Manufacturing method for medical treatment materials

Abstract

To provide a manufacturing method of a medical use treatment material having a physical crosslinking structure due to a hydrogen bond, and capable of guaranteeing sterility while suppressing a shape change and property change before and after sterilization treatment, in a medical use treatment material that has a physical crosslinking structure due to a hydrogen bond and forms hydrogel due to contact with a water content.SOLUTION: A medical use treatment material forming hydrogel by contact with a water content is manufactured according to a method comprising obtaining a film-like solid containing one polymer among a polymer (A) having a structural unit derived from an ethylenically unsaturated monomer having a carboxyl group, and a polymer (B) having a structural unit derived from an ethylenically unsaturated monomer having a functional group capable of forming a hydrogen bond with the carboxyl group (where the polymer (A) is omitted), drying after contacting the film-like solid and a polymer solution containing the other polymer of the polymer (A) and the polymer (B), and sterilizing a dried body by radiation sterilization.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a medical treatment material, and more particularly to a method for producing a medical treatment material that forms a hydrogel upon contact with water. [Background technology]

[0002] Hydrogels that adhere to biological tissues can be used as adhesion inhibitors, hemostatic materials, wound dressings, and the like, and various studies have been conducted on them (see, for example, Patent Document 1). Patent Document 1 proposes a hydrogel-forming material as a medical treatment material that forms a hydrogel through hydrogen bonding between polyacrylic acid and polyvinylpyrrolidone. The technology described in Patent Document 1 involves drying an aqueous solution of either polyacrylic acid or polyvinylpyrrolidone into a film, contacting this film with the other aqueous solution, and then drying, thereby obtaining a dry film or sponge that can form a hydrogel by absorbing water. The films and sponges obtained in this manner rapidly absorb water, such as blood and tissue fluid, and swell when placed on wet biological tissue, such as a wound or a site where bleeding is desired, thereby adhering to the biological tissue. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2014-100462 Summary of the Invention [Problem to be solved by the invention]

[0004] When a hydrogel-forming material is used as a medical treatment material, it is necessary to ensure the sterility of the hydrogel-forming material. Therefore, it is considered to sterilize the hydrogel-forming material before use. However, hydrogel-forming materials having a physically crosslinked structure between two components formed by hydrogen bonds, such as those described in Patent Document 1, tend to shrink during sterilization, raising concerns that they may not be able to maintain their shape after sterilization.

[0005] Furthermore, the hydrogel-forming material described in Patent Document 1 has the property of absorbing water under physiological conditions to form a hydrogel, and then gradually dissociating the physical crosslinks and becoming solubilized. Taking advantage of this property, the hydrogel-forming material can be applied to applications in which it is placed in the body. Furthermore, these properties are required to be maintained even after the hydrogel-forming material is subjected to a sterilization treatment. However, no detailed study has been conducted on how to ensure sterility while suppressing changes in shape and properties before and after sterilization for the hydrogel-forming material containing polyacrylic acid and polyvinylpyrrolidone described in Patent Document 1.

[0006] The present invention has been made in view of the above circumstances, and its object is to provide a method for producing a medical treatment material that has a physically cross-linked structure formed by hydrogen bonds and forms a hydrogel upon contact with water, and that can ensure sterility while suppressing changes in shape and properties before and after sterilization treatment. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems and have completed the present invention. Specifically, the present invention provides the following means.

[0008] [1] A method for producing a medical treatment material that forms a hydrogel upon contact with water, comprising the steps of: obtaining a film-like solid material containing one of a polymer (A) having a structural unit derived from an ethylenically unsaturated monomer having a carboxyl group, and a polymer (B) having a structural unit derived from an ethylenically unsaturated monomer having a functional group capable of forming a hydrogen bond with a carboxyl group (excluding the polymer (A)); bringing the film-like solid material into contact with a polymer solution containing the other of the polymers (A) and (B), followed by drying; and sterilizing the dried material obtained by the drying by radiation sterilization.

[0009] [2] The method for producing a medical treatment material according to [1] above, wherein when the medical treatment material after the sterilization treatment is immersed in a phosphate buffer solution at 37°C, the dissolution rate of the medical treatment material after 10 hours is 90% or more. [3] The method for producing a medical treatment material according to the above [1] or [2], wherein the polymer (A) is a crosslinked polymer. [4] The method for producing a medical treatment material according to any one of the above [1] to [3], wherein the polymer (A) is poly(meth)acrylic acid. [5] The method for producing a medical treatment material according to any one of the above [1] to [4], wherein the polymer (B) has an amide group. [6] The method for producing a medical treatment material according to any one of the above [1] to [5], wherein the polymer (B) is at least one selected from the group consisting of polyvinylpyrrolidone and poly(meth)acrylamide. [7] The method for producing a medical treatment material according to any one of [1] to [6] above, wherein the radiation sterilization is gamma ray sterilization. [8] The method for producing a medical treatment material according to any one of [1] to [7] above, wherein the medical treatment material is used as a hemostatic material. [Effects of the Invention]

[0010] According to the present invention, when producing a medical treatment material that has a physically crosslinked structure due to hydrogen bonds and forms a hydrogel upon contact with water, it is possible to obtain a medical treatment material that is guaranteed to be sterilized while suppressing changes in shape and properties before and after sterilization treatment. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention will be described in detail below. In this specification, "(meth)acrylic" means acrylic and / or methacrylic, and "(meth)acrylate" means acrylate and / or methacrylate.

