基材として有用な水不溶性粉末分散液の製造方法を提供することができる。また、本発明によれば、上記の製造方法によって製造される水不溶性粉末分散液、並びにそれを用いて得られる膜状成形体、癒着防止膜、液状癒着防止材、及び医療用・美容材料を提供することができる。 According to the present invention, the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and since there is no need to use a chemical cross-linking agent during production, the medical treatment is highly safe and can be placed in the affected area evenly. A method for producing a water-insoluble powder dispersion useful as a base material for cosmetics and cosmetics can be provided. In addition, according to the present invention, a water-insoluble powder dispersion produced by the production method described above, and a film-like molded article, an adhesion-preventing film, a liquid adhesion-preventing material, and a medical / beauty material obtained using the same are obtained. Can be provided.
実施例３で得た噴霧剤を噴霧したゼラチンシート（左）を示す図である。It is a figure which shows the gelatin sheet (left) which sprayed the spray agent obtained in Example 3. FIG. 実施例５で製造した膜状成形体（フィルム）の状態を示す図である。6 is a view showing a state of a film-like molded body (film) manufactured in Example 5. FIG. 比較例１で得た網状乾燥物の状態を示す図である。It is a figure which shows the state of the net-like dried material obtained in the comparative example 1.
　以下、本発明の実施の形態について説明するが、本発明は以下の実施の形態に限定されるものではない。なお、本明細書における「平均粒子径」とは、「メディアン径（体積分布基準の５０％粒径（Ｄ５０））」を意味する。 Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments. In the present specification, the “average particle diameter” means “median diameter (50% particle diameter (D50) based on volume distribution)”.
（水不溶性粉末分散液及びその製造方法）
　本発明の水不溶性粉末分散液の製造方法は、ポリアニオン性多糖類の水溶性塩からなる原料粉末を、酸無水物を含む処理液で処理し、原料粉末を水不溶化させて水不溶性粉末を得る工程（水不溶化工程）と、水不溶性粉末を平均粒子径８０μｍ以下に粉砕し、水系溶媒中に分散させて水不溶性粉末分散液を得る工程（分散工程）と、を有する。以下、その詳細について説明する。 (Water-insoluble powder dispersion and production method thereof)
In the method for producing a water-insoluble powder dispersion of the present invention, a raw material powder comprising a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride, and the raw material powder is insolubilized in water to obtain a water-insoluble powder. A step (water insolubilization step), and a step of dispersing the water-insoluble powder to an average particle size of 80 μm or less and dispersing it in an aqueous solvent to obtain a water-insoluble powder dispersion (dispersion step). The details will be described below.
　水不溶化工程で用いる原料粉末は、ポリアニオン性多糖類の水溶性塩によって形成されている。ポリアニオン性多糖類は、カルボキシ基やスルホン酸基等の負電荷を帯びた１以上のアニオン性基をその分子構造中に有する多糖類である。また、ポリアニオン性多糖類の水溶性塩は、ポリアニオン性多糖類中のアニオン性基の少なくとも一部が塩を形成したものである。なお、ポリアニオン性多糖類中のアニオン性基は、多糖類の分子中に導入されたものであってもよい。 The raw material powder used in the water insolubilization step is formed of a water-soluble salt of a polyanionic polysaccharide. The polyanionic polysaccharide is a polysaccharide having one or more negatively charged anionic groups such as a carboxy group and a sulfonic acid group in its molecular structure. The water-soluble salt of the polyanionic polysaccharide is a salt in which at least a part of the anionic group in the polyanionic polysaccharide forms a salt. The anionic group in the polyanionic polysaccharide may be introduced into the polysaccharide molecule.
　ポリアニオン性多糖類の具体例としては、カルボキシメチルセルロースやカルボキシエチルセルロース等のカルボキシアルキルセルロース、カルボキシメチルでんぷん、カルボキシメチルアミロース、コンドロイチン硫酸（コンドロイチン－４－硫酸及びコンドロイチン－６－硫酸を含む）、ヒアルロン酸、ヘパリン、ヘパリン硫酸、ヘパラン硫酸、アルギン酸、ペクチン、カラギーナン、デルマタン硫酸、及びデルマタン－６－硫酸等を挙げることができる。これらのポリアニオン性多糖類は、一種単独で又は二種以上を組み合わせて用いることができる。 Specific examples of the polyanionic polysaccharide include carboxyalkyl cellulose such as carboxymethyl cellulose and carboxyethyl cellulose, carboxymethyl starch, carboxymethyl amylose, chondroitin sulfate (including chondroitin-4-sulfate and chondroitin-6-sulfate), hyaluronic acid, Examples include heparin, heparin sulfate, heparan sulfate, alginic acid, pectin, carrageenan, dermatan sulfate, and dermatan-6-sulfate. These polyanionic polysaccharides can be used singly or in combination of two or more.
