WO2016136885A1 - 医療用材料の製造方法、医療用材料、及び癒着防止材 - Google Patents
医療用材料の製造方法、医療用材料、及び癒着防止材 Download PDFInfo
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- WO2016136885A1 WO2016136885A1 PCT/JP2016/055655 JP2016055655W WO2016136885A1 WO 2016136885 A1 WO2016136885 A1 WO 2016136885A1 JP 2016055655 W JP2016055655 W JP 2016055655W WO 2016136885 A1 WO2016136885 A1 WO 2016136885A1
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- water
- medical material
- polyanionic polysaccharide
- acid
- anhydride
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Classifications
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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
- A61L31/042—Polysaccharides
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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
- A61L31/041—Mixtures of macromolecular compounds
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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
- A61L31/14—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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- 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
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/236—Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
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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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/424—Anti-adhesion agents
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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
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Definitions
- the present invention relates to a method for producing a medical material, a medical material, 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.
- 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 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 producing a medical material having high safety and moderate strength and flexibility because it does not need to be used.
- the place made into the subject of this invention is providing the medical material manufactured by said method, and an adhesion prevention material.
- the manufacturing method of the medical material shown below is provided.
- the first polyanionic polysaccharide powder or granular material that has been insolubilized with the treatment liquid containing the first acid anhydride is dispersed in an aqueous solution of a water-soluble salt of the second polyanionic polysaccharide.
- a step of obtaining the material is provided.
- adhesion prevention material shown below is provided.
- An adhesion preventing material comprising a polyhydric alcohol or a polyhydric alcohol aqueous solution retained in the medical material according to [4].
- the original characteristics of the polyanionic polysaccharide as a raw material are maintained, and since there is no need to use a chemical crosslinking agent, the safety is high, and an appropriate strength and A medical material having flexibility can be easily produced.
- the first polyanionic polysaccharide powder or granular material that has been water-insolubilized with the treatment liquid containing the first acid anhydride is used as the second polyanionic polysaccharide in water.
- a step of obtaining a dispersion by dispersing in an aqueous solution of a salt (dispersion step), a step of obtaining a dry film by drying the obtained dispersion (drying step), and a step of obtaining the resulting dry membrane with a second acid.
- a process for obtaining a medical material by water insolubilization with a treatment liquid containing an anhydride water insolubilization process). The details will be described below.
- the first polyanionic polysaccharide powder or granule used in the dispersion step is, for example, a water-insoluble treatment of a water-soluble salt powder of the first polyanionic polysaccharide with a treatment liquid containing the first acid anhydride. You can get it.
- a sponge-like raw material molded body made of a raw material containing a water-soluble salt of the first polyanionic polysaccharide is subjected to water insolubilization treatment with a treatment liquid containing the first acid anhydride, and then a cutter mill or the like is used.
- the powder or granular material of the first polyanionic polysaccharide can also be obtained by pulverizing and the like.
- the sponge-like raw material molded body can be produced, for example, by pouring an aqueous solution of a water-soluble salt of the first polyanionic polysaccharide into a suitable container, followed by drying or freeze-drying.
- the first 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 first polyanionic polysaccharide is a salt in which at least a part of the anionic group in the first polyanionic polysaccharide forms a salt.
- the anionic group in the first polyanionic polysaccharide may be introduced into the polysaccharide molecule.
- the first 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), Examples include hyaluronic acid, heparin, heparin sulfate, heparan sulfate, alginic acid, pectin, carrageenan, dermatan sulfate, and dermatan-6-sulfate. These 1st polyanionic polysaccharides can be used individually by 1 type or in combination of 2 or more types.
- water-soluble salt of the first polyanionic polysaccharide examples include inorganic salts, ammonium salts, and organic amine salts.
- inorganic salt examples 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 treatment liquid used for water-insolubilizing the powder of the water-soluble salt of the first polyanionic polysaccharide contains the first 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 medium of water and a water-soluble organic solvent, and the first acid anhydride is preferably dissolved or dispersed in this medium.
- the water-soluble salt powder of the first polyanionic polysaccharide can be sufficiently and insoluble in water.
- 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 first acid anhydride in the treatment liquid is usually 0.1 to 50% by mass, and preferably 5 to 30% by mass.
- concentration of the first acid anhydride is less than 0.1% by mass, the degree of water insolubilization tends to be insufficient, or it takes a long time for water insolubilization.
- concentration of the first acid anhydride exceeds 50% by mass, the effect tends to reach a peak.
- the treatment liquid preferably contains water as a medium.