[0012] <<Method for manufacturing medical treatment materials>> The manufacturing method of the present invention (hereinafter also referred to as "the present manufacturing method") is a method for manufacturing a medical treatment material that forms a hydrogel upon contact with water, and includes the following steps 1 to 3. Step 1: A step of obtaining a film-like solid material containing either a polymer (A) having a structural unit derived from an ethylenically unsaturated monomer having a carboxyl group or a polymer (B) having a structural unit derived from an ethylenically unsaturated monomer having a functional group capable of forming a hydrogen bond with a carboxyl group (excluding polymer (A)). Step 2: A step of contacting the film-like solid with a polymer solution containing the other of the polymer (A) and the polymer (B) and then drying the resulting mixture. Step 3: Sterilizing the dried product obtained in step 2 by radiation sterilization

[0013] The medical treatment material obtained by this production method is a hydrogel-forming material that forms a hydrogel upon contact with water. This medical treatment material is a hydrogel-forming article that can be used as an adhesion barrier, hemostatic material, wound dressing, etc., and is in the form of, for example, a film, sponge, sheet, or powder. The medical treatment material obtained by this production method has a crosslinked structure (more specifically, a crosslinked structure formed by physical crosslinking) formed by hydrogen bonding between the carboxyl group of polymer (A) and functional group E of polymer (B), thereby exhibiting water absorption. Below, we will first explain polymer (A) and polymer (B), and then explain the details of each step in this production method.

[0014] <Polymer (A)> As the polymer (A), a polymer mainly composed of structural units derived from an ethylenically unsaturated monomer having a carboxyl group (hereinafter also referred to as "unsaturated monomer (ma)") can be preferably used. Specific examples of the unsaturated monomer (ma) include (meth)acrylic acid, itaconic acid, crotonic acid, maleic acid, fumaric acid, citraconic acid, cinnamic acid, succinic acid monohydroxyethyl (meth)acrylate, ω-carboxy-caprolactone mono(meth)acrylate, β-carboxyethyl (meth)acrylate, and 4-carboxystyrene. Among the unsaturated monomers (ma), (meth)acrylic acid is particularly preferred because it can enhance adhesiveness to biological tissues.

[0015] In the polymer (A), the content of structural units derived from the unsaturated monomer (ma) is preferably 40% by mass or more, more preferably 50% by mass or more, even more preferably 60% by mass or more, even more preferably 70% by mass or more, even more preferably 80% by mass or more, and even more preferably 90% by mass or more, based on the total structural units constituting the polymer (A). When the structural units derived from the unsaturated monomer (ma) in the polymer (A) are in the above range, it is preferable in that a hydrogel having higher adhesiveness to biological tissue can be obtained. The unsaturated monomer (ma) constituting the polymer (A) may be of one type or two or more types.

[0016] In view of excellent adhesiveness to biological tissues, the polymer (A) is particularly preferably poly(meth)acrylic acid. When the polymer (A) is poly(meth)acrylic acid, the polymer (A) preferably contains 70% by mass or more of (meth)acrylic acid units, more preferably 80% by mass or more, even more preferably 90% by mass or more, and even more preferably 95% by mass or more.

[0017] The method for obtaining the polymer (A) is not limited to the method using the unsaturated monomer (ma). For example, the polymer (A) may be obtained by polymerizing a (meth)acrylic acid ester monomer and then hydrolyzing the polymer. Alternatively, the polymer (A) may be obtained by polymerizing a nitrogen-containing monomer such as (meth)acrylamide or (meth)acrylonitrile and then treating the polymer with a strong alkali, or by reacting a polymer having a hydroxyl group with an acid anhydride.

[0018] As the polymer (A), at least one of a crosslinked polymer and a polymer having a weight-average molecular weight of 1,800,000 or more (hereinafter also referred to as a "high molecular weight polymer (AH)") can be preferably used. Of these, a crosslinked polymer is particularly preferred as the polymer (A), because when the sterilized medical treatment material is placed under physiological conditions, the physical crosslinks between the polymer (A) and the polymer (B) are dissociated over a sufficient period of time, gradually solubilizing the hydrogel, and because the polymer (A) has excellent swelling properties when exposed to water and adhesive properties to biological tissues.

[0019] The method for producing the crosslinked polymer is not particularly limited, and examples of the method for producing the crosslinked polymer include the following methods (1) and (2). (1) A method of copolymerizing an ethylenically unsaturated monomer having a crosslinkable functional group (hereinafter also referred to as "unsaturated monomer (mc)") with an unsaturated monomer (ma) (2) A method in which a polymer having a reactive functional group is synthesized and crosslinked by adding a crosslinking agent as needed. Of these, method (1) is preferred because the procedure is simple and the degree of crosslinking can be easily controlled.

[0020] Examples of the unsaturated monomer (mc) include polyfunctional polymerizable monomers having two or more polymerizable unsaturated groups, and self-crosslinking monomers having a crosslinkable functional group capable of self-crosslinking (e.g., a hydrolyzable silyl group). Specific examples of polyfunctional polymerizable monomers include polyfunctional (meth)acrylate compounds, polyfunctional alkenyl compounds, and compounds having both a (meth)acryloyl group and an alkenyl group. Of these, polyfunctional alkenyl compounds are preferred as ethylenically unsaturated monomers having a crosslinkable functional group, since they are more likely to produce a uniform crosslinked structure.