　ポリアニオン性多糖類の水溶性塩としては、無機塩、アンモニウム塩、及び有機アミン塩等を挙げることができる。無機塩の具体例としては、ナトリウム、カリウム等のアルカリ金属塩；カルシウム塩等のアルカリ土類金属塩；亜鉛、鉄等の金属塩等を挙げることができる。 Examples of water-soluble salts of polyanionic polysaccharides include inorganic salts, ammonium salts, and organic amine salts. Specific examples of the inorganic salt include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium salts; metal salts such as zinc and iron.
　原料粉末は、例えば、乾燥したポリアニオン性多糖類の水溶性塩を粉砕して粉体化することによって調製することができる。また、原料粉末を処理するために用いる処理液は、酸無水物を含有する。酸無水物の具体例としては、無水酢酸、無水プロピオン酸、無水コハク酸、無水酪酸、無水フタル酸、及び無水マレイン酸等を挙げることができる。なかでも、無水酢酸及び無水プロピオン酸が好ましい。これらの酸無水物は、一種単独で又は二種以上を組み合わせて用いることができる。 The raw material powder can be prepared, for example, by pulverizing a water-soluble salt of a dried polyanionic polysaccharide. Moreover, the process liquid used in order to process raw material powder contains an acid anhydride. Specific examples of the acid anhydride include acetic anhydride, propionic anhydride, succinic anhydride, butyric anhydride, phthalic anhydride, and maleic anhydride. Of these, acetic anhydride and propionic anhydride are preferable. These acid anhydrides can be used singly or in combination of two or more.
　処理液中の酸無水物の濃度は、通常、０．１～５０質量％であり、５～３０質量％であることが好ましく、１５～２５質量％であることがさらに好ましい。酸無水物の濃度が０．１質量％未満であると、得られる水不溶性粉末の水不溶化の程度が不十分になる、或いは水不溶化に長時間を要する傾向にある。一方、酸無水物の濃度が５０質量％を超えると、効果が頭打ちになる傾向にある。 The concentration of the acid anhydride in the treatment liquid is usually 0.1 to 50% by mass, preferably 5 to 30% by mass, and more preferably 15 to 25% by mass. When the concentration of the acid anhydride is less than 0.1% by mass, the degree of water insolubilization of the obtained water-insoluble powder tends to be insufficient, or it takes a long time for water insolubilization. On the other hand, when the concentration of the acid anhydride exceeds 50% by mass, the effect tends to reach its peak.
　処理液には、ポリアニオン性多糖類の水溶性塩からなる原料粉末が溶解しない範囲で、水を含有させることが好ましい。処理液中の水の含有量は、０．０１～５０質量％であることが好ましく、５～２５質量％であることがさらに好ましい。処理液中の水の含有量が０．０１質量％未満であると、メタノール以外の溶媒では水不溶化が不十分となる場合がある。また、処理液中の水の含有量が５０質量％超であると、原料粉末が溶解しやすくなる場合がある。 The treatment liquid preferably contains water in such a range that the raw material powder composed of the water-soluble salt of the polyanionic polysaccharide is not dissolved. The content of water in the treatment liquid is preferably 0.01 to 50% by mass, and more preferably 5 to 25% by mass. If the content of water in the treatment liquid is less than 0.01% by mass, water insolubilization may be insufficient with a solvent other than methanol. Further, when the content of water in the treatment liquid is more than 50% by mass, the raw material powder may be easily dissolved.
　水不溶化工程においては、酸無水物を含む処理液で原料粉末を処理する。原料粉末を処理液で処理することによって原料粉末がその形状を維持したまま水不溶化され、水不溶性粉末が形成される。処理液で原料粉末を処理する方法は特に限定されないが、原料粉末の全体に処理液が接触するとともに、原料粉末の内部にまで処理液が浸透するように処理することが好ましい。具体的な処理方法としては、原料粉末を処理液中に浸漬する、原料粉末に処理液を塗布又は吹き付ける（噴霧する）等の方法を挙げることができる。 In the water insolubilization step, the raw material powder is treated with a treatment liquid containing an acid anhydride. By treating the raw material powder with the treatment liquid, the raw material powder is insolubilized while maintaining its shape, and a water-insoluble powder is formed. The method for treating the raw material powder with the treatment liquid is not particularly limited, but it is preferable to treat the treatment liquid so that the treatment liquid contacts the entire raw material powder and penetrates into the raw material powder. Specific treatment methods include a method of immersing the raw material powder in the treatment liquid and applying or spraying (spraying) the treatment liquid onto the raw material powder.
