WO2015029892A1 - 水不溶性成形体の製造方法及び水不溶性成形体 - Google Patents
水不溶性成形体の製造方法及び水不溶性成形体 Download PDFInfo
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- 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
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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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
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- A—HUMAN NECESSITIES
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- 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
- A61K8/733—Alginic acid; Salts thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
- C08J2301/08—Cellulose derivatives
- C08J2301/26—Cellulose ethers
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- 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
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- C08J2305/04—Alginic acid; Derivatives thereof
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- 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
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- 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
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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Definitions
- the present invention relates to a method for producing a water-insoluble molded product, a water-insoluble molded product, an adhesion preventing material, an injection material, and a sustained-release preparation.
- 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 for producing a hyaluronic acid gel using an acidic liquid containing alcohol.
- 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.
- 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 easily producing a water-insoluble molded article that is highly safe because it does not need to be used and is useful as a medical material, food material, cosmetic material, or the like.
- the place made into the subject of this invention is providing the water-insoluble molded object manufactured by said method, an adhesion prevention material, an injection material, and a sustained release formulation.
- the present inventors have processed a raw material molded body formed using a water-soluble salt of a polyanionic polysaccharide with a treatment liquid containing an acid anhydride, thereby producing a chemical crosslinking agent.
- the present inventors have found that the above-described problems can be achieved without using the present invention, and have completed the present invention.
- a method for producing a water-insoluble molded body comprising a step of treating a raw material molded body made of a water-soluble salt of a polyanionic polysaccharide with a treatment liquid containing an acid anhydride to insolubilize the raw material molded body.
- the water-insoluble molded object shown below is provided.
- [7] A water-insoluble molded product produced by the production method according to any one of [1] to [6].
- Water which is a molded body made of polyanionic polysaccharide, and the weight of the dried body obtained by repeating the drying operation after being swollen with water twice is 80% or more of the dry weight before the operation Insoluble molding.
- adhesion prevention material shown below is provided.
- the injection material shown below is provided.
- sustained-release preparation comprising the water-insoluble molded product according to any one of [7] to [11] and a pharmaceutically acceptable active ingredient.
- the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and it is not necessary to use a chemical cross-linking agent.
- a water-insoluble molded article useful as a cosmetic material, a cosmetic material, or the like can be easily produced without using a chemical crosslinking agent.
- 2 is an infrared absorption spectrum of a sodium hyaluronate film (before water insolubilization treatment) obtained in Example 1.
- 2 is an infrared absorption spectrum of a water-insoluble film (after water insolubilization treatment) obtained in Example 1.
- 2 is a fluorescent X-ray spectrum of a sodium hyaluronate film (before water insolubilization treatment) obtained in Example 1.
- 2 is a fluorescent X-ray spectrum of a water-insoluble film (after water insolubilization treatment) obtained in Example 1.
- the method for producing a water-insoluble molded product of the present invention comprises treating a raw material molded product comprising a water-soluble salt of a polyanionic polysaccharide with a treatment liquid containing an acid anhydride, and making the raw material molded product insoluble in water, thereby producing a water-insoluble molded product.
- a step of forming (water insolubilization step). The details will be described below.
- the raw material molded body used in the water insolubilization step is formed using 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 molded body can be obtained, for example, by forming an aqueous solution obtained by dissolving a water-soluble salt of a polyanionic polysaccharide in water into a desired shape and then drying the solution.
- 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.
- 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-insolubilized product (water-insoluble molded product) having a shape corresponding to the application is used because the water-insoluble treatment is performed after the polyanionic polysaccharide is molded into a desired shape. Body).
- 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 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.
- the raw material molded body can be sufficiently and quickly insolubilized to obtain a water-insoluble molded body.
- 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.
- the content of water in the treatment liquid is less than 0.01%, insolubilization may be insufficient with a solvent other than methanol.
- the content of water in the treatment liquid is more than 50%, it may be difficult to maintain the shape of the resulting 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 obtained water-insoluble molded product may not have all anionic groups in the molecule in an acid form.