[0021] Specific examples of polyfunctional alkenyl compounds include polyfunctional allyl ether compounds such as trimethylolpropane diallyl ether, trimethylolpropane triallyl ether, pentaerythritol diallyl ether, pentaerythritol triallyl ether, tetraallyloxyethane, and polyallylsucrose; polyfunctional allyl compounds such as diallyl phthalate; polyfunctional vinyl compounds such as divinylbenzene; and alkenyl group-containing (meth)acrylic acid compounds such as allyl (meth)acrylate, isopropenyl (meth)acrylate, butenyl (meth)acrylate, pentenyl (meth)acrylate, and 2-(2-vinyloxyethoxy)ethyl (meth)acrylate. Among these polyfunctional alkenyl compounds, polyfunctional allyl ether compounds having multiple allyl ether groups in the molecule are particularly preferred.

[0022] Specific examples of the self-crosslinking monomer include hydrolyzable silyl group-containing vinyl monomers, etc. Examples of the hydrolyzable silyl group-containing vinyl monomers include vinyl silanes such as vinyltrimethoxysilane, vinyltriethoxysilane, vinylmethyldimethoxysilane, and vinyldimethylmethoxysilane; silyl group-containing (meth)acrylic acid esters such as trimethoxysilylpropyl (meth)acrylate, triethoxysilylpropyl (meth)acrylate, and methyldimethoxysilylpropyl (meth)acrylate; trimethoxysilylpropyl vinyl ether; and vinyl trimethoxysilylundecanoate.

[0023] When the polymer (A) contains the structural unit (mc), the amount of the structural unit (mc) contained in the polymer (A) is preferably 0.01% by mass or more, more preferably 0.1% by mass or more, based on all structural units constituting the polymer (A). The amount of the structural unit (mc) contained in the polymer (A) is preferably 5% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less, based on all structural units constituting the polymer (A). The structural unit (mc) contained in the polymer (A) may be of one type or two or more types.

[0024] The polymer (A) may further have structural units derived from monomers other than the unsaturated monomers (ma) and (mc) (hereinafter also referred to as "other monomers (md)"), provided that the effects of the present invention are not impaired. Examples of other monomers (md) include (meth)acrylic acid alkyl esters, aliphatic cyclic (meth)acrylic acid esters, aromatic (meth)acrylic acid esters, (meth)acrylic acid alkoxyalkyl esters, (meth)acrylic acid hydroxyalkyl esters, and polyalkylene glycol mono(meth)acrylates.

[0025] Specific examples of these include (meth)acrylic acid alkyl esters such as methyl (meth)acrylate, ethyl (meth)acrylate, isopropyl (meth)acrylate, n-propyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, tert-butyl (meth)acrylate, hexyl (meth)acrylate, and 2-ethylhexyl (meth)acrylate.

[0026] Specific examples of the aliphatic cyclic esters of (meth)acrylic acid include cyclohexyl (meth)acrylate, methylcyclohexyl (meth)acrylate, tert-butylcyclohexyl (meth)acrylate, cyclododecyl (meth)acrylate, isobornyl (meth)acrylate, adamantyl (meth)acrylate, dicyclopentenyl (meth)acrylate, and dicyclopentanyl (meth)acrylate, etc. Specific examples of the aromatic esters of (meth)acrylic acid include phenyl (meth)acrylate, benzyl (meth)acrylate, phenoxymethyl (meth)acrylate, 2-phenoxyethyl (meth)acrylate, and 3-phenoxypropyl (meth)acrylate, etc.

[0027] Specific examples of (meth)acrylic acid alkoxyalkyl esters include methoxymethyl (meth)acrylate, methoxyethyl (meth)acrylate, ethoxyethyl (meth)acrylate, n-propoxyethyl (meth)acrylate, n-butoxyethyl (meth)acrylate, methoxypropyl (meth)acrylate, ethoxypropyl (meth)acrylate, n-propoxypropyl (meth)acrylate, n-butoxypropyl (meth)acrylate, methoxybutyl (meth)acrylate, ethoxybutyl (meth)acrylate, n-propoxybutyl (meth)acrylate, and n-butoxybutyl (meth)acrylate.

[0028] Specific examples of the (meth)acrylic acid hydroxyalkyl ester include 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 3-hydroxybutyl (meth)acrylate, and 4-hydroxybutyl (meth)acrylate, etc. Examples of the polyalkylene glycol mono(meth)acrylate include polyethylene glycol mono(meth)acrylate, polypropylene glycol mono(meth)acrylate, and polyethylene glycol-polypropylene glycol mono(meth)acrylate, etc.

[0029] In the polymer (A), the content of structural units derived from other monomers (md) is preferably 5% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less, based on the total structural units constituting the polymer (A). The other monomers constituting the polymer (A) may be one type or two or more types.

[0030] When a crosslinked polymer is used as the polymer (A), commercially available crosslinked polymers can also be used, such as Junron (registered trademark) PW-120, Junron PW-121, and Junron PW-312S (all manufactured by Toagosei Co., Ltd.), Carbopol 934P NF, Carbopol 981, Carbopol Ultrez 10, and Carbopol Ultrez 30 (all manufactured by Lubrizol).

