WO2018043531A1 - Method for producing water-insoluble moulded body, water-insoluble moulded body, and antiadhesive material - Google Patents

Method for producing water-insoluble moulded body, water-insoluble moulded body, and antiadhesive material Download PDF

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Publication number
WO2018043531A1
WO2018043531A1 PCT/JP2017/031077 JP2017031077W WO2018043531A1 WO 2018043531 A1 WO2018043531 A1 WO 2018043531A1 JP 2017031077 W JP2017031077 W JP 2017031077W WO 2018043531 A1 WO2018043531 A1 WO 2018043531A1
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water
acid
insoluble
raw material
producing
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PCT/JP2017/031077
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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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/12—Chemical modification
    • C08J7/14—Chemical modification with acids, their salts or anhydrides

Definitions

  • the present invention relates to a method for producing a water-insoluble molded product, a water-insoluble molded product, and an adhesion preventing 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.
  • Various additives may be added to improve the physical properties of the product.
  • 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 a gel containing hyaluronic acid, a polyhydric alcohol, an acid, and a water-soluble organic solvent.
  • Patent Document 7 describes a cosmetic gel sheet containing carboxy group-containing water-soluble polymer, polyhydric alcohol, and acid as essential components
  • Patent Document 8 discloses a raw material molded body made of sodium hyaluronate. Is described in which water is insolubilized by treatment with acetic anhydride.
  • 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 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 physical properties such as flexibility and stretchability of the water-insoluble molded product to be produced may still be insufficient depending on the application, and there is room for improvement.
  • the present invention has been made in view of such problems of the prior art, and the problem is that the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and a chemical crosslinking agent is used.
  • An object of the present invention is to provide a method for producing a water-insoluble molded article having high safety because it does not need to be used and having moderate flexibility (flexibility), stretchability, and sticking property.
  • the place made into the subject of this invention is providing the water-insoluble molded object and adhesion prevention material which are manufactured by said method.
  • a raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide and 0.2% by mass or more of an acid component, or a water-soluble salt of a polyanionic polysaccharide and an alcohol (excluding glycerin) And a raw material molded body made of a raw material containing an acid anhydride, and a process for producing a water-insoluble molded body (hereinafter referred to as “first production”). Method ”).
  • a raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride and at least one acid component of a polycarboxylic acid and a hydroxy acid
  • a method for producing a water-insoluble molded article comprising a step of water-insolubilizing the raw material molded article (hereinafter also referred to as “second production method”).
  • second production method The method for producing a water-insoluble molded article according to [4], wherein the polycarboxylic acid is at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid.
  • [6] The method for producing a water-insoluble molded article according to [4] or [5], wherein the hydroxy acid is citric acid.
  • [7] The method for producing a water-insoluble molded article according to any one of [1] to [6], wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxymethylcellulose, and alginic acid. .
  • [8] The method for producing a water-insoluble molded article according to any one of [1] to [7], wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.
  • adhesion prevention material shown below is provided.
  • 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, the safety is high, and appropriate flexibility (flexibility), expansion and contraction are achieved.
  • the manufacturing method of the water-insoluble molded object which has adhesiveness and sticking property can be provided.
  • the water-insoluble molded object manufactured by said manufacturing method and the adhesion preventing material using the same can be provided.
  • the method for producing a water-insoluble molded product (first production method) of the present invention comprises a raw material molded product comprising a raw material containing a water-soluble salt of a polyanionic polysaccharide and an acid component or alcohol (excluding glycerin). And a process (water insolubilization process) of treating with a treatment liquid containing an acid anhydride to insolubilize the raw material molded body.
  • the method for producing a water-insoluble molded product of the present invention comprises a raw material molded product comprising a raw material containing a water-soluble salt of a polyanionic polysaccharide, an acid anhydride, a polycarboxylic acid and a hydroxy It has the process (water insolubilization process) of processing with the process liquid containing at least any acid component of an acid, and making a raw material molded object water-insolubilized.
  • water insolubilization process water insolubilization process
  • the raw material molded body used in the water insolubilization step is formed using a raw material containing a water-soluble salt of a polyanionic polysaccharide.
  • the raw material molded object used at the water insolubilization process of a 1st manufacturing method is formed using the raw material which further contains an acid component or alcohol (except glycerol) other than the water-soluble salt of polyanionic polysaccharide.
  • the reason is not clear, but by using a raw material containing an acid component or alcohol, the flexibility, stretchability, and stickiness are higher than when using a raw material not containing an acid component or alcohol. An improved water-insoluble molded product can be produced.
  • the content of the acid component in the raw material is 0.2% by mass or more, preferably 0.25 to 1.0% by mass. By setting the content of the acid component in the raw material to 0.2% by mass or more, it is possible to produce a water-insoluble molded article having excellent flexibility (flexibility), stretchability and sticking property. Further, the content of alcohol in the raw material is preferably 25% by mass or more, and more preferably 50% by mass or more. Further, the raw material may further contain a radiopaque agent such as a contrast agent such as barium sulfate.
  • the acid component it is preferable to use at least one of citric acid and hydrochloric acid. Among these, when citric acid is used, the stretchability and flexibility of the obtained water-insoluble molded product can be further improved. Moreover, as alcohols, it is preferable to use at least one of ethanol and methanol.
  • 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 molded body can be obtained by, for example, forming a raw material (aqueous solution) into a desired shape and then drying it.
  • the shape of the raw material molded body include a film shape, a lump shape, a fiber shape, a rod shape, a tubular shape, a powder shape, a particle shape, and a sponge shape.
  • a water-insoluble molded body having a shape corresponding to the use such as a film shape, a lump shape, a fiber shape, a rod shape, a tubular shape, a powder shape, a particle shape, and a sponge shape is obtained. Can do. If necessary, the obtained water-insoluble molded product may be further molded and processed into a desired shape.
  • an aqueous solution of a water-soluble salt of a polyanionic polysaccharide is poured into a suitable container, and then dried or freeze-dried to obtain a raw material molded body having a film shape (sheet shape) or a block shape (block shape, sponge shape). be able to.
  • a fibrous raw material molded body can be obtained by extruding an aqueous solution of a water-soluble salt of a polyanionic polysaccharide into a poor solvent from a nozzle.
  • a rod-shaped raw material molded body can be obtained by filling an appropriate tube with an aqueous solution of a water-soluble salt of a polyanionic polysaccharide and then drying or freeze-drying.
  • a powdery or particulate raw material molded body can be obtained by pulverizing the dried polyanionic polysaccharide.
  • a water-insoluble molded article having a shape suitable for the use is obtained because the water-insoluble treatment is performed after the polyanionic polysaccharide is molded into a desired shape. Can do.
  • the treatment liquid used for treating the raw material compact 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 treatment liquid used in the water insolubilization step of the second production method further contains at least one acid component of polycarboxylic acid and hydroxy acid in addition to the acid anhydride.
  • the reason is not clear, but by treating the raw material molded body with a treatment liquid containing these acid components, it is more flexible than when the raw material molded body is treated with a treatment liquid not containing these acid components.
  • a water-insoluble molded article having improved stretchability and sticking property can be produced.
  • the content of the acid component in the treatment liquid is preferably 1% by mass or more, and more preferably 1.5 to 5.0% by mass.
  • the acid components blended in the treatment liquid it is preferable to use at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid as the polycarboxylic acid.
  • oxalic acid malonic acid
  • succinic acid succinic acid
  • glutaric acid glutaric acid
  • the treatment liquid preferably further contains at least one of water and a water-soluble organic solvent, and the acid anhydride is preferably dissolved or dispersed in this medium.
  • water-soluble organic solvent examples include methanol, ethanol, propanol, dimethyl sulfoxide (DMSO), acetonitrile, and tetrahydrofuran. Of these, methanol, ethanol, and dimethyl sulfoxide are preferable. These water-soluble organic solvents can be used alone 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.