- the water-insoluble molded product of the present invention is suitable as a food material or a cosmetic material in addition to a medical material such as an adhesion preventing material.
- water-insoluble in this specification means a property that does not easily dissolve in water. More specifically, in the water-insoluble molded product of the present invention comprising a polyanionic polysaccharide, the mass of the dried product obtained by repeating the drying operation after being swollen with water twice is the dry mass before this operation. 80% or more.
- the water-insoluble molded product of the present invention is produced by removing at least a part of the cationic species constituting the salt from the raw material molded product made of a water-soluble salt of a polyanionic polysaccharide.
- the swelling ratio of the water-insoluble molded product of the present invention is preferably 6,000% by mass or less, more preferably 900% by mass or less, particularly preferably 100 to 500% by mass, 150 Most preferred is ⁇ 350% by weight.
- those having a sufficiently low swelling rate are suitable as food materials and cosmetic materials in addition to medical materials such as anti-adhesion materials.
- the “swelling ratio” is the ratio (mass%) of “the mass of the water-insoluble molded product after moisture retention (after swelling)” to “the mass of the water-insoluble molded product before moisture retention (before swelling)”. ).
- a water-insoluble molded article having a relatively low swelling rate for example, 6,000% by mass or less
- a water-insoluble molded article having a relatively low swelling rate for example, 6,000% by mass or less
- the water-insoluble molded product of the present invention is obtained by treating a raw material molded product made of a water-soluble salt of a polyanionic polysaccharide with a treatment liquid containing an acid anhydride without using a chemical crosslinking agent, thereby making the raw material molded product water-insoluble. It was obtained. For this reason, in the water-insoluble molded article of the present invention, the molecules of the polyanionic polysaccharide constituting the same are not substantially crosslinked. Furthermore, a new covalent bond is not substantially formed in the polyanionic polysaccharide.
- the water-insoluble molded product of the present invention is stably water-insoluble in a wide pH range from acidic to alkaline. However, when the water-insoluble molded product of the present invention is contacted or immersed in an aqueous medium having a pH of 12 or more, for example, the physical bond between molecules can be dissociated and easily dissolved.
- the method for producing an antiadhesive material of the present invention includes a step of holding a polyhydric alcohol or a polyhydric alcohol aqueous solution in the water-insoluble molded article.
- polyhydric alcohol examples include ethylene glycol, diethylene glycol, polyethylene glycol, methylglycerol, polyoxyelene 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 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 injection material of the present invention contains a water-insoluble molded product having a powder or particle shape among the above-mentioned water-insoluble molded products.
- the injection material of the present invention may further contain a liquid medium such as an aqueous solution of a water-soluble salt of hyaluronic acid that is not insolubilized in water.
- a liquid medium such as an aqueous solution of a water-soluble salt of hyaluronic acid that is not insolubilized in water.
- the water-insoluble molded article constituting the injection material of the present invention can be produced without using a chemical crosslinking agent, and since the original characteristics of the polyanionic polysaccharide as a raw material are retained, Excellent safety.
- the injection material of the present invention contains a powdery or particulate water-insoluble molded product, it has high fluidity, and by appropriately adjusting the particle size of the powder or particles, the affected part or the like is passed through the injection needle. Can be easily injected. Therefore, the injection material of the present invention is useful as, for example, an intra-articular injection for joint deformation treatment and a subcutaneous injection.
- the sustained-release preparation of the present invention contains the aforementioned water-insoluble molded article and a pharmaceutically acceptable active ingredient.
- the water-insoluble molded article constituting the sustained-release preparation of the present invention can be produced without using a chemical crosslinking agent as described above, and retains the original characteristics of the polyanionic polysaccharide as a raw material. Therefore, it is excellent in safety. 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.
