Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
  • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
  • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
  • A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
  • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
  • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
  • A61L15/28—Polysaccharides or their derivatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
  • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
  • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
  • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
  • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
  • A61L15/42—Use of materials characterised by their function or physical properties
  • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L101/00—Compositions of unspecified macromolecular compounds
  • C08L101/12—Compositions of unspecified macromolecular compounds characterised by physical features, e.g. anisotropy, viscosity or electrical conductivity
  • C08L101/14—Compositions of unspecified macromolecular compounds characterised by physical features, e.g. anisotropy, viscosity or electrical conductivity the macromolecular compounds being water soluble or water swellable, e.g. aqueous gels
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
  • C08L33/24—Homopolymers or copolymers of amides or imides
  • C08L33/26—Homopolymers or copolymers of acrylamide or methacrylamide
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
  • C08L39/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions of derivatives of such polymers
  • C08L39/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member
  • C08L39/06—Homopolymers or copolymers of N-vinyl-pyrrolidones

Definitions

• Patent Document 1 discloses that a flexible dry gel is obtained as a hydrogel-forming material by drying a hydrogel formed by hydrogen bonding between polyacrylic acid and polyvinylpyrrolidone.
• the hydrogel-forming material described in Patent Document 1 absorbs moisture such as blood and tissue fluids and gels when applied to wet biological tissue such as a wound or a site where bleeding is to be stopped, thereby having the function of adhering to the biological tissue.
• hydrogel forming material placed on the biological tissue When a hydrogel forming material is applied to biological tissue, it is desirable for the hydrogel forming material placed on the biological tissue to absorb water and swell quickly (for example, within a few minutes to a few dozen minutes) in order for the hydrogel forming material to adhere quickly to the biological tissue when absorbed (i.e., hydrogel) and thereby quickly exert its function of protecting wounds, hemostasis sites, etc. and stopping bleeding.
• hydrogel forming material when using a hydrogel forming material for purposes such as protecting affected areas, it may be required that the gelled state caused by water absorption be maintained continuously on the biological tissue (for example, for about 30 minutes to several hours) so that the hydrogel can remain adhered to the biological tissue for a certain period of time, and there is a demand for the development of new materials that meet these requirements.
• the present disclosure has been made in consideration of the above circumstances, and its purpose is to provide a hydrogel-forming material that quickly absorbs water and swells upon contact with water, and can maintain the swollen state for a relatively long period of time after contact with water.
• the present inventors have conducted extensive research to solve the above problems, and have discovered that the above problems can be solved by using a specific polymer as one of the components that make up the hydrogel-forming material. Specifically, the present disclosure provides the following means.
• the hydrogel-forming material contains the above-mentioned polymer (A) and polymer (B), it has the ability to rapidly absorb water and swell upon contact with water, and after contact with water, it is able to maintain the swollen state due to water for a relatively long period of time.
• (meth)acrylic means acrylic and/or methacrylic.
• (meth)acrylate means acrylate and/or methacrylate.
• the hydrogel-forming material of the present disclosure forms a hydrogel upon contact with water.
• the hydrogel-forming material of the present disclosure includes a polymer (A) that is a biopolymer or a neutralized product thereof that has a carboxyl group and is different from hyaluronic acid, and a polymer (B) (excluding the polymer (A)) that has a functional group (hereinafter also referred to as "functional group E") that can form a hydrogen bond with the carboxyl group.
• the polymer (A) is a raw material (i.e., a biomass material) derived from a living organism such as a plant or an animal, or a polymer obtained based on the raw material, and is a biological polymer having a carboxyl group and/or "-COO- " .
• the polymer (A) is different from hyaluronic acid or its neutralized product.
• the biomass material refers to a biological resource that can be continuously reproduced in the presence of sunlight, water, and carbon dioxide (typically, a plant that performs photosynthesis), a biological resource produced by a microorganism, or a material produced based on the above.
• biological polymers include "natural product-derived polymers” that use natural products as they are or that are processed from natural products, “resource-derived synthetic polymers” that are obtained by polymerization using organic resources such as L-lactic acid and amino acids as monomers, and “microorganism-derived polymers” that are produced by microorganisms.
• the polymer (A) has a carboxyl group and/or "-COO- " .
• the polymer (A) may be an unneutralized biopolymer having a carboxyl group, a partially neutralized product in which a portion of the carboxyl groups of the biopolymer have been neutralized, or a completely neutralized product in which all of the carboxyl groups of the biopolymer have been neutralized.