  • concentration of the acid anhydride is less than 0.1% by mass, the degree of water insolubilization of the resulting water-insoluble molded article 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 contains water as a medium from the viewpoint of water insolubilization of the raw material molded body more sufficiently and quickly.
  • the content of water in the treatment liquid is preferably set to such an extent that the raw material molded body does not dissolve or swell.
  • the content of water in the treatment liquid is preferably 0.01 to 50% by mass, and more preferably 5 to 20% 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.
  • the content of water in the treatment liquid is more than 50% by mass, it may be difficult to maintain the shape of the obtained water-insoluble molded article.
  • the raw material molded body is treated with a treatment liquid containing an acid anhydride.
  • a treatment liquid containing an acid anhydride By treating the raw material molded body with the treatment liquid, the raw material molded body is insolubilized while maintaining its shape, and a water-insoluble molded body is formed.
  • the method of treating the raw material molded body with the treatment liquid is not particularly limited, but it is preferable to treat the raw material molded body so that the treatment liquid contacts the entire raw material molded body and penetrates into the raw material molded body.
  • Specific examples of the treatment method include a method of immersing the raw material molded body in the treatment liquid and applying or spraying (spraying) the treatment liquid onto the raw material molded body.
  • the powdery or particulate raw material molded body is made of the water-soluble salt of the polyanionic polysaccharide constituting the raw material molded body. Disperse in a poor solvent. Next, the treatment liquid may be added, the powder or particulate raw material molded body dispersed in the poor solvent is brought into contact with the treatment liquid, and the raw material molded body may be treated with the treatment liquid.
  • the poor solvent methanol, ethanol, propanol, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, or the like can be used. These poor solvents can be used alone or in combination of two or more. In addition, this poor solvent may contain a trace amount of water to such an extent that the powdery or particulate raw material molded body does not dissolve.
  • the temperature during the treatment is not particularly limited as long as it does not exceed the boiling point of the treatment liquid.
  • the temperature during the treatment is preferably 0 to 80 ° C, and preferably 0 to 70 ° C. It is more preferable that the temperature is room temperature (25 ° C.) to 60 ° C.
  • the treatment liquid is not volatilized during the treatment, for example, heat treatment or a heat roller, a water-insoluble molded article can be obtained in a shorter time without causing decomposition and modification.
  • the temperature during the treatment is preferably 50 to 90 ° C., and the treatment time is preferably 30 minutes or less.
  • the water-insoluble molded product of the present invention can be obtained by washing with water or a water-soluble organic solvent as necessary.
  • R 1 represents the main chain of the polyanionic polysaccharide
  • R 2 represents the main chain of the alcohol.
  • the water-insoluble molded product of the present invention is suitable as a medical material such as an adhesion preventing material.
  • the thickness of the water-insoluble molded product is not particularly limited, but is preferably 20 to 200 ⁇ m, more preferably 60 to 120 ⁇ m.
  • the anti-adhesion material of the present invention is obtained by holding a polyhydric alcohol or a polyhydric alcohol aqueous solution on the water-insoluble molded article.
  • 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.
  • 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.
  • Examples of a method for holding a polyhydric alcohol or a polyhydric alcohol aqueous solution in a water-insoluble molded body include a method of immersing a water-insoluble molded body in a polyhydric alcohol or a polyhydric alcohol aqueous solution having a predetermined concentration. That is, by immersing a water-insoluble molded article having a predetermined shape in a polyhydric alcohol aqueous solution and replacing the interior of the water-insoluble molded article with the polyhydric alcohol aqueous solution, the polyhydric alcohol aqueous solution having a desired concentration is retained,
  • the adhesion preventing material of the present invention can be obtained.
  • the thickness of the adhesion preventing material of the present invention is not particularly limited, but is preferably 20 to 200 ⁇ m, and more preferably 60 to 120 ⁇ m.
  • the injection material contains a water-insoluble molded body having a powder or particle shape among the water-insoluble molded bodies described above.
  • the injection material may further contain a liquid medium such as an aqueous solution of a water-soluble salt of hyaluronic acid that has not been insolubilized in water.
  • a liquid medium such as an aqueous solution of a water-soluble salt of hyaluronic acid that has not been insolubilized in water.
  • the water-insoluble molded body constituting the injection material can be manufactured without using a chemical crosslinking agent, and since the original characteristics of the polyanionic polysaccharide as a raw material are maintained, it is safe to use. Are better.
  • the injection material contains a powdery or particulate water-insoluble molded product, it has high fluidity and can be easily injected into the affected area via an injection needle by appropriately adjusting the particle size of the powder or particles. can do.
  • the injection material is useful as, for example, an intra-articular injection for joint deformation treatment, a subcutaneous injection, or the like.
  • the sustained-release preparation contains the above-mentioned water-insoluble molded article and a pharmaceutically acceptable active ingredient.
  • the water-insoluble molded article constituting the sustained-release preparation can be produced without using a chemical crosslinking agent, and since the original characteristics of the polyanionic polysaccharide as a raw material are retained, it is safe. Excellent in properties. Further, since the water-insoluble molded article is gradually decomposed and absorbed in the living body, the active ingredient can be gradually released.
  • the type of active ingredient is not particularly limited as long as it is pharmaceutically acceptable.
  • sustained-release preparations include, for example, a water-insoluble molded product formed into a sheet shape impregnated with an active ingredient or a solution thereof, a capsule made of a water-insoluble molded product, and a capsule enclosed in this capsule. And those composed of active ingredients. By appropriately setting the thickness, shape, etc. of the sheet or capsule, the sustained release in vivo can be controlled.
  • reagents used are shown below.
  • water water having an electrical conductivity of 18.0 M ⁇ ⁇ cm or more prepared using an ultrapure water production apparatus (manufactured by Sartorius Japan) was used.
  • Sodium hyaluronate manufactured by Shiseido Co., Ltd., molecular weight 1.5 million Da
  • Citric acid Wako Pure Chemical Industries
  • reagent special grade Glycerin Sakamoto Yakuhin Kogyo Co., Japan Pharmacopoeia Hydrochloric acid: Wako Pure Chemical Industries
  • reagent special grade Ethanol Junsei Chemical Co.
  • reagent special grade Methanol Wako Pure Chemical Industries
  • reagent Special grade Acetic anhydride Wako Pure Chemical Industries
  • reagent special grade Malonic acid Wako Pure Chemical Industries
  • reagent special grade Oxalic acid Wako Pure Chemical Industries
  • reagent special grade Succinic acid Wako Pure Chemical Industries, reagent special grade
  • the membranes produced in Examples 1, 5, and 9 were each immersed in a 10% by volume glycerin aqueous solution, then air-dried and sealed in a sterilization bag.
  • the anti-adhesion membrane was obtained by sterilizing the entire sterilization bag with irradiation of 25 kGy.
  • An adult dog (beagle dog, female, 1.5 years old, weight about 10 kg) was opened after general anesthesia treatment, and the epidermis epidermis was peeled into 3 cm square. The abdomen was closed by placing an adhesion-preventing membrane so as to cover the peeled portion. Two weeks later, the dog was laparotomized after general anesthesia, and no adhesion occurred in any of the membranes.
  • the anti-adhesion membrane placed (implanted) in the dog's body disappeared two weeks after implantation.
  • the carboxy group of hyaluronic acid constituting the anti-adhesion membrane was gradually neutralized by sodium ions etc. in the living body, and changed into soluble hyaluronate, dissolved and absorbed into the living body.
  • adhesion occurred in the peeled portion and the intestine in dogs that were closed without placing an anti-adhesion membrane.
  • the water-insoluble molded product of the present invention can be suitably used, for example, as a constituent material of an adhesion preventing material.