　原料粉末を処理して水不溶化する際には、例えば、ポリアニオン性多糖類の水溶性塩の貧溶媒に原料粉末を分散させる。次いで、処理液を添加し、貧溶媒中に分散させた状態の原料粉末と処理液を接触させればよい。貧溶媒としては、メタノール、エタノール、プロパノール、ジメチルスルホキシド、アセトニトリル、及びテトラヒドロフラン等を用いることができる。なかでも、メタノール、エタノール、及びジメチルスルホキシドが好ましい。これらの貧溶媒は、一種単独で又は二種以上を組み合わせて用いることができる。 When the raw material powder is treated to be insoluble in water, for example, the raw material powder is dispersed in a poor solvent of a water-soluble salt of a polyanionic polysaccharide. Next, the treatment liquid is added, and the raw material powder dispersed in the poor solvent may be brought into contact with the treatment liquid. As the poor solvent, methanol, ethanol, propanol, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, or the like can be used. Of these, methanol, ethanol, and dimethyl sulfoxide are preferable. These poor solvents can be used alone or in combination of two or more.
　ポリアニオン性多糖類のナトリウム塩からなる原料粉末を、無水酢酸のアルコール溶液で処理した場合に想定される反応を以下に示す。なお、想定した反応が水不溶化の一つの要因とはなりうるが、他の水不溶化要因との組み合わせ、あるいは全く別の要因により水不溶化している可能性もある。すなわち、本発明は想定される以下の反応によって何ら限定されるものではない。 The following reactions are assumed when raw material powder made of sodium salt of polyanionic polysaccharide is treated with an acetic anhydride alcohol solution. In addition, although the assumed reaction can be one factor of water insolubilization, there is a possibility that water insolubilization is caused by a combination with other water insolubilization factors or completely different factors. That is, this invention is not limited at all by the following reaction assumed.
Figure JPOXMLDOC01-appb-I000001
Figure JPOXMLDOC01-appb-I000001
　反応式（１）中、Ｒ1はポリアニオン性多糖類の主鎖を示し、Ｒ2はアルコールの主鎖を示す。無水酢酸はアルコール存在下で開裂する際に、ポリアニオン性多糖類のナトリウムを奪い、カルボキシ基がナトリウム塩型から酸型となる。この点については、水不溶性粉末中のＮａ含量の測定、又は水不溶性粉末のアルカリ溶液による滴定によって確認することができる。 In reaction formula (1), R 1 represents the main chain of the polyanionic polysaccharide, and R 2 represents the main chain of the alcohol. When acetic anhydride is cleaved in the presence of alcohol, it deprives the polyanionic polysaccharide of sodium and the carboxy group changes from the sodium salt form to the acid form. This can be confirmed by measuring the Na content in the water-insoluble powder or titrating with an alkaline solution of the water-insoluble powder.
　反応系に水が存在する場合には、上記反応式（１）で示される反応の他に、下記式（２）で示される反応が同時に進行し、カルボキシ基がナトリウム塩型から酸型となると予想される。 When water is present in the reaction system, in addition to the reaction represented by the above reaction formula (1), the reaction represented by the following formula (2) proceeds simultaneously, and the carboxy group changes from the sodium salt type to the acid type. is expected.
Figure JPOXMLDOC01-appb-I000002
Figure JPOXMLDOC01-appb-I000002
　なお、得られる水不溶性粉末は、分子中のすべてのアニオン性基が酸型となっていなくてもよい。 In the water-insoluble powder obtained, all anionic groups in the molecule may not be in the acid form.
　ポリアニオン性多糖類の水溶性塩からなる原料粉末を塩酸等の無機酸や酢酸等の有機酸に浸漬しても、十分に水不溶化した粉末を得ることは極めて困難である。また、処理液中の酸無水物を、この酸無水物に対応する酸に置き換えても水不溶性粉末を得ることはできない。このことから、ポリアニオン性多糖類のアニオン性基が酸型に変化する以外の要因も加わり、水不溶性成形体が得られると予想される。 Even when a raw material powder made of a water-soluble salt of polyanionic polysaccharide is immersed in an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, it is extremely difficult to obtain a sufficiently water-insoluble powder. Further, even if the acid anhydride in the treatment liquid is replaced with an acid corresponding to this acid anhydride, a water-insoluble powder cannot be obtained. From this, it is expected that a water-insoluble molded product is obtained by adding factors other than the change of the anionic group of the polyanionic polysaccharide to the acid type.
　上記の水不溶化工程では化学的架橋剤を用いる必要がないため、得られる水不溶性粉末を構成する分子中に化学的架橋剤に由来する官能基等の構造が取り込まれることがない。このため、上記の工程により得られる水不溶性粉末は、原料であるポリアニオン性多糖類本来の特性が保持されているとともに、安全性が高い。 In the above water insolubilization step, it is not necessary to use a chemical cross-linking agent, so that a structure such as a functional group derived from the chemical cross-linking agent is not incorporated into the molecules constituting the water-insoluble powder obtained. For this reason, the water-insoluble powder obtained by the above process retains the original characteristics of the polyanionic polysaccharide as a raw material and is highly safe.