• an unneutralized polymer of the polymer (A) is referred to as a "biomolar polymer having a carboxyl group” or a “carboxyl group-containing biopolymer”, and a polymer in which some or all of the carboxyl groups have been neutralized is referred to as a "neutralized product of a biopolymer having a carboxyl group” or a "neutralized product of a biopolymer containing a carboxyl group”.
• the neutralized product should be such that at least a portion of the carboxyl groups of the carboxyl group-containing biopolymer are neutralized.
• examples of the counter ion of "-COO- " include various cations such as lithium ion, sodium ion, potassium ion, magnesium ion, calcium ion, aluminum ion, and ammonium ion. From the viewpoint of improving the water swelling property of the hydrogel forming material and application to medical purposes, among these, alkali metal ions are preferred, sodium ion or potassium ion is more preferred, and sodium ion is even more preferred.
• the degree of neutralization of the polymer (A) is preferably 10 mol% or more, more preferably 20 mol% or more, even more preferably 30 mol% or more, even more preferably 40 mol% or more, and even more preferably 50 mol% or more, from the viewpoint of ensuring solubility in aqueous solvents.
• the degree of neutralization of the polymer (A) is a value calculated from the acid value (mgKOH/g) of the polymer obtained by titrating the polymer solution with a potassium hydroxide solution. Details of the method for measuring the acid value follow the method described in the Examples below.
• the weight average molecular weight of polymer (A) is not particularly limited, but from the viewpoint of obtaining a hydrogel-forming material that swells quickly upon contact with moisture and from the viewpoint of improving the handleability of polymer (A) and a polymer solution containing it, it is, for example, 1.8 million or less, and preferably 1.5 million or less.
• the weight average molecular weight of polymer (A) may be 1.2 million or less, 800,000 or less, 700,000 or less, 500,000 or less, or 300,000 or less.
• the lower limit of the weight average molecular weight of polymer (A) is also not particularly limited, and may be 10,000 or more, or 30,000 or more.
• the carboxyl group-containing biopolymer is preferably at least one selected from the group consisting of oxidized cellulose, carboxyalkyl cellulose, pectin, polyglutamic acid, polyaspartic acid, and alginic acid.
• the carboxyalkyl cellulose include carboxymethyl cellulose and carboxypropyl cellulose.
• Oxidized cellulose is cellulose obtained by oxidizing a cellulose-based raw material with an oxidizing agent.
• the cellulose-based raw material may be any material that is mainly composed of cellulose, such as pulp, natural cellulose, regenerated cellulose, and fine cellulose obtained by depolymerizing cellulose through mechanical processing.
• commercially available products such as crystalline cellulose made from pulp can be used as the cellulose-based raw material as is.
• oxidizing agents include 2,2,6,6-tetramethyl-1-piperidine-N-oxy radical (TEMPO), hypochlorous acid or a salt thereof, and the like.
• TEMPO 2,2,6,6-tetramethyl-1-piperidine-N-oxy radical
• hypochlorous acid or a salt thereof and the like.
• the oxidation treatment of the cellulose-based raw material can be carried out by appropriately adopting a known method.
• the oxidized cellulose used as the carboxyl group-containing biopolymer in this disclosure may be fibrous cellulose obtained by oxidizing a cellulosic raw material with an oxidizing agent (i.e., oxidized cellulose before defibration), or may be nanocellulose obtained by defibrating and nano-sizing the fibrous cellulose obtained by oxidizing a cellulosic raw material with an oxidizing agent (i.e., oxidized cellulose after defibration).
• Nanocellulose includes cellulose nanofibers, cellulose nanocrystals, etc.
• oxidized cellulose or its neutralized products can also be used as oxidized cellulose or its neutralized products.
• examples of such commercially available products include Aronfibro (registered trademark) (manufactured by Toagosei Co., Ltd.), Cellenpia TEMPO Oxidized CNF (manufactured by Nippon Paper Industries Co., Ltd.), and Leocrysta (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.).
• Carboxymethylcellulose is a cellulose-based water-soluble polymer in which carboxymethyl groups have been introduced into some or all of the hydroxyl groups of the glucose units that make up cellulose.
• Commercially available carboxymethylcellulose products include, for example, Cellogen (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.); CMC Daicel 1110, 1120, 1130, 1140, 1150, and 1160 (all manufactured by Daicel Miraize Co., Ltd.).