Abstract

Provided is a method for producing a water-insoluble moulded body which maintains the inherent properties of a polyanionic polysaccharide used as a starting material thereof, exhibits high safety due to not needing the use of a chemical crosslinking agent, and exhibits moderate pliability (flexibility), stretchability, and adhesiveness. The method for producing the water-insoluble moulded body is provided with a step in which a starting material moulded body comprising a starting material including a water-soluble salt of a polyanionic polysaccharide, and at least 0.2 mass% of an acid component, or a starting material moulded body comprising a starting material including a water-soluble salt of a polyanionic polysaccharide, and an alcohol (excluding glycerin), is treated with a treatment liquid including an acid anhydride, to make the starting material moulded body water-insoluble.

Description

水不溶性成形体の製造方法、水不溶性成形体、及び癒着防止材Method for producing water-insoluble molded body, water-insoluble molded body, and adhesion preventing material
　本発明は、水不溶性成形体の製造方法、水不溶性成形体、及び癒着防止材に関する。 The present invention relates to a method for producing a water-insoluble molded product, a water-insoluble molded product, and an adhesion preventing 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。また、製品の物性を改良すべく、種々の添加剤を加える場合もある。 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. Various additives may be added to improve the physical properties of the product.
　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、ヒアルロン酸、多価アルコール、酸、及び水溶性有機溶媒を含有するゲルが記載されている。さらに、特許文献７には、カルボキシ基含有水溶性高分子、多価アルコール、及び酸を必須成分とする化粧用ゲルシートが記載されており、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 a gel containing hyaluronic acid, a polyhydric alcohol, an acid, and a water-soluble organic solvent. Furthermore, Patent Document 7 describes a cosmetic gel sheet containing carboxy group-containing water-soluble polymer, polyhydric alcohol, and acid as essential components, and Patent Document 8 discloses a raw material molded body made of sodium hyaluronate. Is described in which water is insolubilized by treatment with acetic anhydride.
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及び７に記載されたゲルシート等には酸やアルコールなどが添加されているが、ゲルそのものは水不溶化していない。このため、飽水させた状態でゲルの形状を維持することは困難であった。 In addition, although acid and alcohol are added to the gel sheets described in Patent Documents 6 and 7, the gel itself is not water-insoluble. For this reason, it was difficult to maintain the gel shape in a saturated state.
　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、製造される水不溶性の成形体の柔軟性や伸縮性等の物性については、用途によっては未だ不十分な場合もあり、改良の余地があった。 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 physical properties such as flexibility and stretchability of the water-insoluble molded product to be produced may still be insufficient depending on the application, and there is room for improvement.
　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、化学架橋剤を用いる必要がないため安全性が高く、かつ、適度な柔軟性（可とう性）、伸縮性、及び貼り付き性を有する水不溶性成形体を製造する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成形体及び癒着防止材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 problem is that the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and a chemical crosslinking agent is used. An object of the present invention is to provide a method for producing a water-insoluble molded article having high safety because it does not need to be used and having moderate flexibility (flexibility), stretchability, and sticking property. Moreover, the place made into the subject of this invention is providing the water-insoluble molded object and adhesion prevention material which are manufactured by said method.
　すなわち、本発明によれば、以下に示す水不溶性成形体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と、０．２質量％以上の酸成分とを含有する原材料からなる原料成形体、又はポリアニオン性多糖類の水溶性塩と、アルコール類（グリセリンを除く）とを含有する原材料からなる原料成形体を、酸無水物を含む処理液で処理し、前記原料成形体を水不溶化させる工程を有する水不溶性成形体の製造方法（以下、「第１の製造方法」とも記す）。
　［２］前記酸成分が、クエン酸及び塩酸の少なくともいずれかである前記［１］に記載の水不溶性成形体の製造方法。
　［３］前記アルコール類が、エタノール及びメタノールの少なくともいずれかである前記［１］に記載の水不溶性成形体の製造方法。
　［４］ポリアニオン性多糖類の水溶性塩を含有する原材料からなる原料成形体を、酸無水物と、ポリカルボン酸及びヒドロキシ酸の少なくともいずれかの酸成分とを含有する処理液で処理し、前記原料成形体を水不溶化させる工程を有する水不溶性成形体の製造方法（以下、「第２の製造方法」とも記す）。
　［５］前記ポリカルボン酸が、シュウ酸、マロン酸、コハク酸、及びグルタル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［４］に記載の水不溶性成形体の製造方法。
　［６］前記ヒドロキシ酸が、クエン酸である前記［４］又は［５］に記載の水不溶性成形体の製造方法。
　［７］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］～［６］のいずれかに記載の水不溶性成形体の製造方法。
　［８］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］～［７］のいずれかに記載の水不溶性成形体の製造方法。 That is, according to the present invention, the following method for producing a water-insoluble molded article is provided.
[1] A raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide and 0.2% by mass or more of an acid component, or a water-soluble salt of a polyanionic polysaccharide and an alcohol (excluding glycerin) And a raw material molded body made of a raw material containing an acid anhydride, and a process for producing a water-insoluble molded body (hereinafter referred to as “first production”). Method ”).
[2] The method for producing a water-insoluble molded article according to [1], wherein the acid component is at least one of citric acid and hydrochloric acid.
[3] The method for producing a water-insoluble molded article according to [1], wherein the alcohol is at least one of ethanol and methanol.
[4] A raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride and at least one acid component of a polycarboxylic acid and a hydroxy acid, A method for producing a water-insoluble molded article comprising a step of water-insolubilizing the raw material molded article (hereinafter also referred to as “second production method”).
[5] The method for producing a water-insoluble molded article according to [4], wherein the polycarboxylic acid is at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid.
[6] The method for producing a water-insoluble molded article according to [4] or [5], wherein the hydroxy acid is citric acid.
[7] The method for producing a water-insoluble molded article according to any one of [1] to [6], wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxymethylcellulose, and alginic acid. .
[8] The method for producing a water-insoluble molded article according to any one of [1] to [7], wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.
　また、本発明によれば、以下に示す水不溶性成形体が提供される。
　［９］前記［１］～［８］のいずれかに記載の製造方法によって製造された水不溶性成形体。 Moreover, according to this invention, the water-insoluble molded object shown below is provided.
[9] A water-insoluble molded product produced by the production method according to any one of [1] to [8].
　さらに、本発明によれば、以下に示す癒着防止材が提供される。
　［１０］前記［９］に記載の水不溶性成形体に多価アルコール又は多価アルコール水溶液が保持されてなる癒着防止材。 Furthermore, according to this invention, the adhesion prevention material shown below is provided.
[10] An adhesion-preventing material obtained by holding a polyhydric alcohol or a polyhydric alcohol aqueous solution on the water-insoluble molded article according to [9].
　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、化学架橋剤を用いる必要がないため安全性が高く、かつ、適度な柔軟性（可とう性）、伸縮性、及び貼り付き性を有する水不溶性成形体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成形体、及びそれを用いた癒着防止材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, the safety is high, and appropriate flexibility (flexibility), expansion and contraction are achieved. The manufacturing method of the water-insoluble molded object which has adhesiveness and sticking property can be provided. Moreover, according to this invention, the water-insoluble molded object manufactured by said manufacturing method and the adhesion preventing material using the same can be provided.
　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。 Hereinafter, embodiments of the present invention will be described, but the present invention is not limited to the following embodiments.
