Medical treatment material and method for producing same

Abstract

Provided is a medical treatment material capable of forming a hydrogel upon the contact with water, the medical treatment material comprising a polymer (A) having a carboxyl group and having the property that the viscosity of a 1-mass% aqueous solution thereof is 500 mPa・s or more at 25°C and a polymer (B) having a functional group capable of forming a hydrogen bond in conjunction with a carboxyl group (provided that the polymer (A) is excluded from the polymer (B)).

Description

Medical treatment material and its manufacturing method

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Japanese Patent Application No. 2021-108067, filed on June 29, 2021, the entire contents of which are incorporated herein by reference. The present disclosure relates to a medical treatment material and a method for manufacturing the same, and more particularly to a medical treatment material that forms a hydrogel upon contact with water and a method for manufacturing the same.

[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. In the technology described in Patent Document 1, an aqueous solution of either polyacrylic acid or polyvinylpyrrolidone is dried into a film, and the film is then contacted with an aqueous solution of the other compound and dried to obtain a dried film or sponge that can form a hydrogel upon absorbing water. The films and sponges thus obtained rapidly absorb water, such as blood or tissue fluid, and swell on wet biological tissue, such as a wound or a site where hemostasis is desired, thereby adhering to the biological tissue.

[0003] JP 2014-100462 A

[0004] According to the investigations conducted by the present inventors, the hydrogel-forming material described in Patent Document 1 does not necessarily have sufficient adhesiveness to biological tissue when swollen due to contact with water. Therefore, there is a concern that when the hydrogel-forming material is attached to biological tissue in a wet state, the hydrogel may peel off from the biological tissue.

[0005] The present disclosure has been made in view of the above circumstances, and its object is to provide a medical treatment material that has excellent adhesiveness to biological tissue.

[0006] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have found that a medical treatment material containing a specific carboxyl group-containing polymer and a polymer capable of forming hydrogen bonds with this polymer does not dissolve in a simulated body fluid but swells appropriately, thereby exhibiting high adhesiveness to biological tissue. Specifically, the present disclosure provides the following means.

[0007] [1] A medical treatment material that forms a hydrogel upon contact with water, comprising: a polymer (A) having a carboxyl group and having a viscosity of 500 mPa·s or more at 25°C when made into a 1% by mass aqueous solution; and a polymer (B) (excluding the polymer (A)) having a functional group capable of forming a hydrogen bond with the carboxyl group. [2] The medical treatment material of [1] above, wherein the polymer (A) is a crosslinked polymer. [3] The medical treatment material of [1] or [2] above, wherein the polymer (A) is poly(meth)acrylic acid.

[0008] [4] The medical treatment material according to any one of [1] to [3] above, having a water swelling degree of 20 to 60, as expressed by the following mathematical formula (1): Water swelling degree = W ２ / W １ …(1) W １ W = mass (g) after drying in a windless dryer at 150 ° C for 60 minutes ２ = mass (g) after swelling with ionic buffer for 1 hour

[0009] [5] The medical treatment material according to any one of [1] to [4] above, wherein the polymer (B) has an amide group. [6] The medical treatment material according to any one of [1] to [5] above, wherein the polymer (B) is at least one selected from the group consisting of polyvinylpyrrolidone, polyacrylamide, and polymethacrylamide. [7] The medical treatment material according to any one of [1] to [6] above, wherein a film-like solid material containing one of the polymers (A) and (B) is contacted with a solution containing the other polymer and the resulting mixture is dried, and wherein the material forms a hydrogel upon absorbing water, and the hydrogel has adhesive properties to biological tissue.

[0010] [8] A method for producing a medical treatment material that forms a hydrogel upon contact with water, the method comprising the steps of obtaining a film-like solid material containing one of the following polymers: polymer (A) and polymer (B): polymer (A): a polymer having a carboxyl group, and having a viscosity of 500 mPa·s or more at 25°C when made into a 1% by mass aqueous solution; polymer (B): a polymer having a functional group that can form a hydrogen bond with a carboxyl group (excluding polymer (A)); and contacting the film-like solid material with a solution containing the other polymer of polymer (A) and polymer (B), followed by drying.