• Pectin is a polysaccharide found in plant tissues (e.g., cell walls and mesophyll), and is a polygalacturonic acid that has galacturonic acid units and galacturonic acid methyl ester units in which some of the galacturonic acid has been methyl-esterified. Pectin can be obtained by acid extraction from citrus fruits, apples, beet pulp, etc. Commercially available pectin products include HM pectin and LM pectin manufactured by Sumitomo Pharma Food & Chemical Co., Ltd.; the GENU pectin series (manufactured by CP Kelco), and the UNIPECTINE series (manufactured by Unitech Foods Co., Ltd.).
• polyglutamic acid examples include ⁇ -polyglutamic acid and ⁇ -polyglutamic acid.
• Polyglutamic acid may be composed of either D-glutamic acid or L-glutamic acid, or may be composed of both.
• Polyglutamic acid can be obtained, for example, by isolating it from the products of various strains of bacteria or microorganisms (e.g., Bacillus subtilis natto and microorganisms of the genus Bacillus).
• Commercially available products of polyglutamic acid or its neutralized products include Meiji Polyglutamic Acid (manufactured by Meiji Food Materials Co., Ltd.).
• Polyaspartic acid can be obtained by thermal polymerization or phosphorus-catalyzed polymerization of aspartic acid.
• Polyaspartic acid may be composed of either D-aspartic acid or L-aspartic acid, or may be composed of both.
• Commercially available products of polyaspartic acid or its neutralized products include poly-( ⁇ , ⁇ )-DL-aspartic acid sodium salt P3418 (manufactured by Sigma-Aldrich).
• Alginic acid is a polysaccharide found in seaweed such as brown algae and red algae, and can be obtained, for example, by treating seaweed with an acid, then heating it in the presence of an alkali and extracting it. Seaweed raw materials include kelp and duckweed. Commercially available products can be used as alginic acid or its neutralized products. Commercially available products of alginic acid include, for example, Chimica algin IL-2, IL-6, I-1, I-3, and I-5 (all manufactured by Chimica Co., Ltd.).
• the polymer (B) has a functional group (functional group E) capable of forming a hydrogen bond with a carboxyl group, and is different from the polymer (A).
• 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 possessed by the polymer (B) may be one type or two or more types. Among them, the functional group E is preferably an amide group and/or a hydroxyl group, and more preferably an amide group, in that a hydrogel forming material having excellent water swelling properties can be obtained.
• polymer (B) examples include polymers having amide groups, which include structural units derived from ethylenically unsaturated monomers having amide groups. Specific examples include polymers obtained using monomers such as (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. Of these, the polymer having an amide group is preferably at least one selected from the group consisting of polyvinylpyrrolidone and poly(meth)acrylamide.
• polymers having hydroxyl groups examples include polyethylene glycol (commercially available products include Macrogol 4000, Macrogol 6000, and Macrogol 20000 manufactured by NOF Corp.), polyoxyethylene hydrogenated castor oil (commercially available products include Cremophor RH40 manufactured by BASF, and HCO-40 and HCO-60 manufactured by Nikko Chemicals), polyoxyethylene polyoxypropylene glycol (commercially available products include Pluronic (registered trademark) F68 manufactured by ADEKA), polyvinyl alcohol, etc. Of these, polyethylene glycol is the preferred polymer having hydroxyl groups.
• the polymer (B) is preferably at least one selected from the group consisting of polyethylene glycol, polyoxyethylene polyoxypropylene glycol, polyvinyl alcohol, and polymers having an amide group.
• the polymer (B) is preferably a polymer having an amide group, and more preferably at least one selected from the group consisting of polyvinylpyrrolidone and poly(meth)acrylamide.
• the polymer (B) is preferably at least one of polyvinylpyrrolidone and polyacrylamide, in view of the excellent polymerizability of the constituent monomers and the ease of production of the polymer (B).
• Polyvinylpyrrolidone is typically a polymer made of N-vinyl-2-pyrrolidone. However, it may contain structural units derived from monomers other than N-vinyl-2-pyrrolidone (hereinafter also referred to as "other monomers") as long as the effects of the present disclosure are not impaired.
• other monomers include (meth)acrylic acid alkyl esters, aliphatic cyclic esters of (meth)acrylic acid, aromatic esters of (meth)acrylic acid, (meth)acrylic acid alkoxyalkyl esters, (meth)acrylic acid hydroxyalkyl esters, polyalkylene glycol mono(meth)acrylates, etc.
• polyvinylpyrrolidone the content of structural units derived from other monomers 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.
