WO2010101031A1 - Treatment instrument to be used in blood vessel - Google Patents

Treatment instrument to be used in blood vessel Download PDF

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Publication number
WO2010101031A1
WO2010101031A1 PCT/JP2010/052539 JP2010052539W WO2010101031A1 WO 2010101031 A1 WO2010101031 A1 WO 2010101031A1 JP 2010052539 W JP2010052539 W JP 2010052539W WO 2010101031 A1 WO2010101031 A1 WO 2010101031A1
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Prior art keywords
water
fine particles
meth
blood vessel
responsive
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PCT/JP2010/052539
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French (fr)
Japanese (ja)
Inventor
崇王 安齊
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テルモ株式会社
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Publication of WO2010101031A1 publication Critical patent/WO2010101031A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
    • A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
    • A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
    • A61B17/12113—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel within an aneurysm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
    • A61B17/12186—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices liquid materials adapted to be injected
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
    • A61B17/1219—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices expandable in contact with liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to an intravascular treatment material, and more particularly to an intravascular treatment material in which outflow from a blood vessel is suppressed, a special catheter is unnecessary, and an embolus can be arbitrarily released in the blood vessel.
  • Vascular embolization is performed as a treatment method for intravascular diseases such as aneurysms, vascular malformations, liver cancer, and uterine fibroids.
  • vascular embolization a vascular embolization material is administered into a blood vessel, and the lumen of the blood vessel is filled and occluded with the embolization material, so that an aneurysm or vascular malformation ruptures a hemorrhagic disease (typically cerebral infarction).
  • This is a therapeutic method for ischemic necrosis of cancer and myoma by prophylactic treatment or by filling and occluding the vegetative blood vessels to cancer and myoma with an embolic material.
  • vascular embolization material As a vascular embolization material, a metal coil, silk thread, resin particles, gelatin sponge and the like have been used. When these embolization materials are used, embolization is achieved in a form in which the thrombus fills the gap between the embolization material and the embolization material in the blood vessel. Therefore, the thrombus is dissolved by the action of the blood fibrinolysis system, and the embolic blood vessel is restarted, and the therapeutic effect as expected may not be obtained.
  • a liquid embolizing material has been developed as a material that has improved these drawbacks.
  • Treatment material containing cyanoacrylate that embolizes blood vessels by polymerizing upon contact with water in blood and polymerizing and depositing as a solid (MV Jayaraman, et al., AJNR Am J Neuroradiol 28: 352 -54, February, 2007) or a liquid in which a polymer insoluble in blood is previously dissolved in an organic solvent is injected into the blood vessel, and the organic solvent diffuses into the blood, so that the polymer precipitates as a solid and the blood vessel is circulated.
  • the embedding polyvinyl alcohol corresponds to that (W. Weber, et al., AJNR Am J Neuroradiol 28: 371-77, February, 2007). Regardless of which material is used, it is possible to block the blood vessel lumen with only the embolic material.
  • Japanese published patent publication No. 2004-528880 discloses pH-sensitive water-swellable polymer fine particles having a diameter of 100 to 900 ⁇ m when dried.
  • the present invention has been made in view of such problems of the prior art, and its purpose is to suppress the outflow from the blood vessel, no special catheter is required, and to arbitrarily release the embolus within the blood vessel. Another object is to provide an intravascular treatment material.
  • An intravascular treatment material comprising pH-responsive water-swellable polymer fine particles that swell with water under a pH of 7 or more and that have an average particle size after water swelling of 50 to 100 ⁇ m.
  • a copolymer in which the pH-responsive water-swellable polymer fine particles include a structural unit derived from the (meth) acrylamide monomer (a1) and a structural unit derived from the unsaturated carboxylic acid (a2).
  • the intravascular treatment material according to (1) above which is fine particles formed from a pH-responsive water-swellable crosslinked polymer (A) crosslinked with a crosslinking agent (a3).
  • the intravascular treatment material of the present invention is excellent in the effect as an embolization material that can fill the blood vessel without gaps.
  • the intravascular treatment material of the present invention can use water as a medium that does not adhere a medical device such as a catheter and a blood vessel wall, a special catheter is unnecessary.
  • the average particle size after water swelling is 50 to 100 ⁇ m, the risk of developing complications due to outflow from veins is low.
  • the pH-responsive water-swellable polymer fine particles of the present invention swell and become solid under a specific pH condition, but have fluidity from a solid state in a blood vessel by adding an acidic aqueous solution. Since the form can be changed to a liquid state, the embolus can be arbitrarily released.
  • the present invention is an intravascular treatment material comprising pH-responsive water-swellable polymer fine particles which are water-swelled under conditions of pH 7 or higher and whose average particle size after water swelling is 50 to 100 ⁇ m.
  • the pH-responsive water-swellable polymer fine particles immediately swell with water under a weakly alkaline condition of pH 7.3 to 7.6 such as blood to increase the contact area between the particles and increase the friction. It becomes a form having almost no fluidity. Therefore, the effect as an embolic material that can fill the blood vessel without gaps can be exhibited. Further, since the intravascular treatment material of the present invention can use water that does not adhere the catheter and the blood vessel wall as a medium, a special catheter is not required, and the average particle diameter after swelling is 50 to 50%. Since it is 100 micrometers, the risk of the complication onset by the outflow from a vein can be reduced, for example. In addition, the pH-responsive water-swellable polymer fine particles can be changed from a solid state to a fluid liquid state in blood vessels by adding an acidic aqueous solution, so that embolization can be arbitrarily released. It becomes possible.
  • the intravascular treatment material of the present invention comprises pH-responsive water-swellable polymer fine particles that swell under conditions of pH 7 or higher and that have an average particle diameter of 50 to 100 ⁇ m after water swelling.
  • the pH-responsive water-swellable polymer fine particle is not particularly limited, but is a co-polymer containing a structural unit derived from the (meth) acrylamide monomer (a1) and a structural unit derived from the unsaturated carboxylic acid (a2).
  • the coalesced particles are preferably fine particles formed from a pH-responsive water-swellable crosslinked polymer (A) crosslinked by a crosslinking agent (a3).
  • a3 crosslinking agent
  • the (meth) acrylamide monomer (a1) that is a monomer component of the pH-responsive water-swellable crosslinked polymer (A) is not particularly limited. Specific examples include (meth) acrylamide, N-methyl (meth) acrylamide, N-ethyl (meth) acrylamide, Nn-propyl (meth) acrylamide, N-isopropyl (meth) acrylamide, N- n-butyl (meth) acrylamide, N-isobutyl (meth) acrylamide, Ns-butyl (meth) acrylamide, Nt-butyl (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-ethyl- N-methyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N-methyl-N-isopropyl (meth) acrylamide, N-methyl-Nn
  • (meth) acrylamide monomers (a1) can be used alone or in combination of two or more.
  • description, such as (meth) acrylic acid and (meth) acrylamide means acrylic acid and methacrylic acid or each of these derivatives.
  • (meth) acrylamide which has a use track record in the orthopedic field etc. and has high safety in the living body is preferable.
  • the unsaturated carboxylic acid (a2) which is a monomer component of the pH-responsive water-swellable crosslinked polymer (A), is not particularly limited, and specific examples thereof include (meth) acrylic acid and maleic acid. Examples include acid, fumaric acid, glutaconic acid, itaconic acid, crotonic acid, sorbic acid and the like.
  • salts of the unsaturated carboxylic acid such as sodium salt, potassium salt and ammonium salt can also be used in the production of the pH-responsive water-swellable crosslinked polymer (A).
  • the structural unit of the unsaturated carboxylic acid (a2) is introduced into the pH-responsive water-swellable crosslinked polymer (A) by performing an acid treatment described later. sell.
  • These unsaturated carboxylic acids (a2) (or salts thereof) can be used alone or in combination of two or more.
  • (meth) acrylic acid or sodium (meth) acrylate is preferred from the viewpoint of exhibiting swelling in a neutral to alkaline region of pH 7 or higher.
  • the crosslinking agent (a3) used in the pH-responsive water-swellable crosslinked polymer (A) is not particularly limited, and examples thereof include a crosslinking agent (a) having two or more polymerizable unsaturated groups, A crosslinking agent (B) having one each of a saturated functional group and a reactive functional group other than the polymerizable unsaturated group, a crosslinking agent (C) having two or more reactive functional groups other than the polymerizable unsaturated group, and the like. Can be mentioned. These crosslinking agents may be used alone or in combination of two or more.
  • cross-linking agent (a) when only the cross-linking agent (a) is used, when the (meth) acrylamide monomer (a1) and the unsaturated carboxylic acid (a2) (or a salt thereof) are copolymerized, a cross-link is formed in the polymerization system.
  • the agent (I) may be added and copolymerized.
  • the crosslinking agent (c) is added after copolymerization of (a1) and (a2), and post-crosslinking by heating, for example, may be performed.
  • crosslinking agent (b) When only the crosslinking agent (b) is used and when two or more of the crosslinking agents (a), (b) and (c) are used, the (meth) acrylamide monomer (a1) and the unsaturated carboxylic acid
  • a crosslinking agent may be added to the polymerization system for copolymerization, and post-crosslinking may be performed, for example, by heating.
  • crosslinking agent (a) having two or more polymerizable unsaturated groups include, for example, N, N′-methylenebisacrylamide, N, N′-methylenebismethacrylamide, N, N′-ethylenebisacrylamide.
  • crosslinking agent (b) each having one polymerizable unsaturated group and one reactive functional group other than the polymerizable unsaturated group include hydroxyethyl (meth) acrylate and N-methylol (meth).
  • examples include acrylamide and glycidyl (meth) acrylate.
  • crosslinking agent (c) having two or more reactive functional groups other than the polymerizable unsaturated group include, for example, polyhydric alcohols (for example, ethylene glycol, diethylene glycol, glycerin, propylene glycol, trimethylolpropane, etc.) , Alkanolamine (for example, diethanolamine), and polyamine (for example, polyethyleneimine).
  • polyhydric alcohols for example, ethylene glycol, diethylene glycol, glycerin, propylene glycol, trimethylolpropane, etc.
  • Alkanolamine for example, diethanolamine
  • polyamine for example, polyethyleneimine
  • crosslinking agent (a) having two or more polymerizable unsaturated groups is preferred, and N, N'-methylenebisacrylamide is more preferred.
  • the production method of the pH-responsive water-swellable crosslinked polymer (A) is not particularly limited, but the (meth) acrylamide monomer (a1), unsaturated carboxylic acid (a2) (or salt thereof), and necessary It is preferable to manufacture by copolymerizing the crosslinking agent (a3) according to the above and further performing post-crosslinking as necessary.
  • the copolymerization method is not particularly limited, and conventionally known methods such as a solution polymerization method using a polymerization initiator, an emulsion polymerization method, a suspension polymerization method, a reverse phase suspension polymerization method, a thin film polymerization method, and a spray polymerization method are known.
  • the method can be used.
  • Examples of the polymerization control method include adiabatic polymerization, temperature controlled polymerization, and isothermal polymerization.
  • a method of initiating polymerization by irradiating with radiation, electron beam, ultraviolet rays or the like can also be employed.
  • a reverse phase suspension polymerization method using a polymerization initiator is preferred.
  • aliphatic organic solvents such as n-hexane, n-heptane, n-octane, n-decane, cyclohexane, methylcyclohexane, liquid paraffin, toluene
  • An organic organic solvent such as an aromatic organic solvent such as xylene and a halogen organic solvent such as 1,2-dichloroethane can be used, but an aliphatic organic solvent such as hexane, cyclohexane and liquid paraffin is more preferable.
  • the said solvent can also be used individually or in mixture of 2 or more types.
  • a dispersion stabilizer can be added to the continuous phase.
  • the particle size of the resulting pH-responsive water-swellable polymer fine particles can be controlled by appropriately selecting the type and amount of the dispersion stabilizer.