- the content of water in the treatment liquid is preferably 0.01 to 50% by mass, 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. Further, when the content of water in the treatment liquid is more than 50% by mass, the water-soluble salt powder of the first polyanionic polysaccharide may be easily dissolved.
- the powder or granular material of the first polyanionic polysaccharide and the aqueous solution of the water-soluble salt of the second polyanionic polysaccharide are mixed and stirred appropriately, the powder of the first polyanionic polysaccharide is added to the aqueous solution.
- a dispersion in which etc. are dispersed can be obtained.
- As a 2nd polyanionic polysaccharide the thing similar to the above-mentioned 1st polyanionic polysaccharide can be used.
- the first polyanionic polysaccharide and the second polyanionic polysaccharide may be the same or different.
- the dispersion may further contain a radiopaque agent such as a contrast agent such as barium sulfate.
- the obtained dispersion is dried to obtain a dry film.
- the dried film obtained in the drying step is water insolubilized with a treatment liquid containing the second acid anhydride to obtain a medical material.
- a 2nd acid anhydride the thing similar to the above-mentioned 1st acid anhydride can be used.
- the first acid anhydride and the second acid anhydride may be the same or different.
- the dry film is treated with a treatment liquid containing the second acid anhydride, so that the dry film is insolubilized while maintaining its shape.
- the method of treating the dry film with the treatment liquid is not particularly limited, but it is preferable to treat the treatment liquid so that the treatment liquid contacts the entire dry film and penetrates into the dry film.
- Specific treatment methods include a method of immersing the dry film in the treatment liquid, and applying or spraying (spraying) the treatment liquid onto the dry film.
- the temperature during the water insolubilization 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 suppressing the volatilization of the medium and by-products, the temperature during the water insolubilization 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 water insolubilization treatment, for example, heat treatment or a heat roller, the medical material can be obtained in a shorter time without causing degradation and modification.
- the temperature during the water insolubilization treatment is preferably 50 to 90 ° C., and the treatment time is preferably 30 minutes or less.
- the medical material of the present invention can be obtained by washing with water or a water-soluble organic solvent as necessary.
- reaction assumed when a molded body formed using a sodium salt of a polyanionic polysaccharide is treated with an alcohol solution of acetic anhydride is shown below.
- 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.
- R 1 represents the main chain of the polyanionic polysaccharide
- R 2 represents the main chain of the alcohol.
- the medical material of the present invention does not require the use of a chemical cross-linking agent during production, structures such as functional groups derived from the chemical cross-linking agent are not incorporated into the molecule. For this reason, the medical material of the present invention retains the original characteristics of the polyanionic polysaccharide as a raw material and has high safety. Further, the medical material of the present invention produced as described above has appropriate strength and flexibility. Therefore, the medical material of the present invention is suitable as an adhesion preventing material. In the case where the medical material of the present invention is used as a constituent material of the adhesion preventing material, the thickness of the medical material is not particularly limited, but is preferably 20 to 200 ⁇ m, more preferably 60 to 120 ⁇ m.
- the molecules of the polyanionic polysaccharide constituting the medical material of the present invention are not substantially crosslinked. Furthermore, a new covalent bond is not substantially formed in the polyanionic polysaccharide. However, it is presumed that physical bonds such as hydrogen bonds, hydrophobic bonds, and van der Waals forces are formed between the molecules of the polyanionic polysaccharide. The fact that such a physical bond is formed between molecules of the polyanionic polysaccharide can be confirmed by measuring an infrared absorption spectrum.
- the medical material of the present invention is stable and water-insoluble in a wide pH range from acidic to alkaline. However, when the medical material of the present invention is brought into contact with or immersed in an aqueous medium having a pH of 12 or more, the physical bond between molecules is dissociated and can be easily dissolved.
- the anti-adhesion material of the present invention is obtained by holding a polyhydric alcohol or a polyhydric alcohol aqueous solution on the aforementioned medical material.
- the polyhydric alcohol 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.
- 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 the method for retaining the polyhydric alcohol or the polyhydric alcohol aqueous solution in the medical material include a method of immersing the medical material in the polyhydric alcohol or a polyhydric alcohol aqueous solution having a predetermined concentration. That is, the medical material is immersed in a polyhydric alcohol aqueous solution, and the inside of the medical material is replaced with the polyhydric alcohol aqueous solution, so that the polyhydric alcohol aqueous solution having a desired concentration is retained, and the desired An anti-adhesion material 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.