• polyacrylamide is typically a polymer made of acrylamide. However, it may contain structural units derived from monomers other than acrylamide, provided that the effect of the present disclosure is not impaired. Specific examples of monomers other than acrylamide include the compounds exemplified above as other monomers.
• 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, relative to the total structural units constituting polyacrylamide.
• Polymethacrylamide is typically a polymer made of methacrylamide. However, it may contain structural units derived from monomers 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 above as other monomers. 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.
• the polymer (B) at least one of a crosslinked polymer and a polymer having a weight-average molecular weight of 6,000 or more (hereinafter also referred to as a "high molecular weight polymer (BH)”) can be preferably used, since it is possible to obtain a hydrogel with excellent adhesiveness to biological tissue.
• the high molecular weight polymer (BH) can be more preferably used as the polymer (B).
• the weight average molecular weight (Mw) of the high molecular weight polymer (BH) is preferably 10,000 or more, more preferably 30,000 or more, and even more preferably 50,000 or more, from the viewpoint of obtaining a hydrogel with excellent adhesiveness to biological tissue while ensuring the mechanical strength and thickening effect of the hydrogel. Also, from the viewpoint of the handleability of the polymer and the polymer solution, 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 weight average molecular weight of the polymer (B) is a polystyrene equivalent value measured by gel permeation chromatography (GPC).
• the hydrogel forming material of the present disclosure can be produced by appropriately combining one or more of the polymers (A) described above with one or more of the polymers (B).
• a preferred specific example of a combination of polymers (A) and (B) is one in which polymer (A) is at least one selected from the group consisting of oxidized cellulose, carboxyalkyl cellulose, pectin, polyglutamic acid, polyaspartic acid, and alginic acid, or a neutralized product thereof, and polymer (B) is at least one selected from the group consisting of polyvinylpyrrolidone and poly(meth)acrylamide.
• the total amount of polymer (A) and polymer (B) contained in the hydrogel-forming material 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, based on the total amount of the hydrogel-forming material, from the viewpoint of obtaining a hydrogel-forming material that has high mechanical strength and easily swells upon contact with water, and from the viewpoint of obtaining a hydrogel that has excellent adhesiveness to biological tissue.
• the content of each polymer in the hydrogel forming material is preferably adjusted so that the polymer (B) is 20 to 500 parts by mass per 100 parts by mass of the polymer (A).
• the content of the polymer (A) and the polymer (B) is within the above range, it is preferable in that a hydrogel can be formed that has a high effect of improving mechanical strength and exhibits excellent adhesiveness to biological tissue.
• the content of the polymer (A) and the polymer (B) is more preferably an amount such that the polymer (B) is 30 to 400 parts by mass per 100 parts by mass of the polymer (A), even more preferably an amount such that the polymer (B) is 50 to 300 parts by mass, even more preferably an amount such that the polymer (B) is 50 to 200 parts by mass, and even more preferably an amount such that the polymer (B) is 75 to 150 parts by mass.
• the polymerization method for producing polymer (B) is not particularly limited.
• Polymer (B) can be obtained by polymerizing monomers using known polymerization methods such as solution polymerization, suspension polymerization, emulsion polymerization, and bulk polymerization.
• solution polymerization for example, an organic solvent and 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 desired polymer.
• a polymerization initiator e.g., an azo compound
• the hydrogel forming material may further contain other components depending on the purpose of use. Examples of other components include hyaluronic acid or its neutralized products. When the hydrogel forming material is applied to medical applications, the hydrogel forming material may contain various other components such as antibacterial agents, anti-inflammatory agents, blood coagulants, anticoagulants, local anesthetics, vasoconstrictors, and vasodilators. The other components may include one or more types. The content of the other components may be appropriately selected according to each component within a range that does not impair the effects of the present disclosure.
• the content of hyaluronic acid or a neutralized product thereof is preferably 0.01 to 20 parts by mass per 100 parts by mass of the total amount of polymer (A) and polymer (B).
• the content of hyaluronic acid or a neutralized product thereof 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 total amount of polymer (A) and polymer (B).
• the upper limit of the content of hyaluronic acid or a neutralized product thereof is more preferably 15 parts by mass or less, and even more preferably 10 parts by mass or less, per 100 parts by mass of the total amount of polymer (A) and polymer (B).
• the hyaluronic acid or a neutralized product thereof one type may be used alone, or two or more types may be used in combination.
• the method for producing the hydrogel-forming material of the present disclosure is not particularly limited.