[0011] According to the present disclosure, by using a combination of a polymer (A) having a carboxyl group and a viscosity of 500 mPa·s or more at 25°C when made into a 1% by mass aqueous solution, and a polymer (B) having a functional group capable of forming a hydrogen bond with the carboxyl group, as the polymer component of a medical treatment material that forms a hydrogel, a medical treatment material with excellent adhesion to biological tissue can be obtained.

[0012] The present disclosure will be described in detail below. In this specification, "(meth)acrylic" means acrylic and / or methacrylic, and "(meth)acrylate" means acrylate and / or methacrylate.

[0013] <<Medical Treatment Material>> The medical treatment material of the present disclosure is a medical treatment material that forms a hydrogel upon contact with water. The medical treatment material is a hydrogel-forming article that can be used as an adhesion barrier, hemostatic material, wound dressing, etc., and is, for example, a film-, sponge-, sheet-, or powder-like hydrogel-forming material. The medical treatment material of the present disclosure contains the following polymer (A) and polymer (B). Polymer (A): a polymer having a carboxyl group and having a viscosity of 500 mPa·s or more at 25°C when made into a 1% by mass aqueous solution. Polymer (B): a polymer having a functional group that can form a hydrogen bond with a carboxyl group (excluding polymer (A)).

[0014] <Polymer (A)> As the polymer (A), a polymer primarily 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, monohydroxyethyl succinate (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 further enhance adhesiveness to biological tissues.

[0015] In the polymer (A), the content of the 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 within 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 one type or two or more types.

[0016] The method for obtaining the polymer (A) is not limited to the above, and the polymer (A) may be obtained, for example, 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.

[0017] When the polymer (A) is prepared into an aqueous solution containing 1% by mass of the polymer (A), the viscosity of the aqueous solution at 25°C is 500 mPa·s or more. By using such a polymer with a relatively high viscosity, a hydrogel-forming material can be obtained that exhibits high swelling properties when contacted with water and excellent adhesiveness to biological tissue. As the polymer (A) exhibiting a viscosity of 500 mPa·s or more in a 1% by mass aqueous solution at 25°C, a crosslinked polymer or 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. Among these, the use of a crosslinked polymer as the polymer (A) is particularly preferred due to its superior swelling properties when contacted with water and adhesiveness to biological tissue.

[0018] The viscosity at 25°C of an aqueous solution containing 1% by mass of polymer (A) is preferably 600 mPa·s or more, more preferably 800 mPa·s or more, even more preferably 900 mPa·s or more, even more preferably 1,500 mPa·s or more, and even more preferably 5,000 mPa·s or more, from the viewpoint of obtaining a hydrogel that has high swelling properties when contacted with water and has excellent adhesive properties to biological tissue. The upper limit of the viscosity at 25°C of an aqueous solution containing 1% by mass of polymer (A) is preferably 30,000 mPa·s or less, more preferably 25,000 mPa·s or less, from the viewpoint of improving handleability. The viscosity of the aqueous solution containing polymer (A) is a value measured at 25°C using a B-type viscometer. Details of the measurement method follow the method described in the Examples below.

[0019] The method for producing a crosslinked polymer is not particularly limited. Examples of methods for producing a 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 of synthesizing a polymer having a reactive functional group and, if necessary, adding a crosslinking agent to crosslink it. Of these, method (1) is preferred because it is simple to operate and the degree of crosslinking can be easily controlled.

[0020] Examples of the unsaturated monomer (mc) include a polyfunctional polymerizable monomer having two or more ethylenically unsaturated groups, and a self-crosslinking monomer having a self-crosslinkable functional group (e.g., a hydrolyzable silyl group). Specific examples of the polyfunctional polymerizable monomer include a polyfunctional (meth)acrylate compound, a polyfunctional alkenyl compound, and a compound having both a (meth)acryloyl group and an alkenyl group. Among these, the polyfunctional alkenyl compound is preferred as the unsaturated monomer (mc) since it is easy to obtain 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. Of these, polyfunctional alkenyl compounds are particularly preferred, including polyfunctional allyl ether compounds having multiple allyl ether groups in the molecule.