- Example 1 1.0 g of sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa) and 99.0 g of water were mixed and stirred in a beaker to obtain a uniform aqueous solution. The obtained aqueous solution was poured into a stainless steel vat and dried at 30 ° C. to obtain a sodium hyaluronate film. The obtained sodium hyaluronate film was immersed in 100 mL of a processing solution (1% by volume acetic anhydride / methanol solution) and left at room temperature for 18 hours for water insolubilization treatment. The water-insolubilized membrane was washed with methanol, 80% by volume methanol aqueous solution, and water in this order to obtain a water-insoluble membrane.
- a processing solution 1% by volume acetic anhydride / methanol solution
- FIG. 1 is an infrared absorption spectrum of the sodium hyaluronate film (before water insolubilization treatment) obtained in Example 1.
- FIG. 2 is an infrared absorption spectrum of the water-insoluble film (after water insolubilization treatment) obtained in Example 1.
- the water insolubilization treatment reduced the absorption of 1400 cm ⁇ 1 (arrow 1 (FIG. 1)) and 1600 cm ⁇ 1 (arrow 2 (FIG. 1)) derived from dissociated carboxy groups.
- the absorption at 1220 cm ⁇ 1 (arrow 3 (FIG. 2)) and 1730 cm ⁇ 1 (arrow 4 (FIG. 2)) derived from the non-dissociated carboxy group increased.
- FIG. 3 is a fluorescent X-ray spectrum of the sodium hyaluronate film (before water insolubilization treatment) obtained in Example 1.
- FIG. 4 is a fluorescent X-ray spectrum of the water-insoluble film (after water insolubilization treatment) obtained in Example 1.
- Examples 2 to 13, Comparative Examples 1 to 3 A water-insoluble membrane was obtained in the same manner as in Example 1 except that the water-soluble salt of polyanionic polysaccharide and the treatment liquid of the type shown in Table 1 were used.
- the swelling ratio of the produced water-insoluble film was measured by the following procedure. The mass of the water-insoluble film in a dry state was measured and was defined as “mass before swelling”. Next, the water-insoluble film was immersed in sufficient water and allowed to stand at room temperature for 1 hour. Excess water adhering to the surface of the sufficiently swollen water-insoluble film was removed with a paper towel or the like, and the mass was measured to obtain the “mass after swelling”. “Swelling rate” means the ratio (mass%) of “mass after swelling” to “mass before swelling”. The results are shown in Table 2. In addition, the water-insoluble film produced in Example 1 was difficult to lift from the immersed water and to remove excess water adhering to the surface, and thus the swelling ratio could not be measured.
- Non-dissolution rate (%) (Y / X) ⁇ 100
- X Mass (g) of dried body of water-insoluble film before swelling / drying treatment (initial stage)
- Y Mass (g) of dry body of water-insoluble film after swelling / drying treatment
- Example 14 1.0 g of sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa) and 99.0 g of water were mixed and stirred in a beaker to obtain a uniform aqueous solution. The obtained aqueous solution was poured into a stainless steel vat and dried at 30 ° C. to obtain a sodium hyaluronate film. The obtained sodium hyaluronate film was immersed in 100 mL of a treatment solution (100% acetic anhydride) and allowed to stand at room temperature for 18 hours, but could not be sufficiently insolubilized in water.
- a treatment solution (100% acetic anhydride
- the obtained sodium hyaluronate film was immersed in 100 mL of a treatment solution (acetic anhydride 100%) and left at room temperature for 10 days for water insolubilization treatment.
- the water-insolubilized membrane was washed with methanol, 80% by volume methanol aqueous solution, and water in this order to obtain a water-insoluble membrane.
- the above-mentioned “solubility test” was performed on the obtained water-insoluble membrane, the original shape of the membrane was maintained for 72 hours or more.
- Example 15 1.0 g of sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa) and 99.0 g of water were mixed and stirred in a beaker to obtain a uniform aqueous solution. The obtained aqueous solution was poured into a stainless steel vat, frozen at ⁇ 30 ° C., and freeze-dried at a shelf heating temperature of 120 ° C. to obtain a sponge-like molded body made of sodium hyaluronate.