　分散工程では、上記の水不溶化工程で得られた水不溶性粉末を、例えば湿式粉砕や乾式粉砕等の粉砕方法によって粉砕し、水系溶媒中に分散させる。これにより、本発明の水不溶性粉末分散液を得ることができる。ここで、本発明の製造方法においては、水不溶化工程で得られた水不溶性粉末を、平均粒子径８０μｍ以下、好ましくは２０μｍ以下に粉砕して水系溶媒中に分散させる。原料粉末を水不溶化して得た水不溶性粉末を所定の粒径となるように粉砕することで、得られる水不溶性粉末分散液中の水不溶性粉末の分散性が向上するとともに、沈降防止効果を得ることが期待される。また、水不溶性粉末を所定の粒径となるように粉砕することで、医療用・美容材料として有用な膜状成形体を製造しうる水不溶性粉末分散液を得ることができる。なお、水不溶化工程で得られた水不溶性粉末を粉砕することなく水系溶媒中に分散させても、分散液を得ることは可能ではある。しかし、水不溶性粉末を粉砕せずに調製した分散液を用いても、医療用・美容材料として有用な膜状成形体を形成することは困難である。 In the dispersion step, the water-insoluble powder obtained in the water insolubilization step is pulverized by a pulverization method such as wet pulverization or dry pulverization, and dispersed in an aqueous solvent. Thereby, the water-insoluble powder dispersion of the present invention can be obtained. Here, in the production method of the present invention, the water-insoluble powder obtained in the water insolubilization step is pulverized to an average particle size of 80 μm or less, preferably 20 μm or less, and dispersed in an aqueous solvent. By pulverizing the water-insoluble powder obtained by insolubilizing the raw material powder so as to have a predetermined particle size, the dispersibility of the water-insoluble powder in the obtained water-insoluble powder dispersion is improved, and an anti-settling effect is obtained. Expected to get. Further, by pulverizing the water-insoluble powder so as to have a predetermined particle size, it is possible to obtain a water-insoluble powder dispersion capable of producing a film-shaped molded article useful as a medical / beauty material. In addition, even if the water-insoluble powder obtained in the water insolubilization step is dispersed in an aqueous solvent without pulverization, a dispersion can be obtained. However, even if a dispersion prepared without pulverizing water-insoluble powder is used, it is difficult to form a film-shaped molded article useful as a medical / beauty material.
（医療・美容材料）
　上記の製造方法によって製造される本発明の水不溶性粉末分散液は、例えば、医療用・美容材料の基材として有用である。すなわち、本発明の水不溶性粉末分散液を用いれば、液状又はペースト状の医療用・美容材料を得ることができる。このような液状又はペースト状の医療用・美容材料は、噴霧剤、軟膏、又は塗布液として用いることができる。また、本発明の水不溶性粉末分散液を乾燥すれば、固体状（膜状又はシート状）の医療用・美容材料を得ることができる。 (Medical / beauty materials)
The water-insoluble powder dispersion of the present invention produced by the above production method is useful, for example, as a base material for medical and cosmetic materials. That is, when the water-insoluble powder dispersion of the present invention is used, a liquid or paste-like medical / beauty material can be obtained. Such a liquid or paste-like medical / beauty material can be used as a spray, an ointment, or a coating solution. Further, if the water-insoluble powder dispersion of the present invention is dried, a solid (film or sheet) medical / beauty material can be obtained.
　液状又はペースト状の医療用・美容材料は、例えば、関節機能改善剤や皮下注入用美容材料等として使用することができる。液状又はペースト状の医療用・美容材料が患部に注入又は塗布されると、水不溶性粉末は患部に残留することになる。このため、本発明の液状又はペースト状の医療用・美容材料を用いれば、水不溶性粉末を噴霧等の方法で患部に注入又は塗布する場合に比べて、より均一かつ適切な範囲に水不溶性粉末を留置することができる。また、水不溶性粉末は、体内の中和作用により徐々に水溶性の塩に変化し、吸収代謝される。このため、液状又はペースト状の医療用・美容材料を用いれば、処置部（患部）で長期にわたって徐々に効果を維持発揮する徐放システムが実現される。 Liquid or paste-like medical / beauty materials can be used as, for example, joint function improving agents or cosmetic materials for subcutaneous injection. When a liquid or paste-like medical / beauty material is injected or applied to the affected area, the water-insoluble powder remains in the affected area. For this reason, when the liquid or paste-like medical / beauty material of the present invention is used, the water-insoluble powder has a more uniform and appropriate range as compared with the case where the water-insoluble powder is injected or applied to the affected area by a method such as spraying. Can be detained. In addition, the water-insoluble powder gradually changes into a water-soluble salt by the neutralizing action in the body and is absorbed and metabolized. For this reason, if a medical or cosmetic material in the form of liquid or paste is used, a sustained release system that gradually maintains the effect over a long period of time at the treatment site (affected site) is realized.
