JP2005139414A - Phosphoric acid adsorbent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a phosphoric acid adsorbent composed of a resin capable of adsorption of phosphoric acid, and a method for phosphoric acid adsorption. <P>SOLUTION: The phosphoric acid adsorbent is composed of a resin shown by general formula [I]. The resin is composed of an anion exchange resin and a chelate resin shown by formulae [VI] and [VII]. The anion exchange resin is capable of adsorption of oxalic acid in addition to phosphoric acid. While the chelate resin also can adsorb lanthanum and aluminum ions. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a phosphoric acid adsorbent, and more particularly to a phosphoric acid adsorbent comprising a resin, a phosphoric acid adsorbing resin using the same, and a phosphoric acid adsorbing method. In addition to phosphate adsorption, this invention can also remove lanthanum ions and oxalic acid in blood.

At present, the number of patients with chronic renal insufficiency in Japan is just over 200,000, and there is concern that the number of patients will increase rapidly as the population ages.
In addition to hemodialysis, treatment of chronic renal failure includes symptomatic treatment with drugs such as antihypertensives, diuretics or erythropoietin, and diet therapy with a low protein diet. Among these, hemodialysis therapy can enable long-term survival of many patients with chronic renal failure, but it must be continued for the rest of the life unless renal transfer is performed. It is a great burden both mentally and physically.

In patients with chronic renal failure, in addition to the accumulation of urea, ammonia, etc., hyperphosphatemia has been observed, and it is possible to suppress the progression of chronic renal failure by adsorbing and removing phosphate. It has been reported that this can be done (Non-patent Document 1).
Therefore, for patients with chronic renal failure, if these toxic substances are removed to improve uremia symptoms and renal osteodystrophy, and the progression of chronic renal failure can be delayed, it will be a great saving. Therefore, oral adsorbents that can adsorb these harmful substances in the digestive tract and excrete them into feces and urine are expected to be used as active drug therapy for diseases such as chronic renal failure. (Patent Document 1). Such oral phosphate adsorbents have been reported to develop hyperphosphatemia even in patients with hypoparathyroidism, and thus are expected to be developed as in the case of chronic renal failure.

  So far, oral phosphate adsorbents such as aluminum hydroxide, calcium carbonate, magnesium carbonate and their analogs have been clinically applied. However, these drugs may accumulate and cause side effects after long-term administration. It has been reported. Accordingly, there is an urgent need to develop an oral adsorbent of phosphoric acid that does not cause or hardly causes side effects even when administered for a long period of time.

  Iron chitosan complexes and acetylated iron chitosan complexes developed as such phosphate adsorbents are known to exhibit high adsorption capacity for phosphoric acid, but cause elution of iron in acidic solutions, resulting in phosphoric acid. It is known that the adsorptive capacity is reduced (Patent Document 2, Non-Patent Document 2).

  On the other hand, as a method for treating liver dysfunction such as liver failure, an anion exchange resin or anion exchange fiber is used as an adsorbent to adsorb and remove harmful polymer materials and protein binding substances such as albumin-bound bilirubin. A blood or plasma perfusion method to be used has been proposed (Patent Documents 3 and 4). However, these adsorbents do not have large adsorbing capacity, are not sufficient for adsorbing bilirubin, and adsorbing albumin, a useful plasma protein, is not sufficient for the treatment of liver failure. There is a need for an adsorbent that does not.

  In order to meet such a demand, an anion exchange resin having a coating layer made of a hydrophilic acrylate-based or methacrylate-based polymer or a polymerizable monomer having an epoxy group is used as a copolymerization component in an amount of 0.1 An adsorbent for purifying blood or plasma made of an anion exchange resin having a coating layer made of a hydrophilic acrylate or methacrylate polymer containing 10 to 10% by weight has been proposed (Patent Document 5).

  A phosphorus adsorbent using a cross-linked anion exchange resin or a salt thereof has also been proposed (Patent Document 6). The crosslinked anion exchange resin can react with the amino group and / or imino group of the polymer (A) in a polymer (A) having two or more amino groups and / or imino groups in total in one molecule. It is obtained by reacting a compound (B) having two or more functional groups, and has a water absorption ratio of 4.0 times or less.

Furthermore, a phosphorus-binding polymer with a general name of sevelamer hydrochloride is commercially available as a therapeutic agent for oral hyperphosphatemia. The generic name sevelamer hydrochloride is a hydrochloride salt of a polymer of prop-2-en-1-amine and 1-chloro-2,3-epoxypropane. This treatment for oral hyperphosphatemia is a treatment for hyperphosphatemia that does not contain any aluminum or calcium. It binds to phosphate ions released from food in the digestive tract and is excreted as it is without being absorbed. In addition, absorption of phosphorus outside the body can be suppressed. However, it has been reported that this therapeutic agent for oral hyperphosphatemia also has some side effects. Therefore, there is a strong demand for the development of a therapeutic agent for oral hyperphosphatemia with fewer side effects.
Japanese Patent Laid-Open No. 7-2903 Japanese Patent Laid-Open No. 3-182259 Japanese Patent Laid-Open No. 54-135497 JP-A-55-106165 JP-A-2-77266 WO 01/66607 Kidney International, 29, p658 (1986); Am. JP Physiol. 254, p. F267 (1988) Chemistry Express, 7, p93 (1992); Bull. Chem. Soc. Jpn. , 65, p 1866 (1992)

In order to meet such demands, the present inventor has conducted extensive research and studies, and as a result, an anion exchange resin comprising a hydrophilic acrylate or methacrylate polymer is useful as a phosphorous adsorbent with few side effects and high phosphate absorption capacity. The present invention was completed by finding something.
Furthermore, as a result of continuing research, it was found that this phosphorus adsorbent can also adsorb lanthanum ions and calcium oxalate which causes urinary calculi. Accordingly, the present invention further includes a phosphorus adsorbent that can also adsorb lanthanum ions and / or calcium oxalate.