• the hydrogel-forming material of the present disclosure can be obtained, for example, by using the following method [1], method [2], or method [3].
• Method [1] A method of contacting a film-like solid containing one of the polymers (A) and (B) with a solution containing the other polymer, followed by drying.
• Method [2] A method of mixing a solution containing the polymer (A) with a solution containing the polymer (B) in the presence of hyaluronic acid or a neutralized product thereof, and removing the solvent.
• Method [3] A method of mixing an alcohol solution containing the polymer (A) with an alcohol solution containing the polymer (B), and removing the solvent.
• a film-like solid containing one of the polymers (A) and (B) (hereinafter also referred to as the "first polymer") is produced.
• methods for producing the film-like solid include a solution drying method and a heat pressing method.
• the solution drying method is preferred in that it can suppress the generation of bubbles and produce a smooth film.
• the first polymer constituting the film-like solid may be the polymer (A) or the polymer (B).
• Solvents 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.
• organic solvents that are soluble in water include methanol, ethanol, and acetone. Of these, water, ethanol, or a mixture of water and ethanol are preferred as the solvent for dissolving the first polymer.
• 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.
• the method for forming a film-like solid on a support is not particularly limited, and known film-forming methods can be appropriately adopted.
• a film-like solid containing the first polymer can be formed on a support by coating the support with a solution of the first polymer, and preferably heating the solution to remove the solvent.
• the heating temperature is, for example, 50 to 120°C
• the heating time is, for example, 0.1 to 30 hours.
• the heat treatment may be performed under reduced pressure or under air blowing.
• the thickness of the film-like solid formed on the support is, for example, 1 to 5,000 ⁇ m.
• the moisture content of the film-like solid is, for example, 10 mass% or less.
• the film-like solid formed on the support is 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.
• a polymer solution hereinafter also referred to as the "second polymer solution”
• the solvent that dissolves the second polymer include the same solvents as those exemplified as the solvent that dissolves 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.
• the method of contacting the film-like solid containing the first polymer with the second polymer solution is not particularly limited.
• Examples of the method of contacting the film-like solid with the second polymer solution include a method of applying, dripping or spraying the second polymer solution onto the surface of the film-like solid; and a method of immersing the film-like solid in the second polymer solution.
• a preferred embodiment is a mode in which the second polymer solution is dripped onto the surface of the film-like solid to form a liquid layer made of the second polymer solution on the film-like solid, and the liquid layer is allowed to stand for a predetermined time (for example, 10 to 180 minutes).
• the thickness of the liquid layer is not particularly limited, but is, for example, 0.1 to 50,000 ⁇ m.
• the first polymer in the film-like solid gradually dissolves in the second polymer solution, forming a hydrogel.
• 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.
• the number of moles of the functional group E in the 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 in total of the carboxyl group and "-COO-" in the polymer (A).
• the hyaluronic acid or its neutralized product may be contained in the film-like solid material or the second polymer solution.
• the second polymer solution contains hyaluronic acid or its neutralized product.
• the hyaluronic acid or its neutralized product may be mixed in advance in the second polymer solution, and the second polymer solution containing hyaluronic acid or its neutralized product may be brought into contact with the film-like solid material.
• the hyaluronic acid or its neutralized product may be added to the second polymer solution.
• the second polymer solution containing hyaluronic acid or its neutralized product in advance is brought into contact with the film-like solid material.
• the content of hyaluronic acid or its neutralized product in the second polymer solution is preferably 0.01 to 30 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.
• the formed hydrogel i.e., the product obtained by contacting the film-like solid containing the first polymer with the second polymer solution (hereinafter also referred to as the "hydrogel product")
• the hydrogel product can be dried to obtain the desired dried product as a hydrogel-forming material.
• any known drying method can be used as appropriate.
• the freezing temperature is, for example, -70°C to -5°C, and preferably -60°C to -5°C.
• the drying process by freeze-drying 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.
• the freeze-drying process may be performed by bringing the hydrogel product into a supercooled state and then freezing it. In this case, it is preferable to cool the hydrogel product through multiple steps with different cooling temperatures. This method makes it possible to obtain a sponge-like hydrogel-forming material that has high mechanical strength and excellent adhesiveness to biological tissues in a water-swollen state in a relatively simple manner.
• the first cooling process is performed by first cooling the hydrogel product at a temperature below 0°C and above -10°C to put the hydrogel product into a supercooled state, and then the second cooling process is performed by cooling the hydrogel product at a temperature lower than -10°C to freeze the hydrogel product.