[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 polymer (A) contains structural unit (mc), the amount of structural unit (mc) contained in polymer (A) is preferably 0.01 mass% or more, more preferably 0.1 mass% or more, based on the total structural units constituting polymer (A).In addition, the amount of structural unit (mc) contained in polymer (A) is preferably 5 mass% or less, more preferably 2 mass% or less, even more preferably 1 mass% or less, based on the total structural units constituting polymer (A).In addition, the structural unit (mc) contained in polymer (A) may be only one type or two or more types.

[0024] The polymer (A) may further have a structural unit derived from a monomer (hereinafter, "other monomer (md)") different from the unsaturated monomer (ma) and the unsaturated monomer (mc) within a range that does not impair the effects of the present disclosure. Examples of the other monomer (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 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, dicyclopentanyl (meth)acrylate, etc. Specific examples of aromatic esters of (meth)acrylic acid include phenyl (meth)acrylate, benzyl (meth)acrylate, phenoxymethyl (meth)acrylate, 2-phenoxyethyl (meth)acrylate, 3-phenoxypropyl (meth)acrylate, etc.

[0027] Specific examples of the (meth)acrylic acid alkoxyalkyl ester 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 hydroxyalkyl (meth)acrylate 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 the structural units derived from the 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 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 × 10 to sufficiently increase the adhesiveness to biological tissues. ６ From the viewpoint of ease of handling, the Mw of the high molecular weight polymer (AH) is preferably 5×10 ７ or less, and more preferably 3×10 ７ or less, and more preferably 1×10 ７ 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 group with trimethylsilyldiazomethane.

[0031] Commercially available products can also be used as the polymer (A), such as Jurrimer (registered trademark) AC-10SHP, Junron (registered trademark) PW-120, Junron PW-121, and Junron PW-312S (all manufactured by Toagosei Co., Ltd.).

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

[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, such as (meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-dimethylaminopropyl(meth)acrylamide, N-methyl(meth)acrylamide, N-vinyl-2-pyrrolidone, or 1-vinyl-4-methyl-2-pyrrolidone.

[0035] Examples of the polymer (B) having a hydroxyl group include polyethylene glycol (commercially available products such as Macrogol 4000, Macrogol 6000, and Macrogol 20000 manufactured by NOF Corporation), polyoxyethylene hydrogenated castor oil (commercially available products such as Cremophor RH40 manufactured by BASF, and HCO-40 and HCO-60 manufactured by Nikko Chemical Co., Ltd.), polyoxyethylene polyoxypropylene glycol (commercially available products such as Pluronic (registered trademark) F68 manufactured by ADEKA Corporation), and polyvinyl alcohol. Of these, polyethylene glycol is preferred as the polymer (B) having a hydroxyl group.

[0036] In the polymer (B), the content of structural units derived from ethylenically unsaturated monomers having a functional group E is preferably 70% by mass or more, more preferably 80% by mass or more, even more preferably 90% by mass or more, and still more preferably 97% by mass or more, based on all structural units constituting the polymer (B).

[0037] As the polymer (B), a crosslinked polymer or 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, and a high molecular weight polymer (BH) can be more preferably used.

[0038] From the viewpoint of obtaining a medical treatment material that forms a highly swellable hydrogel upon contact with water, the polymer (B) is preferably at least one selected from the group consisting of polyvinylpyrrolidone, polyacrylamide, and polymethacrylamide, and more preferably at least one selected from the group consisting of polyvinylpyrrolidone and polyacrylamide, in view of the excellent polymerizability of the constituent monomers and the ease of production of the polymer (B).

[0039] Polyvinylpyrrolidone is typically a polymer composed of N-vinyl-2-pyrrolidone. However, it may contain structural units derived from a monomer other than N-vinyl-2-pyrrolidone, as long as the effects of the present disclosure 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.

[0040] Similarly, polyacrylamide is typically a polymer composed of acrylamide. However, it may contain structural units derived from monomers other than acrylamide, as long as the effects of the present disclosure 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.

[0041] Polymethacrylamide is typically a polymer made of methacrylamide. However, it may contain structural units derived from a monomer other than methacrylamide, as long as the effects of the present disclosure 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.