  • dispersion stabilizer examples include, for example, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, sorbitan sesquioleate, sorbitan trioleate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmi Nonionics such as tate, sorbitan monostearate, sorbitan tristearate, glycerol monostearate, glycerol monooleate, glyceryl stearate, glyceryl caprylate, sorbitan stearate, sorbitan oleate, sorbitan sesquioleate, coconut fatty acid sorbitan
  • a system surfactant is preferably used.
  • the dispersion stabilizer is preferably used in the range of 0.04 to 20% by mass, more preferably in the range of 1 to 12% by mass, based on the continuous phase solvent. If it is said range, the polymer obtained at the time of superposition
  • the concentration of the monomer component in the reverse phase suspension polymerization method is not particularly limited as long as it is a conventionally known range, and is preferably 2 to 7% by mass, for example, and more preferably 3 to 5% by mass.
  • Examples of the polymerization initiator used in the reverse phase suspension polymerization method include persulfates such as potassium persulfate, ammonium persulfate, and sodium persulfate, methyl ethyl ketone peroxide, methyl isobutyl ketone peroxide, and di-t-butyl peroxide.
  • persulfates such as potassium persulfate, ammonium persulfate, and sodium persulfate, methyl ethyl ketone peroxide, methyl isobutyl ketone peroxide, and di-t-butyl peroxide.
  • Peroxides such as oxide, t-butylcumyl peroxide, t-butylperoxyacetate, t-butylperoxyisobutyrate, t-butylperoxypivalate, hydrogen peroxide, 2,2′-azobis [2 -(N-phenylamidino) propane] dihydrochloride, 2,2'-azobis [2- (N-allylamidino) propane] dihydrochloride, 2,2'-azobis ⁇ 2- [1- (2-hydroxy Ethyl) -2-imidazolin-2-yl] propane ⁇ dihydrochloride, 2,2′-azobis ⁇ 2-methyl-N- [1,1-bis ( Droxymethyl) -2-hydroxyethyl] propionamide ⁇ , 2,2′-azobis [2-methyl-N- (2-hydroxyethyl) -propionamide], 4,4′-azobis (4-cyanovaleric acid), etc.
  • azo compounds may be used, and these may be used alone or in combination of two or more.
  • persulfate is preferable, and potassium persulfate, ammonium persulfate, and sodium persulfate are more preferable.
  • the above polymerization initiator is used in combination with a reducing agent such as sodium sulfite, sodium hydrogen sulfite, ferrous sulfate, L-ascorbic acid, N, N, N ′, N′-tetramethylethylenediamine, and redox polymerization is initiated. It can also be used as an agent.
  • a reducing agent such as sodium sulfite, sodium hydrogen sulfite, ferrous sulfate, L-ascorbic acid, N, N, N ′, N′-tetramethylethylenediamine, and redox polymerization is initiated. It can also be used as an agent.
  • the amount of the polymerization initiator used is preferably 2 to 6 parts by mass and more preferably 3 to 5 parts by mass with respect to 100 parts by mass of the total amount of monomers. If it is the range of said usage-amount, since a polymerization reaction will advance efficiently and the molecular weight of the polymer obtained will become large and viscosity will become small, aggregation of a polymer can be suppressed.
  • a chain transfer agent may be used in the copolymerization.
  • the chain transfer agent include, for example, thiols (n-lauryl mercaptan, mercaptoethanol, triethylene glycol dimercaptan, etc.), thiolic acids (thioglycolic acid, thiomalic acid, etc.), secondary alcohols (isopropanol). Etc.), amines (dibutylamine, etc.), hypophosphites (sodium hypophosphite, etc.) and the like.
  • the polymerization conditions in the reverse phase suspension polymerization method are not particularly limited, and for example, the polymerization temperature can be appropriately set depending on the type of catalyst used, but is preferably 35 to 75 ° C, more preferably 40 to 50 ° C. is there. If it is said temperature range, since a polymerization reaction will advance efficiently and it will become difficult to volatilize a dispersion medium, the dispersion state of a monomer component will become favorable.
  • the polymerization time is preferably 1 hour or longer.
  • the pressure in the polymerization system is not particularly limited, and may be any of normal pressure (atmospheric pressure), reduced pressure, and increased pressure.
  • the atmosphere in the reaction system may be an air atmosphere or an inert gas atmosphere such as nitrogen or argon.
  • the timing for adding the crosslinking agent (c) is the monomer polymerization reaction. There is no particular limitation as long as it is after completion.
  • the reaction temperature at the time of the post-crosslinking reaction varies depending on the type of the crosslinking agent (a3) to be used and cannot be determined unconditionally, but is usually 50 to 150 ° C.
  • the reaction time is usually 1 to 48 hours.
  • the pore-forming agent when copolymerization is performed, can be made porous by being supersaturated and suspended in the monomer solution. At this time, it is preferable to use a pore-forming agent that is insoluble in the monomer solution but soluble in the cleaning solution.
  • a pore making agent sodium chloride, potassium chloride, ice, sucrose, sodium hydrogencarbonate, etc. are mentioned preferably, More preferably, it is sodium chloride.
  • a preferable concentration of the pore-forming agent is preferably 5 to 50% by mass, more preferably 10 to 30% by mass in the monomer solution.
  • acid treatment is performed after copolymerization, and the carboxylate portion of pH-responsive water-swellable cross-linked polymer (A) is converted to a carboxyl group It is preferable to keep it.
  • the conditions for the acid treatment are not particularly limited, and for example, the treatment may be carried out in a low pH aqueous solution such as a hydrochloric acid aqueous solution, preferably in a temperature range of 15 to 60 ° C., preferably for 1 to 24 hours.
  • the pH-responsive water-swellable crosslinked polymer (A) thus obtained is subjected to heat-drying, crushing, etc., if necessary, so that the pH-responsive water-swellable polymer fine particles used in the present invention are used. It becomes.
  • the shape of the pH-responsive water-swellable polymer fine particles used in the present invention is not particularly limited, such as a spherical shape, a crushed shape, and an indefinite shape, but is preferably a spherical shape.
  • the average particle diameter of the pH-responsive water-swellable polymer fine particles after water swelling is 50 to 100 ⁇ m, preferably 50 to 80 ⁇ m, more preferably 50 to 60 ⁇ m.
  • the pH-responsive water-swellable polymer particles pass through the anastomosis between the artery and vein and rarely flow out into the vein. Little or no possibility of embolizing blood vessels.
  • the contact area between the pH-swellable water-swellable polymer particles increases and the friction increases, the fluidity of the polymer particles after water swelling can be reduced.
  • the average particle diameter of the pH-responsive water-swellable polymer fine particles before water swelling is preferably 20 to 50 ⁇ m, more preferably The control is preferably performed in the range of 20 to 40 ⁇ m, more preferably 20 to 30 ⁇ m.
  • the shape and average particle size of the pH-responsive water-swellable polymer fine particles are determined according to the production conditions of the pH-responsive water-swellable polymer fine particles (type of monomer, temperature / time during copolymerization, dispersion stabilizer Amount, type, etc.).
  • the average particle diameter of the pH-responsive water-swellable polymer fine particles before water swelling (at the time of drying) is a value measured by a Coulter counter.
  • the average particle diameter of the pH-responsive water-swellable polymer fine particles after water swelling adopts an average value when 100 fine particles photographed with a CCD camera are selected and each particle diameter is measured.
  • the intravascular treatment material of the present invention can use the pH-responsive water-swellable polymer fine particles obtained as described above in powder form, but it is easy to handle, medical devices such as catheters and blood vessel walls. From the standpoint of preventing adhesion with water, it is preferable to use distilled water having a pH of 5 to 6 to form an aqueous dispersion.
  • the concentration of the pH-responsive water-swellable polymer fine particles in the aqueous dispersion is preferably 3% by mass or more, more preferably 3 to 20% by mass, and 3 to 10% by mass. More preferably it is. If it is the said range, when pH-responsive water-swellable polymer microparticles
  • the pH-responsive water-swellable polymer microparticles contained in the intravascular treatment material of the present invention having such a structure is under a weakly alkaline condition of pH 7 or more, preferably pH 7.3 to 7.6 such as blood. Swells with water. If pH is 7 or more, the treatment material for blood vessels of the present invention will be in a solid state with little fluidity. On the other hand, when the pH is less than 7, the pH-responsive water-swellable polymer fine particles do not swell, and the intravascular treatment material of the present invention has fluidity.
  • the pH-responsive water-swellable polymer fine particles swollen with water are brought into contact with an acidic aqueous solution having a pH of less than 4, the pH-responsive water-swellable fine polymer particles contract. Therefore, by utilizing this characteristic, the acidic aqueous solution is injected into the blood vessel using, for example, a catheter or the like, and brought into contact with the pH-responsive water-swellable polymer fine particles forming an embolus, whereby the intravascular use of the present invention.
  • the embolization can be arbitrarily released by imparting fluidity to the treatment material again.
  • the effect of the present invention will be described in further detail using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples.
  • the average particle size of the pH-responsive water-swellable polymer fine particles before water swelling (during drying) was measured with a Coulter counter. Further, the average particle diameter of the pH-responsive water-swellable polymer fine particles after water swelling is an average value when 100 fine particles photographed with a CCD camera are selected and the respective particle diameters are measured.
  • acrylamide, 2.2 g of sodium acrylate, 0.013 g of N, N′-methylenebisacrylamide and 5.4 g of sodium chloride were weighed into a 50 mL brown glass bottle, and 19.9 g of distilled water was added.
  • a monomer aqueous solution was prepared by stirring and dissolving with a tic stirrer.
  • a solution prepared by dissolving 0.27 g of ammonium persulfate in 2.0 g of distilled water was added to the aqueous monomer solution, and then the total amount was added to the continuous phase solvent.
  • the monomer solution was dispersed in the continuous phase solvent by stirring at a rotation speed of 300 rpm.
  • acrylamide, 2.2 g of sodium acrylate, 0.013 g of N, N′-methylenebisacrylamide and 5.4 g of sodium chloride were weighed into a 50 mL brown glass bottle, and 19.9 g of distilled water was added.
  • the mixture was stirred and dissolved with a tic stirrer to prepare an aqueous monomer solution.
  • a solution prepared by dissolving 0.27 g of ammonium persulfate in 2.0 g of distilled water was added to the aqueous monomer solution, and then added to the continuous phase solvent.
  • the monomer solution was dispersed in the continuous phase solvent by stirring at a rotation speed of 300 rpm.
  • acrylamide, 2.2 g of sodium acrylate, 0.013 g of N, N′-methylenebisacrylamide and 5.4 g of sodium chloride were weighed into a 50 mL brown glass bottle, and 19.9 g of distilled water was added.
  • a monomer aqueous solution was prepared by stirring and dissolving with a tic stirrer.
  • a solution prepared by dissolving 0.27 g of ammonium persulfate in 2.0 g of distilled water was added to the aqueous monomer solution, and then the total amount was added to the continuous phase solvent.
  • the monomer solution was dispersed in the continuous phase solvent by stirring at a rotation speed of 300 rpm.
  • Example 1 0.03 g of fine particles having an average particle diameter of 20 ⁇ m prepared in Production Example 1 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 3% by mass. A fine particle dispersion was obtained.
  • Example 2 0.05 g of fine particles having an average particle diameter of 20 ⁇ m prepared in Production Example 1 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 5% by mass. A fine particle dispersion was obtained.
  • Example 3 0.07 g of fine particles having an average particle diameter of 20 ⁇ m prepared in Production Example 1 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 7% by mass. A fine particle dispersion was obtained.
  • Example 4 0.03 g of fine particles having an average particle diameter of 34 ⁇ m prepared in Production Example 2 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 3% by mass. A fine particle dispersion was obtained.
  • Example 5 0.05 g of fine particles having an average particle diameter of 34 ⁇ m produced in Production Example 2 were weighed into a glass test tube (Lalbo Clean Test Tube), and distilled water for injection at pH 5.5 was added to make 1.00 g, with a concentration of 5% by mass. A fine particle dispersion was obtained.
