JP2010082143A - Medical treatment material - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medical treatment material having excellent water swellability and even excellent visibility. <P>SOLUTION: The medical treatment material includes a water swellable crosslinked polymer produced by bonding a pigment compound (B) to at least a part of a carboxyl group in a crosslinked copolymer (A) obtained by crosslinking a copolymer containing a constituent unit derived from a (meth)acrylamide monomer (a1) and a constituent unit derived from an unsaturated carboxylic acid (a2). <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a medical treatment material having excellent water swellability and excellent visibility.

  Particle-shaped hydrogels are used for arterial embolization therapy such as liver cancer and uterine fibroids. Arterial embolization is a means of mixing and dispersing hydrogel particles and a contrast agent in a syringe and then injecting them into a blood vessel through a catheter.

For example, Patent Document 1 discloses a biomedical porous hydrogel particle having a network structure in which a copolymer formed from acrylamide and sodium acrylate is crosslinked with N, N′-methylenebisacrylamide. .
JP 2004-528880 A

  However, although the hydrogel particles described in Patent Document 1 are excellent in expansibility and deformability, they are colorless and transparent, so it is difficult to confirm that they are dispersed in a syringe and have an appropriate volume. It was difficult to administer the gel particles intravascularly.

  This invention is made | formed in view of the subject which such a prior art has, The objective is to provide the medical treatment material which has the outstanding water swelling property and is excellent also in visibility.

  In view of the above problems, the present inventors have made extensive studies. As a result, at least a part of the carboxyl groups in the cross-linked copolymer (A) obtained by cross-linking the copolymer formed from the (meth) acrylamide monomer (a1) and the unsaturated carboxylic acid (a2), The medical treatment material containing the water-swellable crosslinked polymer formed by binding the dye compound (B) has been found to be excellent in water-swellability and visibility, and the present invention has been completed.

  That is, the present invention relates to a crosslinked copolymer obtained by crosslinking a copolymer containing a structural unit derived from a (meth) acrylamide monomer (a1) and a structural unit derived from an unsaturated carboxylic acid (a2) ( A medical treatment material comprising a water-swellable cross-linked polymer obtained by binding the dye compound (B) to at least a part of the carboxyl groups in A).

  ADVANTAGE OF THE INVENTION According to this invention, the medical treatment material excellent in water swellability and excellent in visibility can be provided.

  Embodiments of the present invention will be described below.

(Constitution)
[Crosslinked copolymer (A)]
The cross-linked copolymer (A) constituting the medical treatment material of the present invention includes a structural unit derived from the (meth) acrylamide monomer (a1) and a structural unit derived from the unsaturated carboxylic acid (a2). The copolymer has a structure crosslinked by a crosslinking agent. Hereinafter, although these monomers are demonstrated in detail, the technical scope of this invention is not restrict | limited only to the following form.

<(Meth) acrylamide monomer (a1)>
The (meth) acrylamide monomer (a1) that is a monomer component of the crosslinked copolymer (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 (meth ) 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.

  Content of the structural unit derived from the (meth) acrylamide monomer (a1) is the structural unit derived from the (meth) acrylamide monomer (a1) and the unsaturated carboxylic acid (a2). The total amount is 100 mol%, preferably 65 to 80 mol%, and more preferably 70 to 75 mol%. When the content of the structural unit derived from the (meth) acrylamide monomer (a1) is less than 65 mol%, the crosslinked copolymer (A) may expand excessively. On the other hand, when it exceeds 80 mol%, the cross-linked copolymer (A) becomes excessively hard and brittle and may not be suitable for use in vivo.