[0042] 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 1×10 ４ More preferably, 3×10 ４ or more, and more preferably 5×10 ４ From the viewpoint of ease of handling, the Mw of the high molecular weight polymer (BH) is preferably 1×10 ８ or less, more preferably 5 × 10 ７ or less, and more preferably 3×10 ７ The molecular weight of the polymer (B) is a polystyrene-equivalent value measured by GPC.

[0043] The total amount of polymer (A) and polymer (B) contained in the medical treatment material of the present disclosure 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 being able to form a hydrogel that has excellent adhesiveness to biological tissue and obtaining a medical treatment material that has excellent mechanical strength.

[0044] In the medical treatment material of the present disclosure, 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).

[0045] 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.

[0046] <Other Components> The medical treatment material of the present disclosure may further contain components other than the polymer (A) and the 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 the polymer (A) and the polymer (B). One or more types of other components may be contained. The content of the other components may be selected appropriately depending on each component, as long as it does not impair the effects of the present disclosure.

[0047] The water-soluble polymer (C) can be water-soluble polymers that can be generally used as thickeners, specifically, for example, polysaccharides.The polysaccharides can be, for example, cellulose derivatives such as hydroxyethyl cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose; mucopolysaccharides such as hyaluronic acid and chondroitin sulfate; water-soluble natural polymer polysaccharides such as carrageenan, pectin, locust bean gum, guar gum, xanthan gum and welan gum, and their salts (for example, sodium salts).Among the water-soluble polymers (C), hyaluronic acid or its salts are preferred.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.

[0048] When the medical treatment material of the present disclosure 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 polymer (A) and 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 perspective, 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 polymer (A) and polymer (B). 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 polymer (A) and polymer (B). As the water-soluble polymer (C), one type may be used alone, or two or more types may be used in combination.

[0049] <Method for producing medical treatment material> There are no particular limitations on the method for producing the medical treatment material of the present disclosure, but it is preferable to use the following method [1] or method [2]. Method [1]: A method in which a film-like solid containing one of polymers (A) and (B) is contacted with a solution containing the other polymer, and then dried. Method [2]: A method in which a solution containing polymer (A) and a solution containing polymer (B) are mixed in the presence of water-soluble polymer (C), and then dried.

[0050] 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 adhesion to biological tissue. In contrast, the above-mentioned methods [1] and [2] make it possible to produce a medical treatment material that exhibits excellent water solubility and water swelling.

[0051] (Regarding Method [1]) In Method [1], 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 coat the first polymer solution on a support and dry it. The first polymer constituting the film-like solid material may be polymer (A) or polymer (B).

[0052] 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.

[0053] 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.

[0054] Subsequently, the film-like solid formed on the support is brought into contact with a polymer solution (hereinafter also referred to as a "second polymer solution") obtained by dissolving a polymer (A) and a polymer (B) different from the first polymer (hereinafter also referred to as a "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. The polymer concentration in the second polymer solution is, for example, 0.1 to 30% by mass, and preferably 1 to 20% by mass.

[0055] The method for contacting the film-like solid material containing the first polymer with the second polymer solution is not particularly limited. Examples of methods for contacting the film-like solid material with the polymer solution include applying, dripping, or spraying the second polymer solution onto the surface of the film-like solid material, and immersing the film-like solid material in the second polymer solution. In a preferred embodiment, the second polymer solution is dripped onto the surface of the film-like solid material to form a liquid layer of the second polymer solution on the film-like solid material, and the resulting solid material is 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 film-like solid material to gradually dissolve in the second polymer solution, forming a hydrogel.

[0056] When the film-like solid material containing the first polymer is brought into contact with the second polymer solution, the amount of the second polymer solution to be brought into contact 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).

[0057] 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, it is preferable that the second polymer solution contains the water-soluble polymer (C), and it is more preferable that the second polymer solution containing the water-soluble polymer (C) in advance be brought into contact with the film-like solid.

[0058] When the second polymer solution containing the water-soluble polymer (C) is brought into contact with a film-like solid material, 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.

[0059] 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.

