Classifications

• • 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.

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• Chemical & Material Sciences (AREA)
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• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicinal Chemistry (AREA)
• Polymers & Plastics (AREA)
• Surgery (AREA)
• Heart & Thoracic Surgery (AREA)
• General Chemical & Material Sciences (AREA)
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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Materials For Medical Uses (AREA)
• Treatments Of Macromolecular Shaped Articles (AREA)

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Citations (9)

• 2016
  • 2016-08-30 JP JP2016167488A patent/JP2018033559A/ja not_active Withdrawn
• 2017
  • 2017-08-30 WO PCT/JP2017/031077 patent/WO2018043531A1/ja not_active Ceased

Patent Citations (9)

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