<Unsaturated carboxylic acid (a2)>
The unsaturated carboxylic acid (a2) used in the present invention is not particularly limited, and specific examples include (meth) acrylic acid, maleic acid, fumaric acid, glutaconic acid, itaconic acid, crotonic acid, and sorbine. An acid etc. are mentioned. In addition, a salt such as a sodium salt, potassium salt or ammonium salt of the unsaturated carboxylic acid can also be used in the production of the crosslinked copolymer (A). When a salt of an unsaturated carboxylic acid is used for copolymerization, the structure of the unsaturated carboxylic acid (a2) is obtained by performing an acid treatment after the reaction between the cross-linked copolymer (A) and the dye compound (B) described later. Units can be introduced into the cross-linked copolymer (A). 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 region.

  The content of the structural unit derived from the unsaturated carboxylic acid (a2) is 100 mol of the total amount of the structural unit derived from the (meth) acrylamide monomer (a1) and the structural unit derived from the unsaturated carboxylic acid (a2). % Is preferably 20 to 35 mol%, more preferably 25 to 30 mol%. When the content of the structural unit derived from the unsaturated carboxylic acid (a2) is less than 20 mol%, the expandability of the crosslinked copolymer may be insufficient. On the other hand, when it exceeds 35 mol%, the crosslinked copolymer (A) may expand excessively.

<Crosslinking agent>
The crosslinked copolymer (A) has a structure in which a copolymer containing a structural unit derived from the (meth) acrylamide monomer (a1) and a structural unit derived from the unsaturated carboxylic acid (a2) is crosslinked. . In this case, the crosslinking agent used is not particularly limited. For example, the crosslinking agent (a) having two or more polymerizable unsaturated groups, a reactive functional group other than the polymerizable unsaturated group and the polymerizable unsaturated group. And a crosslinking agent (C) having two or more reactive functional groups other than the polymerizable unsaturated group. 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, poly (n = 2-30) ethylene glycol di (meth) acrylate, propylene glycol di (meth) acrylate, glycerin (di or tri) acrylate, trimethylolpropane triacrylate, tri Allylamine, triallyl cyanurate , Triallyl isocyanurate, 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, 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 amount of the crosslinking agent used is preferably 0.15 to 0.25 parts by mass with respect to 100 parts by mass of the total amount of the (meth) acrylamide monomer (a1) and the unsaturated carboxylic acid (a2). More preferably, it is 20 to 0.23 parts by mass. When the usage-amount of the said crosslinking agent is less than 0.15 mass part, a crosslinked copolymer (A) may become soft too much and may not be suitable for use in the living body. On the other hand, when it exceeds 0.25 part by mass, the cross-linked copolymer (A) becomes excessively hard and brittle and may not be suitable for use in vivo.

[Dye Compound (B)]
The dye compound (B) used in the present invention preferably has a functional group capable of reacting with and binding to the carboxyl group in the crosslinked copolymer (A). Visibility is imparted to the medical treatment material of the present invention by reacting this functional group with the carboxyl group in the crosslinked copolymer (A) to form a bond.

  The dye compound (B) may be an organic dye or an organic pigment as long as it has a functional group capable of reacting with and binding to a carboxyl group. Specific examples include, for example, organic dyes having amino groups such as indoin blue, nile blue A, victoria blue B and astrouble; benzidine orange GG, benzamine brilliant scarlet BB, benzamine red 7B, benzidine yellow G , Benzamine Indigo Blue BRLS, Benzamine Fast Green GFL, Benzamine Black OBS, Benzamine Brilliant Orange R4GS, Benzamine Brilliant Green 3GS, Alizarin Blue Black B, Alizarin Light Gray 2BLW, Alizarin Light Blue B, Alizarin Light Blue SE, Alizarin Rubinol R, Alizarin Sapphire AR, Alizarin Saphirol A, Alizarin Cyanine Green G, Alizarin Sky Blue B, Alizarin Examples include organic pigments having amino groups such as iBlue NA and alizarin fast blue G; organic pigments having hydroxy groups such as alizarin cyanine R, alizarin blue, alizarin, alizarin yellow, alizarin yellow R, and the like. A combination of more than one species can also be used.

