JPH0118052B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a cholesterol-lowering agent, and more particularly to a cholesterol-lowering agent whose main component is an anion exchange resin having an imidazolium salt as a functional group. It is already known that anion exchange resins can be used as so-called cholesterol-lowering agents to lower blood cholesterol (US Pat. No. 3,499,960, US Pat. No. 3,780,171, British Patent No. 9,29391).
No., Japanese Patent Publication No. 53-10386). The mechanism by which blood cholesterol is lowered by taking an anion exchange resin can be considered as follows. In other words, basic anion exchange resins adsorb and fix bile acids present in the intestinal tract, preventing them from being reabsorbed, and promoting the conversion of cholesterol, which is in equilibrium with bile acids, into bile acids in the liver. As a result, blood cholesterol is lowered. A typical basic anion exchange resin conventionally used as a cholesterol lowering agent is an ion exchange resin having an aliphatic quaternary ammonium salt as a functional group (U.S. Pat. No. 3,499,960,
(No. 3780171). Ion exchange resins having an aliphatic quaternary ammonium salt as a functional group are produced by reacting an aliphatic tertiary amine with a haloalkyl group introduced onto a crosslinked polymer. Ion exchange resins are haunted by the foul odor characteristic of aliphatic amines, and cannot be put to practical use as is. Therefore, in practice, the offensive odor is reduced by applying a coating to the surface of the anion exchange resin; however, the dose must be increased due to the reduction in ion exchange capacity due to the surface coating. Further, such conventional anion exchange resins have a drawback that they have a low selective adsorption ability for bile acids in the presence of inorganic ions, and also adsorb and remove useful substances such as vitamins. An object of the present invention is to provide a cholesterol-lowering agent which is free from bad odor and whose main component is a basic anion exchange resin which has a high selective adsorption capacity for bile acids. The basic ion exchange resin used as the main component of the cholesterol-lowering agent of the present invention has the following formula (a): (In the formula, Ra ₁ , Ra ₂ and Ra ₃ may be the same or different and each represents a hydrogen atom, a methyl group or an ethyl group.) More than 5 mol % of the structural unit represented by 30 mol % or less; following formula (b): (In the formula, Rb ₁ , Rb ₂ , Rb ₃ and Rb ₄ may be the same or different, and each is a hydrogen atom,
Represents a methyl group or an ethyl group. ) 0 to 50 mol% of structural units represented by; and the following formula (c): (In the formula, R ¹ represents an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 8 carbon atoms, an aralkyl group having 7 to 8 carbon atoms, or a group -CH ₂ CH(OH)CH ₂ Cl;
R ² represents a hydrogen atom, an alkyl group having 1 to 17 carbon atoms, an aryl group having 6 to 8 carbon atoms, or an aralkyl group having 7 to 8 carbon atoms; R ³ represents an alkylene group having 1 to 3 carbon atoms, or an alkylene group having 2 to 3 carbon atoms; ~3 represents an alkylene carbonyl group or a carbonyl group; R ⁴ represents a hydrogen atom, a methyl group or an ethyl group; X represents a halogen ion, a hydroxide ion or a 1/2 (sulfate ion). ) It is a water-insoluble anion exchange resin composed of 30 to 98 mol% of the structural units shown below. In the above anion exchange resin, the monomer that provides the structural unit represented by formula (a) is divinylbenzene or a derivative thereof, and the monomer that provides the structural unit represented by formula (b) is styrene or a derivative thereof. It is. The structural unit represented by formula (c) provides a functional group to the above-mentioned anion exchange resin and is a portion that plays the most important role in achieving the object of the present invention. Formula (c)
The substituents R ¹ , R ² , R ³ and X in the structural unit represented by are as defined above, but more specifically, R ¹ is methyl, ethyl, propyl, butyl,
1 carbon number such as pentyl, hexyl group, dodecyl group, etc.