- Example 1 1.0 g of sodium hyaluronate powder (molecular weight: 800,000 Da) was dispersed in 100 mL of 80% aqueous ethanol. After heating to 50 ° C. with stirring, 20 mL of acetic acid-free acetic acid was added and the mixture was further heated and stirred for 1 hour. The precipitate collected by centrifugation was washed with ethanol and water, dried and pulverized to obtain a hyaluronic acid powder.
- hyaluronic acid powder-hyaluronic acid composite film had moderate strength and flexibility.
- Example 2 50 mL of a 1% aqueous solution of sodium hyaluronate (molecular weight: 800,000 Da) was poured into a stainless tray having a length of 12 cm and a width of 10 cm and frozen in a ⁇ 80 ° C. freezer. The frozen product was vacuum freeze-dried (vacuum degree-20 Pa, shelf temperature 25 ° C.) to obtain a sponge composed of sodium hyaluronate. The obtained sponge was immersed in a treatment solution (20% acetic anhydride / 80% ethanol solution) and left at 50 ° C. for 1 hour for water insolubilization treatment to obtain a sponge composed of hyaluronic acid.
- a treatment solution (20% acetic anhydride / 80% ethanol solution
- the sponge obtained using the cutter mill was pulverized to obtain a crushed product (granular material) of hyaluronic acid.
- 0.5 g of the obtained crushed material was dispersed in 50 mL of a 1% sodium hyaluronate (molecular weight 800,000 Da) aqueous solution, poured into a stainless steel tray having a length of 12 cm and a width of 10 cm, and then dried in a constant temperature bath at 20 ° C.
- a dry film was obtained.
- the obtained dried film is immersed in a treatment solution (20% acetic anhydride / 80% ethanol solution), left to stand at 50 ° C.
- hyaluronic acid crushed material granular material
- hyaluronic acid composite film had appropriate strength and flexibility.
- Example 3 The composite membrane produced in Example 1 was immersed in a 10% by volume glycerin aqueous solution, then air-dried and sealed in a sterilization bag. By irradiating 25 kGy of radiation and sterilizing the entire sterilization bag, an adhesion prevention film having a thickness of about 50 ⁇ m was obtained.
- 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 anti-adhesion membrane over 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 that constitutes the anti-adhesion membrane is gradually neutralized by sodium ions etc. in the living body, converted 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 medical material of the present invention is useful as a material for constituting an adhesion preventing material.
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Abstract
Description
[1]第1の酸無水物を含む処理液で水不溶化処理された第1のポリアニオン性多糖類の粉末又は粒状物を、第2のポリアニオン性多糖類の水溶性塩の水溶液に分散させて分散液を得る工程と、得られた前記分散液を乾燥させて乾燥膜を得る工程と、得られた前記乾燥膜を、第2の酸無水物を含む処理液で水不溶化処理して医療用材料を得る工程と、を有する医療用材料の製造方法。