  • Example 6 0.07 g of fine particles with an average particle diameter of 34 ⁇ m prepared in Production Example 2 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 7% by mass. A fine particle dispersion was obtained.
  • Comparative Example 1 0.02 g of fine particles having an average particle diameter of 150 ⁇ m prepared in Production Example 3 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 2% by mass. A fine particle dispersion was obtained.
  • Comparative Example 2 0.03 g of fine particles having an average particle diameter of 150 ⁇ m prepared in Production Example 3 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 3% by mass. A fine particle dispersion was obtained.
  • the intravascular treatment materials of Examples 1 to 6 having an average particle diameter after water swelling in the range of the present invention became solid after water swelling and the contents did not fall.
  • the intravascular treatment materials of Comparative Examples 1 to 3 having an average particle diameter after water swelling outside the scope of the present invention did not become solid even after water swelling and the contents dropped.

Abstract

Disclosed is a treatment instrument to be used in a blood vessel the outflow of which from the blood vessel is prevented, which requires no special catheter, and by which an embolus can be arbitrarily removed in the blood vessel. Specifically disclosed is a treatment instrument to be used in a blood vessel comprising microparticles of a pH-responsive water-swellable polymer which swell in water at pH 7 or higher and, after swelling in water, have an average particle diameter of 50-100 μm.

Description

血管内用処置材Endovascular treatment material
　本発明は、血管内用処置材に関し、さらに詳細には、血管からの流出が抑制され、特殊なカテーテルが不要であり、かつ血管内で塞栓を任意に解除しうる血管内用処置材に関する。 The present invention relates to an intravascular treatment material, and more particularly to an intravascular treatment material in which outflow from a blood vessel is suppressed, a special catheter is unnecessary, and an embolus can be arbitrarily released in the blood vessel.
　動脈瘤、血管奇形、肝癌、子宮筋腫などの血管内疾患の治療法として血管塞栓術が行われている。血管塞栓術は、血管内に血管塞栓材を投与し、血管内腔を塞栓材で充填閉塞することによって、動脈瘤、血管奇形の破裂による出血性疾患（代表的な疾患としては脳梗塞）を予防的に処置したり、あるいは癌、筋腫への栄養血管を塞栓材で充填、閉塞することによって、癌、筋腫を虚血壊死させる治療方法である。血管塞栓材としては、金属コイル、絹糸、樹脂製の粒子、ゼラチンスポンジなどが使用されてきた。これらの塞栓材を使用した場合、血管内において、塞栓材と塞栓材の空隙を血栓が埋める形態で塞栓が達成される。そのため、血栓が血液線溶系の働きによって溶解し、塞栓血管が再開通してしまい、思ったとおりの治療効果が得られないことがあった。それらの欠点を改良した材料として、液状の塞栓材が開発されてきている。血液中の水分との接触によって重合が開始してポリマー化し、固体として析出することにより血管を塞栓するシアノアクリレートを含む処置材（Ｍ．Ｖ．Ｊａｙａｒａｍａｎ，ｅｔ　ａｌ．，　ＡＪＮＲ　Ａｍ　Ｊ　Ｎｅｕｒｏｒａｄｉｏｌ　２８：３５２－５４，Ｆｅｂｒｕａｒｙ，２００７）や、あらかじめ血液に不溶のポリマーを有機溶剤に溶かした液体を血管内に注入し、有機溶剤が血液中に拡散することでポリマーが固体として析出することによって血管内を塞栓するポリビニルアルコールがそれに該当する（Ｗ．Ｗｅｂｅｒ，ｅｔ　ａｌ．，　ＡＪＮＲ　Ａｍ　Ｊ　Ｎｅｕｒｏｒａｄｉｏｌ　２８：３７１－７７，Ｆｅｂｒｕａｒｙ，２００７）。いずれの材料を用いても、血管内腔を塞栓材のみで閉塞することが可能である。 Vascular embolization is performed as a treatment method for intravascular diseases such as aneurysms, vascular malformations, liver cancer, and uterine fibroids. In vascular embolization, a vascular embolization material is administered into a blood vessel, and the lumen of the blood vessel is filled and occluded with the embolization material, so that an aneurysm or vascular malformation ruptures a hemorrhagic disease (typically cerebral infarction). This is a therapeutic method for ischemic necrosis of cancer and myoma by prophylactic treatment or by filling and occluding the vegetative blood vessels to cancer and myoma with an embolic material. As a vascular embolization material, a metal coil, silk thread, resin particles, gelatin sponge and the like have been used. When these embolization materials are used, embolization is achieved in a form in which the thrombus fills the gap between the embolization material and the embolization material in the blood vessel. Therefore, the thrombus is dissolved by the action of the blood fibrinolysis system, and the embolic blood vessel is restarted, and the therapeutic effect as expected may not be obtained. A liquid embolizing material has been developed as a material that has improved these drawbacks. Treatment material containing cyanoacrylate that embolizes blood vessels by polymerizing upon contact with water in blood and polymerizing and depositing as a solid (MV Jayaraman, et al., AJNR Am J Neuroradiol 28: 352 -54, February, 2007) or a liquid in which a polymer insoluble in blood is previously dissolved in an organic solvent is injected into the blood vessel, and the organic solvent diffuses into the blood, so that the polymer precipitates as a solid and the blood vessel is circulated. The embedding polyvinyl alcohol corresponds to that (W. Weber, et al., AJNR Am J Neuroradiol 28: 371-77, February, 2007). Regardless of which material is used, it is possible to block the blood vessel lumen with only the embolic material.
　また、日本公表特許公報２００４－５２８８８０号には、乾燥時の直径が１００～９００μｍであるｐＨ感受性水膨潤性高分子微粒子が開示されている。 In addition, Japanese published patent publication No. 2004-528880 discloses pH-sensitive water-swellable polymer fine particles having a diameter of 100 to 900 μm when dried.
　しかしながら、Ｍ．Ｖ．Ｊａｙａｒａｍａｎ，ｅｔ　ａｌ．，　ＡＪＮＲ　Ａｍ　Ｊ　Ｎｅｕｒｏｒａｄｉｏｌ　２８：３５２－５４，Ｆｅｂｒｕａｒｙ，２００７　に記載のシアノアクリレートを用いた場合、血管壁と、血管内へ処置材を投与するマイクロカテーテルとを接着させてしまうという問題があった。また、Ｍ．Ｖ．Ｊａｙａｒａｍａｎ，ｅｔ　ａｌ．，　ＡＪＮＲ　Ａｍ　Ｊ　Ｎｅｕｒｏｒａｄｉｏｌ　２８：３５２－５４，Ｆｅｂｒｕａｒｙ，２００７　に記載のポリビニルアルコールを用いた場合、固体析出が有機溶剤の拡散速度に依存し、塞栓する血管の血流環境によって析出速度が異なるため、標的血管を塞栓するためにポリビニルアルコールの注入速度を微調整する必要があり、注入操作が面倒になるという問題があった。さらに、有機溶剤（媒体）としてジメチルスルホキシドを用いているため、特殊なカテーテルを用いる必要があった。 However, M.M. V. Jayaraman, et al. , AJNR Am J Neuroradiol 28: 352-54, February, 2007, there is a problem that the blood vessel wall and the microcatheter for administering the treatment material into the blood vessel are adhered to each other. In addition, M.M. V. Jayaraman, et al. , AJNR Am J Neuroradiol 28: 352-54, February, 2007, the solid deposition depends on the diffusion rate of the organic solvent, and the deposition rate differs depending on the blood flow environment of the embolized blood vessel. In order to embolize the target blood vessel, it is necessary to finely adjust the injection rate of polyvinyl alcohol, and there is a problem that the injection operation becomes troublesome. Furthermore, since dimethyl sulfoxide is used as the organic solvent (medium), it is necessary to use a special catheter.
　加えて、シアノアクリレートおよびポリビニルアルコールは、いずれも血管内で固体になってしまうと、液体状に戻すことができず、塞栓を解除することができなかった。 In addition, when both cyanoacrylate and polyvinyl alcohol became solid in the blood vessel, they could not be returned to a liquid state and the embolus could not be released.
　さらに、日本公表特許公報２００４－５２８８８０号に記載の高分子微粒子を用いた塞栓材では、水膨潤後の微粒子同士の接触面積が小さく摩擦も小さいため、完全に固形化されず塞栓した部位から流動してしまうという問題があった。 Furthermore, in the embolization material using the polymer fine particles described in Japanese Patent Publication No. 2004-528880, the contact area between the fine particles after water swelling is small and the friction is small, so that the embolization material is not completely solidified and flows from the embolized site. There was a problem of doing.
　本発明は、このような従来技術が有する課題に鑑みてなされたものであり、その目的は、血管からの流出が抑制され、特殊なカテーテルが不要であり、かつ血管内で塞栓を任意に解除しうる血管内用処置材を提供することにある。 The present invention has been made in view of such problems of the prior art, and its purpose is to suppress the outflow from the blood vessel, no special catheter is required, and to arbitrarily release the embolus within the blood vessel. Another object is to provide an intravascular treatment material.
　上記目的は、下記（１）～（４）により達成される。 The above objective is achieved by the following (1) to (4).
　（１）ｐＨ７以上の条件下で水膨潤し、かつ水膨潤後の平均粒子径が５０～１００μｍであるｐＨ応答性水膨潤性高分子微粒子を含む、血管内用処置材。 (1) An intravascular treatment material comprising pH-responsive water-swellable polymer fine particles that swell with water under a pH of 7 or more and that have an average particle size after water swelling of 50 to 100 μm.
　（２）前記ｐＨ応答性水膨潤性高分子微粒子が、（メタ）アクリルアミド系単量体（ａ１）に由来する構成単位および不飽和カルボン酸（ａ２）に由来する構成単位を含む共重合体を、架橋剤（ａ３）により架橋したｐＨ応答性水膨潤性架橋高分子（Ａ）から形成される微粒子である、上記（１）に記載の血管内用処置材。 (2) A copolymer in which the pH-responsive water-swellable polymer fine particles include a structural unit derived from the (meth) acrylamide monomer (a1) and a structural unit derived from the unsaturated carboxylic acid (a2). The intravascular treatment material according to (1) above, which is fine particles formed from a pH-responsive water-swellable crosslinked polymer (A) crosslinked with a crosslinking agent (a3).
　（３）水性分散液の形態である、上記（１）または（２）に記載の血管内用処置材。 (3) The intravascular treatment material according to (1) or (2) above, which is in the form of an aqueous dispersion.
　（４）前記水性分散液中の前記ｐＨ応答性水膨潤性高分子微粒子の濃度が３質量％以上である、上記（３）に記載の血管内用処置材。 (4) The intravascular treatment material according to (3), wherein the concentration of the pH-responsive water-swellable polymer fine particles in the aqueous dispersion is 3% by mass or more.
　本発明の血管内用処置材は、血管内を隙間無く充填出来る塞栓材としての効果に優れる。また、本発明の血管内用処置材は、カテーテルなどの医療用具と血管壁とを接着させない水を媒体とすることが可能であるため、特殊なカテーテルが不要である。さらに、水膨潤後の平均粒子径が５０～１００μｍであることから、静脈からの流出による合併症発症のリスクが低い。さらに、本発明のｐＨ応答性水膨潤性高分子微粒子は、特定のｐＨ条件下で膨潤し固形状となるが、酸性水溶液を添加することによって、血管内で固形状の状態から流動性を有する液状に形態を変化させることが可能であることから、塞栓を任意に解除することが可能となる。 The intravascular treatment material of the present invention is excellent in the effect as an embolization material that can fill the blood vessel without gaps. In addition, since the intravascular treatment material of the present invention can use water as a medium that does not adhere a medical device such as a catheter and a blood vessel wall, a special catheter is unnecessary. Further, since the average particle size after water swelling is 50 to 100 μm, the risk of developing complications due to outflow from veins is low. Furthermore, the pH-responsive water-swellable polymer fine particles of the present invention swell and become solid under a specific pH condition, but have fluidity from a solid state in a blood vessel by adding an acidic aqueous solution. Since the form can be changed to a liquid state, the embolus can be arbitrarily released.
　本発明のさらに他の目的、特徴および特質は、以後の説明に例示される好ましい実施の形態を参酌することによって、明らかになるであろう。 Further objects, features, and characteristics of the present invention will become apparent by considering preferred embodiments exemplified in the following description.
　以下、本発明の実施の形態について説明する。 Hereinafter, embodiments of the present invention will be described.
　本発明は、ｐＨ７以上の条件下で水膨潤し、かつ水膨潤後の平均粒子径が５０～１００μｍであるｐＨ応答性水膨潤性高分子微粒子を含む、血管内用処置材である。 The present invention is an intravascular treatment material comprising pH-responsive water-swellable polymer fine particles which are water-swelled under conditions of pH 7 or higher and whose average particle size after water swelling is 50 to 100 μm.
　前記ｐＨ応答性水膨潤性高分子微粒子は、血液のようなｐＨ７．３～７．６の弱アルカリ性条件下で即時に水膨潤して、粒子同士の接触面積が大きくなって摩擦が大きくなり、流動性をほとんど有さない形態になる。したがって、血管内を隙間無く充填出来る塞栓材としての効果を発揮しうる。また、本発明の血管内用処置材は、カテーテルと血管壁とを接着させない水を媒体とすることが可能であるため、特殊なカテーテルが不要であり、さらに膨潤後の平均粒子径が５０～１００μｍであることから、例えば、静脈からの流出による合併症発症のリスクを低下させうる。また、前記ｐＨ応答性水膨潤性高分子微粒子は、酸性水溶液を添加することによって血管内で固形状の状態から流動性がある液状に形態が変化しうるため、塞栓を任意に解除することも可能となる。 The pH-responsive water-swellable polymer fine particles immediately swell with water under a weakly alkaline condition of pH 7.3 to 7.6 such as blood to increase the contact area between the particles and increase the friction. It becomes a form having almost no fluidity. Therefore, the effect as an embolic material that can fill the blood vessel without gaps can be exhibited. Further, since the intravascular treatment material of the present invention can use water that does not adhere the catheter and the blood vessel wall as a medium, a special catheter is not required, and the average particle diameter after swelling is 50 to 50%. Since it is 100 micrometers, the risk of the complication onset by the outflow from a vein can be reduced, for example. In addition, the pH-responsive water-swellable polymer fine particles can be changed from a solid state to a fluid liquid state in blood vessels by adding an acidic aqueous solution, so that embolization can be arbitrarily released. It becomes possible.
　以下、本発明の血管内用処置材の構成について詳細に説明するが、本発明の技術的範囲は下記の形態のみに制限されるものではない。 Hereinafter, the configuration of the intravascular treatment material of the present invention will be described in detail, but the technical scope of the present invention is not limited to the following forms.
　（構成）
　［ｐＨ応答性水膨潤性高分子微粒子］
　本発明の血管内用処置材は、ｐＨ７以上の条件下で膨潤し、かつ水膨潤後の平均粒子径が５０～１００μｍであるｐＨ応答性水膨潤性高分子微粒子を含む。 (Constitution)
[PH-responsive water-swellable polymer particles]
The intravascular treatment material of the present invention comprises pH-responsive water-swellable polymer fine particles that swell under conditions of pH 7 or higher and that have an average particle diameter of 50 to 100 μm after water swelling.
　前記ｐＨ応答性水膨潤性高分子微粒子は、特に限定されないが、（メタ）アクリルアミド系単量体（ａ１）に由来する構成単位および不飽和カルボン酸（ａ２）に由来する構成単位を含む共重合体を、架橋剤（ａ３）により架橋したｐＨ応答性水膨潤性架橋高分子（Ａ）から形成される微粒子であることが好ましい。以下、このｐＨ応答性水膨潤性架橋高分子（Ａ）に用いられる単量体成分について詳細に説明するが、本発明の技術的範囲は下記の形態のみに制限されない。 The pH-responsive water-swellable polymer fine particle is not particularly limited, but is a co-polymer containing a structural unit derived from the (meth) acrylamide monomer (a1) and a structural unit derived from the unsaturated carboxylic acid (a2). The coalesced particles are preferably fine particles formed from a pH-responsive water-swellable crosslinked polymer (A) crosslinked by a crosslinking agent (a3). Hereinafter, although the monomer component used for this pH-responsive water-swellable crosslinked polymer (A) will be described in detail, the technical scope of the present invention is not limited to only the following forms.
　＜（メタ）アクリルアミド系単量体（ａ１）＞
　ｐＨ応答性水膨潤性架橋高分子（Ａ）の単量体成分である（メタ）アクリルアミド系単量体（ａ１）は、特に制限されない。具体的な例としては、例えば、（メタ）アクリルアミド、Ｎ－メチル（メタ）アクリルアミド、Ｎ－エチル（メタ）アクリルアミド、Ｎ－ｎ－プロピル（メタ）アクリルアミド、Ｎ－イソプロピル（メタ）アクリルアミド、Ｎ－ｎ－ブチル（メタ）アクリルアミド、Ｎ－イソブチル（メタ）アクリルアミド、Ｎ－ｓ－ブチル（メタ）アクリルアミド、Ｎ－ｔ－ブチル（メタ）アクリルアミド 、Ｎ，Ｎ－ジメチル（メタ）アクリルアミド、Ｎ－エチル－Ｎ－メチル（メタ）アクリルアミド、Ｎ，Ｎ－ジエチル（メタ）アクリルアミド、Ｎ－メチル－Ｎ－イソプロピル（メタ）アクリルアミド、Ｎ－メチル－Ｎ－ｎ－プロピル（メタ）アクリルアミド、Ｎ－エチル－Ｎ－イソプロピル（メタ）アクリルアミド、Ｎ－エチル－Ｎ－ｎ－プロピル（メタ）アクリルアミド、Ｎ，Ｎ－ジ－ｎ－プロピル（メタ）アクリルアミド、ジアセトン（メタ）アクリルアミドなどが挙げられる。これら（メタ）アクリルアミド系単量体（ａ１）は、単独でもまたは２種以上を組み合わせても用いることができる。なお、本明細書において、（メタ）アクリル酸、（メタ）アクリルアミド等の記載は、アクリル酸およびメタクリル酸またはこれらの各誘導体を意味する。 <(Meth) acrylamide monomer (a1)>
The (meth) acrylamide monomer (a1) that is a monomer component of the pH-responsive water-swellable crosslinked polymer (A) is not particularly limited. Specific examples include (meth) acrylamide, N-methyl (meth) acrylamide, N-ethyl (meth) acrylamide, Nn-propyl (meth) acrylamide, N-isopropyl (meth) acrylamide, N- n-butyl (meth) acrylamide, N-isobutyl (meth) acrylamide, Ns-butyl (meth) acrylamide, Nt-butyl (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N-ethyl- N-methyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, N-methyl-N-isopropyl (meth) acrylamide, N-methyl-Nn-propyl (meth) acrylamide, N-ethyl-N- Isopropyl (meth) acrylamide, N-ethyl-Nn-propyl (methyl) ) Acrylamide, N, N-di-n-propyl (meth) acrylamide, diacetone (meth) acrylamide and the like. These (meth) acrylamide monomers (a1) can be used alone or in combination of two or more. In addition, in this specification, description, such as (meth) acrylic acid and (meth) acrylamide, means acrylic acid and methacrylic acid or each of these derivatives.
　なかでも、整形外科領域等で使用実績があり、生体内において安全性が高い（メタ）アクリルアミドが好ましい。 Especially, (meth) acrylamide which has a use track record in the orthopedic field etc. and has high safety in the living body is preferable.
　＜不飽和カルボン酸（ａ２）＞
　前記ｐＨ応答性水膨潤性架橋高分子（Ａ）の単量体成分である不飽和カルボン酸（ａ２）は、特に制限されず、具体的な例としては、例えば、（メタ）アクリル酸、マレイン酸、フマル酸、グルタコン酸、イタコン酸、クロトン酸、ソルビン酸などが挙げられる。また、前記不飽和カルボン酸のナトリウム塩、カリウム塩、アンモニウム塩などの塩も、ｐＨ応答性水膨潤性架橋高分子（Ａ）の製造の際に用いることができる。不飽和カルボン酸の塩を共重合に用いた場合は、後述する酸処理を行うことにより、不飽和カルボン酸（ａ２）の構成単位がｐＨ応答性水膨潤性架橋高分子（Ａ）に導入されうる。これら不飽和カルボン酸（ａ２）（またはその塩）は、単独でもまたは２種以上を組み合わせても用いることができる。 <Unsaturated carboxylic acid (a2)>
The unsaturated carboxylic acid (a2), which is a monomer component of the pH-responsive water-swellable crosslinked polymer (A), is not particularly limited, and specific examples thereof include (meth) acrylic acid and maleic acid. Examples include acid, fumaric acid, glutaconic acid, itaconic acid, crotonic acid, sorbic acid and the like. In addition, salts of the unsaturated carboxylic acid such as sodium salt, potassium salt and ammonium salt can also be used in the production of the pH-responsive water-swellable crosslinked polymer (A). When an unsaturated carboxylic acid salt is used for copolymerization, the structural unit of the unsaturated carboxylic acid (a2) is introduced into the pH-responsive water-swellable crosslinked polymer (A) by performing an acid treatment described later. sell. These unsaturated carboxylic acids (a2) (or salts thereof) can be used alone or in combination of two or more.
　なかでも、ｐＨ７以上の中性からアルカリ性領域において膨潤性を示すという観点から、（メタ）アクリル酸または（メタ）アクリル酸ナトリウムが好ましい。 Of these, (meth) acrylic acid or sodium (meth) acrylate is preferred from the viewpoint of exhibiting swelling in a neutral to alkaline region of pH 7 or higher.
　＜架橋剤（ａ３）＞
　前記ｐＨ応答性水膨潤性架橋高分子（Ａ）に用いられる架橋剤（ａ３）としては、特に制限されず、例えば、重合性不飽和基を２個以上有する架橋剤（イ）、重合性不飽和基と重合性不飽和基以外の反応性官能基とをそれぞれ１つずつ有する架橋剤（ロ）、重合性不飽和基以外の反応性官能基を２個以上有する架橋剤（ハ）などが挙げられる。これら架橋剤は、単独でもまたは２種以上を組み合わせて用いてもよい。 <Crosslinking agent (a3)>
The crosslinking agent (a3) used in the pH-responsive water-swellable crosslinked polymer (A) is not particularly limited, and examples thereof include a crosslinking agent (a) having two or more polymerizable unsaturated groups, A crosslinking agent (B) having one each of a saturated functional group and a reactive functional group other than the polymerizable unsaturated group, a crosslinking agent (C) having two or more reactive functional groups other than the polymerizable unsaturated group, and the like. Can be mentioned. These crosslinking agents may be used alone or in combination of two or more.
　前記架橋剤（イ）のみを用いる場合は、（メタ）アクリルアミド系単量体（ａ１）と不飽和カルボン酸（ａ２）（またはその塩）との共重合を行う際に、重合系内に架橋剤（イ）を添加して共重合させればよい。前記架橋剤（ハ）のみを用いる場合は、（ａ１）と（ａ２）との共重合を行ったあとに架橋剤（ハ）を添加して、例えば加熱による後架橋を行えばよい。前記架橋剤（ロ）のみを用いる場合ならびに前記架橋剤（イ）、（ロ）、および（ハ）の２種以上を用いる場合は、（メタ）アクリルアミド系単量体（ａ１）と不飽和カルボン酸（ａ２）との共重合を行う際に重合系内に架橋剤を添加して共重合させ、さらに、例えば加熱による後架橋を行えばよい。 When only the cross-linking agent (a) is used, when the (meth) acrylamide monomer (a1) and the unsaturated carboxylic acid (a2) (or a salt thereof) are copolymerized, a cross-link is formed in the polymerization system. The agent (I) may be added and copolymerized. When only the crosslinking agent (c) is used, the crosslinking agent (c) is added after copolymerization of (a1) and (a2), and post-crosslinking by heating, for example, may be performed. When only the crosslinking agent (b) is used and when two or more of the crosslinking agents (a), (b) and (c) are used, the (meth) acrylamide monomer (a1) and the unsaturated carboxylic acid When copolymerizing with the acid (a2), a crosslinking agent may be added to the polymerization system for copolymerization, and post-crosslinking may be performed, for example, by heating.
　重合性不飽和基を２個以上有する架橋剤（イ）の具体例としては、例えば、Ｎ，Ｎ’－メチレンビスアクリルアミド、Ｎ，Ｎ’－メチレンビスメタクリルアミド、Ｎ，Ｎ’－エチレンビスアクリルアミド、Ｎ，Ｎ’－エチレンビスメタクリルアミド、Ｎ，Ｎ’－ヘキサメチレンビスアクリルアミド、Ｎ，Ｎ’－ヘキサメチレンビスメタクリルアミド、Ｎ，Ｎ’－ベンジリデンビスアクリルアミド、Ｎ，Ｎ’－ビス（アクリルアミドメチレン）尿素、エチレングリコールジ（メタ）アクリレート、ポリエチレングリコールジ（メタ）アクリレート、プロピレングリコールジ（メタ）アクリレート、グリセリン（ジ又はトリ）アクリレート、トリメチロールプロパントリアクリレート、トリアリルアミン、トリアリルシアヌレート、トリアリルイソシアヌレート、テトラアリロキシエタン、ペンタエリスリトールトリアリルエーテル、（ポリ）エチレングリコールジ（メタ）アクリレート、（ポリ）プロピレングリコールジ（メタ）アクリレート、トリメチルロールプロパントリ（メタ）アクリレート、グリセリントリ（メタ）アクリレート、グリセリンアクリレートメタクリレート、エチレンオキサイド変性トリメチロールプロパントリ（メタ）アクリレート、ペンタエリスリトールヘキサ（メタ）アクリレート、トリアリルシアヌレート、トリアリルイソシアヌレート、トリアリルホスフェート、トリアリルアミン、ポリ（メタ）アリロキシアルカン、（ポリ）エチレングリコールジグリシジルエーテル、グリセロールジグリシジルエーテル、エチレングリコール、ポリエチレングリコール、プロピレングリコール、グリセリン、ペンタエリスリトール、エチレンジアミン、エチレンカーボネート、プロピレンカーボネート、グリシジル（メタ）アクリレート等を挙げることができる。 Specific examples of the crosslinking agent (a) having two or more polymerizable unsaturated groups include, for example, N, N′-methylenebisacrylamide, N, N′-methylenebismethacrylamide, N, N′-ethylenebisacrylamide. N, N'-ethylenebismethacrylamide, N, N'-hexamethylenebisacrylamide, N, N'-hexamethylenebismethacrylamide, N, N'-benzylidenebisacrylamide, N, N'-bis (acrylamidemethylene ) Urea, ethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, glycerin (di or tri) acrylate, trimethylolpropane triacrylate, triallylamine, triallyl cyanurate, triallyl Sosocyanurate, tetraallyloxyethane, pentaerythritol triallyl ether, (poly) ethylene glycol di (meth) acrylate, (poly) propylene glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate, glycerin tri (meth) acrylate Glycerin acrylate methacrylate, ethylene oxide modified trimethylolpropane tri (meth) acrylate, pentaerythritol hexa (meth) acrylate, triallyl cyanurate, triallyl isocyanurate, triallyl phosphate, triallylamine, poly (meth) allyloxyalkane, (Poly) ethylene glycol diglycidyl ether, glycerol diglycidyl ether, ethylene glycol, polyethylene Recall, propylene glycol, glycerol, pentaerythritol, ethylenediamine, ethylene carbonate, propylene carbonate, and glycidyl (meth) acrylate.
　重合性不飽和基と重合性不飽和基以外の反応性官能基とをそれぞれ１つずつ有する架橋剤（ロ）の具体例としては、例えば、ヒドロキシエチル（メタ）アクリレート、Ｎ－メチロール（メタ）アクリルアミド、グリシジル（メタ）アクリレート等が挙げられる。 Specific examples of the crosslinking agent (b) each having one polymerizable unsaturated group and one reactive functional group other than the polymerizable unsaturated group include hydroxyethyl (meth) acrylate and N-methylol (meth). Examples include acrylamide and glycidyl (meth) acrylate.
　重合性不飽和基以外の反応性官能基を２個以上有する架橋剤（ハ）の具体例としては、例えば、多価アルコール（例えば、エチレングリコール、ジエチレングリコール、グリセリン、プロピレングリコール、トリメチロールプロパン等）、アルカノールアミン（例えば、ジエタノールアミン等）、およびポリアミン（例えば、ポリエチレンイミン等）等が挙げられる。 Specific examples of the crosslinking agent (c) having two or more reactive functional groups other than the polymerizable unsaturated group include, for example, polyhydric alcohols (for example, ethylene glycol, diethylene glycol, glycerin, propylene glycol, trimethylolpropane, etc.) , Alkanolamine (for example, diethanolamine), and polyamine (for example, polyethyleneimine).
　これらのうち、重合性不飽和基を２個以上有する架橋剤（イ）が好ましく、Ｎ，Ｎ’－メチレンビスアクリルアミドがより好ましい。 Of these, the crosslinking agent (a) having two or more polymerizable unsaturated groups is preferred, and N, N'-methylenebisacrylamide is more preferred.
　前記ｐＨ応答性水膨潤性架橋高分子（Ａ）の製造方法は、特に制限されないが、（メタ）アクリルアミド系単量体（ａ１）、不飽和カルボン酸（ａ２）（またはその塩）、および必要に応じて架橋剤（ａ３）を共重合させ、さらに必要に応じて後架橋を行うことにより製造することが好ましい。 The production method of the pH-responsive water-swellable crosslinked polymer (A) is not particularly limited, but the (meth) acrylamide monomer (a1), unsaturated carboxylic acid (a2) (or salt thereof), and necessary It is preferable to manufacture by copolymerizing the crosslinking agent (a3) according to the above and further performing post-crosslinking as necessary.
　共重合の方法は、特に制限されず、例えば、重合開始剤を使用する溶液重合法、乳化重合法、懸濁重合法、逆相懸濁重合法、薄膜重合法、噴霧重合法など従来公知の方法を用いることができる。重合制御の方法としては、断熱重合法、温度制御重合法、等温重合法などが挙げられる。また、重合開始剤により重合を開始させる方法の他に、放射線、電子線、紫外線等を照射して重合を開始させる方法を採用することもできる。好ましくは、重合開始剤を使用した逆相懸濁重合法である。 The copolymerization method is not particularly limited, and conventionally known methods such as a solution polymerization method using a polymerization initiator, an emulsion polymerization method, a suspension polymerization method, a reverse phase suspension polymerization method, a thin film polymerization method, and a spray polymerization method are known. The method can be used. Examples of the polymerization control method include adiabatic polymerization, temperature controlled polymerization, and isothermal polymerization. In addition to the method of initiating polymerization with a polymerization initiator, a method of initiating polymerization by irradiating with radiation, electron beam, ultraviolet rays or the like can also be employed. A reverse phase suspension polymerization method using a polymerization initiator is preferred.
　前記逆相懸濁重合を行なう場合の連続相の溶媒としては、ｎ－ヘキサン、ｎ－へプタン、ｎ－オクタン、ｎ－デカン、シクロヘキサン、メチルシクロヘキサン、流動パラフィン等の脂肪族系有機溶媒、トルエン、キシレン等の芳香族系有機溶媒、１，２－ジクロロエタン等のハロゲン系有機溶媒等の有機溶媒が使用できるが、ヘキサン、シクロヘキサン、流動パラフィン等の脂肪族系有機溶媒がより好ましい。なお、前記溶媒は、単独でもまたは２種以上を混合して用いることもできる。 As the solvent for the continuous phase in carrying out the reverse phase suspension polymerization, aliphatic organic solvents such as n-hexane, n-heptane, n-octane, n-decane, cyclohexane, methylcyclohexane, liquid paraffin, toluene An organic organic solvent such as an aromatic organic solvent such as xylene and a halogen organic solvent such as 1,2-dichloroethane can be used, but an aliphatic organic solvent such as hexane, cyclohexane and liquid paraffin is more preferable. In addition, the said solvent can also be used individually or in mixture of 2 or more types.
　前記連続相には、分散安定剤を添加することができる。この分散安定剤の種類や使用量を適宜選択することにより、得られるｐＨ応答性水膨潤性高分子微粒子の粒径を制御することができる。 A dispersion stabilizer can be added to the continuous phase. The particle size of the resulting pH-responsive water-swellable polymer fine particles can be controlled by appropriately selecting the type and amount of the dispersion stabilizer.
　前記分散安定剤の例としては、例えば、ポリオキシエチレンラウリルエーテル、ポリオキシエチレンオレイルエーテル、ポリオキシエチレンステアリルエーテル、ソルビタンセスキオレエート、ソルビタントリオレート、ソルビタンモノラウレート、ソルビタンモノオレート、ソルビタンモノパルミテート、ソルビタンモノステアレート、ソルビタントリステアレート、グリセロールモノステアレート、グリセロールモノオレエート、ステアリン酸グリセリル、カプリル酸グリセリル、ステアリン酸ソルビタン、オレイン酸ソルビタン、セスキオレイン酸ソルビタン、ヤシ脂肪酸ソルビタンなどの非イオン系界面活性剤が好適に用いられる。 Examples of the dispersion stabilizer include, for example, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, sorbitan sesquioleate, sorbitan trioleate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmi Nonionics such as tate, sorbitan monostearate, sorbitan tristearate, glycerol monostearate, glycerol monooleate, glyceryl stearate, glyceryl caprylate, sorbitan stearate, sorbitan oleate, sorbitan sesquioleate, coconut fatty acid sorbitan A system surfactant is preferably used.
　前記分散安定剤は、連続相の溶媒に対して、好ましくは０．０４～２０質量％の範囲、より好ましくは１～１２質量％の範囲で用いられる。上記の範囲であれば、重合時に得られる重合体が凝集をほとんど起こさないかまったく起こさず、また、得られる微粒子の粒径のばらつきが低減されうる。 The dispersion stabilizer is preferably used in the range of 0.04 to 20% by mass, more preferably in the range of 1 to 12% by mass, based on the continuous phase solvent. If it is said range, the polymer obtained at the time of superposition | polymerization hardly raise | generates aggregation, or does not raise | generate at all, and the dispersion | variation in the particle size of the microparticles | fine-particles obtained can be reduced.
　前記逆相懸濁重合法における単量体成分の濃度は、従来公知の範囲であれば特に限定されず、例えば、２～７質量％が好ましく、３～５質量％がより好ましい。 The concentration of the monomer component in the reverse phase suspension polymerization method is not particularly limited as long as it is a conventionally known range, and is preferably 2 to 7% by mass, for example, and more preferably 3 to 5% by mass.