- aqueous solution was poured into a stainless steel vat, frozen at ⁇ 30 ° C., and freeze-dried at a shelf heating temperature of 120 ° C. to obtain a sponge-like molded body made of sodium hyaluronate.
- the obtained sponge-like molded product was immersed in 100 mL of a processing solution (10% acetic anhydride / methanol solution) and left at room temperature for 18 hours for water insolubilization treatment.
- the water-insolubilized molded body was washed with methanol, an 80% by volume aqueous methanol solution, and water in this order to obtain a water-insoluble sponge-like molded body.
- a processing solution 10% acetic anhydride / methanol solution
- Example 16 10 g of sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa Co., Ltd.) was dissolved in 90 g of water to obtain a uniform and viscous aqueous sodium hyaluronate solution.
- the obtained sodium hyaluronate aqueous solution was put into a syringe equipped with an 18 gauge needle and extruded to obtain a fibrous shaped body.
- the resulting sponge-like molded product had a high viscosity and was held in a fibrous form.
- the obtained sponge-like molded product was immersed in 100 mL of a processing solution (10% acetic anhydride / methanol solution) and left at room temperature for 18 hours for water insolubilization treatment.
- the water-insolubilized molded body was washed with methanol, 80% by volume methanol aqueous solution, and water in this order to obtain a water-insoluble fibrous molded body.
- a processing solution 10% acetic anhydride / methanol solution
- Example 17 The water-insoluble sponge-like molded product produced in Example 15 was cut into a bowl shape and then impregnated with a commercial lotion. The saddle-shaped sponge-like molded body did not dissolve in the skin lotion. Moreover, since the sticking property to skin was high, it could be used as a cosmetic material for sticking to the eyes.
- Example 18 The water-insoluble membrane produced in Example 5 cut into a size of 12 cm ⁇ 9 cm was immersed in a 10% by volume glycerin aqueous solution, then air-dried and enclosed 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 opened after general anesthesia, and no adhesions occurred.
- 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.
- Example 19 1.0 g of sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa) and 99.0 g of water were mixed and stirred in a beaker to obtain a uniform aqueous solution. The obtained aqueous solution was poured into a stainless steel vat and dried at 30 ° C. to obtain a sodium hyaluronate film. The obtained sodium hyaluronate membrane was immersed in 100 mL of a treatment solution (20% acetic anhydride / methanol solution), and was 18 hours at room temperature (25 ° C.) (Example 19), 1 hour at 50 ° C.
- a treatment solution (20% acetic anhydride / methanol solution
- Example 20 And left at 85 ° C. for 5 minutes (Example 21) for water insolubilization treatment.
- the water-insolubilized membrane was washed with methanol, 80% by volume methanol aqueous solution, and water in this order to obtain a water-insoluble membrane.
- the obtained water-insoluble membrane was subjected to the aforementioned “evaluation 1: solubility test” to evaluate water-insolubility. As a result, all were insolubilized in water, and it was confirmed that the original shape of the membrane was maintained for 72 hours or more.
- the swelling ratio of the obtained water-insoluble film was 244% (Example 19), 192% (Example 20), and 161% (Example 21), respectively.
- the water-insoluble film immersed in the PBS buffer remained in its original form, but the water-insoluble film immersed in the hyaluronidase aqueous solution was completely dissolved. It can be said that the water-insoluble membrane of this embodiment has been degraded by hyaluronidase because it retains the hyaluronic acid skeleton. From the above, it is presumed that the water-insoluble membrane of this embodiment is metabolized by the same metabolic pathway as that of water-soluble hyaluronic acid even when placed in a living body.
- Example 22 1.0 g of powder of sodium hyaluronate (molecular weight (nominal value): 800,000, manufactured by Kikkoman Biochemifa) was added to 64.0 mL of ethanol, and stirred in a beaker to obtain a dispersion. Next, 16.0 mL of water was added and further stirred. After adding 20 mL of acetic anhydride, the mixture was stirred at room temperature for 18 hours for water insolubilization treatment. The water-insolubilized powder was washed with methanol, 80% by volume methanol aqueous solution, and water in this order to obtain a water-insoluble powder (water-insoluble hyaluronic acid powder).