[0031] When a high molecular weight polymer (AH) is used as the polymer (A), the weight average molecular weight (Mw) of the high molecular weight polymer (AH) is preferably 1.8 million or more from the viewpoint of sufficiently increasing adhesiveness to biological tissue. Furthermore, from the viewpoint of ease of handling, the Mw of the high molecular weight polymer (AH) is preferably 50 million or less, more preferably 30 million or less, and even more preferably 10 million or less. The molecular weight of the high molecular weight polymer (AH) is a polystyrene-equivalent value measured by gel permeation chromatography (GPC) using a tetrahydrofuran eluent after methylating the carboxyl groups with trimethylsilyldiazomethane.

[0032] <Polymer (B)> Polymer (B) is not particularly limited as long as it has a structural unit derived from an ethylenically unsaturated monomer having a functional group E capable of forming a hydrogen bond with a carboxyl group in polymer (A) (hereinafter also referred to as "unsaturated monomer (mb)") and is a polymer different from polymer (A). Examples of functional group E include an amide group, a cyano group, a carbonyl group, an amino group, and a hydroxyl group. Polymer (B) may have one type of functional group E, or two or more types of functional groups E.

[0033] Among these, the functional group E is preferably an amide group and / or a hydroxyl group, and particularly preferably an amide group, because a hydrogel-forming material with excellent water swelling properties can be obtained by forming a hydrogen bond between the carboxyl group of the polymer (A) and the functional group E.

[0034] The polymer (B) having an amide group can be produced, for example, by polymerizing an ethylenically unsaturated monomer having an amide group. Examples of the ethylenically unsaturated monomer having an amide group include (meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-dimethylaminopropyl(meth)acrylamide, N-methyl(meth)acrylamide, N-vinyl-2-pyrrolidone, and 1-vinyl-4-methyl-2-pyrrolidone.

[0035] In the polymer (B), the content of structural units derived from the unsaturated monomer (mb) is preferably 70% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and even more preferably 97% by mass or more, based on all structural units constituting the polymer (B).

[0036] As the polymer (B), at least one of a crosslinked polymer and a polymer having a weight-average molecular weight of 10,000 or more (hereinafter also referred to as a "high molecular weight polymer (BH)") can be preferably used. Of these, the high molecular weight polymer (BH) is more preferably used as the polymer (B) from the viewpoint of obtaining a medical treatment material that quickly absorbs water and gels upon contact with water and takes a sufficient time to become soluble under physiological conditions.

[0037] The type of polymer (B) is not particularly limited, but from the viewpoint of obtaining a sponge that forms a highly swellable hydrogel upon contact with water, at least one selected from the group consisting of polyvinylpyrrolidone and poly(meth)acrylamide is preferred. Among these, at least one of polyvinylpyrrolidone and polyacrylamide is more preferred as polymer (B) in terms of excellent polymerizability of the constituent monomers and ease of production of polymer (B).

[0038] Polyvinylpyrrolidone is typically a polymer made of N-vinyl-2-pyrrolidone. However, it may contain structural units derived from a monomer other than N-vinyl-2-pyrrolidone, provided that the effects of the present invention are not impaired. Specific examples of monomers other than N-vinyl-2-pyrrolidone include the compounds exemplified as other monomers that may constitute polymer (A). In polyvinylpyrrolidone, the content of structural units derived from monomers other than N-vinyl-2-pyrrolidone is preferably 3% by mass or less, more preferably 1% by mass or less, and even more preferably 0.5% by mass or less, based on the total structural units constituting polyvinylpyrrolidone.

[0039] Similarly, polyacrylamide is typically a polymer made of acrylamide. However, it may contain structural units derived from monomers other than acrylamide, provided that the effects of the present invention are not impaired. Specific examples of monomers other than acrylamide include the compounds exemplified as other monomers that may constitute polymer (A). In polyacrylamide, the content of structural units derived from monomers other than acrylamide is preferably 3% by mass or less, more preferably 1% by mass or less, and even more preferably 0.5% by mass or less, based on the total structural units constituting polyacrylamide.

[0040] Polymethacrylamide is typically a polymer made of methacrylamide. However, it may contain structural units derived from a monomer other than methacrylamide, provided that the effects of the present invention are not impaired. Specific examples of monomers other than methacrylamide include the compounds exemplified as other monomers that may constitute polymer (A). In polymethacrylamide, the content of structural units derived from monomers other than methacrylamide is preferably 3% by mass or less, more preferably 1% by mass or less, and even more preferably 0.5% by mass or less, based on the total structural units constituting the polymethacrylamide.

[0041] When a high molecular weight polymer (BH) is used as the polymer (B), the weight average molecular weight (Mw) of the high molecular weight polymer (BH) is not particularly limited, but from the viewpoint of ensuring mechanical strength and thickening effect, it is preferably 10,000 or more, more preferably 30,000 or more, and even more preferably 50,000 or more. From the viewpoint of handleability, the Mw of the high molecular weight polymer (BH) is preferably 100 million or less, more preferably 50 million or less, and even more preferably 30 million or less. The molecular weight of the polymer (B) is a polystyrene-equivalent value measured by GPC.

[0042] The polymerization method for producing the polymer (A) and the polymer (B) is not particularly limited. The polymer (A) and the polymer (B) can be obtained by polymerizing the monomers using a known radical polymerization method such as solution polymerization, suspension polymerization, emulsion polymerization, or bulk polymerization. In the case of the solution polymerization method, for example, an organic solvent and the monomers are charged into a reactor, a polymerization initiator (e.g., an azo compound) is added, and the mixture is heated to 40 to 250°C to polymerize, thereby obtaining the target polymer.