（水不溶性成形体及びその製造方法）
　本発明の水不溶性成形体の製造方法（第１の製造方法）は、ポリアニオン性多糖類の水溶性塩と、酸成分又はアルコール類（グリセリンを除く）とを含有する原材料からなる原料成形体を、酸無水物を含む処理液で処理し、原料成形体を水不溶化させる工程（水不溶化工程）を有する。また、本発明の水不溶性成形体の製造方法（第２の製造方法）は、ポリアニオン性多糖類の水溶性塩を含有する原材料からなる原料成形体を、酸無水物と、ポリカルボン酸及びヒドロキシ酸の少なくともいずれかの酸成分とを含有する処理液で処理し、原料成形体を水不溶化させる工程（水不溶化工程）を有する。以下、本発明の水不溶性成形体の製造方法の詳細について説明する。 (Water-insoluble molded product and method for producing the same)
The method for producing a water-insoluble molded product (first production method) of the present invention comprises a raw material molded product comprising a raw material containing a water-soluble salt of a polyanionic polysaccharide and an acid component or alcohol (excluding glycerin). And a process (water insolubilization process) of treating with a treatment liquid containing an acid anhydride to insolubilize the raw material molded body. Further, the method for producing a water-insoluble molded product of the present invention (second production method) comprises a raw material molded product comprising a raw material containing a water-soluble salt of a polyanionic polysaccharide, an acid anhydride, a polycarboxylic acid and a hydroxy It has the process (water insolubilization process) of processing with the process liquid containing at least any acid component of an acid, and making a raw material molded object water-insolubilized. Hereinafter, the detail of the manufacturing method of the water-insoluble molded object of this invention is demonstrated.
　水不溶化工程で用いる原料成形体は、ポリアニオン性多糖類の水溶性塩を含有する原材料を用いて形成される。また、第１の製造方法の水不溶化工程で用いる原料成形体は、ポリアニオン性多糖類の水溶性塩以外にも、酸成分又はアルコール類（グリセリンを除く）をさらに含有する原材料を用いて形成される。理由については明らかではないが、酸成分又はアルコール類を含有する原材料を用いることで、酸成分やアルコール類を含有しない原材料を用いた場合に比べて、柔軟性、伸縮性、及び貼り付き性が向上した水不溶性成形体を製造することができる。 The raw material molded body used in the water insolubilization step is formed using a raw material containing a water-soluble salt of a polyanionic polysaccharide. Moreover, the raw material molded object used at the water insolubilization process of a 1st manufacturing method is formed using the raw material which further contains an acid component or alcohol (except glycerol) other than the water-soluble salt of polyanionic polysaccharide. The The reason is not clear, but by using a raw material containing an acid component or alcohol, the flexibility, stretchability, and stickiness are higher than when using a raw material not containing an acid component or alcohol. An improved water-insoluble molded product can be produced.
　原材料中の酸成分の含有量は、０．２質量％以上であり、０．２５～１．０質量％であることが好ましい。原材料中の酸成分の含有量を０．２質量％以上とすることで、柔軟性（可とう性）とともに、伸縮性及び貼り付き性に優れた水不溶性成形体を製造することができる。また、原材料中のアルコール類の含有量は、２５質量％以上であることが好ましく、５０質量％以上であることがさらに好ましい。また、原材料には、さらに、硫酸バリウム等の造影剤をはじめとするＸ線不透過剤を含有させてもよい。 The content of the acid component in the raw material is 0.2% by mass or more, preferably 0.25 to 1.0% by mass. By setting the content of the acid component in the raw material to 0.2% by mass or more, it is possible to produce a water-insoluble molded article having excellent flexibility (flexibility), stretchability and sticking property. Further, the content of alcohol in the raw material is preferably 25% by mass or more, and more preferably 50% by mass or more. Further, the raw material may further contain a radiopaque agent such as a contrast agent such as barium sulfate.
　酸成分としては、クエン酸及び塩酸の少なくともいずれかを用いることが好ましい。なかでも、クエン酸を用いると、得られる水不溶性成形体の伸縮性及び可とう性をより向上させることができる。また、アルコール類としては、エタノール及びメタノールの少なくともいずれかを用いることが好ましい。 As the acid component, it is preferable to use at least one of citric acid and hydrochloric acid. Among these, when citric acid is used, the stretchability and flexibility of the obtained water-insoluble molded product can be further improved. Moreover, as alcohols, it is preferable to use at least one of ethanol and methanol.
　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 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.
　原料成形体は、例えば、原材料（水溶液）を所望の形状に成形した後、乾燥等させることによって得ることができる。原料成形体の形状としては、例えば、膜状、塊状、繊維状、棒状、管状、粉末状、粒子状、及びスポンジ状等を挙げることができる。これらの形状の原料成形体を水不溶化させることによって、膜状、塊状、繊維状、棒状、管状、粉末状、粒子状、及びスポンジ状等の用途に応じた形状の水不溶性成形体を得ることができる。なお、必要に応じて、得られた水不溶性成形体をさらに成形して所望の形状に加工してもよい。 The raw material molded body can be obtained by, for example, forming a raw material (aqueous solution) into a desired shape and then drying it. Examples of the shape of the raw material molded body include a film shape, a lump shape, a fiber shape, a rod shape, a tubular shape, a powder shape, a particle shape, and a sponge shape. By insolubilizing the raw material molded body of these shapes, a water-insoluble molded body having a shape corresponding to the use such as a film shape, a lump shape, a fiber shape, a rod shape, a tubular shape, a powder shape, a particle shape, and a sponge shape is obtained. Can do. If necessary, the obtained water-insoluble molded product may be further molded and processed into a desired shape.
　例えば、ポリアニオン性多糖類の水溶性塩の水溶液を適当な容器に流し入れた後、乾燥又は凍結乾燥することによって、膜状（シート状）又は塊状（ブロック状、スポンジ状）の原料成形体を得ることができる。また、ポリアニオン性多糖類の水溶性塩の水溶液をノズルから貧溶媒中に押し出すことによって、繊維状の原料成形体を得ることができる。ポリアニオン性多糖類の水溶性塩の水溶液を適当な管に充填した後、乾燥又は凍結乾燥することによって、棒状の原料成形体を得ることができる。また、乾燥したポリアニオン性多糖類を粉砕して粉体化することによって、粉末状又は粒子状の原料成形体を得ることができる。このように、本発明の水不溶性成形体の製造方法によれば、ポリアニオン性多糖類を所望とする形状に成形した後に水不溶化処理するため、用途に応じた形状の水不溶性成形体を得ることができる。 For example, an aqueous solution of a water-soluble salt of a polyanionic polysaccharide is poured into a suitable container, and then dried or freeze-dried to obtain a raw material molded body having a film shape (sheet shape) or a block shape (block shape, sponge shape). be able to. Moreover, a fibrous raw material molded body can be obtained by extruding an aqueous solution of a water-soluble salt of a polyanionic polysaccharide into a poor solvent from a nozzle. A rod-shaped raw material molded body can be obtained by filling an appropriate tube with an aqueous solution of a water-soluble salt of a polyanionic polysaccharide and then drying or freeze-drying. Moreover, a powdery or particulate raw material molded body can be obtained by pulverizing the dried polyanionic polysaccharide. Thus, according to the method for producing a water-insoluble molded article of the present invention, a water-insoluble molded article having a shape suitable for the use is obtained because the water-insoluble treatment is performed after the polyanionic polysaccharide is molded into a desired shape. Can do.
　原料成形体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 treatment liquid used for treating the raw material compact 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.
　また、第２の製造方法の水不溶化工程で用いる処理液は、酸無水物以外にも、ポリカルボン酸及びヒドロキシ酸の少なくともいずれかの酸成分をさらに含有する。理由については明らかではないが、これらの酸成分を含有する処理液によって原料成形体を処理することによって、これらの酸成分を含有しない処理液によって原料成形体を処理した場合に比べて、柔軟性、伸縮性、及び貼り付き性が向上した水不溶性成形体を製造することができる。なお、処理液中の酸成分の含有量は、１質量％以上であることが好ましく、１．５～５．０質量％であることがさらに好ましい。 In addition, the treatment liquid used in the water insolubilization step of the second production method further contains at least one acid component of polycarboxylic acid and hydroxy acid in addition to the acid anhydride. The reason is not clear, but by treating the raw material molded body with a treatment liquid containing these acid components, it is more flexible than when the raw material molded body is treated with a treatment liquid not containing these acid components. In addition, a water-insoluble molded article having improved stretchability and sticking property can be produced. The content of the acid component in the treatment liquid is preferably 1% by mass or more, and more preferably 1.5 to 5.0% by mass.