（膜状成形体）
　上述の水不溶性粉末分散液を乾燥させれば、本発明の膜状成形体を製造することができる。このようにして得られる膜状成形体は、癒着防止膜や、医療用・美容材料の基材として有用である。例えば、本発明の膜状成形体を患部に配置すると、水不溶性粉末は患部に残留することになる。このため、本発明の膜状成形体を用いれば、水不溶性粉末を噴霧等の方法で患部に配置する場合に比べて、より均一かつ適切な範囲に水不溶性粉末を留置することができる。 (Film-shaped molded product)
If the above-mentioned water-insoluble powder dispersion is dried, the film-shaped molded product of the present invention can be produced. The film-like molded product thus obtained is useful as an adhesion-preventing film or a base material for medical / beauty materials. For example, when the membranous molded article of the present invention is disposed in the affected area, the water-insoluble powder remains in the affected area. For this reason, if the film-shaped molded article of the present invention is used, the water-insoluble powder can be placed in a more uniform and appropriate range as compared with the case where the water-insoluble powder is disposed on the affected part by a method such as spraying.
（癒着防止膜、液状癒着防止材）
　本発明の癒着防止膜は、上記の膜状成形体に多価アルコールが保持されてなるものである。また、本発明の液状癒着防止材は、前述の水不溶性粉末分散液と、多価アルコールとを含有するものである。 (Adhesion prevention film, liquid adhesion prevention material)
The anti-adhesion membrane of the present invention is obtained by holding a polyhydric alcohol in the above-mentioned film-like molded product. Moreover, the liquid adhesion preventing material of the present invention contains the water-insoluble powder dispersion described above and a polyhydric alcohol.
　多価アルコールの具体例としては、エチレングルコール、ジエチレングリコール、ポリエチレングリコール、メチルグリセロール、ポリオキシエチレングリコシド、マルチトール、マンニトール、キシリトール、ソルビトール、還元水飴、ジプロピレングリコール、ブチレングリコール、バリン、プロピレングリコール、グリセリン（グリセロール）、ポリグリセリン、グリセリン脂肪酸エステル等を挙げることができる。なかでも、グリセリン、キシリトール、ソルビトール、低分子ポリエチレングリコール等、医療分野や食品分野で使用されている多価アルコールが好適に用いられる。これらの好適に用いられる多価アルコールは、市場から入手してそのまま使用できる。グリセリン、ソルビトール等については、日本薬局方に適合したものを用いることが望ましい。グリセリンは、静脈への注射剤としても使用されるほど安全性の高い素材であるために特に好ましい。 Specific examples of the polyhydric alcohol include ethylene glycol, diethylene glycol, polyethylene glycol, methyl glycerol, polyoxyethylene glycoside, maltitol, mannitol, xylitol, sorbitol, reduced starch syrup, dipropylene glycol, butylene glycol, valine, propylene glycol, Examples thereof include glycerin (glycerol), polyglycerin, and glycerin fatty acid ester. Of these, polyhydric alcohols used in the medical field and food field such as glycerin, xylitol, sorbitol, and low molecular weight polyethylene glycol are preferably used. These suitably used polyhydric alcohols can be obtained from the market and used as they are. As for glycerin, sorbitol, etc., it is desirable to use those suitable for the Japanese Pharmacopoeia. Glycerin is particularly preferable because it is a material that is safe enough to be used as an intravenous injection.
　膜状成形体に多価アルコールを保持させる方法としては、例えば、多価アルコールを添加した水不溶性粉末分散液をトレイ等に流延した後、乾燥する方法などがある。このような方法等によって、膜状成形体に多価アルコールが保持された癒着防止膜を得ることができる。本発明の癒着防止膜の厚さは特に限定されないが、好ましくは２０～２００μｍであり、さらに好ましくは６０～１２０μｍである。厚さを上記の範囲内とすることで、体内に留置した際の生体への負担を低減することができるとともに、癒着防止効果をより有効に発揮させることができる。また、液状癒着防止材は、前述の水不溶性粉末分散液に多価アルコールを添加すること等によって得ることができる。 Examples of the method for retaining the polyhydric alcohol in the film-shaped molded body include a method of casting a water-insoluble powder dispersion added with polyhydric alcohol on a tray and then drying. By such a method or the like, an adhesion preventing film in which a polyhydric alcohol is held on the film-shaped molded body can be obtained. The thickness of the adhesion-preventing film of the present invention is not particularly limited, but is preferably 20 to 200 μm, more preferably 60 to 120 μm. By setting the thickness within the above range, it is possible to reduce the burden on the living body when indwelling in the body and to more effectively exhibit the adhesion preventing effect. The liquid adhesion preventing material can be obtained by adding a polyhydric alcohol to the water-insoluble powder dispersion described above.
　以下、本発明を実施例に基づいて具体的に説明するが、本発明はこれらの実施例に限定されるものではない。なお、実施例、比較例中の「部」及び「％」は、特に断らない限り質量基準である。 Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these examples. In the examples and comparative examples, “parts” and “%” are based on mass unless otherwise specified.