[0043] Next, each step of the present manufacturing method will be described in detail.

[0044] (Process 1: Preparation process) In this production method, first, a film-like solid material containing one of polymer (A) and polymer (B) (hereinafter also referred to as "first polymer") is prepared. Methods for preparing the film-like solid material include, for example, solution drying and heat pressing. Among these, solution drying is preferred because it can suppress the generation of bubbles and produce a smooth film. When producing a film-like solid material by the solution drying method, it is preferable to prepare a polymer solution (hereinafter also referred to as "first polymer solution") by dissolving the first polymer in a solvent, and then apply the first polymer solution to a support and dry it. The first polymer constituting the film-like solid material may be polymer (A) or polymer (B).

[0045] Examples of the solvent for dissolving the first polymer include water, a mixture of a water-soluble organic solvent and water, and an organic solvent that is soluble in water. Examples of the organic solvent that is soluble in water include methanol, ethanol, and acetone. Of these, the solvent for dissolving the first polymer is preferably water, ethanol, or a mixture of water and ethanol. The polymer concentration in the first polymer solution is not particularly limited, but is, for example, 0.01 to 10% by mass, and preferably 0.1 to 5% by mass.

[0046] The method for forming a film-like solid on a support is not particularly limited, and known film-forming methods can be used. For example, a film-like solid containing the first polymer can be formed on a support by applying a first polymer solution to the support and preferably heating it to remove the solvent. When heat treatment is performed, the heating temperature is, for example, 50 to 120°C, and the heating time is, for example, 0.1 to 5 hours. The heat treatment may also be performed under reduced pressure or under airflow. The thickness of the film-like solid formed on the support is, for example, 1 to 5,000 μm. The moisture content of the film-like solid is, for example, 10% by mass or less.

[0047] (Step 2: Contact and drying step) In step 2, the film-like solid formed on the support is first brought into contact with a polymer solution (hereinafter also referred to as the "second polymer solution") obtained by dissolving a polymer (A) and a polymer (B) different from the first polymer (hereinafter also referred to as the "second polymer") in a solvent. Examples of the solvent for dissolving the second polymer include the same solvents as those exemplified as the solvent for dissolving the first polymer. Of these, water is preferred from the viewpoint of efficiently performing the drying step. The polymer concentration in the second polymer solution is, for example, 0.1 to 30% by mass, and preferably 1 to 20% by mass.

[0048] The method for contacting a solid film containing a first polymer with a second polymer solution is not particularly limited. Examples of methods for contacting a solid film with a second polymer solution include applying, dripping, or spraying the second polymer solution onto the surface of the solid film, and immersing the solid film in the second polymer solution. In a preferred embodiment, the second polymer solution is dripped onto the surface of the solid film to form a liquid layer of the second polymer solution on the solid film, which is then allowed to stand for a predetermined period of time (e.g., 10 to 180 minutes). The thickness of the liquid layer is not particularly limited, but is, for example, 0.1 to 50,000 μm. This allows the first polymer in the solid film to gradually dissolve in the second polymer solution, resulting in the formation of a hydrogel as a product of contact between the solid film and the second polymer solution.

[0049] When a film-like solid material containing a first polymer is contacted with a second polymer solution, the amount of the second polymer solution to be contacted with the film-like solid material is preferably selected so that a crosslinked structure is appropriately formed in the resulting hydrogel. Specifically, the amounts of the film-like solid material and the second polymer solution and the polymer concentrations are preferably adjusted so that the number of moles of functional group E in polymer (B) is preferably 0.1 to 10 moles, more preferably 0.2 to 8 moles, and even more preferably 0.5 to 2 moles per mole of carboxyl group in polymer (A).

[0050] The medical treatment material obtained by this production method may further contain components other than polymer (A) and polymer (B) (hereinafter also referred to as "other components") depending on the purpose of use, etc. Examples of other components include various drugs such as antibacterial agents, anti-inflammatory agents, blood coagulants, anticoagulants, local anesthetics, vasoconstrictors and vasodilators, as well as a water-soluble polymer (C) other than polymer (A) and polymer (B). One or more types of other components may be used. The content of the other components can be selected appropriately depending on each component, as long as it does not impair the effects of the present invention.

[0051] Examples of the water-soluble polymer (C) include water-soluble polymers that can be commonly used as thickeners, specifically, polysaccharides. Examples of polysaccharides include cellulose derivatives such as hydroxyethyl cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose; mucopolysaccharides such as hyaluronic acid and chondroitin sulfate; water-soluble natural polymeric polysaccharides such as carrageenan, pectin, locust bean gum, guar gum, xanthan gum, and welan gum, as well as salts thereof (e.g., sodium salts). Among these, hyaluronic acid or its salts are preferred as the water-soluble polymer (C). The number-average molecular weight of the water-soluble polymer (C) is, for example, 200,000 or more. The molecular weight of the water-soluble polymer (C) is a polystyrene-equivalent value measured by GPC.