  Among these, from the viewpoint of strength when bonded to a carboxyl group, organic dyes having amino groups such as indoin blue, nile blue A, victoria blue B and astrouble are preferred, and indoin blue is more preferred.

  The amount of the dye compound (B) bonded to the crosslinked copolymer (A) is not particularly limited. However, from the viewpoint of excellent balance between water swellability and visibility, the total number of carboxyl groups in the cross-linked copolymer (A) is preferably 0.1 to 15 mol%, and preferably 0.1 to 0.1 mol%. It is more preferably 5 mol%, and further preferably 0.2 to 0.5 mol%. If the binding amount is less than 0.1 mol%, the visibility may be insufficient. On the other hand, when the amount of binding exceeds 15 mol%, water swellability may be insufficient. The amount of the dye compound (B) bonded to the crosslinked copolymer (A) can be controlled by the amount of the dye compound (B) used in the reaction between the crosslinked copolymer (A) and the dye compound (B). . In addition, the amount of binding of the dye compound (B) to the crosslinked copolymer (A) can be determined by a method of calculating using the difference in absorbance described in Examples described later.

(Production method)
The method for producing the medical treatment material of the present invention is not particularly limited. For example, after producing the crosslinked copolymer (A), the carboxyl group in the crosslinked copolymer (A) and the dye compound (B) It can be produced by reacting a functional group with, for example, the presence of a condensing agent. Hereinafter, although the manufacturing method of the medical treatment material of this invention is demonstrated in detail, it is not restrict | limited only to the following forms.

[Production of Crosslinked Copolymer (A)]
The cross-linked copolymer (A) is obtained by copolymerizing a (meth) acrylamide monomer (a1), an unsaturated carboxylic acid (a2) (or a salt thereof), and a cross-linking agent as necessary. It can be obtained by post-crosslinking.

  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 solution polymerization method using a polymerization initiator is preferable, and an aqueous solution polymerization method is particularly preferable because it is not necessary to use an organic solvent or the like and is advantageous in terms of production cost.

  If the density | concentration of the monomer component in performing aqueous solution polymerization is a conventionally well-known range, it will not specifically limit, For example, 17-25 mass% is preferable and 20-23 mass% is more preferable.

  Examples of the polymerization initiator used in the present invention include persulfates such as potassium persulfate, ammonium persulfate, and sodium persulfate, methyl ethyl ketone peroxide, methyl isobutyl ketone peroxide, di-t-butyl peroxide, and t-butyl. Cumyl peroxide, t-butyl peroxyacetate, t-butyl peroxyisobutyrate, t-butyl peroxypivalate, peroxides such as hydrogen peroxide, 2,2′-azobis [2- (N-phenyl) Amidino) propane] dihydrochloride, 2,2′-azobis [2- (N-allylamidino) propane] dihydrochloride, 2,2′-azobis {2- [1- (2-hydroxyethyl) -2- Imidazolin-2-yl] propane} dihydrochloride, 2,2′-azobis {2-methyl-N- [1,1-bis (hydroxymeth) ) -2-hydroxyethyl] propionamide}, 2,2′-azobis [2-methyl-N- (2-hydroxyethyl) -propionamide], 4,4′-azobis (4-cyanovaleric acid), etc. An azo compound etc. are mentioned, These may be used independently or may use 2 or more types together. Among these, from the viewpoint of easy availability and easy handling, persulfates are 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.

  The amount of the polymerization initiator used is preferably 0.1 to 0.3 parts by mass, and more preferably 0.1 to 0.25 parts by mass with respect to 100 parts by mass of the total amount of monomers. When the amount of the polymerization initiator used is less than 0.1 part by mass, the polymerization reaction itself may not occur. On the other hand, if the amount exceeds 0.3 parts by mass, the polymerization reaction becomes excessively fast, and the monomer solution may not be injected into the polytetrafluoroethylene tube described later (see Example 1).