＜水不溶性粉末分散液の製造＞
（実施例１）
　ヒアルロン酸ナトリウム（分子量１５０万Ｄａ）の粉末（平均粒子径：１５０μｍ）１．０ｇを７５％エタノール水溶液８０ｍＬに分散させた。撹拌下で５０℃に加温した後、無水酢酸２０ｍＬを添加してさらに１時間加温撹拌した。遠心分離して回収した沈殿をエタノール及び水で洗浄した後に乾燥した。さらに、乾式粉砕して、平均粒子径８０μｍの水不溶性粉末を得た。得られた水不溶性粉末０．５ｇを水５０ｍＬに入れ、ホモジナイザーを用いて均一に分散させて水不溶性粉末分散液を得た。 <Production of water-insoluble powder dispersion>
(Example 1)
1.0 g of sodium hyaluronate (molecular weight 1,500,000 Da) powder (average particle size: 150 μm) was dispersed in 80 mL of a 75% aqueous ethanol solution. After heating to 50 ° C. with stirring, 20 mL of acetic anhydride was added and the mixture was further heated and stirred for 1 hour. The precipitate recovered by centrifugation was washed with ethanol and water and then dried. Furthermore, dry pulverization was performed to obtain a water-insoluble powder having an average particle size of 80 μm. 0.5 g of the obtained water-insoluble powder was placed in 50 mL of water and dispersed uniformly using a homogenizer to obtain a water-insoluble powder dispersion.
（実施例２）
　ヒアルロン酸ナトリウム（分子量８０万Ｄａ）の粉末（平均粒子径：１５０μｍ）１．０ｇを７５％エタノール水溶液１００ｍＬに分散させた。撹拌下で５０℃に加温した後、無水酢酸２０ｍＬを添加してさらに１時間加温撹拌した。ポアサイズ１０μｍのフィルターでろ過して回収した沈殿をエタノール及び水で洗浄した後、乾燥及び粉砕して水不溶性粉末を得た。得られた水不溶性粉末１．０ｇを水１００ｍＬに入れ、湿式粉砕機を用いて水不溶性粉末を平均粒子径２０μｍとなるまで微粉砕し、均一に分散させて水不溶性粉末分散液を得た。 (Example 2)
1.0 g of sodium hyaluronate (molecular weight: 800,000 Da) powder (average particle size: 150 μm) was dispersed in 100 mL of 75% ethanol aqueous solution. After heating to 50 ° C. with stirring, 20 mL of acetic anhydride was added and the mixture was further heated and stirred for 1 hour. The precipitate collected by filtration through a filter having a pore size of 10 μm was washed with ethanol and water, dried and pulverized to obtain a water-insoluble powder. 1.0 g of the obtained water-insoluble powder was put into 100 mL of water, and the water-insoluble powder was finely pulverized to a mean particle size of 20 μm using a wet pulverizer and uniformly dispersed to obtain a water-insoluble powder dispersion.
＜噴霧剤の製造＞
（実施例３）
　実施例２で得た水不溶性粉末５．０ｇを０．５％グリセリン水溶液１００ｍＬに入れ、湿式粉砕機を用いて水不溶性粉末を平均粒子径２０μｍとなるまで微粉砕し、均一に分散させて水不溶性粉末分散液（噴霧剤）を得た。得られた噴霧剤を噴霧器に入れてゼラチンシート上に噴霧した。噴霧剤を噴霧したゼラチンシートを図１の左に示す。なお、図１の右には、噴霧剤を噴霧していないゼラチンシートを示す。図１に示すように、水不溶性粉末（ヒアルロン酸粉末）をゼラチンシート上に均一に塗布することができた。 <Manufacture of propellant>
(Example 3)
5.0 g of the water-insoluble powder obtained in Example 2 was placed in 100 mL of a 0.5% glycerin aqueous solution, and the water-insoluble powder was finely pulverized to a mean particle size of 20 μm using a wet pulverizer, and dispersed uniformly. An insoluble powder dispersion (a spray) was obtained. The obtained propellant was put in a sprayer and sprayed onto a gelatin sheet. The gelatin sheet sprayed with the propellant is shown on the left side of FIG. In addition, the gelatin sheet which has not sprayed the spray agent is shown on the right of FIG. As shown in FIG. 1, a water-insoluble powder (hyaluronic acid powder) could be uniformly coated on a gelatin sheet.
＜塗布剤（ペースト）の製造＞
（実施例４）
　実施例２で得た水不溶性粉末２５．０ｇを０．５％グリセリン水溶液１００ｍＬに入れ、湿式粉砕機を用いて水不溶性粉末を平均粒子径２０μｍとなるまで微粉砕し、均一に分散させて水不溶性粉末分散液（ペースト）を得た。得られたペーストを皮膚に塗り伸ばしたところ、水不溶性粉末（ヒアルロン酸粉末）を皮膚上に均一に塗布することができた。 <Manufacture of coating agent (paste)>
Example 4
25.0 g of the water-insoluble powder obtained in Example 2 was placed in 100 mL of a 0.5% glycerin aqueous solution, and the water-insoluble powder was finely pulverized to a mean particle size of 20 μm using a wet pulverizer, and dispersed uniformly. An insoluble powder dispersion (paste) was obtained. When the obtained paste was spread on the skin, a water-insoluble powder (hyaluronic acid powder) could be uniformly applied on the skin.