-12 alkyl group; C6-8 aryl group such as phenyl, tolyl, xylyl; C7-8 aralkyl group such as benzyl, phenethyl; or group -CH ₂ CH (OH) CH ₂ Cl . R ² is a hydrogen atom; for example, methyl, ethyl,
propyl, butyl, hexyldecyl, dodecyl,
1 to 17 carbon atoms such as pentadecyl and heptadecyl groups
For example, an aryl group having 6 to 8 carbon atoms such as phenyl, tolyl, and xylyl; For example, an aralkyl group having 7 to 8 carbon atoms such as benzyl and phenethyl. R ³ is an alkylene group having 1 to 3 carbon atoms such as methylene, ethylene, and propylene; an alkylene carbonyl group having 2 to 3 carbon atoms such as methylene carbonyl and ethylene carbonyl; or a carbonyl group. X is a halogen ion such as a bromide ion or a chloride ion; a hydroxide ion; or 1/2 (sulfate ion). The polymeric substance constituting the anion exchange resin specified by these substituents is crosslinked so that the polymeric substance exhibits water insolubility. Specific examples of preferred anion exchange resins of the present invention are as follows.

[Table] Furthermore, the porosity of the anion exchange resin of the present invention is preferably such that the pore diameter is preferably 10 ² to ^{10 5} Å and the pore volume is preferably within the range of 0.2 to 2.0 cc/g. . The anion exchange resin having an imidazolium salt as a functional group of the present invention is disclosed in Japanese Patent Application Laid-Open No. 151682/1982 and Japanese Patent Application No. 1983-1989 filed by the present inventors.
Specification No. 50404 (Anion exchange resin and its manufacturing method)
(See Japanese Patent Publication No. 62-28696). That is, an anion exchange resin having an imidazolium salt as a functional group is produced by introducing imidazoles into a crosslinked polymer. The polymer is a crosslinked resin prepared in advance to have groups that react with imidazoles. Groups that react with imidazoles include haloalkyl groups, acid halogen groups, and the like. One of the methods for producing crosslinked polymers with such functional groups (sometimes referred to as functional crosslinked polymers) is
A styrenic monomer having a desired functional group (sometimes referred to as a functional monomer) together with a crosslinking monomer and, if necessary, other ethylenically unsaturated monomers,
This is a method of radical polymerization or other chain polymerization. The polymerization method itself may be any method known to those skilled in the art, and specifically, it may be carried out by emulsion polymerization, suspension polymerization, etc. using a peroxide or an azo compound as a radical polymerization initiator. Monomers having a functional group include haloalkylstyrene (the halogen is suitably chlorine, bromine or iodine, and the alkyl group is suitably C ₁ to C ₃ ), such as chloromethylstyrene, bromomethylstyrene, etc. be. The crosslinking monomer is preferably one having at least two ethylenically unsaturated bonds, and specific examples thereof include divinylbenzene, trivinylbenzene, divinyltoluene, trivinyltoluene, divinylxylene, etc. . Non-crosslinkable ethylenically unsaturated monomers that can be copolymerized with such functional monomers and crosslinkable monomers include aromatic vinyl compounds such as styrene, core or side chain methylstyrene (for example α - methylstyrene, vinyltoluene, vinylxylene), and one or more types of core or side chain ethylstyrene. The quantitative ratio of the functional monomer to the non-functional and non-crosslinkable monomer to the crosslinkable monomer is 98 to 30:0 to more than 50:5 (molar ratio), but Preferably
95 to 60:0 to more than 30:5 to 20 (molar ratio). Another method for producing a crosslinked polymer having a functional group is to use a monomer having a group convertible to the functional group instead of the functional monomer in the above method. In this case, the group that can be converted into a functional group includes a carboxylic acid ester group. After polymerization, it can be converted into an acid halogen group, which is one of the functional groups, by hydrolysis and acid halogenation. Another method for producing a functional crosslinked polymer is to prepare a crosslinked polymer having no functional groups and then subsequently introduce functional groups. For example, a chlorosulfone group can be introduced by reacting a copolymer of styrene and divinylbenzene with chlorosulfonic acid, or a chloromethyl group can be introduced by a known method. The imidazole used in method 1 of reacting with a crosslinked polymer having a functional group as described above is represented by the following general formula. (Here, R ¹ is an alkyl group having 1 to 12 carbon atoms,
represents an arylalkyl group, an aryl group having 6 to 8 carbon atoms, or an aralkyl group having 7 to 8 carbon atoms;
^R2 represents a hydrogen atom, a _C1 to _C17 alkyl group, or an aryl group having 6 to 8 carbon atoms. ) The aryl group is also usually a phenyl, tolyl or xylyl group. Specific examples of such imidazoles are as follows. That is, 1-methylimidazole, 1-ethylimidazole, 1-propylimidazole, 1,2-dimethylimidazole, 1-benzyl-2-methylimidazole, and the like. Amination reaction of a crosslinked polymer with imidazoles The reaction between a crosslinked polymer having a haloalkyl group and a 1-substituted imidazole is carried out by heating both in a solvent. The amount of both to be used is appropriately selected so that the amount of imidazole is 0.5 mol or more based on the haloalkyl group in the crosslinked polymer reacting with the imidazole. There is no limit to the reaction temperature, but
Generally, the reaction rate is higher at higher temperatures, so the temperature is preferably about 50°C or higher (the upper limit is about 200°C). Any solvent that can dissolve the given imidazole can be used as the reaction medium. Specific examples include methanol, ethanol, butanol, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, and the like. These are examples of good solvents for imidazoles, but
The solubility of these imidazoles can also be adjusted by using them in combination with a poor solvent or a non-solvent.
After the reaction is completed, the resin is separated and washed appropriately to obtain the desired resin. In addition to the above-mentioned method, the following method can also be used to introduce imidazoles into the crosslinked polymer. That is, in the above general formula of the imidazole compound, a method is used in which imidazole in which R ¹ is H is bonded to a crosslinkable polymer, and then the imidazole ring is modified with epihalohydrin to form an imidazolium salt. Alternatively, in addition to the above method, the following method may also be adopted. That is, in the above general formula of the imidazole compound, using imidazole in which R ¹ is H, after bonding this to a crosslinked polymer,
A method of preparing an imidazolium salt by adding an alkyl halide having ˜3 or an aralkyl halide having 7 to 8 carbon atoms is used. As a specific example, haloalkylstyrene
polystyrene (molecular weight 5.0 x 10 ⁴ -
1.0×10 ⁶ ) to produce a porous crosslinked polymer, and the above reaction yields an anionic resin. The obtained anion exchange resin has the following properties. Ion exchange capacity: 1.0 to 4.0 meq/g Pore volume: 0.2 to 2.0 cc/g Average pore diameter: 10 ² to 10 ⁵ Å Particle size: 50 to 325 mesh These various properties are described in Production Example 1 below. It was measured based on the method. The essential characteristics of the anion exchange resin having an imidazolium salt as a functional group of the present invention are concretely demonstrated in the following test examples. First, it has high bile acid adsorption activity (even in the presence of inorganic ions). high), second
The third useful substance (vitamin B ₁ ) is odorless.
Furthermore, adsorption of cholesterol itself is possible. Among these effects,
The first and third effects become more pronounced by making the resin matrix porous. Although the reason for selective adsorption of bile acids (in the presence of inorganic ions) and non-adsorption of vitamin _B1 by imidazolium salts is unknown, it is presumed that the resonance structure of imidazolium salts makes a major contribution. Next, the acute toxicity of the anion exchange resin of the present invention will be explained. Using ICR-JCL mice, a suspension of 1% tragacanth solution was orally administered as a dispersion medium, and the LD ₅₀ value was calculated from the mortality rate after 1 week, and the LD ₅₀ was 5.
g/Kg or more. The dose of the cholesterol-lowering drug of the present invention is 1 to 30 g per day for adults, preferably 5 to 10 g, and is usually divided into 2 to 3 doses per day. When administering the cholesterol-lowering agent of the present invention to the human body, oral administration, suppositories, etc. are used, but oral administration is most preferred. For oral administration, the drug may be suspended in water or other liquid and taken before meals. EXAMPLES The present invention will be explained in more detail by presenting production examples and test examples of the present invention below, and its effects will be clarified. Production example 1 60 g (0.40 mol) of chloromethylstyrene, 20 g (0.19 mol) of styrene, 36.4 g (0.15 mol) of divinylbenzene (purity 55%), 100 g of toluene
ml, polystyrene (average molecular weight: 1.8×10 ⁵ ) 10
A homogeneous mixed solution consisting of 0.5 g of azobisisobutyronitrile and 3 g of sodium chloride and 2.4 g of polyvinylpyrrolidone (average molecular weight: 3.6×10 ⁴ )
g, and 0.3 g of sodium pyrophosphate were introduced into an aqueous solution of 300 ml of water. The system was sufficiently stirred to uniformly disperse the monomer phase, and the reaction was carried out by heating at 80° C. for 7 hours while introducing nitrogen gas.
After separating the generated copolymer particles and washing with water,
Excess solvent and water were removed by heating and the mixture was dried. Next, about 5 times the amount of toluene was added to the obtained dry copolymer, and the mixture was stirred at room temperature for 4 hours.
Polystyrene was further extracted by stirring at 80°C for 7 hours. The obtained copolymer was separated, washed with toluene, and then heated and dried. The produced copolymer was white, opaque, and perfectly spherical, and the yield was 111 g. Next, 50 g of the above copolymer was placed in a flask equipped with a stirrer and a reflux condenser together with 28.3 g of 1,2-dimethylimidazole and 200 ml of ethanol, and heated at 80° C. for 8 hours. After the reaction,
The solid obtained by filtration was washed with ethanol. Next, drying was performed by heating, and the obtained solid was pulverized with a ball mill. The obtained anion exchange resin (abbreviated as CR-1) had the following properties. Ion exchange capacity: 2.0 meq/g Pore volume: 0.345 cc/g Average pore diameter: 7 x ~ ^{10 3} Å Particle size: 200 ~ 325 mesh The above properties were determined by the method shown below. It is something. Ion exchange capacity: The value of the total exchange capacity expressed as the sum of the neutral salt decomposition capacity and the medium weak base capacity. A Neutral salt decomposition ability: Take about 3g of resin and 1.0N-
After soaking in 100 ml of NaOH solution for 5 hours, wash with water until neutral. After drying under reduced pressure, dry resin 2~
Accurately weigh 3g (this weight is Ag) and add
Add 100 ml of 0.5N NaCl solution, stir for 4 hours, and leave overnight. After suctioning, drain the liquid.
Titrate with 0.1N-HCl solution (the amount of 0.1N-HCl solution required for titration at this time is Bml).
The neutral salt resolution ability is determined by the following formula. Neutral salt resolution (meq/g) = B x (Titer of HCl solution) / 10A (b) Medium weak base capacity: Remove the resin remaining on the funnel.
Pour into 100 ml of 0.2N-HCl solution and leave overnight, then take 10 ml of the supernatant and titrate with 0.1N-NaOH solution (the amount of 0.1N-NaOH solution required at this time is defined as Cml). Furthermore, the above 0.2N-HCl solution
After taking 10 ml and titrating it with 0.1N-NaOH solution (the amount of 0.1N-NaOH solution required at this time is Dml), determine the medium weak base capacity using the following formula. Medium weak base capacity (meq/g) = (D-C) x (potency of NaOH solution)/A Pore volume, average pore diameter: Mercury Pressure Porosimeter (Mercury manufactured by CARLO ERBA) Measure the resin in a dry state using a Pressure Porosimeter, calculate the pore volume from the amount of mercury injected into the micropores, and calculate the pore diameter from the following formula.
The pore diameter attributable to the highest pore volume was taken as the average pore diameter. d=150000/p (In the formula, p represents pressure (Kg/cm ² ) and d represents pore diameter (Å).) The characteristics of the anion exchange resin obtained in the production example shown below are also as described above. It was determined by the measurement method. Production Example 2 85 g (0.56 mol) of chloromethylstyrene, 27.3 g (0.12 mol) of divinylbenzene (purity 55%), 100 ml of toluene, 10 g (5.6 x 10 -6 ^mol ) of polystyrene (average molecular weight: 1.8 x 10 ^-6 mol), and azo A homogeneous mixture of 0.5 g of bisisobutyronitrile was introduced into an aqueous solution containing 3 g of sodium chloride, 2.4 g of polyvinylpyrrolidone (average molecular weight: 3.6×10 ⁵ ), and 0.3 g of sodium pyrophosphate dissolved in 300 ml of water. Stir the system thoroughly to uniformly disperse the monomer phase, and heat to 80°C while introducing nitrogen gas.
The mixture was heated for 7 hours to carry out the reaction. The produced copolymer particles were separated, washed with water, and then heated to remove excess solvent and water and dried. Next, about 5 times the amount of toluene was added to the obtained dry copolymer, stirred at room temperature for 4 hours, and then heated to 80°C.
The mixture was stirred for 7 hours to extract polystyrene. The obtained copolymer was separated, washed with toluene, and then heated and dried. The copolymer produced is white, opaque, and perfectly spherical, with a yield of 98%.
It was hot at g. Next, add 50 g of the above copolymer to 28.4 g of imidazole.
g, 11.2 g of caustic soda, 100 g of toluene, and 100 g of ethanol were placed in a flask equipped with a stirrer and a reflux condenser, and heated at 80° C. for 6 hours. After filtering the reaction mixture, the obtained solid was washed with water and dried under reduced pressure. (The crosslinked copolymer thus obtained is referred to as intermediate polymer A.) Next, 50 g of the above intermediate polymer A was mixed with 12.5 g of epichlorohydrin, 100 g of toluene, and ethanol.
Together with 100 g, the mixture was placed in a flask equipped with a stirrer and a reflux condenser, and heated at 80° C. for 10 hours. After the reaction mixture was filtered, the obtained solid was washed with methanol, then sequentially with a 3% caustic soda solution and a 3% hydrochloric acid solution, and finally thoroughly washed with water. After washing, the obtained solid was dried by heating and ground in a ball mill. The obtained anion exchange resin (abbreviated as CR-2) had the following characteristics. Ion exchange capacity: 2.9meq/g Pore volume: 0.302cc/g Average pore diameter: 2×10 ⁴ Å Particle size: 200-325 Mesh Production Example 3 Production Example 1 except that 15g of polystyrene was used
), 50 g of the copolymer obtained in the same manner as 1-
50.8 g of benzyl-2-methylimidazole and 200 ml of ethanol were placed in a flask equipped with a stirrer and a reflux condenser, and heated at 80° C. for 8 hours. After the reaction, filtration was performed, and the obtained solid was washed with ethanol, dried by heating, and then ground in a ball mill. The obtained anion exchange resin (abbreviated as CR-3) had the following properties. Ion exchange capacity: 2.2meq/g Pore volume: 0.430cc/g Average pore diameter: 2×10 ⁴ Å Particle size: 200-325 Mesh production example 4 Chloromethylstyrene 90g (0.59 mol), divinylbenzene (purity 55 %), 18.2 g (0.08 mol), 100 ml of toluene, 10 g of polystyrene (average molecular weight 1.8 x 10 ⁵ ), and 0.5 g of azobisisobutyronitrile was mixed with 3.0 g of sodium chloride, polyvinylpyrrolidone (average molecular weight 3.6 x 10 ⁵ ) and 0.3 g of anhydrous sodium pyrophosphate were introduced into an aqueous solution in which a polymerization reaction was carried out in the same manner as in Production Examples 1 and 2, followed by further post-treatment. The produced copolymer was white, opaque, and spherical, and the yield was 108 g. Next, 50 g of the above copolymer was mixed with 42.5 g of 1,2-dimethylimidazole and 200 ml of ethanol.
The mixture was placed in a flask equipped with a stirrer and a reflux condenser, and heated at 80°C for 8 hours. After the reaction, filtration was performed, and the obtained solid was washed with ethanol, dried, and pulverized. The obtained anion exchange resin (abbreviated as CR-4) had the following properties. Ion exchange capacity: 3.1meq/g Pore volume: 0.679cc/g Average pore diameter: 7×10 ⁴ Å Particle size: 200-325 Mesh production example 5 Chloromethylstyrene 80g (0.53 mol), divinylbenzene (purity 55 %), 100 ml of toluene, 10 g of polystyrene (average molecular weight: 1.8 x 10 ⁵ ), and 0.5 g of azobisisobutyronitrile was mixed with 3.0 g of sodium chloride and polyvinylpyrrolidone (average molecular weight: 3.6). ×10 ⁵ ) 2.4 g and 0.3 g of anhydrous sodium pyrophosphate were introduced into an aqueous solution dissolved in water,
A polymerization reaction was carried out in the same manner as in Production Example 1. The produced copolymer was white, opaque, and spherical, and the yield was 110 g. Next, 50 g of the above copolymer was placed in a flask equipped with a stirrer and a reflux condenser, along with 32.2 g of 1-methylimidazole and 200 ml of ethanol.
Heating was carried out at ℃ for 8 hours. After the reaction, the solid obtained by filtration was washed with ethanol, dried and pulverized. The obtained anion exchange resin (abbreviated as CR-5) had the following properties. Ion exchange capacity: 2.5meq/g Pore volume: 0.378cc/g Average pore diameter: 1.1×10 ⁴ Å Particle size: 200-325 Mesh Production Example 6 Copolymer obtained in Production Example 5) 50g, 1-ethylimidazole 37.3g, ethanol 200g
ml into a flask equipped with a stirrer and a reflux condenser, and heated at 80°C for 8 hours. After the reaction,
The solid obtained by filtration was washed with ethanol, dried, and then ground. The obtained anion exchange resin (abbreviated as CR-6) had the following properties. Ion exchange capacity: 2.2meq/g Pore volume: 0.378cc/g Average pore diameter: 1.1×10 ⁴ Å Particle size: 200-325 Mesh Production Example 7 Copolymer obtained in Production Example 5) 50g, 1-propylimidazole 43.2g, ethanol
The mixture was placed in a flask equipped with a stirrer and a reflux condenser along with 200 ml of the solution, and heated at 80°C for 8 hours. After the reaction, the solid obtained by filtration was washed with ethanol, dried and pulverized. The obtained anion exchange resin (abbreviated as CR-7) had the following properties. Ion exchange capacity: 2.0 meq/g Pore volume: 0.378 cc/g Average pore diameter: 1.1×10 ⁴ Å Particle size: 200 to 325 Mesh production example 8 Except for using polystyrene with a molecular weight of 6.0×10 ⁵ The copolymer obtained in the same manner as in Example 1-) was reacted and post-treated in the same manner as in Production Example 1-). The obtained anion exchange resin (abbreviated as CR-8) had the following properties. Ion exchange capacity: 2.0meq/g Pore volume: 0.420cc/g Average pore diameter: 5×10 ⁴ Å Particle size: 200-325 Mesh Production Example 9 Copolymer obtained in Production Example 1) 10 g was placed in a flask equipped with a stirrer and a reflux condenser together with 21.7 g of 1-dodecyl-2-ethyl-4-methylimidazole and 40 ml of ethanol, and heated at 80° C. for 8 hours. After the reaction, the solid obtained by filtration was washed with ethanol. Next, drying was performed by heating, and the obtained solid was pulverized with a ball mill. The obtained anion exchange resin (abbreviated as CR-9) had the following properties. Ion exchange capacity: 1.3 meq/g Pore volume: 0.345 cc/g Average pore diameter: 7×10 ³ Å Particle size: 200-325 Mesh Production Example 10 Copolymer obtained in Production Example 1) 3g to 5.5g of 1-ethyl-2-undecylimidazole
and 40 ml of ethanol were placed in a flask equipped with a stirrer and a reflux condenser, and heated at 80° C. for 12 hours. After the reaction, the solid obtained by filtration was washed with ethanol. Next, heat drying is performed,
The resulting solid was ground in a ball mill. The obtained anion exchange resin (abbreviated as CR-10) had the following properties. Ion exchange capacity: 1.4meq/g Pore volume: 0.345cc/g Average pore diameter: 7×10 ³ Å Particle size: 200-325 Mesh Production Example 11 Copolymer obtained in Production Example 1) 10g
was placed in a flask equipped with a stirrer and a reflux condenser together with 11.2 g of 2-phenylimidazole, 20 ml of ethanol, 20 ml of toluene, and 1.6 g of caustic soda, and heated at 80° C. for 6 hours. After the reaction,
The solid obtained by filtration was washed with water and further washed with ethanol. Then, it was dried by heating. The obtained copolymer is referred to as intermediate polymer C. 10 g of intermediate copolymer C and 2.1 g of epichlorohydrin
g, together with 20 ml of toluene and 20 ml of ethanol, in a flask equipped with a stirrer and a reflux condenser;
Heating was performed at 80°C for 12 hours. After the reaction, the reaction mixture was filtered and washed with methanol, followed by successive washing with a 3% aqueous solution of caustic soda and a 3% aqueous hydrochloric acid solution, and finally with water. Next, the solid obtained by heating and drying was pulverized with a ball mill. The obtained anion exchange resin (abbreviated as CR-11) had the following properties. Ion exchange capacity: 1.6meq/g Pore volume: 0.345cc/g Average pore diameter: 7×10 ³ Å Particle size: 200-325 Mesh Production Example 12 Copolymer obtained in Production Example 1) 10g
was placed in a flask equipped with a stirrer and a reflux condenser with 5.37 g of imidazole, 20 ml of ethanol, 20 ml of toluene, and 1.6 g of caustic soda, and heated at 80°C for 6 hours.
Heating was carried out for a period of time. The solid obtained by filtration was washed with water and ethanol. Then, the copolymer obtained by heating and drying is designated as intermediate polymer D. 10 g of Intermediate Polymer D was placed in a flask equipped with a stirrer and a reflux condenser together with 12.6 g of ethyl iodide, 20 ml of toluene, and 20 ml of ethanol, and heated at 80° C. for 12 hours. After the reaction, it was filtered and washed with methanol, and further washed successively with a 3% aqueous sodium hydroxide solution and a 3% aqueous hydrochloric acid solution, and finally with water.
Next, the solid obtained by heating and drying was pulverized with a ball mill. The obtained anion exchange resin (abbreviated as CR-12) had the following properties. Ion exchange capacity: 1.4 meq/g Pore volume: 0.345 cc/g Average pore diameter: 7 x 10 ³ Å Particle size: 200-325 mesh Test example 1 In vitro test 1 Sodium cholate with various anion exchange resins In vitro adsorption test of 0.43 concentration prepared using artificial intestinal fluid (described in the 9th revised Japanese Pharmacopoeia, PH: 7.4) in an Erlenmeyer flask.
50 ml of mg/ml sodium bile acid solution was added, and 50 mg each of CR-1 to CR-12 and cholestyramine were added thereto. After incubation at 37°C for 24 hours, centrifugation was performed to collect the supernatant, and residual sodium cholate was removed using an enzymatic reaction method [using a reagent for measuring bile acid concentration manufactured by Daiichi Kagaku Co., Ltd. (sterognost-3α kit)]. Quantitated. Table of results-1
It was shown to. Table 1 Percentage of bound bile salts (%) Cholestyramine 22 CR-1 48 CR-2 43 CR-3 45 CR-4 42 CR-5 42 CR-6 40 CR-7 39 CR-8 41 CR-9 31 CR-10 35 CR-11 30 CR-12 34 From the results shown in Table-1, anion exchange resin CR
-1, CR-2, CR-3, CR-4, CR-5,
It is clear that CR-6, CR-7 and CR-8 adsorb large amounts of sodium bile acids in artificial intestinal fluid. 2. In vitro adsorption test of sodium cholate when changing the buffer concentration and type of buffer.Pour 30 ml of sodium bile acid solution with a concentration of 0.43 mg/ml prepared using each buffer into an Erlenmeyer flask. Furthermore, 30 mg of each resin was added, and an adsorption test was conducted using the method described in 1) to quantify the residual sodium bile acid. The results are shown in Table-2.

[Table] Phosphate buffer: using potassium dihydrogen phosphate Carbonate buffer: using sodium hydrogen carbonate From the results shown in Table 2, the anion exchange resins CR-1 and CR-2 of the present invention are Among them, the concentration dependence of the decrease in adsorption rate is small, and it also has a high ability to adsorb sodium bile acid even in carbonate buffer. That is, the anion exchange resin of the present invention can selectively adsorb bile acids even in the presence of various inorganic ions. This suggests that the anion exchange resin of the present invention is extremely useful in the intestinal tract where various inorganic ions are present. 3 In-vitro adsorption test of sodium cholate when changing the PH Place 30 ml of a sodium cholate solution with a concentration of 0.43 mg/ml prepared using phosphate buffer solutions with various PH values in an Erlenmeyer flask, and then An adsorption test was carried out using the method described in 1) by adding 30 mg of the resin, and the residual sodium bile acid was quantified. The results are shown in Table 3.

[Table] Phosphate buffer: Add sodium hydrogen phosphate in the amount listed in Table 3,
Thereafter, the pH was adjusted with hydrochloric acid or caustic soda. As a result, the anion exchange resin of the present invention has a high adsorption capacity for sodium bile acid under conditions considered to be close to in vivo conditions (in the intestinal tract), that is, at a buffer concentration of 0.25M and a pH of 6 to 8. it is obvious. 4. In vitro adsorption test of sodium bile acid with varying amounts of anion exchange resin. 30 ml of a sodium bile acid solution with a concentration of 0.43 mg/ml prepared using a phosphate buffer (PH 7.5) was placed in an Erlenmeyer flask, and various weights of anion exchange resin were added thereto. An adsorption test was carried out by the method of 1), and the residual sodium bile acid was quantified. The results are shown in Table-4.

[Table] From the results in Table 4, it can be seen that the anion exchange resin of the present invention has excellent adsorption activity. 5 In vitro adsorption test of sodium cholate with varying bile acid concentrations. Concentrations of 0.43, 1.29, and 2.15 were prepared using phosphate buffer (PH7.5) in Erlenmeyer flasks, respectively.
30 ml of mg/ml sodium bile acid solution was added, and 30 mg of each resin was added thereto. An adsorption test was carried out using the method described in 1), and the residual sodium bile acid was quantified. The results are shown in Table-5. The amount of sodium bile acid adsorbed in the table is expressed in mg.