　処理液に配合される酸成分のうち、ポリカルボン酸としては、シュウ酸、マロン酸、コハク酸、及びグルタル酸からなる群より選択される少なくとも一種を用いることが好ましい。なかでも、マロン酸を用いると、得られる水不溶性成形体の伸縮性、貼り付き性、及び可とう性をより向上させることができる。また、処理液に配合される酸成分のうち、ヒドロキシ酸としては、クエン酸を用いることが好ましい。クエン酸を用いることで、得られる水不溶性成形体の伸縮性、貼り付き性、及び可とう性をより向上させることができる。 Among the acid components blended in the treatment liquid, it is preferable to use at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid as the polycarboxylic acid. Especially, when malonic acid is used, the stretchability, stickability, and flexibility of the resulting water-insoluble molded product can be further improved. Moreover, it is preferable to use a citric acid as a hydroxy acid among the acid components mix | blended with a process liquid. By using citric acid, the stretchability, sticking property, and flexibility of the obtained water-insoluble molded product can be further improved.
　処理液は、水及び水溶性有機溶媒の少なくともいずれかの媒体をさらに含むとともに、この媒体中に酸無水物が溶解又は分散していることが好ましい。このような媒体中に酸無水物が溶解又は分散した処理液を使用することで、原料成形体を十分かつ速やかに水不溶化することができる。 The treatment liquid preferably further contains at least one of water and a water-soluble organic solvent, and the acid anhydride is preferably dissolved or dispersed in this medium. By using a treatment liquid in which an acid anhydride is dissolved or dispersed in such a medium, it is possible to sufficiently and quickly insolubilize the raw material molded body.
　水溶性有機溶媒の具体例としては、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（ＤＭＳＯ）、アセトニトリル、及びテトラヒドロフラン等を挙げることができる。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。これらの水溶性有機溶媒は、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。 Specific examples of the water-soluble organic solvent include methanol, ethanol, propanol, dimethyl sulfoxide (DMSO), acetonitrile, and tetrahydrofuran. Of these, methanol, ethanol, and dimethyl sulfoxide are preferable. These water-soluble organic solvents can be used alone 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、得られる水不溶性成形体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. When the concentration of the acid anhydride is less than 0.1% by mass, the degree of water insolubilization of the resulting water-insoluble molded article 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.
　なお、ポリアニオン性多糖類は親水性が高いため、原料成形体をより十分かつ速やかに水不溶化させる観点から、処理液が媒体として水を含有することが好ましい。処理液中の水の含有量は、原料成形体が溶解又は膨潤しない程度とすることが好ましい。具体的には、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、５～２０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、得られる水不溶性成形体の形状維持が困難となる場合がある。 In addition, since the polyanionic polysaccharide has high hydrophilicity, it is preferable that the treatment liquid contains water as a medium from the viewpoint of water insolubilization of the raw material molded body more sufficiently and quickly. The content of water in the treatment liquid is preferably set to such an extent that the raw material molded body does not dissolve or swell. Specifically, the content of water in the treatment liquid is preferably 0.01 to 50% by mass, and more preferably 5 to 20% 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. Moreover, when the content of water in the treatment liquid is more than 50% by mass, it may be difficult to maintain the shape of the obtained water-insoluble molded article.
　水不溶化工程においては、酸無水物を含む処理液で原料成形体を処理する。原料成形体を処理液で処理することによって原料成形体がその形状を維持したまま水不溶化され、水不溶性成形体が形成される。処理液で原料成形体を処理する方法は特に限定されないが、原料成形体の全体に処理液が接触するとともに、原料成形体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、原料成形体を処理液中に浸漬する、原料成形体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 molded body is treated with a treatment liquid containing an acid anhydride. By treating the raw material molded body with the treatment liquid, the raw material molded body is insolubilized while maintaining its shape, and a water-insoluble molded body is formed. The method of treating the raw material molded body with the treatment liquid is not particularly limited, but it is preferable to treat the raw material molded body so that the treatment liquid contacts the entire raw material molded body and penetrates into the raw material molded body. Specific examples of the treatment method include a method of immersing the raw material molded body in the treatment liquid and applying or spraying (spraying) the treatment liquid onto the raw material molded body.
　なお、粉末状又は粒子状の原料成形体を処理して水不溶化させる場合には、先ず、粉末状又は粒子状の原料成形体を、原料成形体を構成するポリアニオン性多糖類の水溶性塩の貧溶媒に分散させる。次いで、処理液を添加し、貧溶媒中に分散させた状態の粉末状又は粒子状の原料成形体と処理液を接触させ、原料成形体を処理液で処理すればよい。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。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。なお、この貧溶媒は、粉末状又は粒子状の原料成形体が溶解しない程度の微量な水を含有していてもよい。 In the case where the powdery or particulate raw material molded body is treated to make it water-insoluble, first, the powdery or particulate raw material molded body is made of the water-soluble salt of the polyanionic polysaccharide constituting the raw material molded body. Disperse in a poor solvent. Next, the treatment liquid may be added, the powder or particulate raw material molded body dispersed in the poor solvent is brought into contact with the treatment liquid, and the raw material molded body may be treated with the treatment liquid. As the poor solvent, methanol, ethanol, propanol, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, or the like can be used. These poor solvents can be used alone or in combination of two or more. In addition, this poor solvent may contain a trace amount of water to such an extent that the powdery or particulate raw material molded body does not dissolve.
　また、処理の際の温度は、処理液の沸点を超えない温度であればよく、特に限定されない。ポリアニオン性多糖類の分解変性を抑制する観点、及び媒体や副生成物等の揮散を抑制する観点からは、処理の際の温度は０～８０℃とすることが好ましく、０～７０℃とすることがさらに好ましく、室温（２５℃）～６０℃とすることが特に好ましい。但し、処理の際に処理液が揮散しない条件、例えば、ヒートプレスや熱ローラー等により処理すれば、分解変性等が生ずることなく、より短時間で水不溶性成形体を得ることができる。例えば、ヒートプレスや熱ローラー等により処理する場合、処理の際の温度は５０～９０℃とすることが好ましく、処理時間は３０分以下とすることが好ましい。水不溶化工程の後、必要に応じて水や水溶性有機溶媒等を用いて洗浄すること等によって、本発明の水不溶性成形体を得ることができる。 Further, the temperature during the treatment is not particularly limited as long as it does not exceed the boiling point of the treatment liquid. From the viewpoint of suppressing the degradation and modification of the polyanionic polysaccharide and from the viewpoint of suppressing the volatilization of the medium and by-products, the temperature during the treatment is preferably 0 to 80 ° C, and preferably 0 to 70 ° C. It is more preferable that the temperature is room temperature (25 ° C.) to 60 ° C. However, if the treatment liquid is not volatilized during the treatment, for example, heat treatment or a heat roller, a water-insoluble molded article can be obtained in a shorter time without causing decomposition and modification. For example, when the treatment is performed by a heat press or a heat roller, the temperature during the treatment is preferably 50 to 90 ° C., and the treatment time is preferably 30 minutes or less. After the water insolubilization step, the water-insoluble molded product of the present invention can be obtained by washing with water or a water-soluble organic solvent as necessary.
　ポリアニオン性多糖類のナトリウム塩を用いて形成した原料成形体を、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 a raw material molded body formed using a sodium salt of a 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、水不溶性成形体中のＮａ含量の測定、又は水不溶性成形体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 molded article or titrating the water-insoluble molded article with an alkaline solution.