[0052] When a dried product containing the water-soluble polymer (C) is obtained as a medical treatment material, the water-soluble polymer (C) may be contained in the film-like solid or the second polymer solution. When the water-soluble polymer (C) is contained in the second polymer solution, the water-soluble polymer (C) may be blended in advance with the second polymer solution, and the second polymer solution containing the water-soluble polymer (C) may be brought into contact with the film-like solid. Alternatively, the water-soluble polymer (C) may be added to the second polymer solution after the film-like solid is brought into contact with the second polymer solution. From the viewpoint of favorable formation of a hydrogel upon contact with water in the resulting medical treatment material, it is preferable that the second polymer solution contains the water-soluble polymer (C). It is more preferable to prepare a second polymer solution containing the water-soluble polymer (C) in advance and then contact the second polymer solution containing the water-soluble polymer (C) with the film-like solid.

[0053] When the second polymer solution containing the water-soluble polymer (C) is brought into contact with a film-like solid, the content of the water-soluble polymer (C) in the second polymer solution is preferably 0.01 to 50 parts by mass, more preferably 0.1 to 20 parts by mass, and even more preferably 0.5 to 15 parts by mass, per 100 parts by mass of the second polymer.

[0054] The resulting hydrogel is then dried to obtain the desired dried product. There are no particular limitations on the method for drying the hydrogel, and any known drying method can be used as appropriate. From the perspective of obtaining a hydrogel-forming material that has excellent adhesiveness to biological tissue and mechanical strength, freeze-drying is particularly preferred.

[0055] In the freeze-drying process, the freezing temperature is, for example, −70° C. to −5° C., preferably −60° C. to −5° C. The freeze-drying process conditions are not particularly limited, but it is preferably carried out at room temperature under reduced pressure. The pressure during the freeze-drying process is, for example, 50 Pa or less, preferably 20 Pa or less, and more preferably 10 Pa or less.

[0056] In this specification, the term "dry" refers not only to a state in which moisture has been completely removed, but also to a state in which moisture remains during the drying process. The moisture content of the dried product obtained by the drying treatment is, for example, 10% by mass or less, and preferably 5% by mass or less. When the obtained dried product is in the form of a film, the thickness of the dried product is, for example, 0.1 to 50,000 μm. This allows for the production of a dried product of a hydrogel formed by contacting a film-like solid containing one of the polymers (A) and (B) with a solution containing the other polymer.

[0057] (Process 3: Sterilization process) Step 3 is a step of sterilizing the dried body obtained in step 2 by irradiating it with radiation. Examples of radiation used for the sterilization in this step include gamma (γ) rays, electron beams, and bremsstrahlung radiation (X-rays). Among these, sterilization by gamma ray irradiation (gamma ray sterilization) is preferred because it has high penetrating power and can sufficiently sterilize the center of the dried body.

[0058] Gamma ray sterilization is a sterilization treatment method using gamma rays from a radiation source containing a radioisotope. The irradiation conditions for gamma ray sterilization are not particularly limited as long as they can achieve a Sterility Assurance Level (SAL). The irradiation conditions for gamma ray sterilization can be, for example, an absorbed dose of 10 to 150 kGy, preferably 20 to 100 kGy, and more preferably 25 to 80 kGy.

[0059] The sterility assurance level (SAL) is an index that indicates the standard of sterilization established by ISO (International Organization for Standardization). The sterility assurance level currently adopted by ISO is 10 -6 The following is the result.

[0060] Here, if an aqueous solution of polymer (A) and an aqueous solution of polymer (B) are simply mixed, a hydrogel is formed very quickly due to hydrogen bonding between the carboxyl group of polymer (A) and the functional group E of polymer (B). However, the hydrogel obtained in this manner has insufficient solubility and swelling in water and poor adhesiveness to biological tissue. In contrast, the present production method makes it possible to produce a hydrogel-forming material that exhibits excellent water solubility and swelling in water and has high adhesiveness to biological tissue.

[0061] In the resulting medical treatment material, the total amount of polymer (A) and polymer (B) is preferably 70% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and even more preferably 95% by mass or more, relative to the total amount of the medical treatment material, from the viewpoint of obtaining a hydrogel that has high mechanical strength and excellent adhesiveness to biological tissues upon contact with water.

[0062] The contents of polymer (A) and polymer (B) are preferably adjusted so that the amount of polymer (B) is 20 to 500 parts by mass per 100 parts by mass of polymer (A). The contents of polymer (A) and polymer (B) within the above ranges are advantageous in that they are highly effective in improving mechanical strength and can form a hydrogel that exhibits excellent adhesiveness to biological tissue. From this perspective, the contents of polymer (A) and polymer (B) are more preferably adjusted so that the amount of polymer (B) is 30 to 400 parts by mass, and even more preferably 50 to 300 parts by mass, per 100 parts by mass of polymer (A).

[0063] Furthermore, when the medical treatment material contains a water-soluble polymer (C), the content of the water-soluble polymer (C) is preferably 0.01 to 50 parts by mass per 100 parts by mass of the combined total of the polymer (A) and the polymer (B). By setting the content of the water-soluble polymer (C) within the above range, it is possible to improve the water retention of the hydrogel. From this viewpoint, the content of the water-soluble polymer (C) is more preferably 0.1 parts by mass or more, and even more preferably 0.5 parts by mass or more, per 100 parts by mass of the combined total of the polymer (A) and the polymer (B). Furthermore, the upper limit of the content of the water-soluble polymer (C) is more preferably 20 parts by mass or less, and even more preferably 15 parts by mass or less, per 100 parts by mass of the combined total of the polymer (A) and the polymer (B). As the water-soluble polymer (C), one type may be used alone, or two or more types may be used in combination.