[0060] When drying a hydrogel by the solution drying method, freeze-drying is preferred. 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 is preferably performed at room temperature under reduced pressure. The pressure during freeze-drying is, for example, 50 Pa or less, preferably 20 Pa or less, and more preferably 10 Pa or less. In this specification, the term “dry” refers to a state in which moisture is completely removed, as well as a state in which moisture remains during the drying process. The moisture content of the dried product obtained by the drying process is, for example, 10% by mass or less, preferably 5% by mass or less. When the resulting 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 formed by contacting a film-like solid containing one of the polymers (A) and (B) with a solution containing the other polymer and drying the resulting product.

[0061] (Regarding Method [2]) In Method [2], a solution containing the polymer (A) and a solution containing the polymer (B) are mixed in the presence of the water-soluble polymer (C), and then the mixture is dried to produce a dried product as a medical treatment material.

[0062] In the solution containing polymer (A) (hereinafter also referred to as "polymer solution A") and the solution containing polymer (B) (hereinafter also referred to as "polymer solution B"), examples of the solvent for dissolving the polymer include the same solvents as those exemplified as the solvent for dissolving the first polymer. Of these, it is preferable to use water alone from the viewpoint of efficiently performing the drying step. In polymer solution A and polymer solution B, the polymer concentration is, for example, 0.001 to 5% by mass, and preferably 0.01 to 1% by mass.

[0063] In addition, the amounts and concentrations of the polymer (A) and polymer (B) in the polymer solution A and polymer solution B are preferably adjusted so that the content of the polymer (B) is 20 to 500 parts by mass relative to 100 parts by mass of the polymer (A). The amounts of the polymer (A) and polymer (B) are more preferably 30 to 400 parts by mass, and even more preferably 50 to 300 parts by mass, relative to 100 parts by mass of the polymer (A).

[0064] The water-soluble polymer (C) used in method [2] can be the same as the specific examples of the water-soluble polymer (C) exemplified above. Among these, hyaluronic acid or a salt thereof can be preferably used. The amount of the water-soluble polymer (C) used 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 polymer (A). The water-soluble polymer (C) is preferably used as an aqueous solution.

[0065] Subsequently, the mixed solution containing the polymer (A), polymer (B), and water-soluble polymer (C) obtained as described above is subjected to a drying treatment to obtain the target dried product. The drying treatment is preferably freeze-drying. Freeze-drying can be carried out according to a conventional method. For example, the mixed solution is poured into a mold and frozen, and the formed frozen product is freeze-dried to obtain the target product (dried product) having the desired shape. The moisture content of the dried product is, for example, 10% by mass or less, preferably 5% by mass or less.

[0066] <Physical Properties of Medical Treatment Material> The medical treatment material obtained as described above does not dissolve in ionic buffer solutions such as body fluids, and swells appropriately when in contact with water. Specifically, the medical treatment material of the present disclosure preferably has a water swelling degree (hereinafter also referred to as "water swelling degree θ") expressed by the following mathematical formula (1) of 20 to 60. Water swelling degree θ = W ２ / W １ …(1) W １ W = mass (g) after drying in a windless dryer at 150 ° C for 60 minutes ２= mass (g) after swelling with ionic buffer for 1 hour

[0067] When the water swelling degree θ of the medical treatment material is 20 or more, the hydrogel can have excellent adhesiveness to biological tissue. Furthermore, when the water swelling degree θ is 60 or less, the volume of the medical treatment material (i.e., the hydrogel) after absorbing water does not become too large, and pressure on biological tissue can be suppressed. From this perspective, the water swelling degree θ of the medical treatment material is more preferably 30 or more, even more preferably 40 or more, and even more preferably 44 or more. Furthermore, the upper limit of the water swelling degree θ is more preferably 55 or less, and even more preferably 50 or less.

[0068] <Use of Medical Treatment Material> The medical treatment material of the present disclosure is a dry solid (i.e., a dried body) before use, and upon contact with water, absorbs water and swells to become a hydrogel (i.e., a swollen body). The medical treatment material of the present disclosure is a flexible dry body before contact with water, and 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, tissue fluid), and mixtures thereof. Furthermore, the medical treatment material of the present disclosure is not bioabsorbable and gradually decomposes and solubilizes under physiological conditions, making it highly safe and allowing it to be placed in the body. Such medical treatment materials of the present disclosure are particularly suitable for various medical treatment materials, such as adhesion barriers, hemostatic materials, and wound dressings.