  The persulfate may be dissolved in various solvents, preferably water, and added in the form of a persulfate solution (preferably an aqueous solution). The concentration when used as the persulfate solution (preferably an aqueous solution) is preferably 15 to 25% by mass, more preferably 17 to 22% by mass.

  The polymerization conditions are not particularly limited, and for example, the polymerization temperature can be appropriately set depending on the type of catalyst used, but is preferably 20 to 30 ° C. The polymerization time is preferably 2 hours or longer.

  In this step, 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.

  As described above, the polymerization method is preferably aqueous solution polymerization, but if necessary, the polymerization may be carried out in the presence of water and a water-soluble organic solvent. Examples of the water-soluble organic solvent include alcohol solvents (methanol, ethanol, etc.), ketone solvents (acetone, methyl ethyl ketone, etc.), amide solvents (N, N-dimethylformamide, N-methylpyrrolidone, etc.), sulfoxide solvents. (Dimethyl sulfoxide and the like), and a mixture of two or more of these.

  When a crosslinking agent (c) having two or more reactive functional groups other than the above-mentioned polymerizable unsaturated groups is used as the crosslinking agent, the timing of adding the crosslinking agent (c) is after the completion of the monomer polymerization reaction. There is no particular limitation as long as it is present.

  The reaction temperature at the time of the post-crosslinking reaction varies depending on the type of the crosslinking agent (b) or (c) 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, a crosslinked copolymer (A) 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 the copolymerization is carried out by aqueous solution polymerization, the resulting cross-linked copolymer (A) becomes a hydrogel, but in order to efficiently proceed the reaction with the dye compound (B) in the next step, a dye compound ( It is preferable to cut the crosslinked copolymer (A) before the reaction with B).

[Reaction between Crosslinked Copolymer (A) and Dye Compound (B)]
In this step, the carboxyl group of the crosslinked copolymer (A) and the functional group in the dye compound (B) are reacted, for example, in a solvent in the presence or absence of a condensing agent, so that the dye compound (B) A bonded water-swellable crosslinked polymer is obtained.

  Examples of the solvent used in this step include organic solvents such as methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, DMF, toluene, or dichloromethane, or phosphate buffers. When the reaction is performed in a phosphate buffer, the phosphate buffer is prepared so that the pH range is preferably 7.0 to 8.5.

  The amount of the dye compound (B) used in this step may be such that the concentration in the reaction solution is preferably 0.5 to 1500 μg / ml, more preferably 1 to 1000 μg / ml.

  Specific examples of the condensing agent include, for example, N-ethyl-N ′-(3-diethylaminopropyl) carbodiimide, N, N′-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N '-Carbonyldiimidazole, diphenylphosphoryl azide, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), 4- (4,6-dimethoxy [1.3.5] triazin-2-yl ) -4-methylmorpholinium chloride (DMT-MM), fluoro-N, N, N ′, N′-tetramethylformamidinium hexafluorophosphate (TFFH) and the like. These condensing agents can be used alone or in combination of two or more.

  The amount of the condensing agent used is usually 1 mol per 1 mol of the dye compound (B), but can be appropriately set within the range of 1 to 20 mol.

  The reaction temperature in this step is preferably 0 to 60 ° C, more preferably 10 to 30 ° C. When the reaction temperature is less than 0 ° C., the reaction itself may not occur. On the other hand, when the reaction temperature exceeds 60 ° C., the crosslinked copolymer (A) itself may become unstable. The reaction time is preferably 5 to 48 hours, more preferably 12 to 24 hours.

  When a salt of unsaturated carboxylic acid (a2) is used in the copolymerization, acid treatment is performed after completion of the reaction with the dye compound (B), and the carboxylate portion to which the dye compound is not bonded is converted into a carboxyl group. It is preferable to convert it. By performing such a treatment, the medical treatment material of the present invention has pH responsiveness that swells and contracts selectively. 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 25 ° C., and preferably for 40 to 60 hours.