- the water-insoluble molded product of the present invention is useful as a medical material, a food material, a cosmetic material, and the like.
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Abstract
Description
[1]ポリアニオン性多糖類の水溶性塩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。
[2]前記原料成形体の形状が、膜状、塊状、繊維状、棒状、管状、粉末状、粒子状、又はスポンジ状である前記[1]に記載の水不溶性成形体の製造方法。
[3]前記ポリアニオン性多糖類が、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、コンドロイチン硫酸、ヒアルロン酸、ヘパリン、アルギン酸、ペクチン、及びカラギーナン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]又は[2]に記載の水不溶性成形体の製造方法。
[4]前記酸無水物が、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]~[3]のいずれかに記載の水不溶性成形体の製造方法。
[5]前記処理液が、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前記[1]~[4]のいずれかに記載の水不溶性成形体の製造方法。
[6]前記水溶性有機溶媒が、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からなる群より選択される少なくとも一種である前記[5]に記載の水不溶性成形体の製造方法。
[7]前記[1]~[6]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。
[8]ポリアニオン性多糖類の水溶性塩からなる原料成形体から塩を構成するカチオン種の少なくとも一部を除去してなり、膨潤率が6,000質量%以下である水不溶性成形体。
[9]ポリアニオン性多糖類からなる成形体であり、水により膨潤状態とした後に乾燥する操作を2回繰り返して得た乾燥体の質量が、前記操作前の乾燥質量の80%以上である水不溶性成形体。
[10]pH12以上の水性媒体に溶解する前記[7]~[9]のいずれかに記載の水不溶性成形体。
[11]医療用材料、食品用材料、又は化粧品用材料である前記[7]~[10]のいずれかに記載の水不溶性成形体。
[12]前記[7]~[11]のいずれか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。
[13]前記[7]~[11]のいずれかに記載の粉末状又は粒子状の水不溶性成形体を含有する注入材。
[14]ヒアルロン酸の水溶性塩の水溶液をさらに含有する前記[13]に記載の注入材。
[15]関節変形治療用関節内注入材又は皮下注入材である前記[13]又は[14]に記載の注入材。
[16]前記[7]~[11]のいずれかに記載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。
本発明の水不溶性成形体の製造方法は、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て水不溶性成形体を形成する工程(水不溶化工程)を有する。以下、その詳細について説明する。
次に、本発明の癒着防止材の製造方法について説明する。本発明の癒着防止材の製造方法は、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を保持させる工程を有する。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。
本発明の注入材は、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。本発明の注入材は、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。本発明の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、本発明の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、本発明の注入材は、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。