[0064] The medical treatment material obtained by this production method is a dry solid before use, but upon contact with water, it absorbs water and swells to become a hydrogel. That is, the medical treatment material is a flexible dry body before contact with water, but upon contact with water, it changes from a dry body to a swollen body, thereby exhibiting adhesive properties to biological tissue. Here, water includes water, water-soluble organic solvents (e.g., ethanol), body fluids (e.g., blood, saliva, tissue fluid), and mixtures thereof. The medical treatment material obtained by this production method is not bioabsorbable, and under physiological conditions, the physical crosslinks between polymer (A) and polymer (B) gradually dissociate and become soluble. Therefore, the medical treatment material is highly safe and can be placed in the body. Such medical treatment materials are particularly suitable for various medical treatment applications, such as adhesion barriers, hemostatic agents, and wound dressings.

[0065] When the medical treatment material obtained by this production method is used for hemostasis or to protect affected areas, the hydrogel formed by the medical treatment material absorbing water preferably gradually solubilizes in body fluids so that it remains at the affected area for a suitably long period of time. Specifically, when the medical treatment material obtained by this production method after sterilization by gamma ray sterilization is immersed in a phosphate buffer solution at 37°C, the time required for the dissolution rate of the medical treatment material to reach 90% is preferably 1 hour or more, more preferably 3 hours or more, even more preferably 8 hours or more, and even more preferably 10 hours or more.

[0066] From the viewpoint of fully ensuring hemostatic effects and protective effects on the affected area, when a medical treatment material that has been sterilized by radiation is immersed in a phosphate buffer solution at 37°C, it is preferable that the dissolution rate of the medical treatment material after 10 hours is 90% or more.

[0067] Here, if a medical treatment material having a physically crosslinked structure formed by hydrogen bonding between polymer (A) and polymer (B) is subjected to radiation sterilization, chemical crosslinking between polymer (A) and polymer (B) may occur, resulting in insufficient water absorption when applied to biological tissue, or in failure to exhibit the property of solubility due to gradual dissociation of the crosslinked structure under physiological conditions. Therefore, gas sterilization has been proposed for conventional medical treatment materials in which hydrogels are formed by hydrogen bonding between polyacrylic acid and polyvinylpyrrolidone (see Patent Document 1 above). Known gas sterilization methods include autoclaved steam sterilization and ethylene oxide gas sterilization. However, the present inventors' investigations revealed that autoclaved steam sterilization or ethylene oxide gas sterilization of film- or sponge-shaped hydrogel-forming materials causes the hydrogel-forming materials to shrink and fail to maintain their shape.

[0068] Based on the above findings, the inventors further pursued an intensive study and, from among various sterilization methods, conducted a sterilization treatment by radiation sterilization, which was predicted to promote chemical crosslinking, on a medical treatment material having a physically crosslinked structure formed by hydrogen bonding between polymer (A) and polymer (B). Surprisingly, they found that even after sterilization, the crosslinked structure was able to gradually dissociate and become soluble under physiological conditions, and that there was little change in shape or properties before and after sterilization, making it possible to produce a medical treatment material with guaranteed sterility.

[0069] The shape of the medical treatment material is not particularly limited, and it can be used in the form of, for example, a film, a sponge, a sheet, or a powder. The medical treatment material may be provided in a state where it is supported on a support, or in a state where it is enclosed in a package such as a film. The shape and material of the support are not particularly limited, and examples include fabrics such as woven fabrics and nonwoven fabrics; and resin substrates such as polystyrene, polypropylene, and polyethylene. Because the films and sponges obtained using polymer (A) and polymer (B) have high mechanical strength and excellent flexibility, the medical treatment material of the present invention can be preferably used, among others, as a hydrogel-forming film or a hydrogel-forming sponge. [Example]

[0070] The present invention will be specifically described below based on examples, but the present invention is not limited to these examples. In the following, "parts" and "%" mean "parts by mass" and "% by mass", respectively, unless otherwise specified.

[0071] Hydrogel-forming sponges were produced according to the methods described in the following Examples 1 and 2 and Comparative Examples 1 and 2. Furthermore, the hydrogel-forming sponges obtained were subjected to the following evaluations (sterility evaluation, measurement of the sponge shrinkage rate due to sterilization treatment, and evaluation of dissolution in phosphate buffer at 37°C).

[0072] [Example 1] A silicone rubber sheet (thickness 10mm) with a 25mm x 7mm opening was placed on a 50mm x 50mm polypropylene substrate, and 1.5mL of a 1.2% cross-linked polyacrylic acid (manufactured by Toagosei Co., Ltd., Junron (registered trademark) PW-120, hereinafter also referred to as "PAA") aqueous solution was cast and dried at 70 ° C for 20 hours to produce a PAA film. Next, on the surface of the PAA film, a mixed solution of 0.6mL of a 4.6% polyvinylpyrrolidone (manufactured by BASF, Kollidon 90F, polystyrene equivalent weight average molecular weight 320,000 (dimethylformamide eluent), hereinafter also referred to as "PVP") aqueous solution and 0.9mL of a 0.4% sodium hyaluronate (manufactured by Kewpie Corporation, Hyaluronsan HA-LQH, hereinafter also referred to as "HA") aqueous solution was dropped, and after standing for 60 minutes, it was frozen at -50 ° C. The frozen product was freeze-dried at room temperature under reduced pressure (5 Pa) to obtain a hydrogel-forming sponge (size: 25 mm x 7 mm x 7 mm) as a medical treatment material. The mixing ratio was PAA:PVP:HA = 1:1.53:0.2 (mass ratio). The obtained sponge was sterilized by gamma irradiation (Nordion, JS-8500) at 50 kGy in an air atmosphere. The sterilized sponge was certified to sterility assurance standards (100%) in accordance with ISO11737-2:2019 (Sterilization of healthcare products - Microbiological methods - Part 2: Sterility tests for the definition, validation, and maintenance of sterilization processes). -6 The size of the sponge before and after sterilization was measured with a vernier caliper, and the shrinkage rate of the sponge due to sterilization was measured.