＜膜状成形体（フィルム）の製造＞
（実施例５）
　実施例２で得た水不溶性粉末分散液１００ｇにグリセリン０．２ｇを加えて撹拌した後、縦１２ｃｍ×横１０ｃｍのステンレストレイ内に流し込み、２０℃の恒温槽内で乾燥させた。その結果、図２に示すような、ヒアルロン酸粉末を含有する厚さ約８０μｍの膜状成形体（フィルム）を得た。 <Manufacture of film-like molded product (film)>
(Example 5)
After adding 0.2 g of glycerin to 100 g of the water-insoluble powder dispersion obtained in Example 2 and stirring, it was poured into a stainless tray having a length of 12 cm and a width of 10 cm and dried in a constant temperature bath at 20 ° C. As a result, a film-like molded body (film) having a thickness of about 80 μm containing hyaluronic acid powder as shown in FIG. 2 was obtained.
（比較例１）
　ヒアルロン酸ナトリウム（分子量８０万Ｄａ）の粉末（平均粒子径：１５０μｍ）１．０ｇを７５％エタノール水溶液１００ｍＬに分散させた。撹拌下で５０℃に加温した後、無水酢酸２０ｍＬを添加してさらに１時間加温撹拌した。ポアサイズ１０μｍのフィルターでろ過して回収した沈殿をエタノール及び水で洗浄した後、乾燥して水不溶性粉末を得た。得られた水不溶性粉末１．０ｇを水１００ｍＬに入れ、均一に分散させて水不溶性粉末分散液を得た。得られた水不溶性粉末分散液１００ｇにグリセリン０．２ｇを加えて撹拌した後、縦１２ｃｍ×横１０ｃｍのステンレストレイ内に流し込んだ。次いで、２０℃の恒温槽内で乾燥させた。その結果、図３に示すような網状乾燥物が形成され、膜状成形体（フィルム）を形成することはできなかった。 (Comparative Example 1)
1.0 g of sodium hyaluronate (molecular weight: 800,000 Da) powder (average particle size: 150 μm) was dispersed in 100 mL of 75% ethanol aqueous solution. After heating to 50 ° C. with stirring, 20 mL of acetic anhydride was added and the mixture was further heated and stirred for 1 hour. The precipitate collected by filtration through a filter having a pore size of 10 μm was washed with ethanol and water and then dried to obtain a water-insoluble powder. 1.0 g of the obtained water-insoluble powder was put into 100 mL of water and uniformly dispersed to obtain a water-insoluble powder dispersion. To 100 g of the obtained water-insoluble powder dispersion, 0.2 g of glycerin was added and stirred, and then poured into a stainless tray having a length of 12 cm and a width of 10 cm. Subsequently, it was dried in a constant temperature bath at 20 ° C. As a result, a net-like dried product as shown in FIG. 3 was formed, and a film-like molded body (film) could not be formed.
＜癒着防止膜の製造＞
（実施例６）
　実施例５で得たフィルムを滅菌用袋に封入し、エチレンオキサイドガスにより滅菌用袋ごと滅菌して癒着防止膜を得た。 <Manufacture of anti-adhesion membrane>
(Example 6)
The film obtained in Example 5 was sealed in a sterilization bag, and the sterilization bag was sterilized with ethylene oxide gas to obtain an adhesion prevention film.
＜評価＞
（動物実験）
　成犬（ビーグル犬、雌、１．５歳、体重約９．８ｋｇ）を全身麻酔処置後に開胸し、肺を１０分間外気にさらした後、実施例６で得た癒着防止膜を開胸部の傷口直下の肺上に処置し、生理食塩水をかけて膜を膨潤させた。膜は処置した場所から移動することはなかった。引き続き閉胸した。４週間後、同犬を全身麻酔処置後に開胸したところ、癒着は発生していなかった。また、犬の体内に配置（埋植）した癒着防止膜は消失していた。生体内のナトリウムイオン等によって癒着防止膜を構成するヒアルロン酸のカルボキシ基が徐々に中和され、可溶性のヒアルロン酸塩に変化して溶解し、生体内に吸収されたものと推測される。これに対して、癒着防止膜を配置することなく閉胸した犬については、開胸後に縫合した部分と肺表面とに癒着が生じていることが観察された。 <Evaluation>
(Animal experimentation)
An adult dog (beagle dog, female, 1.5 years old, weight about 9.8 kg) was opened after general anesthesia treatment, and the lungs were exposed to the open air for 10 minutes, and then the adhesion preventing membrane obtained in Example 6 was opened at the thoracotomy The membrane was treated on the lung just below the wound, and saline was applied to swell the membrane. The membrane did not move from the treated location. She continued to close her chest. After 4 weeks, the dog was opened after general anesthesia, and no adhesions occurred. In addition, the anti-adhesion membrane placed (implanted) in the dog's body had disappeared. It is presumed that the carboxy group of hyaluronic acid constituting the antiadhesion membrane is gradually neutralized by sodium ions or the like in the living body, converted into soluble hyaluronate, dissolved, and absorbed into the living body. On the other hand, it was observed that dogs closed with no anti-adhesion membrane closed had adhesion between the sutured portion and the lung surface after thoracotomy.