本発明の徐放性製剤は、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。本発明の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。
ヒアルロン酸ナトリウム(分子量(公称値):80万、キッコーマンバイオケミファ社製)1.0gと水99.0gを混合し、ビーカー中で撹拌して均一な水溶液を得た。得られた水溶液をステンレス製バットに流し入れ、30℃で乾燥してヒアルロン酸ナトリウム膜を得た。得られたヒアルロン酸ナトリウム膜を100mLの処理液(1体積%無水酢酸/メタノール溶液)に浸漬し、室温で18時間放置して水不溶化処理した。水不溶化処理した膜をメタノール、80体積%メタノール水溶液、及び水の順で洗浄して水不溶性膜を得た。
表1に示す種類のポリアニオン性多糖類の水溶性塩及び処理液を用いたこと以外は、前述の実施例1と同様にして水不溶性膜を得た。
2cm角に切断した水不溶性膜を直径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で振盪した。水不溶性膜の経時的な状態変化を目視観察し、以下に示す評価基準にしたがって膜の水不溶性を評価した。結果を表2に示す。
◎:膜は水不溶化されており、原形が保持されていた。
○:膜は水不溶化されていたが、断片化していた。
△:膜は水不溶性のゲルとなっており、原形は保持されていなかった。
×:膜は水不溶化されておらず、溶解していた。
以下の手順によって、作製した水不溶性膜の膨潤率を測定した。乾燥状態の水不溶性膜の質量を測定し「膨潤前質量」とした。次に、水不溶性膜を十分な水に浸漬し、室温で1時間静置した。十分膨潤した水不溶性膜の表面に付着した余分な水分を紙タオル等で除去し、質量を測定して「膨潤後質量」とした。「膨潤率」とは、「膨潤前質量」に対する「膨潤後質量」の割合(質量%)を意味する。結果を表2に示す。なお、実施例1で製造した水不溶性膜は、浸漬した水から持ち上げること、及びその表面に付着した余分な水分を除去することが困難であったため、膨潤率を測定することができなかった。
作製した水不溶性膜を十分な量の水(25℃)に1時間浸漬して膨潤させた後、クリーンベンチ等の送風下にて乾燥させた。膨潤と乾燥を2回繰り返す膨潤・乾燥処理を行った後、得られた乾燥体の質量を測定した。そして、下記式にしたがって非溶解率を算出した。結果を表2に示す。なお、実施例1で製造した水不溶性膜は、浸漬した水から持ち上げることが困難であったため、非溶解率を測定することができなかった。
非溶解率(%)=(Y/X)×100
X:膨潤・乾燥処理前(初期)の水不溶性膜の乾燥体の質量(g)
Y:膨潤・乾燥処理後の水不溶性膜の乾燥体の質量(g)
ヒアルロン酸ナトリウム(分子量(公称値):80万、キッコーマンバイオケミファ社製)1.0gと水99.0gを混合し、ビーカー中で撹拌して均一にした後、1N塩酸を添加してpH2.5の水溶液を調製した。得られた水溶液をステンレス製バットに流し入れ、30℃で乾燥して膜を形成した。形成した膜について前述の「溶解度試験」を実施したところ、膜は吸水して塊状に膨潤し、原形を留めなかった。また、塊状に膨潤した膜は徐々に溶解して小さくなっていった。
ヒアルロン酸ナトリウム(分子量(公称値):80万、キッコーマンバイオケミファ社製)1.0gと水99.0gを混合し、ビーカー中で撹拌して均一な水溶液を得た。得られた水溶液をステンレス製バットに流し入れ、30℃で乾燥してヒアルロン酸ナトリウム膜を得た。得られたヒアルロン酸ナトリウム膜を100mLの処理液(無水酢酸100%)に浸漬して室温で18時間放置したが、十分に水不溶化させることはできなかった。一方、得られたヒアルロン酸ナトリウム膜を100mLの処理液(無水酢酸100%)に浸漬し、室温で10日間放置して水不溶化処理した。水不溶化処理した膜をメタノール、80体積%メタノール水溶液、及び水の順で洗浄して水不溶性膜を得た。得られた水不溶性膜について前述の「溶解度試験」を実施したところ、膜の原形は72時間以上保持されていた。
ヒアルロン酸ナトリウム(分子量(公称値):80万、キッコーマンバイオケミファ社製)1.0gと水99.0gを混合し、ビーカー中で撹拌して均一な水溶液を得た。得られた水溶液をステンレス製バットに流し入れ、-30℃で凍結させた後、棚加熱温度120℃で凍結乾燥することにより、ヒアルロン酸ナトリウムからなるスポンジ状の成形体を得た。得られたスポンジ状の成形体を100mLの処理液(10%無水酢酸/メタノール溶液)に浸漬し、室温で18時間放置して水不溶化処理した。水不溶化処理した成形体をメタノール、80体積%メタノール水溶液、及び水の順で洗浄して、水不溶性のスポンジ状成形体を得た。得られた水不溶性のスポンジ状成形体について、前述の「溶解度試験」を実施したところ、スポンジ状の原形が72時間以上保持されていた。
