Embolizing agents and vascular embolization kits

Abstract

To provide an embolic agent that has blood vessel embolization properties comparable to conventional embolic agents, but is excellent in injectability with a syringe and in stability and safety in vivo.SOLUTION: The embolic agent is a copolymer of cationic functional group-containing monomer and an aromatic group-containing monomer, and contains as an active ingredient a copolymer which at least partly has a structure expressed by general formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to an embolizing agent and a kit for vascular embolization. [Background technology]

[0002] Embolization involves partial or complete occlusion of a blood vessel, restricting blood flow through it. In therapy, embolization is used to treat various conditions such as cerebral and peripheral artery aneurysms, arteriovenous malformations, and uterine fibroids, reducing or blocking blood flow to tumors. Embolisms are formed by various means, including the use of polymer microspheres, metal coils, metal or polymer plugs, and liquid embolic materials. The appropriate method is selected from these based on the size of the blood vessel to be occluded, the desired duration of occlusion, or the type of disease or condition to be treated.

[0003] Conventional liquid embolic materials include N-butylcyanoacrylate (NBCA; trade name "TRUFILL®" manufactured by Codman & Shurtleff, etc.) and ethylene vinyl alcohol copolymer (EVOH; trade name "Onyx®" manufactured by ev3 Endovascular, etc.) (see, for example, Patent Document 1). The main mechanisms of action are polymerization reaction with blood for NBCA and precipitation and aggregation in the blood for EVOH, thereby embolizing blood vessels.

[0004] On the other hand, the inventors have developed a cationic π polymer (poly(cation-adj-π)) having an adjacent cationic functional group-aromatic group arrangement (see, for example, Non-Patent Document 1). They have reported that this cationic π polymer exhibits strong yet reversible adhesion to negatively charged surfaces in an aqueous solution containing a salt content similar to that of seawater (0.7 M NaCl aqueous solution). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Special Publication No. 2000-517298 [Non-patent literature]

[0006] [Non-Patent Document 1] Fan H et al., “Adjacent cationic-aromatic sequences yield strong electrostatic adhesion of hydrogels in seawater.”, NATURE COMMUNICATIONS, Vol. 10, No. 5127, 2019. [Non-Patent Document 2] "Approval Review Report (New Medical Device)" issued by the Pharmaceuticals and Medical Devices Agency (PMDA), generic name: Other tubes and catheter-related peripheral devices (vascular embolization set 100420997), August 1, 2008. [Overview of the project] [Problems that the invention aims to solve]

[0007] However, with conventional liquid embolic materials such as NBCA and EVOH, the embolic material may adhere to the catheter tip, potentially damaging the vascular wall or catheter insertion site and causing bleeding during catheter withdrawal. EVOH requires the use of dimethyl sulfoxide (DMSO) as a solvent, and according to the approval review report (new medical device) (Non-Patent Literature 2) issued by the Pharmaceuticals and Medical Devices Agency (PMDA), there is a description regarding commercially available EVOH products concerning the possibility of local nerve damage and damage to the vascular wall due to DMSO. Therefore, only an amount of EVOH that can be dissolved in a DMSO amount that does not cause neurotoxicity can be administered, and multiple administrations may be necessary. Furthermore, EVOH requires the use of special catheters and syringes suitable for using DMSO for administration, which places a significant cost burden on patients.

[0008] The present invention has been made in view of the above circumstances, and provides an embolizing agent that has the same vascular embolizing properties as conventional embolizing agents, while being injectable by syringe and having superior safety and stability in vivo, as well as a vascular embolization kit equipped with the embolizing agent. [Means for solving the problem]

[0009] As a result of diligent research to achieve the above objectives, the inventors have discovered that a copolymer having at least a portion of a structure consisting of alternating arrangements of cationic functional group-containing monomer units and aromatic group-containing monomer units, developed by the inventors, exhibits good injectability with a syringe, exhibits almost no resistance when withdrawing a catheter from a blood vessel, and that administering the copolymer intravascularly forms a safe and stable thrombus-like gel mass through electrostatic interaction with blood components, thus completing the present invention.

[0010] In other words, the present invention includes the following embodiments. (1) An embolizing agent containing as an active ingredient a copolymer of a cationic functional group-containing monomer and an aromatic group-containing monomer, wherein the copolymer has at least a part of the structure represented by the following general formula (I).

[0011] [ka]

[0012] (In general formula (I), R 11 and R 12 is a hydrogen atom, or an alkyl group having 1 to 20 carbon atoms which may have substituents, and the relational formula is R 11 =R 12 It satisfies Y 11 and Y 12 Each of these is an alkylene group having 1 to 20 carbon atoms, which may independently contain one or more single bonds or selected from the group consisting of a hydroxyl group, an ester bond, an ether bond, a sulfide group, a carbonyl group, an amide bond, and a phosphodiester bond. 11is an aromatic hydrocarbon group having 6 to 16 carbon atoms which may have a substituent. X 11 is an ammonium group or an amino group. n11 is an integer of 10 or more and 1000 or less. )

[0013] (2) In the general formula (I), the Ar 11 is a phenyl group which may have a substituent, and the embolization agent according to (1). (3) In the general formula (I), the X 11 is a quaternary ammonium group, and the embolization agent according to (1) or (2). (4) In the general formula (I), the absolute value of the difference in the number of carbon atoms of the Y 11 with respect to the number of carbon atoms of the Y 12 is 0 or more and 3 or less, and the embolization agent according to any one of (1) to (3). (5) The structure represented by the general formula (I) is the structure represented by the following general formula (I-1), and the embolization agent according to any one of (1) to (4).

[0014]

Chemical formula

[0015] (In the general formula (I-1), R 111 and R 112 are a hydrogen atom or a methyl group, and the relational expression: R 111 =R 112 is satisfied. Y 111 and Y 112 are each independently an alkylene group having 1 to 20 carbon atoms which may contain one or more selected from the group consisting of a hydroxyl group, an ether bond, a sulfide group, and a phosphodiester bond. Ar 111 is a phenyl group which may have a substituent. X 111 is a quaternary ammonium group. n111 is an integer of 10 or more and 1000 or less. )

[0016] (6) The embolizing agent according to any one of (1) to (5), wherein the copolymer has a molar ratio of units derived from the cationic functional group-containing monomer to units derived from the aromatic group-containing monomer of 1:4 to 4:1. (7) A vascular embolization kit comprising an embolizing agent described in any one of (1) to (6) and a contrast agent. [Effects of the Invention]

[0017] According to the above embodiment of the embolizing agent, it is possible to provide an embolizing agent that has the same vascular embolizing properties as conventional embolizing agents, while also being injectable by syringe and having superior safety and stability in vivo. [Brief explanation of the drawing]