• the first cooling process it is preferable to gradually lower the temperature from the viewpoint of efficiently creating a supercooled state.
• the second cooling process it is preferable to set the cooling temperature to -15°C or lower, more preferably -20°C or lower, and even more preferably -25°C or lower, from the viewpoint of obtaining a hydrogel forming material that has high mechanical strength and excellent adhesion to biological tissue in a water-swollen state.
• the cooling times of the first and second cooling processes are not particularly limited and can be set appropriately, for example, 3 minutes to 5 hours. In the first and/or second cooling processes, the cooling process may be performed in multiple steps with different cooling temperatures.
• dry refers to a state in which moisture has been 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, and preferably 5% by mass or less.
• a solution containing polymer (A) and a solution containing polymer (B) are mixed in the presence of hyaluronic acid or its neutralized product, and the solvent is then removed from the resulting mixed liquid to produce a dried product as a hydrogel-forming material.
• polymer solution A the solution containing polymer (A)
• polymer solution B the solution containing polymer (B)
• 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.
• the polymer concentration is, for example, 0.001 to 5% by mass, and preferably 0.01 to 1% by mass.
• the amount and concentration of polymer solution A and polymer solution B are preferably adjusted so that the content of polymer (A) and polymer (B) is 20 to 500 parts by mass per 100 parts by mass of polymer (A).
• the amount of polymer (A) and polymer (B) is more preferably 30 to 400 parts by mass, and even more preferably 50 to 300 parts by mass, per 100 parts by mass of polymer (A).
• the amount of hyaluronic acid or its neutralized product used is preferably 0.01 to 30 parts by mass, more preferably 0.1 to 30 parts by mass, and even more preferably 0.5 to 20 parts by mass, per 100 parts by mass of polymer (A).
• the hyaluronic acid or its neutralized product is preferably used as an aqueous solution.
• the mixed liquid containing the polymer (A), the polymer (B), and hyaluronic acid or its neutralized product obtained as described above is subjected to a drying process to remove the solvent, thereby obtaining the target dried product.
• the drying process is preferably freeze-drying. Freeze-drying can be performed according to a conventional method. For example, the mixed liquid is placed in a mold and frozen, and the molded frozen product is freeze-dried to obtain the target product (dried product) having the desired shape.
• the freeze-drying process is preferably performed by a method in which the hydrogel product is brought to a supercooled state and then frozen. Details of this method are as explained in Method [1].
• method [3] an alcohol solution containing polymer (A) is mixed with an alcohol solution containing polymer (B), and then the solvent is removed from the resulting mixed solution to produce a dried product as a hydrogel-forming material. Note that method [3] is advantageous in that a high-quality hydrogel-forming material can be obtained in the presence of hyaluronic acid or its neutralized product without mixing polymer solutions.
• alcohol solution containing polymer (A) hereinafter also referred to as “alcohol solution A”
• alcohol solution containing polymer (B) hereinafter also referred to as “alcohol solution B”
• a linear or branched alcohol having 1 to 5 carbon atoms is preferably used as the alcohol.
• the alcohols used to prepare alcohol solution A and alcohol solution B may be the same type or different types.
• one type of alcohol may be used alone, or two or more types of alcohol may be used in combination.
• the alcohol used in preparing alcohol solution A and alcohol solution B is preferably a linear or branched alcohol having 1 to 3 carbon atoms among the above. Furthermore, considering application to medical applications, at least one selected from the group consisting of ethanol, n-propanol, and isopropanol is preferable, and ethanol is particularly preferable.
• the polymer concentration in alcohol solution A and alcohol solution B is, for example, 0.1 to 30% by mass, and preferably 0.5 to 20% by mass.
• the amount and concentration of the polymer (A) and the polymer (B) are preferably adjusted so that the content of the polymer (B) is 20 to 500 parts by mass per 100 parts by mass of the polymer (A).
• the amount of the polymer (A) and the polymer (B) is more preferably 30 to 400 parts by mass, and even more preferably 50 to 300 parts by mass per 100 parts by mass of the polymer (A).
• at least one of the alcohol solution A and the alcohol solution B may contain hyaluronic acid or a neutralized product thereof.
• the content of hyaluronic acid or a neutralized product thereof in the alcohol solution A and/or the alcohol solution B is, for example, 0.01 to 15 parts by mass per 100 parts by mass of the polymer.
• the mixed liquid containing the polymer (A), the polymer (B) and the alcohol obtained as described above is subjected to a drying process to remove the solvent, thereby obtaining the target dried product.