[0069] The shape of the medical treatment material of the present disclosure 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 of the present disclosure may be provided in a state held on a support, or in a state 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. The medical treatment material of the present disclosure has high mechanical strength and excellent flexibility, and is therefore preferably used as a hydrogel-forming film or a hydrogel-forming sponge.

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

[0071] <Production of Hydrogel-Forming Sponge> [Example 1] A silicone rubber sheet (10 mm thick) with a 25 mm x 7 mm opening was placed on a 50 mm x 50 mm polypropylene substrate, and 1.5 mL of an aqueous solution containing 1.2% uncrosslinked polyacrylic acid (manufactured by Toagosei Co., Ltd., Jurimmer AC-10SHP, hereinafter also referred to as "PAA1") was cast and dried at 70 ° C. for 20 hours to produce a PAA1 film. Next, 5 mL of a mixed solution of 0.6 mL of a 4.6% aqueous solution of polyvinylpyrrolidone (hereinafter also referred to as "PVP") and 0.9 mL of a 0.4% aqueous solution of sodium hyaluronate (hereinafter also referred to as "HA") was dropped onto the surface of the PAA1 film, and the mixture was left to stand for 60 minutes, followed by freezing 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 × 7 mm × 7 mm) as a medical treatment material. The mixing ratio was PAA1:PVP:HA=1:1.53:0.2 (mass ratio).

[0072] Examples 2 to 4 and Comparative Example 1 Except for using the raw materials as shown in Table 1, the same procedure as in Example 1 was carried out to obtain hydrogel-forming sponges as medical treatment materials.

[0073] <Evaluation Method> The hydrogel-forming sponges of Examples 1 to 4 and Comparative Example 1 were subjected to the following measurements and evaluations. The results are shown in Table 1. Measurement and Evaluation of Adhesion Strength to Biological Tissue (Skin) Protein leather (Protein Leather PBZ13001-BK, manufactured by Ideatex Japan Co., Ltd.) was used as a pseudo-skin, and the surface adhesion strength of the hydrogel-forming sponge to the protein leather was measured. First, two 50 mL centrifuge tube lids were prepared by attaching 3 cm square pieces of protein leather to the lids using instant adhesive (Aron Alpha (registered trademark), manufactured by Toagosei Co., Ltd.). An appropriate amount of water was applied to each protein leather with a cotton swab, and the hydrogel-forming sponge was sandwiched between the pieces. A 300 g weight was then placed on each piece and allowed to stand for one minute. One minute after removing the weight, the maximum stress generated when tensioned at 25°C and 120 mm / min using a tensile tester was measured.

[0074] Measurement and evaluation of viscosity of 1% aqueous solution of carboxyl group-containing polymer A carboxyl group-containing polymer was dissolved in pure water to prepare an aqueous solution with a polymer concentration of 1%. The prepared aqueous solution was stored at a liquid temperature of 25±1°C for 1 hour, and then the viscosity of the aqueous solution was measured at 25°C using a Brookfield viscometer (measurement time: 90 seconds) at 6 rpm.

[0075] Measurement and evaluation of water swelling The hydrogel-forming sponge obtained above was dried at 150°C for 60 minutes in a windless dryer (device name: DX-40 manufactured by Yamato Scientific Co., Ltd.), and the mass of the hydrogel-forming sponge was measured. Next, the dried hydrogel-forming sponge was placed in a phosphate buffer solution (0.1 mol / L phosphate buffer, pH 7.2, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as an ion buffer, and left to stand for 1 hour. The mass of the hydrogel-forming sponge after being left to stand for 1 hour was measured, and the water swelling degree θ was calculated using the following mathematical formula (1). Water swelling degree θ = W ２ / W １ …(1) W １ W = mass (g) after drying in a windless dryer at 150 ° C for 60 minutes ２ = mass (g) after swelling with ionic buffer for 1 hour

[0076]