[0018] [Figure 1A] This graph shows the NMR spectrum in Example 1. [Figure 1B] This graph shows the NMR spectrum in Example 1. [Figure 1C] This graph shows the NMR spectrum in Example 1. [Figure 1D] This graph shows the NMR spectrum in Example 1. [Figure 1E] This graph shows the copolymerization rates of the cationic functional group-containing monomer (ATAC) and the aromatic group-containing monomer (PEA) in Example 1. [Figure 2A] This figure shows the protocol for the qualitative blood agglutination test in Example 2. [Figure 2B] This image shows the results of the qualitative blood agglutination test in Example 2. [Figure 3] This graph shows the results of the quantitative blood agglutination test in Example 2. [Figure 4] This graph shows the results of the rheological test in Example 2. [Figure 5A] This is a schematic diagram of the syringe used in the injection force test in Example 3. [Figure 5B]This graph shows the results of the injection force test using a syringe in Example 3. [Figure 5C] This graph shows the results of the injection force test using a syringe in Example 3. [Figure 6A] This is a schematic diagram of the syringe and microcatheter used in the injection force test in Example 3. [Figure 6B] This graph shows the results of the injection force test using a syringe and microcatheter in Example 3. [Figure 7A] The images on the left and the schematic diagram on the right show the apparatus used in the traction force test in Example 4. [Figure 7B] This graph shows the results of the traction force test in Example 4. [Figure 7C] This graph shows the results of the traction force test in Example 4. [Figure 8A] This graph shows the results of the biochemical tests in Example 5. [Figure 8B] These are hematoxylin and eosin (H&E) stained images of tissue sections from the polymer hydrogel implantation site in Example 5. [Figure 9] These are visual observation images (top) and thermographic images (bottom) of the hind limb in Example 6. [Figure 10] These are bright-field images (left), H&E stained images (middle), and acid blue stained images (right) of tissue sections around the femoral artery of the hind limb injected with polymer in Example 6. [Figure 11] This is a computed tomography (CT) image from Example 7. [Modes for carrying out the invention]

[0019] ≪Embrogants≫ The embolizing agent of this embodiment is a copolymer of a cationic functional group-containing monomer and an aromatic group-containing monomer, and contains as an active ingredient a copolymer having at least a part of the structure represented by the following general formula (I) (hereinafter sometimes referred to as "structure (I)").

[0020] [ka]

[0021] (In general formula (I), R 11 and R 12 is a hydrogen atom, or an alkyl group having 1 to 20 carbon atoms which may have substituents, and the relational formula is R 11 =R 12 It satisfies Y 11 and Y 12 Each of these is an alkylene group having 1 to 20 carbon atoms, which may independently contain one or more single bonds or selected from the group consisting of a hydroxyl group, an ester bond, an ether bond, a sulfide group, a carbonyl group, an amide bond, and a phosphodiester bond. 11 X is an aromatic hydrocarbon group having 6 to 16 carbon atoms, which may have substituents. 11 is either an ammonium group or an amino group. n11 is an integer between 10 and 1000. (Note that the wavy line represents a bond.)

[0022] The embolizing agent of this embodiment, having the above configuration, possesses vascular embolizing properties equivalent to conventional embolizing agents, while also offering superior ease of injection by syringe and excellent safety and stability in vivo.

[0023] In this specification, "contained as an active ingredient" means containing a therapeutically effective amount of copolymer. "Therapeutally effective amount" here means the amount of copolymer, or a combination of copolymer and one or more activators, that elicits the biological or medical effect or response desired by a physician, clinician, veterinarian, researcher, or other appropriate professional when administered according to the desired therapeutic measures. A preferred therapeutically effective amount is one that improves the symptoms of diseases requiring intravascular embolization. Specific examples of such diseases will be discussed later.

[0024] <Copolymer> The copolymer is formed by copolymerizing a monomer containing a cationic functional group with a monomer containing an aromatic group, and has at least a portion of the above structure (I). Structure (I) consists of an arrangement in which the monomer containing a cationic functional group and the monomer containing an aromatic group are arranged alternately. Alternatively, structure (I) can be described as a continuous structure in which units consisting of one molecule of the monomer containing a cationic functional group and one molecule of the monomer containing an aromatic group are arranged.

[0025] The mechanism of blood coagulation by copolymers involves the binding of negatively charged blood components (red blood cells, white blood cells, platelets, etc.) and proteins in the blood to cationic functional groups in the copolymer via electrostatic interactions, forming a thrombus-like gel mass containing blood (hereinafter referred to as blood gel), thereby embolizing blood vessels. It is presumed that aromatic groups in the blood gel form a hydrophobic field, stabilizing the blood gel in the body. In this embodiment of the embolizing agent, the above mechanism is merely one example, and the agent is not limited to this mechanism as long as it can achieve the desired effect.

[0026] [R 11 and R 12 ] R 11 and R 12 This is a hydrogen atom, or an alkyl group having 1 to 20 carbon atoms, which may have substituents. Also, the relationship formula is: R 11 =R 12 The above relationship is satisfied. By using a cationic functional group-containing monomer and an aromatic group-containing monomer that satisfy the above relationship, a copolymer having structure (I) in at least part can be obtained.

[0027] R 11 and R 12 The alkyl group having 1 to 20 carbon atoms is preferably in a chain-like structure. The chain-like alkyl group may be linear or branched. The chain-like alkyl group is preferably one with 1 to 6 carbon atoms, and specifically, examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, and the like.

[0028] R 11 and R 12 Examples of substituents in this compound include halogen atoms. Examples of halogen atoms include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0029] Among them, R 11 and R 12 Preferably, the atom is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; more preferably, a hydrogen atom, a methyl group, or an ethyl group; and even more preferably, a hydrogen atom or an ethyl group.

[0030] [Y 11 and Y 12 ] Y 11 and Y 12 Each of these is an alkylene group having 1 to 20 carbon atoms, which may independently contain one or more single bonds or one or more selected from the group consisting of a hydroxyl group, an ester bond, an ether bond, a sulfide group, a carbonyl group, an amide bond, and a phosphodiester bond.

[0031] Y 11 and Y 12 Examples of alkylene groups with 1 to 20 carbon atoms in Y include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tetradecylene, hexadecylene, octadecylene, nonadecylene, and ecosilene. Among these, Y 11 and Y 12 The alkylene group in is preferably a methylene group, ethylene group, propylene group, butylene group, pentylene group, hexylene group, heptylene group, octylene group, nonylene group, or desilene group; more preferably a methylene group, ethylene group, propylene group, butylene group, pentylene group, hexylene group, heptylene group, or octylene group; and even more preferably a methylene group, ethylene group, propylene group, or butylene group.

[0032] Among them, Y 11and Y 12 Preferably, the alkylene group has 1 to 10 carbon atoms and may contain one or more selected from the group consisting of a hydroxyl group, an ester bond, an ether bond, a sulfide group, and a phosphodiester bond.

[0033] Furthermore, due to the ease of interaction between cationic functional groups and aromatic groups, the linker Y is used to bring these functional groups closer together. 11 and Y 12 Preferably, the lengths are of similar length, Y 11 Y for the number of carbon atoms 12 It is more preferable that the absolute value of the difference in the number of carbon atoms is between 0 and 3.