• the method of drying is not particularly limited, and may be, for example, natural drying, heating, blowing air, or a combination thereof, or freeze-drying. Details of the freeze-drying process are as described in Method [1] and Method [2].
• the hydrogel-forming material obtained as described above is insoluble or poorly soluble in an ionic buffer solution such as body fluids, and swells appropriately when in contact with water.
• W1 mass (g) of the hydrogel-forming material after drying the hydrogel-forming material in a windless dryer at 150° C. for 60 minutes
• W2 mass (g) of the hydrogel-forming material after swelling the hydrogel-forming material in an ionic buffer solution for a predetermined time
• W2 mass (g) of the hydrogel-forming material after swelling the hydrogel-forming material in an ionic buffer solution for a predetermined time
• the ratio of W2 to W1 is defined as the "water-swelling degree ⁇ ”
• W 1 mass (g) after drying in a windless dryer at 150° C. for 60 minutes
• W2 mass (g) after swelling with ionic buffer for a given time
• the hydrogel-forming material of the present disclosure preferably has a water swelling degree ⁇ (hereinafter also referred to as "water swelling degree ⁇ 10 ”) when swollen with an ionic buffer solution for 10 minutes of 3 or more, more preferably 5 or more, and even more preferably 8 or more.
• the upper limit of the water swelling degree ⁇ 10 when swollen with an ionic buffer solution for 10 minutes is preferably 60 or less, more preferably 55 or less, and even more preferably 50 or less, from the viewpoint of preventing the volume of the hydrogel-forming material (i.e., hydrogel) after absorbing water from becoming excessively large, thereby preventing pressure on biological tissue.
• the hydrogel-forming material of the present disclosure can maintain the water-swelled state for a relatively long time after absorbing water through contact with water and becoming water-swollen.
• the hydrogel-forming material of the present disclosure can protect the biological tissue by maintaining the state of being adhered to the biological tissue for a relatively long time (for example, about 30 minutes to several hours) after adhering to the biological tissue through water absorption.
• the hydrogel-forming material of the present disclosure has a water swelling degree ⁇ (hereinafter also referred to as "water swelling degree ⁇ 60 ”) when swollen with an ionic buffer for 60 minutes, preferably 2 or more, more preferably 4 or more, and even more preferably 5 or more.
• the upper limit of the water swelling degree ⁇ 60 when swollen with an ionic buffer for 60 minutes is preferably 50 or less, more preferably 40 or less, and even more preferably 30 or less, from the viewpoint of suppressing pressure on the biological tissue by making the hydrogel-forming material in a water-swollen state have an appropriate size.
• the hydrogel-forming material of the present disclosure is a solid in a dry state (i.e., a dry body) before use, and when it comes into contact with moisture, it absorbs water and swells to become a hydrogel (i.e., a swollen body).
• the moisture is not limited to water, but may be, for example, a water-soluble organic solvent (e.g., ethanol), a body fluid (e.g., blood, tissue fluid, etc.), or a mixture thereof.
• the shape of the hydrogel-forming material (dried body) of the present disclosure is not particularly limited, and examples include a film, sheet, sponge, powder, etc.
• the size is also not particularly limited.
• the thickness of the dried body is usually about 0.1 to 50,000 ⁇ m.
• the hydrogel-forming material of the present disclosure may be provided in a state held on a support, in a state enclosed in a package such as a film, or in the form of a spray.
• the shape and material of the support are not particularly limited, but examples include fabrics such as woven fabrics and nonwoven fabrics; and resin substrates such as polystyrene, polypropylene, and polyethylene.
• the hydrogel-forming material of the present disclosure has high mechanical strength and excellent flexibility, and therefore can be preferably used as a hydrogel-forming film or hydrogel-forming sponge.
• the hydrogel-forming material of the present disclosure is in a flexible dry form before contact with water, and changes from a dry form to a swollen form upon contact with water, thereby exhibiting adhesive properties to biological tissue. Furthermore, the hydrogel-forming material of the present disclosure is not bioabsorbable, and gradually decomposes and dissolves under physiological conditions. For this reason, the hydrogel-forming material of the present disclosure is highly safe and can be placed in the body.
• Such a hydrogel-forming material of the present disclosure is suitable as a medical treatment material, and specifically, is particularly suitable as a variety of medical treatment materials such as adhesion prevention materials, hemostatic materials, and wound dressing materials.
• the degree of neutralization of the polymer used in the production of the hydrogel-forming material was measured by the following method.