[Table] From the results in Table 5, it can be seen that the anion exchange resin of the present invention has high adsorption activity even under aqueous sodium bile acid solutions of various concentrations. 6. In vitro adsorption test of cholesterol using various anion exchange resins In a test tube, put 2 ml of a cholesterol solution with a concentration of 2 mg/ml dissolved in dimethylformamide and 1 ml of a buffer solution (hydrochloric acid-trisaminomethane, PH8.0), and Add 20mg of resin. After shaking at room temperature for 30 minutes, the mixture was centrifuged and 2 ml of supernatant was collected. Add 4 ml of chloroform-methanol (2:1) solution to this, shake for 20 minutes, centrifuge, and remove the supernatant.
Residual cholesterol was quantified by ultraviolet absorption method (UV method) [using Cholesterol Test Wako Kitsu (manufactured by Wako Pure Chemical Industries, Ltd.]). The results are shown in Table-6.

[Table] From the results in Table 6, it can be seen that the anion exchange resin of the present invention has cholesterol adsorption ability. 7 Vitamin _B1 by various anion exchange resins
In vitro adsorption test of vitamin B ₁ at a concentration of 0.34 mg/ml in an Erlenmeyer flask.
30 ml of hydrochloride aqueous solution (PH7.5) was added, and 30 mg of various anion exchange resins were added. 37℃,
After incubation for 6 hours, the supernatant was collected by centrifugation, and the remaining amount of vitamin B ₁ was determined by UV method (λ268 nm). The results are shown in Table-7.

[Table] The results show that the adsorption of vitamin B ₁ by the anion exchange resin of the present invention is small. Test Example 2 In Vivo Test Using Mice Male ICR-JOL mice weighing approximately 18 g were used in groups of 5 mice. In the first group of mice, 1% cholesterol was added to the mouse powder sample made by CLEA Japan.
10g of body weight per day mixed with 0.5% ox bile powder
Mice in the second, third, and fourth groups were further given CR-1, CR-2, and cholestyramine resin. The amount of resin used was 2.5%.
Seven days after high cholesterol diet and drug administration,
Blood was collected from the fundus vein of mice, and the total cholesterol amount in the centrifuged plasma was quantified. Display the results.
8.

[Table] From these data, it is clear that the anion exchange resin of the present invention has a cholesterol-lowering effect in vivo. Test Example 3 In vivo test using rabbits Male New Zealand rabbits weighing 2.2 kg were used in groups of 5 to 7 rabbits. The rabbits in the first group were given 40 g/kg of 0.67% cholesterol per day in Oriental feed, and the rabbits in the second and third groups were further given CR-1 and cholestyramine resin.
The amount of resin used was 0.5%. Blood was collected from the auricular vein of the rabbits 7 and 14 days after the high-cholesterol diet and drug administration, and the total cholesterol amount in the centrifuged plasma was measured using a Wako test kit. The results are shown in Table-9. From these data, it is clear that the anion exchange resin of the present invention has a cholesterol-lowering effect in vivo.

【table】

Claims (1)

[Claims] Primary formula (a): (In the formula, Ra ₁ , Ra ₂ and Ra ₃ may be the same or different and each represents a hydrogen atom, a methyl group or an ethyl group.) More than 5 mol% of the structural unit represented by 30 mol% or less; following formula (b): (In the formula, Rb ₁ , Rb ₂ , Rb ₃ and Rb ₄ may be the same or different, and each is a hydrogen atom,
Represents a methyl group or an ethyl group. ) 0 to 50 mol% of structural units represented by; and the following formula (c): (In the formula, R ¹ represents an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 8 carbon atoms, an aralkyl group having 7 to 8 carbon atoms, or a group -CH ₂ CH(OH)CH ₂ Cl;
R ² represents a hydrogen atom, an alkyl group having 1 to 17 carbon atoms, an aryl group having 6 to 8 carbon atoms, or an aralkyl group having 7 to 8 carbon atoms; R ³ represents an alkylene group having 1 to 3 carbon atoms, or an alkylene group having 2 to 3 carbon atoms; ~3 represents an alkylene carbonyl group or a carbonyl group; R ⁴ represents a hydrogen atom, a methyl group or an ethyl group; X represents a halogen ion, a hydroxide ion or a 1/2 (sulfate ion). ) A cholesterol-lowering agent whose main component is a water-insoluble anion exchange resin composed of 30 to 98 mol% of structural units represented by the following.