[0034] Preferred Y 11 and Y 12 More specifically, examples include the bases represented by the following general formulas (Iy-1) to (Iy-7) (hereinafter sometimes referred to as "base (Iy-1)", etc.). Note that bases (Iy-1) to (Iy-7) are preferred Y 11 and Y 12 This is just one example, a favorable Y 11 and Y 12 These are not limited to these. In base (Iy-1) to (Iy-7), the wavy line on the left is R 111 or R 112 This is the bonding site with the carbon atom to which it is bonded, and the wavy line on the right is X 11 Or Ar 11 This is the junction site.

[0035] [ka]

[0036] [Ar 11 ] Ar 11 This is an aromatic hydrocarbon group having 6 to 16 carbon atoms, which may have substituents. Ar 11 Examples of aromatic hydrocarbon groups having 6 to 16 carbon atoms include phenyl groups, naphthyl groups, and anthracenyl groups. Ar 11 Examples of substituents in R include alkyl groups and halogen atoms. Examples of alkyl groups and halogen atoms include the above R 11 and R 12 Examples similar to those exemplified in [the previous section] can be given. Among them, Ar 11 A phenyl group, which may have substituents, is preferred.

[0037] [X 11 ] X 11 X is a cationic functional group, which is either an ammonium group or an amino group. 11 It is preferably an ammonium group, and more preferably a quaternary ammonium group.

[0038] Preferred quaternary ammonium groups include, for example, the groups represented by the following general formulas (Ix-1) to (Ix-7) (hereinafter sometimes referred to as "group (Ix-1)", etc.). Note that groups (Ix-1) to (Ix-7) are merely examples of preferred quaternary ammonium groups, and preferred quaternary ammonium groups are not limited to these. Note that the dashed line represents Y. 11 This shows the binding site.

[0039] [ka]

[0040] Quaternary ammonium groups are usually supplied in a state of ionic bonding with a suitable anion. Examples of anions that ionically bond with quaternary ammonium groups include halogen ions such as chloride ions, bromide ions, fluoride ions, and iodide ions, as well as hydroxide ions, sulfate ions, and acetate ions, with chloride ions being preferred among them.

[0041] [n11] n11 is an integer between 10 and 1000, preferably between 30 and 1000, more preferably between 50 and 1000, even more preferably between 70 and 1000, and particularly preferably between 100 and 1000.

[0042] In structure (I), the wavy lines on the monomer unit containing the cationic functional group and the wavy lines on the monomer unit containing the aromatic group are, independently, bonding sites to one of the following: 1) Hydrogen atom; 2) Units derived from polymerization initiators; 3) In the case of the wavy line portion on the side of the cationic functional group-containing monomer unit, it refers to one or more molecules of cationic functional group-containing monomer unit; 4) In the case of the wavy line on the aromatic group-containing monomer unit side, it refers to one or more aromatic group-containing monomer units.

[0043] A copolymer can have one or more structures (I). That is, if a monomer unit containing a cationic functional group is A and a monomer unit containing an aromatic group is B, an example of a copolymer may have the following sequence. The following sequence is merely one example of a copolymer sequence, and the copolymer sequence is not limited to this. In the following sequence, H represents a hydrogen atom, M represents a unit derived from a polymerization initiator, n11 is the same as n11 above, and n12 and n13 are each independent integers of 1 or more. 1) H-(AB) n11 -H; 2) M-(AB) n11 -H; 3) H-(AB) n11 -M; 4) M-(AB) n11 -M; 5) A-(AB) n11 -B; 6) A-(AB) n11 -(B) n12 -(AB) n11 -B; 7) A-(AB) n11 -(B) n12 -(A)n13 -(AB) n11 -B

[0044] Preferred structure (I) includes, for example, a structure represented by the following general formula (I-1) (hereinafter sometimes referred to as "structure (I-1)"). Note that structure (I-1) is only an example of preferred structure (I), and preferred structure (I) is not limited thereto.

[0045]

Chemical formula

[0046] (In general formula (I-1), R 111 and R 112 are a hydrogen atom or a methyl group, and satisfy the relational expression: R 111 = R 112 . Y 111 and Y 112 are each independently an alkylene group having 1 to 20 carbon atoms which may contain one or more selected from the group consisting of a hydroxyl group, an ether bond, a sulfide group, and a phosphodiester bond. Ar 111 is a phenyl group which may have a substituent. X 111 is a quaternary ammonium group. n111 is an integer of 10 or more and 1000 or less. The wavy line represents a bond.)

[0047] [R 111 and R 112 R 111 and R 112 are a hydrogen atom or a methyl group, and satisfy the relational expression: R 111 = R 112 .

[0048] [Y 111 and Y 112 Y 111 and Y 112 are each independently an alkylene group having 1 to 20 carbon atoms which may contain one or more selected from the group consisting of a hydroxyl group, an ether bond, a sulfide group, and a phosphodiester bond.​​

[0049] Y 111 and Y 112 The alkylene group having 1 to 20 carbon atoms in the above Y 11 and Y 12 Examples similar to those exemplified in [the previous section] can be given. Among them, Y 111 and Y 112 Preferably, the alkylene group having 1 to 10 carbon atoms may contain one or more selected from the group consisting of a hydroxyl group, an ether bond, a sulfide group, and a phosphodiester bond; more preferably, the alkylene group having 1 to 6 carbon atoms may contain one or more selected from the group consisting of a hydroxyl group, an ether bond, a sulfide group, and a phosphodiester bond; and even more preferably, the alkylene group having 1 to 4 carbon atoms may contain one or more selected from the group consisting of a hydroxyl group, an ether bond, a sulfide group, and a phosphodiester bond.

[0050] [Ar 111 ] Ar 111 This is a phenyl group which may have substituents. Examples of substituents include the above-mentioned Ar 11 Examples similar to those exemplified in [the previous section] can be given.

[0051] [X 111 ] X 111 This is a quaternary ammonium group. As a quaternary ammonium group, the above X 11 Examples similar to those exemplified in [the previous section] can be given.

[0052] [n111] n111 is an integer between 10 and 1000, preferably between 30 and 1000, more preferably between 50 and 1000, even more preferably between 70 and 1000, and particularly preferably between 100 and 1000.

[0053] In structure (I-1), the wavy lines on the cationic functional group-containing monomer unit side and the wavy lines on the aromatic group-containing monomer unit side are the same as the wavy lines on the cationic functional group-containing monomer unit side and the wavy lines on the aromatic group-containing monomer unit side in structure (I) above.

[0054] Examples of preferred structures (I-1) include those represented by the following general formulas (I-1-1) to (I-1-6). Note that structures (I-1-1) to (I-1-6) are merely examples of preferred structures (I-1), and preferred structures (I-1) are not limited to these.