[0073] Furthermore, the time required for the dissolution rate to reach 90% (hereinafter also referred to as "time to reach 90% dissolution rate") of the obtained hydrogel-forming sponge was measured in a phosphate buffer solution at 37°C. Details of the measurement method are as follows. (Measurement of time to reach 90% dissolution rate) An appropriate amount of water was applied to a protein leather (Protein Leather PBZ13001-BK, manufactured by Ideatex Japan Co., Ltd.) serving as a simulated skin, using a cotton swab. A hydrogel-forming sponge was then attached and allowed to stand for 5 minutes. Several hydrogel-forming sponges attached to the protein leather were prepared as measurement samples and immersed in a simulated body fluid (37°C phosphate buffer solution, 0.1 mol / L phosphate buffer, pH 7.2, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). Each measurement sample was removed every hour from the start of immersion and dried in a 100°C air dryer for 24 hours. The mass of the sponge remaining on the protein leather was measured. The time required for the sponge to lose 90% of its initial mass after immersion in phosphate buffer was calculated as the time to 90% dissolution. In Example 1, the same procedure as above was also carried out on the hydrogel-forming sponge before gamma irradiation, and the time required for the dissolution rate to reach 90% was measured.

[0074] [Example 2] A hydrogel-forming sponge was obtained by carrying out the same operations as in Example 1, except that the crosslinked polyacrylic acid was changed to uncrosslinked polyacrylic acid (Jurymer (registered trademark) AC-10LHPK, weight-average molecular weight 1.5 million, manufactured by Toagosei Co., Ltd.). The results of evaluation in the same manner as in Example 1 are shown in Table 1. Note that in Example 2 as well, the time to reach 90% of the dissolution rate was measured for each hydrogel-forming sponge before and after gamma-ray irradiation.

[0075] [Comparative Example 1] A hydrogel-forming sponge was produced in the same manner as in Example 1. The obtained hydrogel-forming sponge was placed in an autoclave and subjected to high-pressure steam sterilization by heat treatment at 121°C for 20 minutes in the presence of water. The hydrogel-forming sponge after sterilization was evaluated in the same manner as in Example 1, and the results are shown in Table 1.

[0076] Comparative Example 2 A hydrogel-forming sponge was produced in the same manner as in Example 1. Ethylene oxide gas sterilization was carried out under conditions of a temperature of 50°C, a humidity of 40%, an ethylene oxide gas concentration of 800 mg / L, and an action time of 5 hours. The hydrogel-forming sponge after sterilization was evaluated in the same manner as in Example 1, and the results are shown in Table 1.

[0077] [Table 1]

[0078] <Evaluation results> As is clear from the results in Table 1, in Examples 1 and 2 in which gamma ray sterilization was performed, -6 The following sterility assurance level (SAL) was achieved while the shrinkage rate of the sponge after sterilization was suppressed to 1.0% or less. Furthermore, in the hydrogel-forming sponges of Examples 1 and 2, even after sterilization, the physical crosslinks gradually dissociated under physiological conditions, so the sponges became soluble, and the solubility before sterilization was maintained. In contrast, in Comparative Example 1, in which high-pressure steam sterilization was performed, and Comparative Example 2, in which ethylene oxide gas sterilization was performed, the shrinkage rate of the sponges was large due to the sterilization process, making them less practical.

Claims

1. A method for producing a medical treatment material that forms a hydrogel upon contact with water, comprising: a step of obtaining a film-like solid material containing one of a polymer (A) having a structural unit derived from an ethylenically unsaturated monomer having a carboxyl group and a polymer (B) having a structural unit derived from an ethylenically unsaturated monomer having a functional group capable of forming a hydrogen bond with a carboxyl group (excluding the polymer (A)); a step of contacting the film-like solid with a polymer solution containing the other of the polymer (A) and the polymer (B), and then drying the resulting mixture; a step of sterilizing the dried body obtained by the drying by gamma ray sterilization; Including, The method for producing a medical treatment material, wherein the polymer (B) is polyvinylpyrrolidone.

2. 2. The method for manufacturing a medical treatment material according to claim 1, wherein when the medical treatment material after the sterilization treatment is immersed in a phosphate buffer solution at 37°C, the dissolution rate of the medical treatment material after 10 hours is 90% or more.

3. 3. The method for producing a medical treatment material according to claim 1, wherein the polymer (A) is a crosslinked polymer.

4. The method for producing a medical treatment material according to any one of claims 1 to 3, wherein the polymer (A) is poly(meth)acrylic acid.

5. The method for producing a medical treatment material according to any one of claims 1 to 4, wherein the medical treatment material is used as a hemostatic material.

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