[0077] Details of the compounds used in Table 1 are shown below. PAA1: Uncrosslinked polyacrylic acid [Jurymer AC-10SHP, manufactured by Toagosei Co., Ltd.] PAA2: Medium crosslinked polyacrylic acid [Junron PW-121, manufactured by Toagosei Co., Ltd.] PAA3: High crosslinked polyacrylic acid [Junron PW-120, manufactured by Toagosei Co., Ltd.] PAA4: Uncrosslinked polyacrylic acid [Jurymer AC-10LHPK, weight average molecular weight 1.5 million, manufactured by Toagosei Co., Ltd.] PVP: Polyvinylpyrrolidone [Kollidon 90F, manufactured by BASF Corporation, weight average molecular weight = 320,000 in terms of polystyrene (dimethylformamide eluent)] HA: Sodium hyaluronate [Hyaluronic acid HA-LQH, manufactured by Kewpie Corporation]

[0078] <Evaluation Results> As is clear from the results in Table 1, the hydrogel-forming sponges of Examples 1 to 4 containing the polymer (A) and the polymer (B) had an adhesive strength to the skin of 2.5 N / cm ２ In particular, Examples 1, 2, and 4, which used PAA1 as the carboxyl group-containing polymer, which had a sufficiently high viscosity of 900 mPa·s or more at 25°C when made into a 1% by mass aqueous solution, had an adhesive strength to skin of 3.0 N / cm ２ Among these, Examples 2 and 4, in which a crosslinked polymer was used as the carboxyl group-containing polymer, showed an adhesive strength to the skin of 3.5 N / cm or more. ２ showed even higher values.

[0079] In contrast, when PAA4, which has a low viscosity of 2 mPa s at 25°C when made into a 1% by mass aqueous solution, was used as the carboxyl group-containing polymer, the adhesive strength to the skin was low and inferior to Examples 1 to 4 (Comparative Example 1).

[0080] The present invention is not limited to the above-described embodiments, and encompasses various modifications and equivalent modifications within the scope of the spirit of the present invention. Therefore, in light of the above teachings, various combinations and forms, as well as other combinations and forms including only one element, more than one element, or less than one element, are to be understood as falling within the scope and spirit of the present invention.

Claims

1. A medical treatment material that forms a hydrogel upon contact with water, A polymer (A) having a carboxyl group and having a viscosity of 500 mPa·s or more at 25°C when formed into a 1% by mass aqueous solution; A polymer (B) having a functional group capable of forming a hydrogen bond with a carboxyl group (excluding the polymer (A)), A medical treatment material comprising:

2. The medical treatment material according to claim 1 , wherein the polymer (A) is a crosslinked polymer.

3. 3. The medical treatment material according to claim 1, wherein the polymer (A) is poly(meth)acrylic acid.

4. 3. The medical treatment material according to claim 1, wherein the water swelling degree represented by the following mathematical formula (1) is 20 to 60. Water swelling degree = W ２ / W １ …(1) W １ = Mass (g) after drying at 150°C for 60 minutes in a windless dryer W ２ = mass (g) after swelling with ionic buffer for 1 hour

5. The medical treatment material according to claim 1 or 2, wherein the polymer (B) has an amide group.

6. 3. The medical treatment material according to claim 1, wherein the polymer (B) is at least one selected from the group consisting of polyvinylpyrrolidone, polyacrylamide, and polymethacrylamide.

7. a film-like solid material containing one of the polymers (A) and (B) is brought into contact with a solution containing the other polymer, and the resulting product is dried; 3. The medical treatment material according to claim 1, which forms a hydrogel when it absorbs moisture, and the hydrogel has adhesiveness to biological tissue.

8. A method for producing a medical treatment material that forms a hydrogel upon contact with water, comprising the steps of: The following polymer (A) and polymer (B) Polymer (A): A polymer having a carboxyl group and having a viscosity of 500 mPa·s or more at 25° C. when made into a 1% by mass aqueous solution. Polymer (B): A polymer having a functional group capable of forming a hydrogen bond with a carboxyl group (excluding the polymer (A)). obtaining a film-like solid material containing one of the polymers; a step of contacting the film-like solid with a solution containing the other of the polymer (A) and the polymer (B) and then drying the film-like solid; A method for producing a medical treatment material, comprising: