JP2012100680A - Treatment instrument to be used in blood vessel - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an intravascular treatment instrument in which the outflow from a blood vessel is prevented, a special catheter is not required and an embolus can be arbitrarily removed in the blood vessel.SOLUTION: The intravascular treatment instrument includes microparticles of a pH-responsive water-swellable polymer which swell in water at ≥pH 7 and, after swelling in water, have an average particle diameter of 50-100 μm.

Description

  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 not required, and embolism can be arbitrarily released in the blood vessel.

  Vascular embolization is performed as an intravascular treatment method for aneurysms, vascular malformations, liver cancer, uterine fibroids and the like. 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. 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. Polymerization is initiated by contact with water in the blood to polymerize, and a treatment material containing cyanoacrylate that embolizes blood vessels by depositing as a solid (for example, see Non-Patent Document 1) or a polymer insoluble in blood in advance. Polyvinyl alcohol (for example, refer to Non-Patent Document 2) that injects a liquid dissolved in an organic solvent into a blood vessel, and the organic solvent diffuses into the blood to cause the polymer to precipitate as a solid, thereby embedding the inside of the blood vessel. To do. Regardless of which material is used, it is possible to block the blood vessel lumen with only the embolic material.

  Patent Document 1 discloses pH-sensitive water-swellable polymer fine particles having a dry diameter of 100 to 900 μm.

Special table 2004-528880 gazette

M.M. V. Jayaraman, et al. , “Treatment of Traumatic Industrial Artificial Fistulas with N-butyl-2-Cyanoacrylate” AJNR Am J Neuroradiol 28: 352-54, February, 2007. W. Weber, et al. , “Endovascular Treatment of Intracranial Artificial Malformations with Onyx: Technical Aspects” AJNR Am J Neuroradiol 28: 371-77, February 7

  However, when the cyanoacrylate described in Non-Patent Document 1 is used, there is a problem in that the blood vessel wall and the microcatheter for administering the treatment material into the blood vessel are adhered. Further, when the polyvinyl alcohol described in Non-Patent Document 2 is used, 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 blood vessel to be embedding. There was a problem that the injection speed of the alcohol had to be finely adjusted, and the injection operation was troublesome. Furthermore, since dimethyl sulfoxide is used as a medium, it is necessary to use a special catheter.

  In addition, when both cyanoacrylate and polyvinyl alcohol become solid in the blood vessel, they cannot be returned to a liquid state and the embolism cannot be released.

  Furthermore, in the embolization material using the polymer fine particles described in Patent Document 1, the contact area between the fine particles after water swelling is small and the friction is also small, so the problem is that the embolization material does not completely solidify but flows from the plugged site. was there.

  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. An object of the present invention is to provide an intravascular treatment material.

  In view of the above problems, the present inventors have made extensive studies. As a result, water swells under a weakly alkaline condition of pH 7 or higher, particularly pH 7.3 to 7.6 such as blood, and the pH-responsive water swellability with the average particle diameter after the water swelling in a specific range. The treatment material for intravascular use using polymer fine particles suppresses the outflow from the blood vessel, can be embolized without using a special catheter, and arbitrarily releases the embolus within the blood vessel by changing the pH condition. As a result, the present invention has been completed.

  That is, the present invention is an intravascular treatment material containing pH-responsive water-swellable polymer fine particles that are water-swelled under conditions of pH 7 or more and that have an average particle diameter after water swelling of 50 to 100 μm.

  The treatment material for blood vessels 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. Furthermore, since the average particle diameter after water swelling is 50 to 100 μm, the risk of 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.

  The present invention is an intravascular treatment material comprising pH-responsive water-swellable polymer microparticles 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.

  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, and the contact area between the particles increases to increase 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. In addition, 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 unnecessary, 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.

  Hereinafter, although the structure of the intravascular treatment agent of this invention is demonstrated in detail, the technical scope of this invention is not restrict | limited only to the following form.

(Constitution)
[PH-responsive water-swellable polymer particles]
The intravascular treatment material of the present invention includes 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.

  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.

<(Meth) acrylamide monomer (a1)>
The (meth) acrylamide monomer (a1) which 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 (me ) 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 of (meth) acrylic acid, (meth) acrylamide, etc. means acrylic acid and methacrylic acid, or each derivative thereof.

  Especially, (meth) acrylamide which has a use track record in the orthopedic field etc. and has high safety | security in a living body is preferable.

<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 acids, 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.

  Of these, (meth) acrylic acid or sodium (meth) acrylate is preferred from the viewpoint of exhibiting expansibility in a neutral to alkaline region of pH 7 or higher.

<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.

  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.

  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 Cyanurate, 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 glycol Call, propylene glycol, glycerol, pentaerythritol, ethylenediamine, ethylene carbonate, propylene carbonate, and glycidyl (meth) acrylate.

  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.

  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).

  Among these, the crosslinking agent (a) having two or more polymerizable unsaturated groups is preferable, and N, N′-methylenebisacrylamide is more preferable.