[2]前記第1のポリアニオン性多糖類及び前記第2のポリアニオン性多糖類が、それぞれ、ヒアルロン酸、カルボキシメチルセルロース、及びアルギン酸からなる群より選択される少なくとも一種である前記[1]に記載の医療用材料の製造方法。
[3]前記第1の酸無水物及び前記第2の酸無水物が、それぞれ、無水酢酸及び無水プロピオン酸の少なくともいずれかである前記[1]又は[2]に記載の医療用材料の製造方法。
[4]前記[1]~[3]のいずれかに記載の製造方法によって製造された医療用材料。
[5]前記[4]に記載の医療用材料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。
本発明の医療用材料の製造方法は、第1の酸無水物を含む処理液で水不溶化処理された第1のポリアニオン性多糖類の粉末又は粒状物を、第2のポリアニオン性多糖類の水溶性塩の水溶液に分散させて分散液を得る工程(分散工程)と、得られた分散液を乾燥させて乾燥膜を得る工程(乾燥工程)と、得られた乾燥膜を、第2の酸無水物を含む処理液で水不溶化処理して医療用材料を得る工程(水不溶化処理工程)とを有する。以下、その詳細について説明する。
本発明の癒着防止材は、前述の医療用材料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。
ヒアルロン酸ナトリウム(分子量80万Da)の粉末1.0gを80%エタノール水溶液100mLに分散させた。撹拌下で50℃に加熱した後、無酢酢酸20mLを添加してさらに1時間加熱撹拌した。遠心分離して回収した沈殿をエタノール及び水で洗浄した後、乾燥及び粉砕して、ヒアルロン酸粉末を得た。得られたヒアルロン酸粉末0.5gを1%ヒアルロン酸ナトリウム(分子量80万Da)水溶液50mL中に分散させ、縦12cm×横10cmのステンレストレイに流し込んだ後、20℃の恒温槽内で乾燥させて乾燥膜を得た。得られた乾燥膜を処理液(20%無水酢酸/80%エタノール溶液)に浸漬し、50℃で1時間放置して水不溶化処理して、厚さ約50μmのヒアルロン酸粉末-ヒアルロン酸複合膜を得た。得られたヒアルロン酸粉末-ヒアルロン酸複合膜は、適度な強度及び柔軟性を有していた。
1%ヒアルロン酸ナトリウム(分子量80万Da)水溶液50mLを縦12cm×横10cmのステンレストレイに流し込み、-80℃冷凍庫内で凍結させた。凍結したものを真空凍結乾燥(真空度-20Pa、棚温度25℃)し、ヒアルロン酸ナトリウムからなるスポンジを得た。得られたスポンジを処理液(20%無水酢酸/80%エタノール溶液)に浸漬し、50℃で1時間放置して水不溶化処理して、ヒアルロン酸からなるスポンジを得た。カッターミルを用いて得られたスポンジを粉砕し、ヒアルロン酸の破砕物(粒状物)を得た。得られた破砕物0.5gを1%ヒアルロン酸ナトリウム(分子量80万Da)水溶液50mL中に分散させ、縦12cm×横10cmのステンレストレイに流し込んだ後、20℃の恒温槽内で乾燥させて乾燥膜を得た。得られた乾燥膜を処理液(20%無水酢酸/80%エタノール溶液)に浸漬し、50℃で1時間放置して水不溶化処理して、厚さ約60μmのヒアルロン酸破砕物(粒状物)-ヒアルロン酸複合膜を得た。得られたヒアルロン酸破砕物(粒状物)-ヒアルロン酸複合膜は、適度な強度及び柔軟性を有していた。
各実施例で製造した複合膜を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、いずれの複合膜についても、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、72時間後の膨潤率(膨潤膜/乾燥膜(質量比))は2.4であった。
1%ヒアルロン酸ナトリウム(分子量80万Da)水溶液50mLを縦12cm×横10cmのステンレストレイに流し込んだ後、20℃の恒温槽内で乾燥させて乾燥膜を得た。得られた乾燥膜を処理液(20%無水酢酸/80%エタノール溶液)に浸漬し、50℃で1時間放置して水不溶化処理して、厚さ約50μmの水不溶化ヒアルロン酸膜を得た。
JIS K 7311(ポリウレタン系熱可塑性エラストマーの試験方法)に準拠した引張試験を実施し、実施例1で製造した複合膜の引張強度を測定した。まず、蒸留水により十分膨潤させた複合膜をダンベルカッターにより打ち抜き、試験片を作製した。次いで、シングルコラム型の材料試験機(商品名「STA-1150」、エーアンドディ社製)を使用し、クロスヘッド速度10mm/秒で破断強度を測定し、複合膜の引張強度を算出した。実施例1で製造した複合膜の引張強度は、3N/mm2であった。また、同様の手順で測定及び算出した、比較例1で製造した水不溶化ヒアルロン酸膜の引張強度は、1.5N/mm2であった。
実施例1で製造した複合膜を、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厚さ約50μmの癒着防止膜を得た。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に変化して溶解し、生体内に吸収されたものと推測される。これに対して、癒着防止膜を配置することなく閉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。
Claims (5)
- 第1の酸無水物を含む処理液で水不溶化処理された第1のポリアニオン性多糖類の粉末又は粒状物を、第2のポリアニオン性多糖類の水溶性塩の水溶液に分散させて分散液を得る工程と、
得られた前記分散液を乾燥させて乾燥膜を得る工程と、
得られた前記乾燥膜を、第2の酸無水物を含む処理液で水不溶化処理して医療用材料を得る工程と、を有する医療用材料の製造方法。 - 前記第1のポリアニオン性多糖類及び前記第2のポリアニオン性多糖類が、それぞれ、ヒアルロン酸、カルボキシメチルセルロース、及びアルギン酸からなる群より選択される少なくとも一種である請求項1に記載の医療用材料の製造方法。
- 前記第1の酸無水物及び前記第2の酸無水物が、それぞれ、無水酢酸及び無水プロピオン酸の少なくともいずれかである請求項1又は2に記載の医療用材料の製造方法。
- 請求項1~3のいずれか一項に記載の製造方法によって製造された医療用材料。
- 請求項4に記載の医療用材料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。
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