　本発明の水不溶性粉末分散液は、例えば、医療用・美容材料の基材として好適に用いることができる。 The water-insoluble powder dispersion of the present invention can be suitably used, for example, as a base material for medical / beauty materials.

Claims (11)

  1. 　ポリアニオン性多糖類の水溶性塩からなる原料粉末を、酸無水物を含む処理液で処理し、前記原料粉末を水不溶化させて水不溶性粉末を得る工程と、
    　前記水不溶性粉末を平均粒子径８０μｍ以下に粉砕し、水系溶媒中に分散させて水不溶性粉末分散液を得る工程と、を有する水不溶性粉末分散液の製造方法。     Treating a raw material powder comprising a water-soluble salt of a polyanionic polysaccharide with a treatment liquid containing an acid anhydride, insolubilizing the raw material powder with water to obtain a water-insoluble powder;
    Pulverizing the water-insoluble powder to an average particle size of 80 μm or less and dispersing it in an aqueous solvent to obtain a water-insoluble powder dispersion.
  2. 　前記ポリアニオン性多糖類が、ヒアルロン酸、カルボキシメチルセルロース、及びアルギン酸からなる群より選択される少なくとも一種である請求項１に記載の水不溶性粉末分散液の製造方法。 The method for producing a water-insoluble powder dispersion according to claim 1, wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxymethylcellulose, and alginic acid.
  3. 　前記酸無水物が、無水酢酸及び無水プロピオン酸の少なくともいずれかである請求項１又は２に記載の水不溶性粉末分散液の製造方法。 The method for producing a water-insoluble powder dispersion according to claim 1 or 2, wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.
  4. 　前記水不溶性粉末を湿式粉砕する請求項１～３のいずれか一項に記載の水不溶性粉末分散液の製造方法。 The method for producing a water-insoluble powder dispersion according to any one of claims 1 to 3, wherein the water-insoluble powder is wet-pulverized.
  5. 　請求項１～４のいずれか一項に記載の水不溶性粉末分散液の製造方法により製造された水不溶性粉末分散液。 A water-insoluble powder dispersion produced by the method for producing a water-insoluble powder dispersion according to any one of claims 1 to 4.
  6. 　請求項５に記載の水不溶性粉末分散液を乾燥させて得られる膜状成形体。 A film-like molded body obtained by drying the water-insoluble powder dispersion according to claim 5.
  7. 　請求項６に記載の膜状成形体に多価アルコールが保持されてなる癒着防止膜。 An adhesion-preventing membrane in which a polyhydric alcohol is held on the membrane-like molded product according to claim 6.
  8. 　請求項５に記載の水不溶性粉末分散液と、多価アルコールとを含有する液状癒着防止材。 A liquid adhesion preventing material comprising the water-insoluble powder dispersion according to claim 5 and a polyhydric alcohol.
  9. 　請求項５に記載の水不溶性粉末分散液を基材とする医療用・美容材料。 A medical / beauty material using the water-insoluble powder dispersion according to claim 5 as a base material.
  10. 　噴霧剤、軟膏、又は塗布液である請求項９に記載の医療用・美容材料。 The medical / beauty material according to claim 9, which is a spray, an ointment, or a coating liquid.
  11. 　請求項６に記載の膜状成形体を基材とする医療用・美容材料。 A medical / beauty material comprising the film-like molded product according to claim 6 as a base material.
PCT/JP2017/031078 2016-08-30 2017-08-30 Method for producing water-insoluble powder dispersion, water-insoluble powder dispersion, and film-like moulded body WO2018043532A1 (en)

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WO2015029892A1 (en) * 2013-08-29 2015-03-05 大日精化工業株式会社 Method for manufacturing water-insoluble molded article and water-insoluble molded article
JP2015053977A (en) * 2013-09-10 2015-03-23 大日精化工業株式会社 Method for producing water-insoluble molded body, and water-insoluble molded body

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Publication number Priority date Publication date Assignee Title
WO2015029892A1 (en) * 2013-08-29 2015-03-05 大日精化工業株式会社 Method for manufacturing water-insoluble molded article and water-insoluble molded article
JP2015053977A (en) * 2013-09-10 2015-03-23 大日精化工業株式会社 Method for producing water-insoluble molded body, and water-insoluble molded body

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7455990B2 (en) 2021-11-30 2024-03-26 キユーピー株式会社 hyaluronic acid powder

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