  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. 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.

  As the solvent of the continuous phase in the case of 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 Organic solvents such as aromatic organic solvents such as xylene and halogen organic solvents such as 1,2-dichloroethane can be used, but aliphatic organic solvents such as hexane, cyclohexane and liquid paraffin are more preferable. In addition, 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.

  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.

  The dispersion stabilizer is preferably used in a range of 0.04 to 20% by mass, more preferably in a range of 1 to 12% by mass with respect to the solvent of the continuous phase. When the amount of the dispersion stabilizer used is less than 0.04% by mass, the polymer obtained at the time of polymerization may aggregate. On the other hand, when it exceeds 20 mass%, the dispersion | variation in the particle size of the obtained fine particle may become large.

  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, 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. 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 (H) Roxymethyl) -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.

  The 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 started. It can also be used as an agent.

  2-6 mass parts is preferable with respect to 100 mass parts of total amounts of monomers, and, as for the usage-amount of a polymerization initiator, 3-5 mass parts is more preferable. When the amount of the polymerization initiator used is less than 2 parts by mass, the polymerization reaction itself may not proceed. On the other hand, when the amount exceeds 6 parts by mass, the polymer may be aggregated because the molecular weight of the obtained polymer is small and the viscosity is large.

  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.

  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. When the polymerization temperature is less than 35 ° C., the polymerization reaction itself may not proceed. On the other hand, when the polymerization temperature exceeds 70 ° C., the dispersion medium may volatilize and the dispersion state of the monomer component may deteriorate. The polymerization time is preferably 2 hours 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. Also, the atmosphere in the reaction system may be an air atmosphere or an inert gas atmosphere such as nitrogen or argon.

  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.

  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 therefore cannot be determined unconditionally, but is usually 50 to 150 ° C. The reaction time is usually 1 to 48 hours.

  Moreover, when performing copolymerization, it can also be made porous by suspending a pore-forming agent in a monomer solution in a supersaturated state. 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. The preferable concentration of the pore-forming agent is preferably in the range of 5 to 50% by mass, more preferably 10 to 30% by mass in the monomer solution.

  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. For example, the treatment may be performed in a low pH aqueous solution such as a hydrochloric acid aqueous solution, preferably in a temperature range of 15 to 60 ° C., and 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 μm, preferably 50 to 80 μm, more preferably 50 to 60 μm. When the average particle diameter after swelling is less than 50 μm, the pH-responsive water-swellable polymer fine particles pass through the anastomosis part between the artery and the vein and flow into the vein, thereby causing a nutrient blood vessel to a healthy organ. The possibility of embolization increases. On the other hand, if it exceeds 100 μm, the contact area between the pH-swellable water-swellable polymer fine particles becomes small and the friction becomes small, so that it does not completely solidify and flows.

  In order to obtain an 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. Preferably, it may be controlled in the range of 20 to 40 μm, more preferably 20 to 30 μm.

  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

  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 the liquid, it is preferable to use distilled water having a pH of 5 to 6 to form an aqueous dispersion.

  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. When the concentration is less than 3% by mass, even when the pH-responsive water-swellable polymer fine particles are swollen with water, the friction between the particles is small, and a decrease in fluidity may not be obtained.

  The pH-responsive water-swellable polymer microparticles contained in the intravascular treatment material of the present invention having such a configuration is pH 7 or higher, preferably weakly alkaline conditions such as blood such as pH 7.3 to 7.6. 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.

  The effects 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.

(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 for reverse phase suspension polymerization. The dissolved oxygen was removed by passing a nitrogen stream for 30 minutes. On the other hand, 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 are weighed into a 50 mL brown glass bottle, 19.9 g of distilled water is added, and a magnetic stirrer is added. The monomer aqueous solution was prepared by stirring and dissolving. 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 spheronized with a stainless steel sieve to obtain fine particles having an average particle size of 20 μm.

(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 for reverse phase suspension polymerization. The dissolved oxygen was removed by passing a nitrogen stream for 30 minutes. On the other hand, 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 are weighed into a 50 mL brown glass bottle, 19.9 g of distilled water is added, and a magnetic stirrer is added. The solution was stirred and dissolved in to prepare an aqueous monomer solution. A solution obtained 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.

(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. On the other hand, 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 are weighed into a 50 mL brown glass bottle, 19.9 g of distilled water is added, and a magnetic stirrer is added. The monomer aqueous solution was prepared by stirring and dissolving. 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.

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.

(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.

(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.

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.

(Example 5)
0.05 g of the 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), added with distilled water for injection at pH 5.5 to give 1.00 g, and 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 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.

(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.

(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.

(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.

  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.

Claims (4)

  An intravascular treatment material comprising pH-responsive water-swellable polymer microparticles that swell with water under a pH of 7 or more and that have an average particle size of 50 to 100 μm after water swelling.   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).   The intravascular treatment material according to claim 1 or 2, which is in the form of an aqueous dispersion.   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.