ヒアルロン酸ナトリウム(分子量(公称値):80万、キッコーマンバイオケミファ社製)10gを水90gに溶解させて、均一で粘稠なヒアルロン酸ナトリウム水溶液を得た。得られたヒアルロン酸ナトリウム水溶液を18ゲージ針を装着したシリンジに入れて押し出すことにより、繊維状の成形体を得た。得られたスポンジ状の成形体は粘度が高いため、繊維状に保持されていた。得られたスポンジ状の成形体を100mLの処理液(10%無水酢酸/メタノール溶液)に浸漬し、室温で18時間放置して水不溶化処理した。水不溶化処理した成形体をメタノール、80体積%メタノール水溶液、及び水の順で洗浄して、水不溶性の繊維状成形体を得た。得られた水不溶性の繊維状成形体について、前述の「溶解度試験」を実施したところ、繊維状の原形が72時間以上保持されていた。
実施例15で製造した水不溶性のスポンジ状成形体を繭型に切り出した後、市販の化粧水を含浸させた。繭型のスポンジ状成形体は、化粧水に溶解することはなかった。また、肌への貼り付き性が高いため、目元貼付用の化粧材として使用することができた。
12cm×9cmのサイズに切り出した実施例5で製造した水不溶性膜を、10体積%グリセリン水溶液に浸漬した後、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、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。
ヒアルロン酸ナトリウム(分子量(公称値):80万、キッコーマンバイオケミファ社製)1.0gと水99.0gを混合し、ビーカー中で撹拌して均一な水溶液を得た。得られた水溶液をステンレス製バットに流し入れ、30℃で乾燥してヒアルロン酸ナトリウム膜を得た。得られたヒアルロン酸ナトリウム膜を100mLの処理液(20%無水酢酸/メタノール溶液)に浸漬し、室温(25℃)で18時間(実施例19)、50℃で1時間(実施例20)、及び85℃で5分間(実施例21)放置して水不溶化処理した。水不溶化処理した膜をメタノール、80体積%メタノール水溶液、及び水の順で洗浄して水不溶性膜を得た。得られた水不溶性膜について、前述の「評価1:溶解度試験」を行って水不溶性を評価した。その結果、いずれも水不溶化されており、72時間以上膜の原形が保持されることを確認した。また、得られた水不溶性膜の膨潤率は、それぞれ244%(実施例19)、192%(実施例20)、及び161%(実施例21)であった。
実施例5で製造した水不溶性膜1gを10体積%炭酸ナトリウム水溶液に浸漬したところ、30分後に溶解した。一方、実施例5で製造した水不溶性膜1gを水に浸漬したところ、30分経過しても溶解せず、原形を留めていた。以上より、本実施形態の水不溶性膜は、ナトリウム塩(ナトリウムイオン)存在下においてヒアルロン酸のカルボキシ基が中和され、可溶性のヒアルロン酸塩と変化して徐々に溶解することが確認された。
実施例5で製造した水不溶性膜1gを5000ユニット/mLのヒアルロニダーゼ水溶液に浸漬し、37℃に調整した振盪機に入れて10~20rpmで振盪した。一方、実施例5で製造した水不溶性膜1gをPBS緩衝液(pH6.8)に浸漬し、37℃に調整した振盪機に入れて10~20rpmで振盪する対照試験も行った。5日後、PBS緩衝液に浸漬した水不溶性膜は原形を留めていたが、ヒアルロニダーゼ水溶液に浸漬した水不溶性膜は完全に溶解していた。本実施形態の水不溶性膜はヒアルロン酸骨格を保持しているため、ヒアルロニダーゼによって分解されたといえる。以上より、本実施形態の水不溶性膜は、生体内に配置された場合においても、水溶性ヒアルロン酸と同様の代謝経路によって代謝されると推測される。
実施例5で製造した水不溶性膜を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で振盪した。その結果、3ヶ月以上経過しても膜の原形が保持されていることが判明した。
ヒアルロン酸ナトリウム(分子量(公称値):80万、キッコーマンバイオケミファ社製)の粉末1.0gをエタノール64.0mLに加え、ビーカー中で撹拌して分散液を得た。次に、水16.0mLを加えてさらに撹拌した。無水酢酸20mLを加えた後、室温で18時間撹拌を続けて水不溶化処理した。水不溶化処理した粉末をメタノール、80体積%メタノール水溶液、及び水の順で洗浄して、水不溶性粉末(水不溶性のヒアルロン酸粉末)を得た。得られた水不溶性粉末について、前述の「評価1:溶解度試験」を行って水不溶性を評価した。その結果、粉末の質量が72時間以上保持されることを確認した。また、得られた水不溶性粉末を実施例18と同様の動物実験に供試した。その結果、癒着防止効果を有することを確認した。
Claims (16)
- ポリアニオン性多糖類の水溶性塩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。
- 前記原料成形体の形状が、膜状、塊状、繊維状、棒状、管状、粉末状、粒子状、又はスポンジ状である請求項1に記載の水不溶性成形体の製造方法。