　前記逆相懸濁重合法で用いられる重合開始剤としては、例えば、過硫酸カリウム、過硫酸アンモニウム、過硫酸ナトリウム等の過硫酸塩、メチルエチルケトンパーオキシド、メチルイソブチルケトンパーオキシド、ジ－ｔ－ブチルパーオキシド、ｔ－ブチルクミルパーオキシド、ｔ－ブチルパーオキシアセテート、ｔ－ブチルパーオキシイソブチレート、ｔ－ブチルパーオキシピバレート、過酸化水素等の過酸化物、２，２’－アゾビス〔２－（Ｎ－フェニルアミジノ）プロパン〕２塩酸塩、２，２’－アゾビス〔２－（Ｎ－アリルアミジノ）プロパン〕２塩酸塩、２，２’－アゾビス｛２－〔１－（２－ヒドロキシエチル）－２－イミダゾリン－２－イル〕プロパン｝２塩酸塩、２，２’－アゾビス｛２－メチル－Ｎ－〔１，１－ビス（ヒドロキシメチル）－２－ヒドロキシエチル〕プロピオンアミド｝、２，２’－アゾビス〔２－メチル－Ｎ－（２－ヒドロキシエチル）－プロピオンアミド〕、４，４’－アゾビス（４－シアノ吉草酸）等のアゾ化合物等が挙げられ、これらは、単独で用いても２種以上を併用してもよい。これらのなかでは、入手が容易で取り扱いが容易であるという観点から、過硫酸塩が好ましく、過硫酸カリウム、過硫酸アンモニウム及び過硫酸ナトリウムがより好ましい。 Examples of the polymerization initiator used in the reverse phase suspension polymerization method include persulfates such as potassium persulfate, ammonium persulfate, and sodium persulfate, methyl ethyl ketone peroxide, methyl isobutyl ketone peroxide, and di-t-butyl peroxide. Peroxides such as oxide, t-butylcumyl peroxide, t-butylperoxyacetate, t-butylperoxyisobutyrate, t-butylperoxypivalate, hydrogen peroxide, 2,2′-azobis [2 -(N-phenylamidino) propane] dihydrochloride, 2,2'-azobis [2- (N-allylamidino) propane] dihydrochloride, 2,2'-azobis {2- [1- (2-hydroxy Ethyl) -2-imidazolin-2-yl] propane} dihydrochloride, 2,2′-azobis {2-methyl-N- [1,1-bis ( Droxymethyl) -2-hydroxyethyl] propionamide}, 2,2′-azobis [2-methyl-N- (2-hydroxyethyl) -propionamide], 4,4′-azobis (4-cyanovaleric acid), etc. These azo compounds may be used, and these may be used alone or in combination of two or more. Among these, from the viewpoint of easy availability and easy handling, persulfate is preferable, and potassium persulfate, ammonium persulfate, and sodium persulfate are more preferable.
　なお、上記重合開始剤は、亜硫酸ナトリウム、亜硫酸水素ナトリウム、硫酸第一鉄、Ｌ－アスコルビン酸、Ｎ、Ｎ，Ｎ’，Ｎ’－テトラメチルエチレンジアミン等の還元剤と併用して、レドックス重合開始剤として用いることもできる。 The above polymerization initiator is used in combination with a reducing agent such as sodium sulfite, sodium hydrogen sulfite, ferrous sulfate, L-ascorbic acid, N, N, N ′, N′-tetramethylethylenediamine, and redox polymerization is initiated. It can also be used as an agent.
　重合開始剤の使用量は、単量体の総量１００質量部に対して、２～６質量部が好ましく、３～５質量部がより好ましい。上記の使用量の範囲であれば、重合反応が効率よく進行し、また、得られる重合体の分子量が大きくなり粘性が小さくなるため重合体の凝集を抑制することができる。 The amount of the polymerization initiator used is preferably 2 to 6 parts by mass and more preferably 3 to 5 parts by mass with respect to 100 parts by mass of the total amount of monomers. If it is the range of said usage-amount, since a polymerization reaction will advance efficiently and the molecular weight of the polymer obtained will become large and viscosity will become small, aggregation of a polymer can be suppressed.
　必要に応じて、共重合の際に連鎖移動剤を使用してもよい。前記連鎖移動剤の例としては、例えば、チオール類（ｎ－ラウリルメルカプタン、メルカプトエタノール、トリエチレングリコールジメルカプタン等）、チオール酸類（チオグリコール酸、チオリンゴ酸等）、２級アルコール類（イソプロパノ－ル等）、アミン類（ジブチルアミン等）、次亜燐酸塩類（次亜燐酸ナトリウム等）等を挙げることができる。 If necessary, a chain transfer agent may be used in the copolymerization. Examples of the chain transfer agent include, for example, thiols (n-lauryl mercaptan, mercaptoethanol, triethylene glycol dimercaptan, etc.), thiolic acids (thioglycolic acid, thiomalic acid, etc.), secondary alcohols (isopropanol). Etc.), amines (dibutylamine, etc.), hypophosphites (sodium hypophosphite, etc.) and the like.
　前記逆相懸濁重合法における重合条件は特に制限されず、例えば、重合温度は使用する触媒の種類によって適宜設定することができるが、好ましくは３５～７５℃、より好ましくは４０～５０℃である。上記の温度範囲であれば、重合反応が効率よく進行し、また、分散媒が揮発しにくくなるため、単量体成分の分散状態が良好となる。重合時間は、好ましくは１時間以上である。 The polymerization conditions in the reverse phase suspension polymerization method are not particularly limited, and for example, the polymerization temperature can be appropriately set depending on the type of catalyst used, but is preferably 35 to 75 ° C, more preferably 40 to 50 ° C. is there. If it is said temperature range, since a polymerization reaction will advance efficiently and it will become difficult to volatilize a dispersion medium, the dispersion state of a monomer component will become favorable. The polymerization time is preferably 1 hour or longer.
　重合系内の圧力は、特に限定されるものではなく、常圧（大気圧）下、減圧下、加圧下のいずれであってもよい。また、反応系内の雰囲気も、空気雰囲気であってもよいし、窒素、アルゴンなどの不活性ガス雰囲気下であってもよい。 The pressure in the polymerization system is not particularly limited, and may be any of normal pressure (atmospheric pressure), reduced pressure, and increased pressure. Also, the atmosphere in the reaction system may be an air atmosphere or an inert gas atmosphere such as nitrogen or argon.
　架橋剤（ａ３）として、上記の重合性不飽和基以外の反応性官能基を２個以上有する架橋剤（ハ）を用いる場合、架橋剤（ハ）を添加する時期は単量体の重合反応終了後であればよく、特に限定されない。 When the crosslinking agent (c) having two or more reactive functional groups other than the above-mentioned polymerizable unsaturated groups is used as the crosslinking agent (a3), the timing for adding the crosslinking agent (c) is the monomer polymerization reaction. There is no particular limitation as long as it is after completion.
　後架橋反応を行う際の反応温度は、使用する架橋剤（ａ３）の種類等によっても異なるため、一概には決定できないが、通常５０～１５０℃である。また、反応時間は、通常１～４８時間である。 The reaction temperature at the time of the post-crosslinking reaction varies depending on the type of the crosslinking agent (a3) to be used and cannot be determined unconditionally, but is usually 50 to 150 ° C. The reaction time is usually 1 to 48 hours.
　また、共重合を行う際、単量体溶液中に造孔剤を過飽和懸濁させることによって多孔質とすることもできる。この際、単量体溶液には不溶であるが洗浄溶液には可溶である造孔剤を用いることが好ましい。造孔剤の例としては、塩化ナトリウム、塩化カリウム、氷、スクロース、または炭酸水素ナトリウムなどが好ましく挙げられ、より好ましくは塩化ナトリウムである。造孔剤の好ましい濃度は、単量体溶液中、好ましくは５～５０質量％、より好ましくは１０～３０質量％の範囲である。 In addition, when copolymerization is performed, the pore-forming agent can be made porous by being supersaturated and suspended in the monomer solution. At this time, it is preferable to use a pore-forming agent that is insoluble in the monomer solution but soluble in the cleaning solution. As an example of a pore making agent, sodium chloride, potassium chloride, ice, sucrose, sodium hydrogencarbonate, etc. are mentioned preferably, More preferably, it is sodium chloride. A preferable concentration of the pore-forming agent is preferably 5 to 50% by mass, more preferably 10 to 30% by mass in the monomer solution.
　共重合の際に不飽和カルボン酸（ａ２）の塩を用いた場合、共重合後に酸処理を行い、ｐＨ応答性水膨潤性架橋高分子（Ａ）のカルボン酸塩の部分をカルボキシル基に変換しておくことが好ましい。酸処理の条件は特に限定されず、例えば、塩酸水溶液などの低ｐＨ水溶液中で、好ましくは１５～６０℃の温度範囲で、好ましくは１～２４時間処理すればよい。 When salt of unsaturated carboxylic acid (a2) is used during copolymerization, acid treatment is performed after copolymerization, and the carboxylate portion of pH-responsive water-swellable cross-linked polymer (A) is converted to a carboxyl group It is preferable to keep it. The conditions for the acid treatment are not particularly limited, and for example, the treatment may be carried out in a low pH aqueous solution such as a hydrochloric acid aqueous solution, preferably in a temperature range of 15 to 60 ° C., preferably for 1 to 24 hours.
　このようにして得られるｐＨ応答性水膨潤性架橋高分子（Ａ）は、必要に応じて、加熱乾燥、解砕等を行うことにより、本発明で用いられるｐＨ応答性水膨潤性高分子微粒子となる。本発明で用いられるｐＨ応答性水膨潤性高分子微粒子の形状は、球状、破砕状、不定形状等特に限定されるものではないが、球状であることが好ましい。 The pH-responsive water-swellable crosslinked polymer (A) thus obtained is subjected to heat-drying, crushing, etc., if necessary, so that the pH-responsive water-swellable polymer fine particles used in the present invention are used. It becomes. The shape of the pH-responsive water-swellable polymer fine particles used in the present invention is not particularly limited, such as a spherical shape, a crushed shape, and an indefinite shape, but is preferably a spherical shape.
　前記ｐＨ応答性水膨潤性高分子微粒子の水膨潤後の平均粒子径は、５０～１００μｍであり、好ましくは５０～８０μｍであり、より好ましくは５０～６０μｍである。上記の粒子径の範囲であれば、ｐＨ応答性水膨潤性高分子微粒子が動脈と静脈との吻合部を通過して静脈へ流出することがほとんどないか全くないため、健常な臓器への栄養血管を塞栓する可能性がほとんどないか全くない。また、ｐＨ膨潤性水膨潤性高分子微粒子同士の接触面積が大きくなり摩擦も大きくなるため、水膨潤後の高分子微粒子の流動性が低下しうる。 The average particle diameter of the pH-responsive water-swellable polymer fine particles after water swelling is 50 to 100 μm, preferably 50 to 80 μm, more preferably 50 to 60 μm. When the particle size is within the above range, the pH-responsive water-swellable polymer particles pass through the anastomosis between the artery and vein and rarely flow out into the vein. Little or no possibility of embolizing blood vessels. In addition, since the contact area between the pH-swellable water-swellable polymer particles increases and the friction increases, the fluidity of the polymer particles after water swelling can be reduced.
　上記のような範囲の水膨潤後の平均粒子径とするためには、前記ｐＨ応答性水膨潤性高分子微粒子の水膨潤前（乾燥時）の平均粒子径を、好ましくは２０～５０μｍ、より好ましくは２０～４０μｍ、さらに好ましくは２０～３０μｍの範囲に制御すればよい。 In order to obtain the average particle diameter after water swelling in the above range, the average particle diameter of the pH-responsive water-swellable polymer fine particles before water swelling (at the time of drying) is preferably 20 to 50 μm, more preferably The control is preferably performed in the range of 20 to 40 μm, more preferably 20 to 30 μm.