[0055] [ka]

[0056] [ka]

[0057] (In the general formula above, n112 is the same as n111 above.)

[0058] [Cationic functional group-containing monomers] A monomer containing a cationic functional group can be any monomer having both a cationic functional group and a polymerizable functional group, for example, a compound represented by the following general formula (Ia) (hereinafter sometimes referred to as "compound (Ia)").

[0059] [ka]

[0060] (In general formula (Ia), R a11 , Y a11 , and X a11 These are the R values ​​mentioned above. 11 , Y 11 , and X 11 It is the same as this.

[0061] Examples of preferred compound (Ia) include the compound represented by the following general formula (Ia-1) (hereinafter sometimes referred to as "compound (Ia-1)"). Compound (Ia-1) is a monomer having a (meth)acrylic acid ester skeleton. Note that compound (Ia-1) is merely one example of preferred compound (Ia), and preferred compound (Ia) is not limited to this.

[0062] [ka]

[0063] (In general formula (Ia-1), R a111 , Y a111 , and X a111 These are the R values ​​mentioned above. 111 , Y 111 , and X 111 It is the same as this.

[0064] Examples of preferred compounds (Ia-1) include compounds represented by the following general formulas (Ia-1-1) to (Ia-1-4) (hereinafter sometimes referred to as "compounds (Ia-1-1), etc."). Compounds (Ia-1-1) to (Ia-1-4) are monomers having a (meth)acrylic acid ester skeleton. Note that compounds (Ia-1-1) to (Ia-1-4) are merely examples of preferred compounds (Ia-1), and preferred compounds (Ia-1) are not limited to these.

[0065] [ka]

[0066] Compound (Ia-1-1) is 2-(acryloyloxy)ethyl trimethylammonium. Compound (Ia-1-2) is 2-(acryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate. Compound (Ia-1-3) is 2-(metacryloyloxy)ethyl trimethylammonium. Compound (Ia-1-4) is 2-(metacryloyloxy)ethyl 2-(trimethylammonio)ethyl phosphate.

[0067] [Aromatic group-containing monomers] Aromatic group-containing monomers can be any monomer having an aromatic group and a polymerizable functional group, for example, compounds represented by the following general formula (Ib) (hereinafter sometimes referred to as "compound (Ib)").

[0068] [ka]

[0069] (In general formula (Ib), R b11 , Y b11 , and Ar b11 These are the R values ​​mentioned above. 12 , Y 12 , and Ar 11 It is the same as this.

[0070] Examples of preferred compound (Ib) include the compound represented by the following general formula (Ib-1) (hereinafter sometimes referred to as "compound (Ib-1)"). Compound (Ib-1) is a monomer having a (meth)acrylic acid ester skeleton. Note that compound (Ib-1) is merely one example of preferred compound (Ib), and preferred compound (Ib) is not limited to this.

[0071] [ka]

[0072] (In general formula (Ib-1), R b111 , Y b111 , and Ar b111 These are the R values ​​mentioned above. 112 , Y 112 , and Ar 111It is the same as this.

[0073] Examples of preferred compounds (Ib-1) include compounds represented by the following general formulas (Ib-1-1) to (Ib-1-10) (hereinafter sometimes referred to as "compounds (Ib-1-1), etc."). Compounds (Ib-1-1) to (Ib-1-10) are monomers having a (meth)acrylic acid ester skeleton. Note that compounds (Ib-1-1) to (Ib-1-10) are merely examples of preferred compounds (Ib-1), and preferred compounds (Ib-1) are not limited to these.

[0074] [ka]

[0075] [ka]

[0076] Compound (Ib-1-1) is benzyl acrylate. Compound (Ib-1-2) is 2-phenoxyethyl acrylate (PEA). Compound (Ib-1-3) is 2-(2-phenoxyethoxy)ethyl acrylate. Compound (Ib-1-4) is 2-(phenylsulfanyl)ethyl acrylate. Compound (Ib-1-5) is 2-hydroxy-3-phenoxypropyl acrylate. Compound (Ib-1-6) is benzyl metacrylate. Compound (Ib-1-7) is 2-phenoxyethyl metacrylate. Compound (Ib-1-8) is 2-(2-phenoxyethoxy)ethyl metacrylate. Compound (Ib-1-9) is 2-(phenylsulfanyl)ethyl metacrylate. Compound (Ib-1-10) is 2-hydroxy-3-phenoxypropyl metacrylate.

[0077] [Other monomers] The copolymer may contain units derived from other monomers in addition to the units derived from the above-mentioned cationic functional group-containing monomer and the above-mentioned aromatic group-containing monomer.

[0078] Other monomers can be those that do not have cationic functional groups or aromatic groups, but have polymerizable functional groups that can polymerize with the cationic functional group-containing monomers and the aromatic group-containing monomers. Examples of such other monomers are listed below. These may be used individually or in combination of two or more. (i) Methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, sec-butyl (meth)acrylate, tert-butyl (meth)acrylate, pentyl (meth)acrylate, isopentyl (meth)acrylate, hexyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, heptyl (meth)acrylate, octyl (meth)acrylate, isooctyl (meth)acrylate, nonyl (meth)acrylate (Meth)acrylic acid esters such as (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, (meth)acrylate, etc. (ii) Hydroxylated (meth)acrylic acid esters such as (meth)acrylate-2-hydroxyethyl, (meth)acrylate-2-hydroxypropyl, (meth)acrylate-2-hydroxybutyl, (meth)acrylate-4-hydroxylbutyl, (meth)acrylate-6-hydroxyhexyl, and (meth)acrylate-8-hydroxyoctyl. (iv) (meth)acrylic acid esters having polyvalent hydroxyl groups, such as (meth)acrylic acid monoester of glycerin and (meth)acrylic acid monoester of trimethylolpropane. (v) Unsaturated carboxylic acids such as acrylic acid, methacrylic acid, maleic acid, and itaconic acid. (vi) Unsaturated amides such as N-methylolacrylamide, diacetoneacrylamide, and dimethylaminopropylacrylamide. (vii) (meth)acrylic acid esters having an epoxy group, such as glycidyl (meth)acrylic acid. (viii) (meth)acrylic acid esters having a carboxyl group, such as 2-carboxyethyl (meth)acrylic acid. (ix) vinyl acetate, (meth)acrylonitrile, etc.

[0079] [Copolymer Structure] In the copolymer, the molar ratio of units derived from a cationic functional group-containing monomer to units derived from an aromatic group-containing monomer can be 1:10 to 10:1, 1:8 to 8:1, 1:5 to 5:1, preferably 1:4 to 4:1, more preferably 1:2 to 2:1, even more preferably 1.5:1 to 1:1.5, even more preferably 1.2:1 to 1:1.2, particularly preferably 1.1:1 to 1:1.1, and most preferably 1:1.

[0080] [Method for producing copolymers] The copolymer is obtained by mixing the above cationic functional group-containing monomer and the above aromatic group-containing monomer in a predetermined solvent in the presence of a polymerization initiator and performing solution polymerization. The cationic functional group-containing monomer and the aromatic group-containing monomer are R in the above general formula (Ia). 11a and R in the above general formula (Ib) 11b They use the same thing.

[0081] Furthermore, by mixing the cationic functional group-containing monomer and the aromatic group-containing monomer in a predetermined solvent before the polymerization reaction, the cationic functional group-containing monomer units and the aromatic group-containing monomer units are more likely to be arranged alternately due to the interaction between the cationic functional group and the aromatic group, thereby increasing the proportion of the above structure (I) in the copolymer.

[0082] Furthermore, when other monomers are used in addition to the cationic functional group-containing monomers and aromatic group-containing monomers, they can be mixed before or after the mixing of the cationic functional group-containing monomers and aromatic group-containing monomers.

[0083] The mixing temperature can be, for example, between 19°C and 35°C.

[0084] The ratio (molar ratio) of the amount of cationic functional group-containing monomer to aromatic group-containing monomer used can be 1:10 to 10:1, 1:8 to 8:1, 1:5 to 5:1, preferably 1:4 to 4:1, more preferably 1:2 to 2:1, even more preferably 1.5:1 to 1:1.5, even more preferably 1.2:1 to 1:1.2, particularly preferably 1.1:1 to 1:1.1, and most preferably 1:1.

[0085] The amount of other monomers used should be determined within a range that does not hinder the alternating arrangement of cationic functional group-containing monomer units and aromatic group-containing monomer units. Specifically, it can be 50 mol% or less, 30 mol% or less, preferably 10 mol% or less, more preferably 5 mol% or less, even more preferably 1 mol% or less, and particularly preferably 0 mol%, relative to the total molar amount of cationic functional group-containing monomers and aromatic group-containing monomers.

[0086] The polymerization initiator can be any compound that initiates the polymerization reaction by heat or light, such as 2-oxoglutaric acid, benzoyl peroxide, azobisisobutyronitrile, potassium persulfate, and sodium persulfate.

[0087] The amount of polymerization initiator used can be 0.001 mol% to 0.100 mol%, 0.005 mol% to 0.050 mol%, or 0.010 mol% to 0.030 mol%, relative to the total molar amount of monomer used in the polymerization reaction.

[0088] Dimethyl sulfoxide (DMSO) is preferred as the organic solvent used in solution polymerization.

[0089] The amount of organic solvent used is preferably such that the total concentration of monomers used in the polymerization reaction is 1 mol / L or more. The upper limit of the total concentration of monomers in the reaction solution is sufficient as long as the viscosity of the reaction solution does not become too high; for example, it can be 2 mol / L.

[0090] The polymerization reaction is initiated by heating the reaction solution to a temperature of, for example, between 50°C and 100°C, or by irradiating it with light such as UV light.

[0091] The polymerization reaction temperature can be set appropriately depending on the type of monomer and polymerization initiator used, but for example, it can be set to between 20°C and 100°C.

[0092] The polymerization reaction time can be between 1 hour and 12 hours.

[0093] The copolymer may be purified after the polymerization reaction. The copolymer is purified by known methods, followed by post-treatment as necessary, to isolate the copolymer. Specifically, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration are performed individually or in combination of two or more as appropriate, and the copolymer is purified by concentration, reprecipitation, column chromatography, etc.

[0094] The structure of the copolymer can be confirmed using known methods such as nuclear magnetic resonance (NMR) spectroscopy and infrared spectroscopy (IR).

[0095] Furthermore, in order to remove as many organic solvents that are toxic to living organisms as possible, it is preferable to replace the solvent in the obtained copolymer from an organic solvent to water by dialysis or the like.

[0096] After purification or solvent replacement of the copolymer, drying may be performed. Examples of drying methods include forced-air drying, drying in a constant-temperature bath, reduced-pressure drying, hot-air circulation drying, and freeze-drying. Freeze-drying is preferred among these. When freeze-drying is performed, a cryoprotectant may be further included from the viewpoint of more effectively suppressing the increase in particle size of the fine particles formed by the copolymer.

[0097] The cryoprotectant is not particularly limited as long as it is known as a "freeze-protectant" or "freeze-drying protectant," and examples include disaccharides, sorbitol, dextran, polyethylene glycol, propylene glycol, glycerin, glycerol, polyvinylpyrrolidone, dimethyl sulfoxide, and the like.

[0098] The disaccharides are not particularly limited and include, for example, sucrose, lactulose, maltose, trehalose, cellobiose, kordibiose, nigerose, isomaltose, isotrehalose, neotrehalose, sophorose, laminaribiose, genthiobiose, turanose, maltulose, palatinose, genthiobiulose, mannobiose, melibiose, melibiulose, neolactose, galactosucrose, sylabiose, neohesperidose, rutinose, rutinulose, bicyanose, xylobiose, and primeverose.

[0099] The amount of frost protection agent to be used is not particularly limited and can be appropriately determined by those skilled in the art according to known methods.

[0100] Copolymers can be in solid, semi-solid, or liquid form. In the case of a solid, examples of forms include powder, granules, and tablets. Among these, freeze-dried powder is preferred as the solid. Examples of semi-solid forms include gels and similar structures. In the case of liquids, examples include aqueous solutions or suspensions obtained by dissolving the powder in water or the like.

[0101] When the embolizing agent of this embodiment is a liquid, it is preferable that it be an aqueous solution in which the copolymer concentration is 10 mg / L or more and 100 mg / L or less, preferably 20 mg / L or more and 70 mg / L or less, and more preferably 30 mg / L or more and 50 mg / L or less. By having a copolymer concentration above the lower limit, it can interact with blood to form an embolism more efficiently. On the other hand, by having a concentration below the upper limit, the increase in viscosity is more suppressed even when stored for a long period of time of about one month, and it can be stored in a stable state. Furthermore, as shown in the examples described later, when administered into the body, it is easier to inject using a syringe or microcatheter, and when withdrawing them from the blood vessel, they can be withdrawn with almost no resistance and more safely.

[0102] The animals to which the embolizing agent of this embodiment can be administered are not limited, but include, for example, humans, monkeys, dogs, cattle, horses, sheep, pigs, rabbits, mice, rats, guinea pigs, hamsters, and the like. Among these, mammals are preferred, and humans are particularly preferred.

[0103] Since the copolymer interacts with blood to form a gel, administration to patients or affected animals is preferably done locally to the site where embolism formation is desired.

[0104] Specific administration methods include, for example, intra-arterial injection, intravenous injection, and other methods known to those skilled in the art using syringes, microcatheters, etc.

[0105] The dosage will vary depending on the patient's weight, age, symptoms, and method of administration, but a person skilled in the art can appropriately select a suitable dosage. The embolizing agent of this embodiment is administered in the form of an injectable preparation, with a copolymer concentration preferably between 20 mg / L and 60 mg / L.

[0106] Commercially available Onyx is generally limited to a dose of approximately 4.5 mL or less per day for adults (assuming a body weight of 60 kg) due to the toxicity of its solvent, DMSO. However, since the embolizing agent of this embodiment is water-soluble, it can be administered without using DMSO. Therefore, the embolizing agent of this embodiment can be administered in a higher dose than Onyx, for example, more than approximately 4.5 mL per day for adults (assuming a body weight of 60 kg). Alternatively, if the required amount at the administration site is small, the amount can be approximately 4.5 mL or less per day for adults (assuming a body weight of 60 kg).

[0107] The number of administrations may be a single dose of the above-mentioned dosage, or the above-mentioned dosage may be administered once every 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or 6 months, or two or more times. Furthermore, the embolizing agent of this embodiment is water-soluble and, unlike conventional embolizing agents such as EVOH, can have a composition that does not contain organic solvents harmful to the body such as DMSO, so the required local dose can be administered as a single dose.

[0108] ≪Pharmaceutical Compositions≫ The embolic agent of this embodiment can be used as a pharmaceutical composition in combination with a pharmaceutically acceptable carrier.

[0109] Pharmaceutically acceptable carriers can be those commonly used in the formulation of pharmaceutical compositions, without any particular limitations. More specifically, examples include water, ethanol, glycerin, and other solvents for injectable preparations.

[0110] The pharmaceutical composition may further contain additives. Examples of additives include lubricants such as calcium stearate and magnesium stearate; stabilizers such as benzyl alcohol and phenol; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; and preservatives.

[0111] The pharmaceutical composition can be formulated by appropriately combining the above-mentioned embolic agent with the above-mentioned pharmaceutically acceptable carrier and additives and mixing them in a unit dose form generally accepted for pharmaceutical production.

[0112] The pharmaceutical composition is preferably in the form of an injection.

[0113] The pharmaceutical composition is preferably used in the treatment of diseases to which known embolizing agents are applied. Such diseases include arteriovenous malformations of the brain; uterine fibroids, brain tumors, liver cancer (the embolizing agent of this embodiment can be applied to arterial embolization in these diseases); cerebral aneurysms; dural arteriovenous fistulas; coronary arteriovenous fistulas; bleeding due to vascular damage caused by trauma; epistaxis; obstetric hemorrhage (atonic hemorrhage, placental abruption), etc.

[0114] <<Other Embodiments>> In one embodiment, the present invention provides a method for treating a disease, comprising administering a therapeutically effective amount of the embolizing agent to a patient in need of treatment. Examples of diseases include those similar to those exemplified in the above-mentioned pharmaceutical compositions.

[0115] In one embodiment, the present invention provides the use of the above-mentioned embolic agent for manufacturing a pharmaceutical composition for the treatment of a disease.

[0116] In one embodiment, the embolizing agent and contrast agent can be combined into a vascular embolization kit. Examples of contrast agents include gadolinium, Gd-DTPA, Gd-DTPA-BMA, Gd-HP-DO3A, iodine, iron, iron oxide, chromium, manganese, tantalum, and their complexes and chelate complexes. [Examples]

[0117] The present invention will be described below with reference to examples, but the present invention is not limited to the following examples.

[0118] [Example 1] (Manufacturing of cationic π polymer (poly(cation-adj-π))) Cationic π polymers (poly(cation-adj-π)) are prepared by dissolving a cationic functional group-containing monomer (0.5M), an aromatic group-containing monomer (0.5M), and 2-oxoglutaric acid (0.25mM) as a photopolymerization initiator in DMSO, and then shining 365nm UV light (4mW / cm²) on the resulting mixture. 2 The material was irradiated at room temperature (approximately 25°C) for 11 hours to copolymerize and obtain a cationic π polymer. The combinations of cationic functional group-containing monomers and aromatic group-containing monomers used are shown in the table below.

[0119] [Table 1]

[0120] As a representative result, Figure 1A shows the NMR spectrum of a cationic π polymer (P(ATAC-adj-PEA)) dissolved in DMSO, prepared using ATAC and PEA. In Figure 1A, P(ATAC-co-PEA) is a random copolymer of ATAC and PEA, prepared by dissolving a cationic functional group-containing monomer (0.5M), an aromatic group-containing monomer (0.5M), and 2-oxoglutaric acid (0.25mM) as a photopolymerization initiator in dimethyl sulfide (DMS), and irradiating the resulting mixture with 365 nm UV light at room temperature (approximately 25°C) for 11 hours to random copolymerize it. P(PEA) is a homopolymer obtained by homopolymerizing PEA. The circled + represents ATAC, and the hexagon represents PEA.

[0121] Also, 1 The measurement conditions for H-NMR were as follows: Each polymer was treated with deuterated DMSO (DMSO-) at a concentration of 1-5 mg / mL. d6 ) Dissolve in solution, 1 Analysis was performed using 1H-NMR (Agilent 500MHz).

[0122] As shown in Figure 1A, in P(ATAC-adj-PEA), the phenyl proton signal showed a symmetrical broadening around the phenyl proton peak of the aromatic group-containing monomer, indicating that the cationic functional group and aromatic group were dispersed adjacently on the polymer chain. On the other hand, in P(ATAC-co-PEA), the phenyl proton signal, similar to the signal of the homopolymer of the aromatic group-containing monomer, had a new broad peak at high magnetic fields, indicating that the aromatic group-containing monomer was homopolymerized in the long segment of the polymer difference.

[0123] Furthermore, the NMR spectra of P(ATAC-adj-BZA), P(ATAC-adj-PDEA), and P(ATAC-adj-PSEA) are shown in Figures 1B to 1D, respectively.

[0124] As shown in Figures 1B to 1D, in P(ATAC-adj-BZA), P(ATAC-adj-PDEA), and P(ATAC-adj-PSEA), the phenyl proton signal was located at a higher chemical shift than the signal of the homopolymer of aromatic group-containing monomers. Furthermore, in P(ATAC-adj-BZA), P(ATAC-adj-PDEA), and P(ATAC-adj-PSEA), the phenyl proton signal peak showed a broader shape than the phenyl proton signal peak of the homopolymer of aromatic group-containing monomers. These differences indicate that in P(ATAC-adj-BZA), P(ATAC-adj-PDEA), and P(ATAC-adj-PSEA), the cationic functional group and aromatic group are dispersed adjacently on the polymer chain.

[0125] Furthermore, P(ATAC-adj-PEA) was prepared in the same manner as above, using a total monomer concentration of 1.0 M, 0.25 mM 2-oxoglutaric acid as a polymerization initiator, and DMSO as the solvent, while varying the molar ratio of ATAC to PEA. Polymers with different reaction times were then prepared. 1 The copolymerization rates of cationic functional group-containing monomers (ATAC) and aromatic group-containing monomers (PEA) were determined by analysis using 1H-NMR (Agilent 500MHz). The results are shown in Figure 1E. In Figure 1E, f represents the molar ratio of PEA. For example, f0.243 corresponds to the use of 0.757M ATAC and 0.243M PEA.

[0126] As shown in Figure 1E, polymers were formed at similar rates within the range of ATAC:PEA = 0.757M:0.243M to 0.346M:0.654M. Therefore, it was confirmed that P(ATAC-adj-PEA) can be produced within the above molar ratio range.

[0127] Next, each obtained cationic π polymer was subjected to dialysis to change the solvent from DMSO to distilled water, freeze-dried (held under vacuum (<30 Pa) and at -40°C for several hours to several days, depending on the amount), and then dissolved in water to prepare aqueous polymer solutions of 30 mg / mL, 40 mg / mL, and 50 mg / mL.

[0128] [Example 2] (Qualitative and quantitative blood agglutination tests) The qualitative blood agglutination test involved adding 150 μL of polymer solution at different concentrations (30 mg / mL, 40 mg / mL, or 50 mg / mL) to a well plate and covering the entire bottom surface with polymer. Next, an equal amount of citrate-treated blood was added to each well. The wells were repeatedly washed with physiological saline until the solution became clear, removing all non-agglutinating blood components (see Figure 2A). 150 μL of citrate-treated blood containing 0.1 M calcium chloride (CaCl2) was used as a control. The results are shown in Figure 2B.

[0129] As shown in Figure 2B, the blood gels formed using each cationic π polymer remained stable even after washing with physiological saline. On the other hand, the blood gel formed using the ATAC homopolymer disintegrated and flowed away when washed with physiological saline. The results above clearly demonstrate that cationic π polymers can form stable gels with blood under physiological conditions.

[0130] Next, a quantitative blood agglutination test was performed as follows. First, 500 μL of citrated blood was added to a microcentrifuge tube, and different amounts (42 μL to 320 μL) of polymer (P(ATAC-adj-PEA)) aqueous solution at different concentrations (30 mg / mL, 40 mg / mL, or 50 mg / mL) were slowly added to the blood. Immediately after injection, the aggregates were removed and the surface liquid was removed. The weight of the aggregates was then measured. The results are shown in Figure 3.

[0131] As shown in Figure 3, the mass of the blood gel remained nearly constant at concentrations of 100 μL or more of the polymer aqueous solution. In other words, it became clear that a saturation mass of blood gel exists in a given amount of blood.

[0132] Furthermore, rheological tests were performed on agglomerates obtained by adding 600 μL of a 40 mg / mL polymer (P(ATAC-adj-PEA)) aqueous solution to 1 mL of citrated blood, using an ARES-G2 rheometer (TA Instruments). A control coagulation was obtained by adding 150 μL of a 0.1 M calcium chloride (CaCl2) aqueous solution to 500 μL of citrated blood. The results are shown in Figure 4. In Figure 4, "as-prepared coagulation" shows the control coagulation, "as-prepared agglomerate" shows the blood gel formed using the polymer (P(ATAC-adj-PEA)) aqueous solution, and "60 days agglomerate" shows the blood gel stored for 60 days in physiological saline at 37°C (changed daily). The vertical axis of the graph shows shear stress (Pa), "G'" shows the storage modulus (spring elasticity), and "G''" shows the loss modulus (viscous portion). The horizontal axis represents frequency (rad / s).

[0133] As shown in Figure 4, the blood gel was found to be soft, viscoelastic, and stable over a long period of time.

[0134] [Example 3] (Injection test) An injection force test was performed using a 1 mL plastic syringe (see Figure 5A). To prevent movement of the syringe during the test, the syringe (needle size: 32 gauge (G), ID 0.26 mm) was fixed to the tester, and injections were performed at rates of 1 mL / min and 1.5 mL / min, respectively, and the injection pressure (N) was measured. In the injection needle test, 1 mL of aqueous polymer (P(ATAC-adj-PEA)) aqueous solution of different concentrations (30 mg / mL, 40 mg / mL, or 50 mg / mL) was added to the syringe and injected. A similar test was performed using physiological saline as a control. The results are shown in Figures 5B and 5C.

[0135] As shown in Figures 5B and 5C, it was confirmed that aqueous solutions of the polymer (P(ATAC-adj-PEA)) at any concentration could be smoothly injected with a relatively small force of approximately 4N to 8N.

[0136] Next, injection tests were conducted using a 1 mL plastic syringe and a microcatheter (see Figure 6A). An aqueous solution (40 mg / mL) of polymer (P(ATAC-adj-PEA)) containing tantalum powder (0.25 mg / mL) was injected from the syringe into anticoagulated blood via a 150 cm long microcatheter (ID 0.017 inches (0.43 mm)) used in clinical practice, at a rate of 1 mL / min, with a 7-second injection followed by a 3-second pause, repeated four times. The injection pressure (N) was then measured. A similar test was performed using the conventional embolic material EVOH (trade name "Onyx®" manufactured by ev3 Endovascular) as a control. The results are shown in Figure 6B.

[0137] As shown in Figure 6B, with Onyx, the injection pressure tended to increase with each infusion / pause cycle. On the other hand, with the polymer (P(ATAC-adj-PEA)) aqueous solution, it was confirmed that the injection could be smoothly administered by a microcatheter without increasing the injection pressure, even with repeated infusion / pause cycles at an injection pressure of approximately 11N or less.

[0138] [Example 4] (Towing force test) Polyethylene tubes (ID 0.28 mm, OD 0.61 mm) filled with aqueous solutions of polymer (P(ATAC-adj-PEA)) at different concentrations (30 mg / mL, 40 mg / mL, or 50 mg / mL) were passed through a thicker polyethylene tube (ID 1.4 mm, OD 1.9 mm) containing 0.1 mL of citrated blood, and the same amount of each polymer solution was injected. After standing for 30 minutes, the force (N) when the thinner polyethylene tube was withdrawn at a speed of 1.0 mm / min was measured (see Figure 7A). The same test was performed using conventional embolic material EVOH (trade name "Onyx®" manufactured by ev3 Endovascular) and physiological saline as controls. The results are shown in Figures 7B and 7C.

[0139] As shown in Figures 7B and 7C, with Onyx, a force of approximately 0.25 N was required to extract it due to fixation by adhesion. On the other hand, with the polymer (P(ATAC-adj-PEA)) aqueous solution, there was no fixation by adhesion after reaction with blood, and the extraction force was at almost the same level as with physiological saline.

[0140] [Example 5] (In vivo safety testing) Under anesthesia, a 1 cm long skin incision was made on the right dorsal side of 8-week-old male Sprague-Dawley rats to create a subcutaneous pocket. A 40 mg / mL polymer (P(ATAC-adj-PEA)) and a hydrogel disc (5 mm in diameter, 1 mm thick) of polymer (P(ATAC-adj-PEA)) were placed in the subcutaneous pocket.