  After completion of the reaction with the dye compound (B) or after completion of the acid treatment, the obtained product is cut into blocks or particles as necessary, and then dried. The temperature in the drying step is usually 40 to 60 ° C, preferably 45 ° C to 55 ° C, and the drying time is usually 6 to 24 hours, preferably 12 to 20 hours.

  The drying device may be a commonly used device, and examples thereof include an oven, a hot air dryer, and a vacuum dryer. These drying apparatuses can also be used in combination.

  The shape of the medical treatment material of the present invention thus obtained is not particularly limited, such as a spherical shape, a crushed shape, and an indeterminate shape. For example, when used as a vascular embolization material, it has a spherical shape or an indefinite shape. Preferably there is.

  The medical treatment material of the present invention can be suitably used for various applications. Specific examples include vascular embolization materials, submucosal prosthetic materials, tissue markers, and the like. These uses are preferable because the effects of the present invention can be further exhibited.

  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.

Example 1
(1) Production of cross-linked copolymer (A) In a brown sample tube, 3.8 g of acrylamide (manufactured by Wako Pure Chemical Industries, Ltd.), 2.13 g of sodium acrylate (synthetic product), N, N-methylenebisacrylamide ( 0.013 g) (manufactured by Wako Pure Chemical Industries, Ltd.) was weighed, 19.9 g of distilled water was added to the same brown sample tube, and dissolved with a magnetic stirrer. 5.4 g of sodium chloride (manufactured by Naigai Co., Ltd.) was added to the same sample tube and stirred with a magnetic stirrer to prepare a monomer solution. Deaeration was performed for 5 minutes or more in a vacuum desiccator that was depressurized using a pump. Separately, 0.2 g of ammonium persulfate (manufactured by Wako Pure Chemical Industries, Ltd.) is weighed into a test tube, and distilled water is added and dissolved so that the total mass becomes 1.0 g, thereby preparing a 20 mass% ammonium persulfate aqueous solution. did. While stirring with a magnetic stirrer, 0.127 ml of N, N, N ′, N′-tetramethylethylenediamine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the prepared monomer aqueous solution. Further, 100 μl of a 20 mass% ammonium persulfate aqueous solution was added and injected into a polytetrafluoroethylene tube. After polymerization at 23 ° C. for 2 hours, it was dried under reduced pressure in a 55 ° C. oven at 0 Pa for 5 hours. The dried polymer was left in distilled water to remove unreacted monomers and sodium chloride. The obtained thread-like hydrogel was cut at regular intervals to obtain a crosslinked copolymer (A) swollen with water.

(2) Binding of the dye compound (B) to the crosslinked copolymer (A) As the dye compound (B), indoine blue (made by Sigma Aldrich Japan Co., Ltd.) is used so that the concentration becomes 1 μg / ml. It was prepared by adding to 10 mM phosphate buffer (pH 7.5, manufactured by Takara Bio Inc.). 196 mg of DMT-MM (4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride, manufactured by Kokusan Chemical Co., Ltd.) was weighed into a glass sample bottle, 5 ml of the indoin blue-containing phosphate buffer prepared above was added to dissolve DMT-MM. Immediately after dissolution of DMT-MM, the 3 cm long cross-linked copolymer (A) prepared in (1) above was added. The mixture was stirred with a mix rotor at 23 ° C. for 20 hours. The hydrogel particles were transferred to another glass sample bottle, ethanol was added and washed for 2 hours. Thereafter, ethanol was discarded and washed with RO water for 2 hours to obtain hydrogel particles bound with indoin blue.

(3) Protonation (acid treatment) of the sodium salt portion remaining in the crosslinked copolymer (A) to which the dye is bound
Prepare 2.5N hydrochloric acid (manufactured by Kanto Chemical Co., Inc.), add the hydrogel particles combined with indoin blue obtained in (2) above to 2.5N hydrochloric acid, and heat to 55 ° C. For 48 hours. Hydrochloric acid was discarded, RO water was added, and RO water was exchanged until the pH of the RO water did not change. Then, it dried under reduced pressure for 15 hours on 55 degreeC and 0 Pa conditions, and obtained the sample of the water-swellable bridge | crosslinking polymer in which all the remaining sodium salt part was protonated and became the carboxyl group.