　上記のｐＨ応答性水膨潤性高分子微粒子の形状および平均粒子径は、ｐＨ応答性水膨潤性高分子微粒子の製造条件（単量体の種類、共重合時の温度・時間、分散安定剤の量・種類等）により制御されうる。なお、本発明において、水膨潤前（乾燥時）のｐＨ応答性水膨潤性高分子微粒子の平均粒子径は、コールターカウンターにより測定した値を採用するものとする。また、水膨潤後のｐＨ応答性水膨潤性高分子微粒子の平均粒子径は、ＣＣＤカメラで撮影した該微粒子を１００個選択して、それぞれの粒子径を測定したときの平均値を採用するものとする。 The shape and average particle size of the pH-responsive water-swellable polymer fine particles are determined according to the production conditions of the pH-responsive water-swellable polymer fine particles (type of monomer, temperature / time during copolymerization, dispersion stabilizer Amount, type, etc.). In the present invention, the average particle diameter of the pH-responsive water-swellable polymer fine particles before water swelling (at the time of drying) is a value measured by a Coulter counter. In addition, the average particle diameter of the pH-responsive water-swellable polymer fine particles after water swelling adopts an average value when 100 fine particles photographed with a CCD camera are selected and each particle diameter is measured. And
　本発明の血管内用処置材は、上記のようにして得られるｐＨ応答性水膨潤性高分子微粒子を粉末状でそのまま用いることができるが、取り扱いの容易さ、カテーテルなどの医療用具と血管壁との接着を防ぐなどの観点から、ｐＨ５～６の蒸留水を用いて水性分散液の形態とすることが好ましい。 The intravascular treatment material of the present invention can use the pH-responsive water-swellable polymer fine particles obtained as described above in powder form, but it is easy to handle, medical devices such as catheters and blood vessel walls. From the standpoint of preventing adhesion with water, it is preferable to use distilled water having a pH of 5 to 6 to form an aqueous dispersion.
　この際、該水性分散液中のｐＨ応答性水膨潤性高分子微粒子の濃度は、３質量％以上であることが好ましく、３～２０質量％であることがより好ましく、３～１０質量％であることがさらに好ましい。上記範囲であれば、ｐＨ応答性水膨潤性高分子微粒子が水膨潤した際に微粒子間の摩擦が大きくなり、流動性が低下しうる。 At this time, the concentration of the pH-responsive water-swellable polymer fine particles in the aqueous dispersion is preferably 3% by mass or more, more preferably 3 to 20% by mass, and 3 to 10% by mass. More preferably it is. If it is the said range, when pH-responsive water-swellable polymer microparticles | fine-particles will swell with water, the friction between microparticles | fine-particles will become large and fluidity | liquidity may fall.
　かような構成を有する本発明の血管内用処置材に含まれるｐＨ応答性水膨潤性高分子微粒子は、ｐＨ７以上、好ましくは血液のようなｐＨ７．３～７．６の弱アルカリ性の条件下で水膨潤する。ｐＨが７以上であれば、本発明の血管内用処置材は、流動性がほとんどない固形状の状態となる。一方、ｐＨが７未満の場合、前記ｐＨ応答性水膨潤性高分子微粒子は水膨潤せず、本発明の血管内用処置材は流動性を有する。そして、水膨潤した前記ｐＨ応答性水膨潤性高分子微粒子をｐＨが４未満の酸性水溶液に接触させた場合、前記ｐＨ応答性水膨潤性高分子微粒子は収縮する。したがって、この特性を利用し、例えばカテーテル等を用いて該酸性水溶液を血管内に注入して、塞栓を形成するｐＨ応答性水膨潤性高分子微粒子に接触させることにより、本発明の血管内用処置材に再度流動性を付与させて、塞栓を任意に解除することができる。 The pH-responsive water-swellable polymer microparticles contained in the intravascular treatment material of the present invention having such a structure is under a weakly alkaline condition of pH 7 or more, preferably pH 7.3 to 7.6 such as blood. Swells with water. If pH is 7 or more, the treatment material for blood vessels of the present invention will be in a solid state with little fluidity. On the other hand, when the pH is less than 7, the pH-responsive water-swellable polymer fine particles do not swell, and the intravascular treatment material of the present invention has fluidity. When the pH-responsive water-swellable polymer fine particles swollen with water are brought into contact with an acidic aqueous solution having a pH of less than 4, the pH-responsive water-swellable fine polymer particles contract. Therefore, by utilizing this characteristic, the acidic aqueous solution is injected into the blood vessel using, for example, a catheter or the like, and brought into contact with the pH-responsive water-swellable polymer fine particles forming an embolus, whereby the intravascular use of the present invention. The embolization can be arbitrarily released by imparting fluidity to the treatment material again.
　本発明の効果を、下記の実施例および比較例を用いてさらに詳細に説明する。ただし、本発明の技術的範囲が、下記の実施例のみに制限されるわけではない。なお、水膨潤前（乾燥時）のｐＨ応答性水膨潤性高分子微粒子の平均粒子径は、コールターカウンターにより測定した。また、水膨潤後のｐＨ応答性水膨潤性高分子微粒子の平均粒子径は、ＣＣＤカメラで撮影した該微粒子を１００個選択して、それぞれの粒子径を測定したときの平均値である。 The effect of the present invention will be described in further detail using the following examples and comparative examples. However, the technical scope of the present invention is not limited to the following examples. The average particle size of the pH-responsive water-swellable polymer fine particles before water swelling (during drying) was measured with a Coulter counter. Further, the average particle diameter of the pH-responsive water-swellable polymer fine particles after water swelling is an average value when 100 fine particles photographed with a CCD camera are selected and the respective particle diameters are measured.
　（製造例１：水膨潤前の平均粒子径が２０μｍのｐＨ応答性水膨潤性高分子微粒子の製造）
　３００ｍＬのビーカーにシクロヘキサン１５０ｇ、流動パラフィン１５０ｇ、セスキオレイン酸ソルビタン１５．９ｇを添加、マグネチックスターラーで攪拌し、逆相懸濁重合の連続相を調製した。窒素気流を３０分間通じて溶存酸素の除去を行った。一方、５０ｍＬ容量の褐色ガラス瓶にアクリルアミド３．８ｇ、アクリル酸ナトリウム２．２ｇ、Ｎ，Ｎ’－メチレンビスアクリルアミド０．０１３ｇ、塩化ナトリウム５．４ｇを秤量し、蒸留水１９．９ｇを添加、マグネチックスターラーで攪拌、溶解しモノマー水溶液を調製した。過硫酸アンモニウム０．２７ｇを２．０ｇの蒸留水に溶解したものを前記モノマー水溶液に添加した後、前記連続相溶媒に、全量加えた。３００ｒｐｍの回転数で攪拌し、モノマー溶液を連続相溶媒中に分散させた。３０分間攪拌した後、４０℃まで昇温し、Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルエチレンジアミン　１００μＬを添加した。更に攪拌を１時間継続した後、ビーカー内容物を３Ｌのビーカーに移した。ｎ－ヘキサン１Ｌを加え、５分間攪拌した後、デカンテーションして上澄みを除去した。沈殿物を５００ｍＬのノルマルヘキサンで２回洗浄した。蒸留水を１Ｌ加え沈殿物を溶解した後、エタノール２Ｌを加え、重合物を析出させた。デカンテーションして沈澱した重合物のみを回収、エタノール中で攪拌、解砕した。解砕物に２．５規定の塩酸を添加し、５５℃のオーブンに２４時間静置した。酸処理後の解砕物を蒸留水中に移し、蒸留水のｐＨ変化がなくなるまで蒸留水を交換した。洗浄後の解砕物にエタノールを添加し、脱水後、ステンレス製篩で分球し、平均粒子径が２０μｍである微粒子を得た。 (Production Example 1: Production of pH-responsive water-swellable polymer fine particles having an average particle size of 20 μm before water swelling)
In a 300 mL beaker, 150 g of cyclohexane, 150 g of liquid paraffin, and 15.9 g of sorbitan sesquioleate were added and stirred with a magnetic stirrer to prepare a continuous phase of reverse phase suspension polymerization. The dissolved oxygen was removed by passing a nitrogen stream for 30 minutes. Meanwhile, 3.8 g of acrylamide, 2.2 g of sodium acrylate, 0.013 g of N, N′-methylenebisacrylamide and 5.4 g of sodium chloride were weighed into a 50 mL brown glass bottle, and 19.9 g of distilled water was added. A monomer aqueous solution was prepared by stirring and dissolving with a tic stirrer. A solution prepared by dissolving 0.27 g of ammonium persulfate in 2.0 g of distilled water was added to the aqueous monomer solution, and then the total amount was added to the continuous phase solvent. The monomer solution was dispersed in the continuous phase solvent by stirring at a rotation speed of 300 rpm. After stirring for 30 minutes, the temperature was raised to 40 ° C., and 100 μL of N, N, N ′, N′-tetramethylethylenediamine was added. After further stirring for 1 hour, the contents of the beaker were transferred to a 3 L beaker. After adding 1 L of n-hexane and stirring for 5 minutes, the supernatant was removed by decantation. The precipitate was washed twice with 500 mL normal hexane. 1 L of distilled water was added to dissolve the precipitate, and then 2 L of ethanol was added to precipitate a polymer. Only the polymer precipitated by decantation was collected, stirred and crushed in ethanol. 2.5N hydrochloric acid was added to the crushed material, and the mixture was allowed to stand in an oven at 55 ° C. for 24 hours. The crushed material after acid treatment was transferred into distilled water, and the distilled water was exchanged until there was no pH change in the distilled water. Ethanol was added to the crushed material after washing, and after dehydration, it was spheroidized with a stainless steel sieve to obtain fine particles having an average particle size of 20 μm.
　（製造例２：水膨潤前の平均粒子径が３４μｍのｐＨ応答性水膨潤性高分子微粒子の製造）
　３００ｍＬのビーカーにシクロヘキサン１５０ｇ、流動パラフィン１５０ｇ、セスキオレイン酸ソルビタン１５．９ｇを添加、マグネチックスターラーで攪拌し、逆相懸濁重合の連続相を調製した。窒素気流を３０分間通じて溶存酸素の除去を行った。一方、５０ｍＬ容量の褐色ガラス瓶にアクリルアミド３．８ｇ、アクリル酸ナトリウム２．２ｇ、Ｎ，Ｎ’－メチレンビスアクリルアミド０．０１３ｇ、塩化ナトリウム５．４ｇを秤量し、蒸留水１９．９ｇを添加、マグネチックスターラーで攪拌、溶解し、モノマー水溶液を調製した。過硫酸アンモニウム０．２７ｇを２．０ｇの蒸留水に溶解したものを前記モノマー水溶液に添加した後、前記連続相溶媒に全量加えた。３００ｒｐｍの回転数で攪拌し、モノマー溶液を連続相溶媒中に分散させた。３０分間攪拌した後、４０℃まで昇温し、Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルエチレンジアミン　１００μＬを添加した。更に攪拌を１時間継続した後、ビーカー内容物を３Ｌのビーカーに移した。ｎ－ヘキサン１Ｌを加え、５分間攪拌した後、デカンテーションして上澄みを除去した。沈殿物を５００ｍＬのノルマルヘキサンで２回洗浄した。蒸留水を１Ｌ加え沈殿物を溶解した後、エタノール２Ｌを加え、重合物を析出させた。デカンテーションして沈澱した重合物のみを回収、エタノール中で攪拌、解砕した。解砕物に２．５規定の塩酸を添加し、５５℃のオーブンに２４時間静置した。酸処理後の解砕物を蒸留水中に移し、蒸留水のｐＨ変化がなくなるまで蒸留水を交換した。洗浄後の解砕物にエタノールを添加し、脱水後、ステンレス製篩で分球し、平均粒子径３４μｍの微粒子を得た。 (Production Example 2: Production of pH-responsive water-swellable polymer fine particles having an average particle size of 34 μm before water swelling)
In a 300 mL beaker, 150 g of cyclohexane, 150 g of liquid paraffin, and 15.9 g of sorbitan sesquioleate were added and stirred with a magnetic stirrer to prepare a continuous phase of reverse phase suspension polymerization. The dissolved oxygen was removed by passing a nitrogen stream for 30 minutes. Meanwhile, 3.8 g of acrylamide, 2.2 g of sodium acrylate, 0.013 g of N, N′-methylenebisacrylamide and 5.4 g of sodium chloride were weighed into a 50 mL brown glass bottle, and 19.9 g of distilled water was added. The mixture was stirred and dissolved with a tic stirrer to prepare an aqueous monomer solution. A solution prepared by dissolving 0.27 g of ammonium persulfate in 2.0 g of distilled water was added to the aqueous monomer solution, and then added to the continuous phase solvent. The monomer solution was dispersed in the continuous phase solvent by stirring at a rotation speed of 300 rpm. After stirring for 30 minutes, the temperature was raised to 40 ° C., and 100 μL of N, N, N ′, N′-tetramethylethylenediamine was added. After further stirring for 1 hour, the contents of the beaker were transferred to a 3 L beaker. After adding 1 L of n-hexane and stirring for 5 minutes, the supernatant was removed by decantation. The precipitate was washed twice with 500 mL normal hexane. 1 L of distilled water was added to dissolve the precipitate, and then 2 L of ethanol was added to precipitate a polymer. Only the polymer precipitated by decantation was collected, stirred and crushed in ethanol. 2.5N hydrochloric acid was added to the crushed material, and the mixture was allowed to stand in an oven at 55 ° C. for 24 hours. The crushed material after acid treatment was transferred into distilled water, and the distilled water was exchanged until there was no pH change in the distilled water. Ethanol was added to the crushed material after washing, and after dehydration, it was spheroidized with a stainless steel sieve to obtain fine particles having an average particle size of 34 μm.