　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、得られる水不溶性成形体は、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 molded product 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を用いて形成した原料成形体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成形体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成形体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 if a raw material molded body formed using a water-soluble salt of a 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 molded body sufficiently water-insoluble. Further, even if the acid anhydride in the treatment liquid is replaced with an acid corresponding to this acid anhydride, a water-insoluble molded product 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.
　本発明の水不溶性成形体の製造方法においては化学的架橋剤を用いる必要がないため、得られる水不溶性成形体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、上記の製造方法によって製造される本発明の水不溶性成形体は、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。したがって、本発明の水不溶性成形体は癒着防止材等の医療用材料として好適である。なお、本発明の水不溶性成形体を癒着防止材の構成材料として用いる場合、水不溶性成形体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。 Since it is not necessary to use a chemical crosslinking agent in the method for producing a water-insoluble molded article of the present invention, a structure such as a functional group derived from the chemical crosslinking agent is incorporated in the molecule constituting the obtained water-insoluble molded article. There is nothing. For this reason, the water-insoluble molded product of the present invention produced by the above production method retains the original characteristics of the polyanionic polysaccharide as a raw material and has high safety. Therefore, the water-insoluble molded product of the present invention is suitable as a medical material such as an adhesion preventing material. In the case where the water-insoluble molded product of the present invention is used as a constituent material of the adhesion preventing material, the thickness of the water-insoluble molded product is not particularly limited, but is preferably 20 to 200 μm, more preferably 60 to 120 μm.
（癒着防止材）
　本発明の癒着防止材は、前述の水不溶性成形体に多価アルコール又は多価アルコール水溶液が保持されてなるものである。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。 (Adhesion prevention material)
The anti-adhesion material of the present invention is obtained by holding a polyhydric alcohol or a polyhydric alcohol aqueous solution on the water-insoluble molded article. 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.
　水不溶性成形体に多価アルコール又は多価アルコール水溶液を保持させる方法としては、例えば、水不溶性成形体を多価アルコール又は所定濃度の多価アルコール水溶液に浸漬する方法等がある。すなわち、所定形状の水不溶性成形体を多価アルコール水溶液に浸漬し、水不溶性成形体の内部を多価アルコール水溶液で置換することで、所望とする濃度の多価アルコール水溶液を保持させて、所望とする本発明の癒着防止材を得ることができる。なお、本発明の癒着防止材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。 Examples of a method for holding a polyhydric alcohol or a polyhydric alcohol aqueous solution in a water-insoluble molded body include a method of immersing a water-insoluble molded body in a polyhydric alcohol or a polyhydric alcohol aqueous solution having a predetermined concentration. That is, by immersing a water-insoluble molded article having a predetermined shape in a polyhydric alcohol aqueous solution and replacing the interior of the water-insoluble molded article with the polyhydric alcohol aqueous solution, the polyhydric alcohol aqueous solution having a desired concentration is retained, The adhesion preventing material of the present invention can be obtained. The thickness of the adhesion preventing material of the present invention is not particularly limited, but is preferably 20 to 200 μm, and more preferably 60 to 120 μm.
（注入材）
　注入材は、前述の水不溶性成形体のうち、その形状が粉末状又は粒子状の水不溶性成形体を含有する。注入材は、水不溶化していないヒアルロン酸の水溶性塩の水溶液等の液媒体をさらに含有してもよい。注入材を構成する水不溶性成形体は、前述の通り、化学的架橋剤を用いることなく製造されうるものであり、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ため、安全性に優れている。また、注入材は粉末状又は粒子状の水不溶性成形体を含有するために流動性が高く、粉末又は粒子の粒径を適宜調整することで、患部等に注射針を経由して容易に注入することができる。このため、注入材は、例えば、関節変形治療用関節内注入剤、及び皮下注入剤等として有用である。 (Injection material)
The injection material contains a water-insoluble molded body having a powder or particle shape among the water-insoluble molded bodies described above. The injection material may further contain a liquid medium such as an aqueous solution of a water-soluble salt of hyaluronic acid that has not been insolubilized in water. As described above, the water-insoluble molded body constituting the injection material can be manufactured without using a chemical crosslinking agent, and since the original characteristics of the polyanionic polysaccharide as a raw material are maintained, it is safe to use. Are better. In addition, since the injection material contains a powdery or particulate water-insoluble molded product, it has high fluidity and can be easily injected into the affected area via an injection needle by appropriately adjusting the particle size of the powder or particles. can do. For this reason, the injection material is useful as, for example, an intra-articular injection for joint deformation treatment, a subcutaneous injection, or the like.
（徐放性製剤）
　徐放性製剤は、前述の水不溶性成形体と、薬学的に許容される有効成分とを含む。徐放性製剤を構成する水不溶性成形体は、前述の通り、化学的架橋剤を用いることなく製造されうるものであり、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ため、安全性に優れている。また、水不溶性成形体は生体内で徐々に分解して吸収されるので、有効成分を徐々に放出することができる。なお、有効成分の種類は薬学的に許容されるものであれば特に限定されない。 (Slow release formulation)
The sustained-release preparation contains the above-mentioned water-insoluble molded article and a pharmaceutically acceptable active ingredient. As described above, the water-insoluble molded article constituting the sustained-release preparation can be produced without using a chemical crosslinking agent, and since the original characteristics of the polyanionic polysaccharide as a raw material are retained, it is safe. Excellent in properties. Further, since the water-insoluble molded article is gradually decomposed and absorbed in the living body, the active ingredient can be gradually released. The type of active ingredient is not particularly limited as long as it is pharmaceutically acceptable.
　徐放性製剤の態様としては、例えば、シート状に成形された水不溶性成形体に有効成分又はその溶液等を含浸させたものや、水不溶性成形体からなるカプセルと、このカプセル内に封入された有効成分とからなるもの等を挙げることができる。シートやカプセルの厚みや形状等を適宜設定することで、生体内での徐放性を制御することができる。 Examples of sustained-release preparations include, for example, a water-insoluble molded product formed into a sheet shape impregnated with an active ingredient or a solution thereof, a capsule made of a water-insoluble molded product, and a capsule enclosed in this capsule. And those composed of active ingredients. By appropriately setting the thickness, shape, etc. of the sheet or capsule, the sustained release in vivo can be controlled.
　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.
　使用した試薬の詳細を以下に示す。水としては、超純水製造装置（ザルトリウスジャパン社製）を使用して調製した、導電率１８．０ＭΩ・ｃｍ以上の水を用いた。
　　ヒアルロン酸ナトリウム：資生堂社製、分子量１５０万Ｄａ
　　クエン酸：和光純薬社製、試薬特級
　　グリセリン：阪本薬品工業社製、日本薬局方
　　塩酸：和光純薬株式会社、試薬特級
　　エタノール：純正化学社製、試薬特級
　　メタノール：和光純薬社製、試薬特級
　　無水酢酸：和光純薬社製、試薬特級
　　マロン酸：和光純薬社製、試薬特級
　　シュウ酸：和光純薬社製、試薬特級
　　コハク酸：和光純薬社製、試薬特級 Details of the reagents used are shown below. As the water, water having an electrical conductivity of 18.0 MΩ · cm or more prepared using an ultrapure water production apparatus (manufactured by Sartorius Japan) was used.