(Examples 2 to 8)
Prepare indoin blue-containing phosphate buffers with indoin blue concentrations of 5, 10, 20, 200, 500, 800, and 1000 μg / ml, and crosslink the dye compound in the same manner as in (2) above. It was made to couple | bond with the copolymer (A) particle | grains. Except for this, a sample of a water-swellable crosslinked polymer was obtained in the same manner as in Example 1.

(Comparative example)
A sample of a water-swellable crosslinked polymer was obtained in the same manner as in Example 1 except that the operation (2) was not performed.

(Evaluation 1: Evaluation of visibility (reflection absorbance measurement))
Each sample of Examples 1 to 8 prepared above was placed in a measurement unit of a dual wavelength chromatographic scanner CS-930 (manufactured by Shimadzu Corporation), and the reflection absorbance at 560 nm which was the maximum absorption wavelength of indoin blue was measured. . The measurement was performed four times, and the average value of the reflected absorbance when there was no sample was subtracted from the average value and corrected (white correction). The results are shown in Table 1 and FIG.

  Visually, the visibility of the sample (Example 1) manufactured using the indoin blue phosphate buffer having a concentration of 1 μg / ml was not sufficient. Samples (Examples 2 to 8) produced using an indoin blue phosphate buffer having a concentration of 5 μg / ml or more had sufficient visibility. FIG. 2 is a photograph of the samples obtained in Comparative Example, Example 3, and Example 4. As can be seen from FIG. 2, the sample of the comparative example is colorless and transparent and difficult to visually recognize, but the samples of Examples 3 and 4 have sufficient visibility.

(Evaluation 2: Evaluation of swelling)
The samples obtained in Examples 1 to 8 were added to 5 ml of 10 mM phosphate buffer (pH 7.5) and placed in an oven heated to 37 ° C. for 4 hours. Then, each sample was image | photographed with high-definition digital microscope VH-6300 (made by Keyence Corporation), and the swelling diameter of each sample was measured. The ratio of swelling diameter (swelling ratio) when the swelling diameter of the sample of the comparative example was 100.0% was calculated. The results are shown in Table 2 and FIG. Samples (Examples 1 to 7) produced using an indoin blue phosphate buffer having a concentration of 800 μg / ml or less had sufficient water swellability. The sample (Example 8) produced using an indoin blue phosphate buffer having a concentration of 1000 μg / ml resulted in slightly poor water swellability.

  Furthermore, in order to investigate the pH response of water swelling, an experiment was conducted using the sample of Example 3 (particle size before swelling: 400 μm). The sample of Example 3 was added to pure water (pH 5.5) and phosphate buffer (pH 7.5), respectively, and placed in an oven heated to 37 ° C. for 4 hours. Thereafter, the swelling diameter of the sample was measured by the method described in Evaluation 2 above. The results are shown in FIG. As apparent from FIG. 4, the sample of Example 3 was not swollen in pure water, but was swollen in a phosphate buffer, and was found to have pH responsiveness.

(Evaluation 3: Measurement of bound carboxyl group content of colored gel)
10 ml of a phosphate buffer containing indoin blue at a concentration of 1, 5, 10, 20, 200, 500, 800, 1000 μg / ml was prepared. Absorbance at 560 nm was measured using 5 ml of each of these 8 types of phosphate buffer solutions using a spectrophotometer (manufactured by Hitachi, Ltd., U-3010). From the measurement results, a relational expression between the concentration x of the indoin blue in the phosphate buffer and the absorbance y was obtained, and the relational expression was calculated as shown in Equation 1 below (see FIG. 5).