• (Degree of Neutralization of Polymer) 0.2 g of the polymer was weighed out in a polypropylene cup, about 50 mL of tetrahydrofuran (THF) was added, and the mixture was stirred and dissolved with a magnetic stirrer. About 5 mL of pure water was added to the obtained polymer solution, and the resulting solution was used as a measurement sample. The solution was titrated with a 0.1 mol/L potassium hydroxide/ethanol solution using an automatic titrator (HIRANUMA COM-A19) to measure the acid value (mgKOH/g) of the polymer. The degree of neutralization (mol%) of the polymer was calculated from the obtained acid value.
• HIRANUMA COM-A19 automatic titrator
• a silicone rubber sheet (thickness 10 mm) having an opening of 25 mm x 7 mm was placed on a polypropylene substrate of 50 mm x 50 mm, and 1.5 mL of the above mixed solution containing PVP, HA, and 90 mol% neutralized PGluNa was cast thereon, and cooled (precooled) at 0°C for 0.5 h and then at -4°C for 0.5 h, and then frozen at -35°C for 1 h.
• the frozen product was freeze-dried at room temperature under reduced pressure (5 Pa) to obtain a hydrogel-forming material (size: 25 mm ⁇ 7 mm ⁇ 7 mm).
• Example 3 A silicone rubber sheet (thickness 10 mm) having an opening of 25 mm x 7 mm was placed on a 50 mm x 50 mm polypropylene substrate, and 1.5 mL of 5.13 mass% 100 mol% Na neutralized oxidized cellulose (polymer (A)) aqueous solution was cast and dried at 70 ° C. for 20 hours to prepare a film of 100 mol% Na neutralized oxidized cellulose.
• Example 4 The same procedure as in Example 3 was carried out except that the raw materials were changed as shown in Table 1, to obtain a hydrogel-forming material.
• the hydrogel forming material obtained above was dried at 150°C for 60 minutes using a windless dryer (apparatus name: DX-40 manufactured by Yamato Scientific Co., Ltd.), and the mass of the hydrogel forming material (W 1 in the above formula (1), unit: g) was measured. Next, the dried hydrogel forming material was placed in a phosphate buffer solution (0.1 mol/L phosphate buffer solution, pH 7.2, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) as an ionic buffer solution, and left to stand for 10 minutes.
• a phosphate buffer solution 0.1 mol/L phosphate buffer solution, pH 7.2, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
• the mass of the hydrogel forming material after being left in the ionic buffer solution for 10 minutes was measured, and the water swelling degree ⁇ 10 when the hydrogel forming material was allowed to swell in the ionic buffer solution for 10 minutes was calculated using the above formula (1).
• the time for which the hydrogel-forming material was left in the phosphate buffer solution after being placed in the solution was changed from 10 minutes to 60 minutes, and the mass of the hydrogel-forming material after swelling in the ionic buffer solution for 60 minutes ( W2 in the above formula (1), unit: g) was measured.
• the same operations were performed as above to calculate the water swelling degree ⁇ 60 when the hydrogel-forming material was swollen in the ionic buffer solution for 60 minutes.
• the hydrogel-forming materials (Examples 1 to 5) containing polymer (A) which is a biopolymer having a carboxyl group or a neutralized product thereof, and polymer (B) which has a functional group capable of forming a hydrogen bond with a carboxyl group, had high water swelling degrees ⁇ ( ⁇ 10 , ⁇ 60 ) both 10 minutes and 60 minutes after contact with water. From these results, it can be said that the hydrogel-forming materials of Examples 1 to 5 are capable of quickly absorbing water such as blood and tissue fluid and swelling, and are capable of maintaining this swollen state for a relatively long period of time.
• the hydrogel-forming material of Comparative Example 1 in which uncrosslinked polyacrylic acid was used as the polymer having a carboxyl group instead of the polymer (A) of Examples 1 to 5, had a water swelling degree ⁇ 10 10 minutes after contact with water equivalent to those of Examples 1 to 5, but had a water swelling degree ⁇ 60 60 minutes after contact with water lower than those of Examples 1 to 5, and the water-swelled state disappeared quickly.
• hydrogel-forming material containing polymer (A), which is a biopolymer having a carboxyl group or its neutralized product, and polymer (B), which has a functional group capable of forming a hydrogen bond with a carboxyl group has the ability to rapidly absorb water upon contact with water, and can maintain a state of swelling with water for a relatively long period of time after contact with water.

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