Sodium hyaluronate: manufactured by Shiseido Co., Ltd., molecular weight 1.5 million Da
Citric acid: Wako Pure Chemical Industries, reagent special grade Glycerin: Sakamoto Yakuhin Kogyo Co., Japan Pharmacopoeia Hydrochloric acid: Wako Pure Chemical Industries, reagent special grade Ethanol: Junsei Chemical Co., reagent special grade Methanol: Wako Pure Chemical Industries, reagent Special grade Acetic anhydride: Wako Pure Chemical Industries, reagent special grade Malonic acid: Wako Pure Chemical Industries, reagent special grade Oxalic acid: Wako Pure Chemical Industries, reagent special grade Succinic acid: Wako Pure Chemical Industries, reagent special grade
＜水不溶性成形体（ヒアルロン酸膜）の製造（１）＞
（実施例１～４、比較例１～３）
　各成分を表１の上段に示す配合比（単位：％）となるように混合してヒアルロン酸ナトリウム水溶液を調製した。調製した水溶液１００ｇを縦１２ｃｍ×横１０ｃｍのステンレストレイに流し込み、２０℃の恒温槽内で乾燥させてヒアルロン酸ナトリウム膜を得た。得られた膜を処理液（無水酢酸：７５％エタノール溶液＝８０：２０）に浸漬し、５０℃で１時間放置して水不溶化処理し、水不溶性のヒアルロン酸膜を得た。 <Production of water-insoluble molded product (hyaluronic acid film) (1)>
(Examples 1 to 4, Comparative Examples 1 to 3)
Each component was mixed so that it might become the mixture ratio (unit:%) shown in the upper stage of Table 1, and sodium hyaluronate aqueous solution was prepared. 100 g of the prepared aqueous solution 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. to obtain a sodium hyaluronate film. The obtained film was immersed in a treatment solution (acetic anhydride: 75% ethanol solution = 80: 20) and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble hyaluronic acid film.
＜水不溶性成形体（ヒアルロン酸膜）の製造（２）＞
（実施例５～８）
　各成分を表２の上段に示す配合量（単位：ｇ）となるように混合してヒアルロン酸ナトリウム水溶液を調製した。調製した水溶液全量を縦１２ｃｍ×横１０ｃｍのステンレストレイに流し込み、２０℃の恒温槽内で乾燥させてヒアルロン酸ナトリウム膜を得た。得られた膜を処理液（無水酢酸：７５％エタノール溶液＝８０：２０）に浸漬し、５０℃で１時間放置して水不溶化処理し、水不溶性のヒアルロン酸膜を得た。 <Production of water-insoluble molded product (hyaluronic acid film) (2)>
(Examples 5 to 8)
Each component was mixed so that it might become the compounding quantity (unit: g) shown in the upper stage of Table 2, and sodium hyaluronate aqueous solution was prepared. The total amount of the prepared aqueous solution 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. to obtain a sodium hyaluronate film. The obtained film was immersed in a treatment solution (acetic anhydride: 75% ethanol solution = 80: 20) and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble hyaluronic acid film.
＜水不溶性成形体（ヒアルロン酸膜）の製造（３）＞
（実施例９～１４、比較例４）
　ヒアルロン酸ナトリウムの粉末１部を含む水溶液１００部を調製した。調製した水溶液１００ｇを縦１２ｃｍ×横１０ｃｍのステンレストレイに流し込み、２０℃の恒温槽内で乾燥させてヒアルロン酸ナトリウム膜を得た。一方、各成分を表３の上段に示す配合比（単位：％）となるように混合して処理液を調製した。調製した処理液に得られた膜をそれぞれ浸漬し、５０℃で１時間放置して水不溶化処理し、水不溶性のヒアルロン酸膜を得た。 <Production of water-insoluble molded product (hyaluronic acid film) (3)>
(Examples 9 to 14, Comparative Example 4)
100 parts of an aqueous solution containing 1 part of sodium hyaluronate powder was prepared. 100 g of the prepared aqueous solution 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. to obtain a sodium hyaluronate film. On the other hand, each component was mixed so as to have a blending ratio (unit:%) shown in the upper part of Table 3 to prepare a treatment liquid. The obtained films were immersed in the prepared treatment solution and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a water-insoluble hyaluronic acid film.
＜評価＞
（伸縮性）
　製造した水不溶性のヒアルロン酸膜を水に浸漬して十分に膨潤させたものを用いて、以下に示す評価基準にしたがって伸縮性を評価した。結果を表１～３に示す。
　Ａ：引っ張って破断するまでに、全長の１０％以上の伸びがある。
　Ｂ：引っ張って破断するまでに、全長の５％以上１０％未満の伸びがある。
　Ｃ：引っ張って破断するまでに、全長の１％以上５％未満の伸びがある。
　Ｄ：引っ張って破断するまでの伸びが、全長の１％未満である。 <Evaluation>
(Elasticity)
The produced water-insoluble hyaluronic acid film was immersed in water and sufficiently swollen, and the stretchability was evaluated according to the following evaluation criteria. The results are shown in Tables 1 to 3.
A: There is an elongation of 10% or more of the total length before pulling and breaking.
B: There is an elongation of 5% or more and less than 10% of the total length before pulling and breaking.
C: There is an elongation of 1% or more and less than 5% of the total length until it is pulled and broken.
D: Elongation until pulling and breaking is less than 1% of the total length.
（貼り付き性）
　製造した水不溶性のヒアルロン酸膜を水に浸漬して十分に膨潤させたものを用いて、以下に示す評価基準にしたがって貼り付き性を評価した。結果を表１～３に示す。
　ａ：手に貼り付けると、まとわりついて剥がしにくい。
　ｂ：手に貼り付けると、容易には剥がせない。
　ｃ：手に貼り付くが、容易に剥がすことができる。
　ｄ：手に貼り付かず、手を動かすと容易に移動する。 (Adhesiveness)
The produced water-insoluble hyaluronic acid film was immersed in water and sufficiently swollen, and the sticking property was evaluated according to the following evaluation criteria. The results are shown in Tables 1 to 3.
a: When affixed to a hand, it clings and is difficult to peel off.
b: When attached to a hand, it cannot be easily peeled off.
c: Affixed to the hand, but can be easily peeled off.
d: It does not stick to the hand and moves easily when the hand is moved.
（可とう性）
　製造した水不溶性のヒアルロン酸膜を水に浸漬して十分に膨潤させたものを用いて、以下に示す評価基準にしたがって可とう性を評価した。結果を表１～３に示す。
　１：ふたつ折にし、折り目を強くしごいても割れない。
　２：ふたつ折にし、折り目を強く押しても割れない。
　３：ふたつ折にできるが、折り目を強く押すと割れる。
　４：ふたつ折にすると割れる。 (Flexibility)
Using the produced water-insoluble hyaluronic acid film immersed in water and sufficiently swollen, the flexibility was evaluated according to the following evaluation criteria. The results are shown in Tables 1 to 3.
1: It is not broken even if it is made into two folds and the crease is strongly crushed.
2: Even if it is made into two folds and the crease is pushed strongly, it does not break.
3: Can be folded into two folds, but breaks when pressed strongly.
4: Cracked when folded in two.
Figure JPOXMLDOC01-appb-I000003
Figure JPOXMLDOC01-appb-I000003
Figure JPOXMLDOC01-appb-I000004
Figure JPOXMLDOC01-appb-I000004
Figure JPOXMLDOC01-appb-I000005
Figure JPOXMLDOC01-appb-I000005
　表１に示す結果から、ヒアルロン酸ナトリウム膜を形成する原材料に所定量の酸成分を添加することで、得られる水不溶性のヒアルロン酸膜の伸縮性及び可とう性が改善されることがわかる。なかでも、クエン酸による改善効果が大きいことがわかる。 From the results shown in Table 1, it is understood that the stretchability and flexibility of the water-insoluble hyaluronic acid film obtained can be improved by adding a predetermined amount of an acid component to the raw material for forming the sodium hyaluronate film. Especially, it turns out that the improvement effect by a citric acid is large.
　表２に示す結果から、ヒアルロン酸ナトリウム膜を形成する原材料にアルコール類を添加することで、得られる水不溶性のヒアルロン酸膜の伸縮性及び可とう性が改善されることがわかる。なお、エタノールによる改善効果とメタノールによる改善効果は、ほぼ同等であった。 From the results shown in Table 2, it can be seen that the addition of alcohols to the raw material for forming the sodium hyaluronate film improves the stretchability and flexibility of the resulting water-insoluble hyaluronic acid film. The improvement effect by ethanol and the improvement effect by methanol were almost the same.