  The dye compound was bound to the crosslinked copolymer in the same manner as in (2) above using 5 ml of each of the 8 kinds of indoin blue-containing phosphate buffers. The indyne blue-containing phosphate buffer solution after the reaction was recovered, and the absorbance at 560 nm was measured using a spectrophotometer (manufactured by Hitachi, Ltd., U-3010) (see FIG. 6). The difference in absorbance between the indoin blue phosphate buffer before and after the reaction was calculated. The calculation results of the absorbance difference are shown in Table 3 below.

  Using the absorbance difference values in Table 3 above, the number of moles of indoin blue remaining in the phosphate buffer after the reaction was calculated from Equation 1 above. From the difference between the number of moles of indoin blue contained in the phosphate buffer before the reaction and the number of moles of indoin blue remaining in the phosphate buffer after the reaction, the crosslinked copolymer (A) The number of moles of indoin blue bound to was calculated. From the calculation result, a relational expression between the concentration x of indoin blue in the phosphate buffer and the number of moles y of indoin blue bonded to the crosslinked copolymer (A) was obtained. (See FIG. 7).

  Moreover, the ratio of the carboxyl group in the crosslinked copolymer (A) to which indoin blue is bonded was calculated from the number of moles of indoin blue bonded to the crosslinked copolymer (A). Along with the values obtained by quantifying the visibility evaluation results and the swelling evaluation results, the number of moles of indoin blue and the proportion of carboxyl groups in the crosslinked copolymer (A) to which indoin blue is bound Table 4 shows the calculation results.

  As shown in Table 4, it was found that the visibility was good when 0.1 mol% or more of the carboxyl groups present in the crosslinked copolymer were bonded to indoin blue. In addition, when the amount of carboxyl groups present in the crosslinked copolymer bonded to indoin blue was 15.0 mol% or less, sufficient water swelling was obtained in 10 mM phosphate buffer. It was found that when the amount of the carboxyl group in the cross-linked copolymer (A) bound to 15.0 mol% exceeds 15.0 mol%, the water swellability decreases.

It is a graph which shows the relationship between the density | concentration of indoin blue in a phosphate buffer, and a reflected light absorbency. It is a photograph of the sample obtained in the comparative example, Example 3, and Example 4. It is a graph which shows the swelling ratio of the sample obtained by the comparative example and the Example. In the sample of Example 3, it is a graph which shows the relationship between pH of aqueous solution, and a swelling diameter. It is a graph which shows the relationship between the density | concentration of an indoin blue containing phosphate buffer, and a light absorbency. It is a graph which shows the light absorbency of the phosphate buffer measured before reaction with a pigment compound (B) and after reaction. It is a graph which shows the relationship between the density | concentration of indoin blue in a phosphate buffer, and the number of moles of indoin blue couple | bonded with the crosslinked copolymer (A).

Claims (6)

  Carboxyl group in cross-linked copolymer (A) obtained by cross-linking a copolymer containing a structural unit derived from (meth) acrylamide monomer (a1) and a structural unit derived from unsaturated carboxylic acid (a2) A medical treatment material comprising a water-swellable cross-linked polymer obtained by binding the dye compound (B) to at least a part thereof.   The medical use according to claim 1, wherein the proportion of the carboxyl group to which the dye compound (B) is bonded is 0.1 to 15 mol% with respect to the total number of carboxyl groups in the crosslinked copolymer (A). Treatment material.   The medical treatment material according to claim 1 or 2, wherein the unsaturated carboxylic acid (a2) is (meth) acrylic acid.   The medical treatment material according to any one of claims 1 to 3, wherein the pigment compound (B) is an organic dye having an amino group.   The medical treatment material according to claim 4, wherein the organic dye having an amino group is at least one selected from the group consisting of indoin blue, Nile blue A, Victoria blue B, and astrouble.   The medical treatment material according to any one of claims 1 to 5, which is a vascular embolization material, a submucosal prosthesis material, or a tissue marker.