[0141] The hydrogel of the polymer (P(ATAC-adj-PEA)) was prepared by the following method and then cut to the above size. First, monomers (ATAC 1.2M and PEA 1.2M) and 2-oxoglutaric acid (6 mM) as a polymerization initiator were dissolved in DMSO. Next, the mixture was poured into a reaction cell consisting of a pair of glass plates. 365 nm UV light (4 mW / cm²) was applied at 1 mm intervals inside a glove box. 2The material was irradiated at room temperature (approximately 25°C) for 11 hours to induce polymerization. After polymerization, the prepared hydrogel was immersed in a large amount of physiological saline to wash away DMSO and residual monomers, thereby obtaining the hydrogel.

[0142] Next, the incision was sutured. Rats that underwent only surgical incision were used as controls. Blood biochemical tests were performed on postoperative days 7 and 28. Serum was obtained by centrifugation of rat venous blood for testing. The concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), and blood urea nitrogen (BUN) in the serum were measured at a specialized laboratory (SRL, Icn., Tokyo, Japan). Generally, blood levels of ALT and AST are indicators of liver function, and blood levels of CREA and BUN are indicators of kidney function. The results are shown in Figure 8A.

[0143] As shown in Figure 8A, even on postoperative day 28, blood levels of ALT and AST, as well as blood levels of CREA and BUN, were similar to those of the control group, and no abnormalities were observed in liver or kidney function.

[0144] Furthermore, after euthanizing the rats on postoperative days 7 and 28, tissue sections were prepared from the areas where 40 mg / mL polymer (P(ATAC-adj-PEA)) was injected, the areas where hydrogel was implanted, and the surgically incised areas. Histological analysis (hematoxylin and eosin (H&E) staining) was also performed. The results are shown in Figure 8B. In Figure 8B, the scale bar represents 2 mm.

[0145] As shown in Figure 8B, no severe inflammatory response was observed at the transplant site after transplantation.

[0146] [Example 6] (Intravascular administration study) Under anesthesia, a 1 cm longitudinal incision was made in the forethigh of the right hind limb of an 8-week-old male Sprague-Dawley rat, exposing the femoral artery under a surgical microscope. Then, 0.1 mL of a 40 mg / mL polymer (P(ATAC-adj-PEA)) aqueous solution was injected distally into the artery using a 32-gauge needle. The incision was then closed, and the rat was allowed to recover from anesthesia. A rat injected with the same amount of saline solution served as a control. Five minutes after surgery, the skin color of the hind limb was visually observed. Surface temperature of the hind limb was also measured using thermography (Optris PI640i). The results are shown in Figure 9.

[0147] As shown in Figure 9, five minutes after the surgery, the skin color of the hind limbs changed and the surface temperature decreased, indicating that an embolism had occurred.

[0148] Five minutes after surgery, the rats were euthanized, and the right hind limb was collected. Tissue sections were prepared, and histological analysis (H&E staining for tissue observation and acid blue staining for polymer observation) was performed. The results are shown in Figure 10. In Figure 10, the scale bar is 100 μm. The arrows in the stained images represent the nuclei of leukocytes stained with hematoxylin.

[0149] As shown in Figure 10, it was confirmed that the embolic material was formed from blood components and polymers.

[0150] [Example 7] (Computed Tomography (CT) Imaging) A 40 mg / mL aqueous solution of polymer (P(ATAC-adj-PEA)) containing tantalum powder (0.25 g / mL) was prepared preoperatively and tested at different injection doses (0.1 mL or 2 μL to 3 μL). In the first test, 0.1 mL of the tantalum powder-containing polymer aqueous solution was injected into the right femoral artery of 8-week-old male Sprague-Dawley rats within 5 seconds. Forty-five minutes after injection, a CT scan of the right hind limb was taken to confirm embolus formation. The results are shown on the left side of Figure 11. In the next experiment, a tantalum powder-containing polymer aqueous solution was injected as a single shot (2 μL to 3 μL) into the right femoral artery of 8-week-old male Sprague-Dawley rats using the same procedure as above. Three hours after injection, a CT scan of the right hind limb was taken to confirm embolus formation. The results are shown on the right side of Figure 11.

[0151] The CT image on the left in Figure 11 confirms that the embolism has reached distal to the injection site. The CT image on the right side of Figure 11 confirmed embolus formation at the injection site. These results demonstrate that by appropriately adjusting the injection volume and selecting the injection site, it is possible to form embolisms at desired locations and within a desired range within the body. [Industrial applicability]

[0152] The embolizing agent of this embodiment provides an embolizing agent that has the same vascular embolizing properties as conventional embolizing agents, while also being injectable by syringe and having superior safety and stability in vivo.

Claims

1. An embolizing agent containing as an active ingredient a copolymer of a cationic functional group-containing monomer and an aromatic group-containing monomer, wherein the copolymer has at least a part of the structure represented by the following general formula (I). 【Chemistry 1】 (In general formula (I), R １１ and R １２ is a hydrogen atom, or an alkyl group having 1 to 20 carbon atoms which may have substituents, and the relational formula is R １１ = R １２ It satisfies Y １１ and Y １２ Each of these is an alkylene group having 1 to 20 carbon atoms, which may independently contain one or more single bonds or selected from the group consisting of a hydroxyl group, an ester bond, an ether bond, a sulfide group, a carbonyl group, an amide bond, and a phosphodiester bond. １１ X is an aromatic hydrocarbon group having 6 to 16 carbon atoms, which may have substituents. １１ (This is an ammonium group. n11 is an integer between 10 and 1000.)

2. In the general formula (I), the Ar １１ is a phenyl group which may have a substituent, and the plugging agent according to claim 1.

3. In the above general formula (I), the X １１ The embolic agent according to claim 1 or 2, wherein is a quaternary ammonium group.

4. In the above general formula (I), Y １１ The Y with respect to the number of carbon atoms １２ The embolic agent according to any one of claims 1 to 3, wherein the absolute value of the difference in the number of carbon atoms is 0 or more and 3 or less.

5. The embolic agent according to any one of claims 1 to 4, wherein the structure represented by the general formula (I) is the structure represented by the following general formula (I-1). 【Chemistry 2】 (In general formula (I-1), R １１１ and R １１２ is a hydrogen atom or a methyl group, and the relationship is given by: R １１１ = R １１２ It satisfies Y １１１ and Y １１２ Each of these is an alkylene group having 1 to 20 carbon atoms, which may independently contain one or more selected from the group consisting of a hydroxyl group, an ether bond, a sulfide group, and a phosphodiester bond. １１１ X is a phenyl group which may have substituents. １１１ (This is a quaternary ammonium group. n111 is an integer between 10 and 1000.)

6. The embolizing agent according to any one of claims 1 to 5, wherein the copolymer has a molar ratio of units derived from the cationic functional group-containing monomer to units derived from the aromatic group-containing monomer of 1:4 to 4:

1.

7. A vascular embolization kit comprising an embolizing agent according to any one of claims 1 to 6 and a contrast agent.

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