　表３に示す結果から、処理液にポリカルボン酸やヒドロキシ酸を添加することで、得られる水不溶性のヒアルロン酸膜の伸縮性、貼り付き性、及び可とう性が改善されることがわかる。なかでも、マロン酸やクエン酸による改善効果が大きいことがわかる。 From the results shown in Table 3, it can be seen that the addition of polycarboxylic acid or hydroxy acid to the treatment liquid improves the stretchability, stickiness, and flexibility of the resulting water-insoluble hyaluronic acid film. Especially, it turns out that the improvement effect by malonic acid or a citric acid is large.
（溶解度試験）
　製造した水不溶性のヒアルロン酸膜を２ｃｍ角に切断し、直径３．５ｃｍ、深さ１．５ｃｍの容器に入れ、ＰＢＳ緩衝液（ｐＨ６．８）５ｍＬを加えた。この容器を３７℃に調整した振盪機に入れ、１０～２０ｒｐｍで振盪し、経時的な状態変化を目視観察した。その結果、いずれの膜についても、７２時間後であっても膜の原形が保持されており、水不溶化されていることが分かった。また、膨潤度（膨潤膜／乾燥膜（質量比））は、いずれの膜も１．８～２．５の範囲であった。 (Solubility test)
The produced water-insoluble hyaluronic acid film was cut into 2 cm square, placed in a container having a diameter of 3.5 cm and a depth of 1.5 cm, and 5 mL of PBS buffer (pH 6.8) was added. This container was placed in a shaker adjusted to 37 ° C., shaken at 10 to 20 rpm, and the state change over time was visually observed. As a result, it was found that the original form of the film was retained and water insolubilized for each film even after 72 hours. The degree of swelling (swelled film / dry film (mass ratio)) was in the range of 1.8 to 2.5 for all films.
（動物実験）
　実施例１、５、及び９で製造した膜を１０体積％グリセリン水溶液にそれぞれ浸漬した後、風乾して滅菌用袋に封入した。２５ｋＧｙの放射線を照射して滅菌用袋ごと滅菌して癒着防止膜を得た。成犬（ビーグル犬、雌、１．５歳、体重約１０ｋｇ）を全身麻酔処置後に開腹し、腹側壁表皮を３ｃｍ角に剥離した。剥離部分を覆うように癒着防止膜を配置して閉腹した。２週間後、同犬を全身麻酔処置後に開腹したところ、いずれの膜でも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、埋植後２週間で消失していた。これは、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と変化して溶解し、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腹した犬については、剥離部分と腸に癒着が生じていることが観察された。 (Animal experimentation)
The membranes produced in Examples 1, 5, and 9 were each immersed in a 10% by volume glycerin aqueous solution, then air-dried and sealed in a sterilization bag. The anti-adhesion membrane was obtained by sterilizing the entire sterilization bag with irradiation of 25 kGy. An adult dog (beagle dog, female, 1.5 years old, weight about 10 kg) was opened after general anesthesia treatment, and the epidermis epidermis was peeled into 3 cm square. The abdomen was closed by placing an adhesion-preventing membrane so as to cover the peeled portion. Two weeks later, the dog was laparotomized after general anesthesia, and no adhesion occurred in any of the membranes. In addition, the anti-adhesion membrane placed (implanted) in the dog's body disappeared two weeks after implantation. This is presumed that the carboxy group of hyaluronic acid constituting the anti-adhesion membrane was gradually neutralized by sodium ions etc. in the living body, and changed into soluble hyaluronate, dissolved and absorbed into the living body. The On the other hand, it was observed that adhesion occurred in the peeled portion and the intestine in dogs that were closed without placing an anti-adhesion membrane.
　本発明の水不溶性成形体は、例えば、癒着防止材の構成材料として好適に用いることができる。 The water-insoluble molded product of the present invention can be suitably used, for example, as a constituent material of an adhesion preventing material.

Claims (10)

  1. 　ポリアニオン性多糖類の水溶性塩と、０．２質量％以上の酸成分とを含有する原材料からなる原料成形体、又はポリアニオン性多糖類の水溶性塩と、アルコール類（グリセリンを除く）とを含有する原材料からなる原料成形体を、酸無水物を含む処理液で処理し、前記原料成形体を水不溶化させる工程を有する水不溶性成形体の製造方法。 A raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide and 0.2% by mass or more of an acid component, or a water-soluble salt of a polyanionic polysaccharide, and alcohols (excluding glycerin) A method for producing a water-insoluble molded article, comprising a step of treating a raw material molded body made of the raw material contained with a treatment liquid containing an acid anhydride to insolubilize the raw material molded body.
  2. 　前記酸成分が、クエン酸及び塩酸の少なくともいずれかである請求項１に記載の水不溶性成形体の製造方法。 The method for producing a water-insoluble molded article according to claim 1, wherein the acid component is at least one of citric acid and hydrochloric acid.
  3. 　前記アルコール類が、エタノール及びメタノールの少なくともいずれかである請求項１に記載の水不溶性成形体の製造方法。 The method for producing a water-insoluble molded article according to claim 1, wherein the alcohol is at least one of ethanol and methanol.
  4. 　ポリアニオン性多糖類の水溶性塩を含有する原材料からなる原料成形体を、酸無水物と、ポリカルボン酸及びヒドロキシ酸の少なくともいずれかの酸成分とを含有する処理液で処理し、前記原料成形体を水不溶化させる工程を有する水不溶性成形体の製造方法。 A raw material molded body made of a raw material containing a water-soluble salt of a polyanionic polysaccharide is treated with a treatment liquid containing an acid anhydride and at least one acid component of a polycarboxylic acid and a hydroxy acid, and the raw material molding is performed. A method for producing a water-insoluble molded article comprising a step of water-insolubilizing a body.
  5. 　前記ポリカルボン酸が、シュウ酸、マロン酸、コハク酸、及びグルタル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４に記載の水不溶性成形体の製造方法。 The method for producing a water-insoluble molded article according to claim 4, wherein the polycarboxylic acid is at least one selected from the group consisting of oxalic acid, malonic acid, succinic acid, and glutaric acid.
  6. 　前記ヒドロキシ酸が、クエン酸である請求項４又は５に記載の水不溶性成形体の製造方法。 The method for producing a water-insoluble molded article according to claim 4 or 5, wherein the hydroxy acid is citric acid.
  7. 　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１～６のいずれか一項に記載の水不溶性成形体の製造方法。 The method for producing a water-insoluble molded product according to any one of claims 1 to 6, wherein the polyanionic polysaccharide is at least one selected from the group consisting of hyaluronic acid, carboxymethylcellulose, and alginic acid.
  8. 　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１～７のいずれか一項に記載の水不溶性成形体の製造方法。 The method for producing a water-insoluble molded product according to any one of claims 1 to 7, wherein the acid anhydride is at least one of acetic anhydride and propionic anhydride.
  9. 　請求項１～８のいずれか一項に記載の製造方法によって製造された水不溶性成形体。 A water-insoluble molded product produced by the production method according to any one of claims 1 to 8.
  10. 　請求項９に記載の水不溶性成形体に多価アルコール又は多価アルコール水溶液が保持されてなる癒着防止材。 10. An adhesion preventing material comprising a water-insoluble molded product according to claim 9, wherein a polyhydric alcohol or a polyhydric alcohol aqueous solution is retained.
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JP2002308903A (en) * 2001-04-12 2002-10-23 Denki Kagaku Kogyo Kk Method for controlling solubility of hyaluronic acid made hardly water soluble
JP2004051531A (en) * 2002-07-19 2004-02-19 Denki Kagaku Kogyo Kk Adhesion inhibitor containing slightly water-soluble carboxymethylcellulose
JP2008155014A (en) * 2006-11-30 2008-07-10 Yasuharu Noisshiki Medical material for obstructing accretion
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