　（製造例３：水膨潤前の平均粒子径が１５０μｍのｐＨ応答性水膨潤性高分子微粒子の製造）
　３００ｍＬのビーカーにシクロヘキサン１５０ｇ、流動パラフィン１５０ｇ、セスキオレイン酸ソルビタン２．０ｇを添加、マグネチックスターラーで攪拌し、逆相懸濁重合の連続相を調製した。窒素気流を３０分間通じて溶存酸素の除去を行った。一方、５０ｍＬ容量の褐色ガラス瓶にアクリルアミド３．８ｇ、アクリル酸ナトリウム２．２ｇ、Ｎ，Ｎ’－メチレンビスアクリルアミド０．０１３ｇ、塩化ナトリウム５．４ｇを秤量し、蒸留水１９．９ｇを添加、マグネチックスターラーで攪拌、溶解しモノマー水溶液を調製した。過硫酸アンモニウム０．２７ｇを２．０ｇの蒸留水に溶解したものを前記モノマー水溶液に添加した後、前記連続相溶媒に、全量加えた。３００ｒｐｍの回転数で攪拌し、モノマー溶液を連続相溶媒中に分散させた。３０分間攪拌した後、４０℃まで昇温し、Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルエチレンジアミン　１００μＬを添加した。更に攪拌を１時間継続した後、ビーカー内容物を３Ｌのビーカーに移した。ノルマルヘキサン１Ｌを加え、５分間攪拌した後、デカンテーションして上澄みを除去した。沈殿物を５００ｍＬのｎ－ヘキサンで２回洗浄した。蒸留水を１Ｌ加え沈殿物を溶解した後、エタノール２Ｌを加え、重合物を析出させた。デカンテーションして沈澱した重合物のみを回収、エタノール中で攪拌、解砕した。解砕物に２．５規定の塩酸を添加し、５５℃のオーブンに２４時間静置した。酸処理後の解砕物を蒸留水中に移し、蒸留水のｐＨ変化がなくなるまで蒸留水を交換した。洗浄後の解砕物にエタノールを添加し、脱水後、ステンレス製篩で分球し、平均粒子径１５０μｍの微粒子を得た。 (Production Example 3: Production of pH-responsive water-swellable polymer fine particles having an average particle size of 150 μm before water swelling)
In a 300 mL beaker, 150 g of cyclohexane, 150 g of liquid paraffin, and 2.0 g of sorbitan sesquioleate were added and stirred with a magnetic stirrer to prepare a continuous phase of reverse phase suspension polymerization. The dissolved oxygen was removed by passing a nitrogen stream for 30 minutes. Meanwhile, 3.8 g of acrylamide, 2.2 g of sodium acrylate, 0.013 g of N, N′-methylenebisacrylamide and 5.4 g of sodium chloride were weighed into a 50 mL brown glass bottle, and 19.9 g of distilled water was added. A monomer aqueous solution was prepared by stirring and dissolving with a tic stirrer. A solution prepared by dissolving 0.27 g of ammonium persulfate in 2.0 g of distilled water was added to the aqueous monomer solution, and then the total amount was added to the continuous phase solvent. The monomer solution was dispersed in the continuous phase solvent by stirring at a rotation speed of 300 rpm. After stirring for 30 minutes, the temperature was raised to 40 ° C., and 100 μL of N, N, N ′, N′-tetramethylethylenediamine was added. After further stirring for 1 hour, the contents of the beaker were transferred to a 3 L beaker. After adding 1 L of normal hexane and stirring for 5 minutes, the supernatant was removed by decantation. The precipitate was washed twice with 500 mL of n-hexane. 1 L of distilled water was added to dissolve the precipitate, and then 2 L of ethanol was added to precipitate a polymer. Only the polymer precipitated by decantation was collected, stirred and crushed in ethanol. 2.5N hydrochloric acid was added to the crushed material, and the mixture was allowed to stand in an oven at 55 ° C. for 24 hours. The crushed material after acid treatment was transferred into distilled water, and the distilled water was exchanged until there was no pH change in the distilled water. Ethanol was added to the crushed material after washing, and after dehydration, it was spheronized with a stainless steel sieve to obtain fine particles having an average particle size of 150 μm.
　（実施例１）
　製造例１で作製した平均粒子径２０μｍの微粒子０．０３ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が３質量％である微粒子分散液を得た。 Example 1
0.03 g of fine particles having an average particle diameter of 20 μm prepared in Production Example 1 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 3% by mass. A fine particle dispersion was obtained.
　（実施例２）
　製造例１で作製した平均粒子径２０μｍの微粒子０．０５ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が５質量％である微粒子分散液を得た。 (Example 2)
0.05 g of fine particles having an average particle diameter of 20 μm prepared in Production Example 1 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 5% by mass. A fine particle dispersion was obtained.
　（実施例３）
　製造例１で作製した平均粒子径２０μｍの微粒子０．０７ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が７質量％である微粒子分散液を得た。 (Example 3)
0.07 g of fine particles having an average particle diameter of 20 μm prepared in Production Example 1 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 7% by mass. A fine particle dispersion was obtained.
　（実施例４）
　製造例２で作製した平均粒子径３４μｍの微粒子０．０３ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が３質量％である微粒子分散液を得た。 Example 4
0.03 g of fine particles having an average particle diameter of 34 μm prepared in Production Example 2 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 3% by mass. A fine particle dispersion was obtained.
　（実施例５）
　製造例２で作製した平均粒子径３４μｍの微粒子０．０５ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が５質量％である微粒子分散液を得た。 (Example 5)
0.05 g of fine particles having an average particle diameter of 34 μm produced in Production Example 2 were weighed into a glass test tube (Lalbo Clean Test Tube), and distilled water for injection at pH 5.5 was added to make 1.00 g, with a concentration of 5% by mass. A fine particle dispersion was obtained.
　（実施例６）
　製造例２で作製した平均粒子径３４μｍの微粒子０．０７ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が７質量％である微粒子分散液を得た。 (Example 6)
0.07 g of fine particles with an average particle diameter of 34 μm prepared in Production Example 2 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 7% by mass. A fine particle dispersion was obtained.
　（比較例１）
　製造例３で作製した平均粒子径１５０μｍの微粒子０．０２ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が２質量％である微粒子分散液を得た。 (Comparative Example 1)
0.02 g of fine particles having an average particle diameter of 150 μm prepared in Production Example 3 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 2% by mass. A fine particle dispersion was obtained.
　（比較例２）
　製造例３で作製した平均粒子径１５０μｍの微粒子０．０３ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が３質量％である微粒子分散液を得た。 (Comparative Example 2)
0.03 g of fine particles having an average particle diameter of 150 μm prepared in Production Example 3 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to give 1.00 g, with a concentration of 3% by mass. A fine particle dispersion was obtained.
　（比較例３）
　製造例３で作製した平均粒子径１５０μｍの微粒子０．０５ｇをガラス製試験管（ラルボ清浄試験管）に秤量し、ｐＨ５．５の注射用蒸留水を加え１．００ｇとし、濃度が５質量％である微粒子分散液を得た
　（評価）
　実施例１～６および比較例１～３で得られた微粒子分散液に、１Ｍ　炭酸水素ナトリウムを０．１ｍＬ添加し、分散液のｐＨを７．３～７．６にしたときの微粒子分散液の流動性を試験し、さらに膨潤後の微粒子の平均粒子径を測定した。なお、流動性試験は、試験管を逆さまにしたときに内容物の落下がない場合「固形化」とし、落下した場合「固形化していない」とした。結果を表１に示す。 (Comparative Example 3)
0.05 g of fine particles having an average particle diameter of 150 μm prepared in Production Example 3 were weighed into a glass test tube (Lalbo Clean Test Tube), and added with distilled water for injection at pH 5.5 to make 1.00 g, with a concentration of 5% by mass. (Evaluation)
A fine particle dispersion obtained by adding 0.1 mL of 1M sodium hydrogen carbonate to the fine particle dispersions obtained in Examples 1 to 6 and Comparative Examples 1 to 3, and adjusting the pH of the dispersion to 7.3 to 7.6. The fluidity of the particles was tested, and the average particle size of the fine particles after swelling was measured. In addition, in the fluidity test, when the test tube was turned upside down, the content was not “dropped” when the content was not dropped, and when it was dropped, “not solidified”. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１から明らかなように、水膨潤後の平均粒子径が本発明の範囲である実施例１～６の血管内用処置材は、水膨潤後固形状になり内容物が落下しなかった。一方、水膨潤後の平均粒子径が本発明の範囲外である比較例１～３の血管内用処置材は、水膨潤後でも固形状にならず内容物が落下した。 As is apparent from Table 1, the intravascular treatment materials of Examples 1 to 6 having an average particle diameter after water swelling in the range of the present invention became solid after water swelling and the contents did not fall. On the other hand, the intravascular treatment materials of Comparative Examples 1 to 3 having an average particle diameter after water swelling outside the scope of the present invention did not become solid even after water swelling and the contents dropped.
　なお、本出願は、２００９年３月４日に出願された日本特許出願第２００９－０５１００９号に基づいており、その開示内容は、参照により全体として引用されている。 Note that this application is based on Japanese Patent Application No. 2009-051009 filed on Mar. 4, 2009, the disclosure of which is incorporated by reference in its entirety.

Claims (4)

  1. 　ｐＨ７以上の条件下で水膨潤し、かつ水膨潤後の平均粒子径が５０～１００μｍであるｐＨ応答性水膨潤性高分子微粒子を含む、血管内用処置材。 An intravascular treatment material containing pH-responsive water-swellable polymer fine particles that swell with water under conditions of pH 7 or higher and that have an average particle diameter after water swelling of 50 to 100 μm.
  2. 　前記ｐＨ応答性水膨潤性高分子微粒子が、（メタ）アクリルアミド系単量体（ａ１）に由来する構成単位および不飽和カルボン酸（ａ２）に由来する構成単位を含む共重合体を、架橋剤（ａ３）により架橋したｐＨ応答性水膨潤性架橋高分子（Ａ）から形成される微粒子である、請求項１に記載の血管内用処置材。 A copolymer in which the pH-responsive water-swellable polymer fine particles include a structural unit derived from the (meth) acrylamide monomer (a1) and a structural unit derived from the unsaturated carboxylic acid (a2) is used as a crosslinking agent. The treatment material for intravascular use according to claim 1, which is a fine particle formed from the pH-responsive water-swellable crosslinked polymer (A) crosslinked by (a3).
  3. 　水性分散液の形態である、請求項１または２に記載の血管内用処置材。 The intravascular treatment material according to claim 1 or 2, which is in the form of an aqueous dispersion.
  4. 　前記水性分散液中の前記ｐＨ応答性水膨潤性高分子微粒子の濃度が３質量％以上である、請求項３に記載の血管内用処置材。 The intravascular treatment material according to claim 3, wherein the concentration of the pH-responsive water-swellable polymer fine particles in the aqueous dispersion is 3% by mass or more.
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