- 前記ポリアニオン性多糖類が、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、コンドロイチン硫酸、ヒアルロン酸、ヘパリン、アルギン酸、ペクチン、及びカラギーナン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又は2に記載の水不溶性成形体の製造方法。
- 前記酸無水物が、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1~3のいずれか一項に記載の水不溶性成形体の製造方法。
- 前記処理液が、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請求項1~4のいずれか一項に記載の水不溶性成形体の製造方法。
- 前記水溶性有機溶媒が、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5に記載の水不溶性成形体の製造方法。
- 請求項1~6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。
- ポリアニオン性多糖類の水溶性塩からなる原料成形体から塩を構成するカチオン種の少なくとも一部を除去してなり、膨潤率が6,000質量%以下である水不溶性成形体。
- ポリアニオン性多糖類からなる成形体であり、水により膨潤状態とした後に乾燥する操作を2回繰り返して得た乾燥体の質量が、前記操作前の乾燥質量の80%以上である水不溶性成形体。
- pH12以上の水性媒体に溶解する請求項7~9のいずれか一項に記載の水不溶性成形体。
- 医療用材料、食品用材料、又は化粧品用材料である請求項7~10のいずれか一項に記載の水不溶性成形体。
- 請求項7~11のいずれか一項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。
- 請求項7~11のいずれか一項に記載の粉末状又は粒子状の水不溶性成形体を含有する注入材。
- ヒアルロン酸の水溶性塩の水溶液をさらに含有する請求項13に記載の注入材。
- 関節変形治療用関節内注入材又は皮下注入材である請求項13又は14に記載の注入材。
- 請求項7~11のいずれか一項に記載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。
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WO2017085964A1 (ja) * | 2015-11-17 | 2017-05-26 | 株式会社リタファーマ | 水溶性ヒアルロン酸ゲル及びその製造方法 |
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WO2018043532A1 (ja) * | 2016-08-30 | 2018-03-08 | 大日精化工業株式会社 | 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 |
WO2018043531A1 (ja) * | 2016-08-30 | 2018-03-08 | 大日精化工業株式会社 | 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 |
WO2019044519A1 (ja) | 2017-09-04 | 2019-03-07 | 大日精化工業株式会社 | 医療用・美容材料の製造方法及び医療用・美容材料 |
JP2019089962A (ja) * | 2017-11-16 | 2019-06-13 | 大日精化工業株式会社 | 高分子成形体の製造方法 |
JP2019119769A (ja) * | 2017-12-28 | 2019-07-22 | 大日精化工業株式会社 | 水不溶性成形体の製造方法及び水不溶性成形体 |
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US20180100048A1 (en) | 2018-04-12 |
US20160208064A1 (en) | 2016-07-21 |
US9879124B2 (en) | 2018-01-30 |
EP3040367A4 (en) | 2017-04-19 |
JP6077663B2 (ja) | 2017-02-08 |
KR101821073B1 (ko) | 2018-01-22 |
KR20160048876A (ko) | 2016-05-04 |
EP3040367A1 (en) | 2016-07-06 |
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