Accordingly, an object of the present invention is to provide a resin that can be used as a phosphorus adsorbent with few side effects and high phosphorus absorption ability.
Another object of the present invention is to provide a phosphorus adsorption method and a phosphorus removal method using such a phosphorus adsorbent.
Furthermore, an object of the present invention is to provide a phosphorus adsorbent capable of adsorbing lanthanum ions and / or calcium oxalate, and an adsorption method and removal method thereof.

In order to achieve the above object, the present invention provides a resin having a phosphorus adsorption capacity or a lanthanum ion and / or a calcium oxalate adsorption capacity, and a phosphorus adsorption resin. As a preferred embodiment of the present invention, a resin comprising an anion exchange resin or a chelate resin is provided.
In another aspect of the present invention, a phosphorus adsorption method and a phosphorus removal method comprising adsorbing phosphorus or adsorbing lanthanum ions and / or calcium oxalate using the resin or the phosphorus adsorption resin. Provide a method.

The resin according to the present invention has the general formula [I]:

{In the formula, Z represents the general formula [II]:

[Wherein Y1 represents a biridyl group or a general formula [III]:
ANR1R2R3 [III]
(In the formula, A means a single bond, a carbonyl group, an alkylene group having 1 to 8 carbon atoms, an arylene group or an aralkylene group;
R1, R2 and R3 all represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, and when bonded to a nitrogen atom (N) to form a quaternary ammonium group May have a counter ion, but R1, R2, and R3 are not simultaneously hydrogen atoms)
Means a nitrogen-containing group represented by
A substituted methylene group represented by

（式中、Ｙ２は一般式［ＩＩＩ］と同じ意味を有する）
で表されるフェニル置換エチレン基、または一般式［Ｖ］：Formula [IV]:

(Wherein Y2 has the same meaning as in general formula [III])
Or a phenyl-substituted ethylene group represented by the general formula [V]:

(Wherein R4 means an alkyl group having 1 to 4 carbon atoms)
A pyridyl-substituted ethylene group represented by:
x and y mean a ratio of 0.1: 99.9 to 15:85 (x: y ratio). }
Or the formula [VI]:

で表される。

It is represented by

で表されるキレート樹脂も更に包含される。In addition, the resin of the present invention includes the formula [VII]:

The chelate resin represented by these is further included.

In the above general formula, the pyridyl group may have a lower alkyl group such as a methyl group and a substituent such as a hydroxyl group.
In the above general formula, an alkyl group having up to 4 carbon atoms means a linear or branched monovalent lower aliphatic hydrocarbon, such as a methyl group, an ethyl group, a propyl group, or a butyl group. And an isopropyl group. Among these alkyl groups, the substituted alkyl group may have a substituent such as a hydroxyl group, and examples of the substituted alkyl group include a hydroxymethyl group and a hydroxyethyl group.

  In the above general formula, the aryl group means a monovalent aromatic hydrocarbon, and examples thereof include a phenyl group. The aralkyl group means an alkyl group having up to 8 carbon atoms means a linear or branched divalent aliphatic hydrocarbon to which the aryl group is bonded. For example, a methylene group, an ethylene group And a propylene group.

（式中、ｎは１ないし５の整数を意味する。）More specifically, examples of the group represented by the general formula [II] include the groups shown below.

(In the formula, n means an integer of 1 to 5.)

  The hydrophilic acrylate or methacrylate polymer used in the present invention can be obtained by copolymerizing a hydrophilic acrylate or methacrylate monomer. Examples of such acrylate monomers include hydroxy-substituted or alkoxy-substituted acrylates such as hydroxyalkyl acrylates and alkoxyalkyl acrylates, amino-substituted and alkylamino-substituted acrylates such as amino acrylates and alkylamino acrylates, and the like. (Alkylene glycol) acrylates can be mentioned. Such hydrophilic methacrylate monomers include, for example, hydroxy-substituted or alkoxy-substituted methacrylates such as hydroxyalkyl methacrylates and alkoxyalkyl methacrylates, amino-substituted or alkylamino-substituted such as amino methacrylates and alkylamino methacrylates. Examples include methacrylates and poly (alkylene glycol) methacrylates.

The resin according to the present invention can be obtained by copolymerizing the acrylate or methacrylate monomer with a compound having a molecule represented by the general formula [III], [IV] or [V]. This copolymerization can be performed by a method known to those skilled in the art such as the method described in Patent Document 1, for example.
In the resin according to the present invention, the ratio (x) of the acrylate or methacrylate component and the ratio (y) of the molecular component represented by the general formula [VIII] are 0.1: 99.9 to 15:85 (x: y ratio), preferably 2:98 to 12:88, more preferably 5:95 to 10:90, particularly preferably 7:98 to 9:91, more specifically 8:92. It is good to make it a ratio.

  Among the resins according to the present invention, the chelate resin represented by the above general formula [VI] or [VII] can be produced by a known method described in the literature (Tohoku Industrial Technology Laboratory). Document No. 1, March 1986; JP-A-59-30802; JP-A-59-47205; JP-A-59-179606).

  The present invention will be described in more detail with reference to examples. However, the following examples are described only to explain the present invention more specifically and exemplarily, and the present invention is limited in any sense. It is not a thing.

Preparation of ethylene glycol dimethacrylate cross-linked 3-amino-2-hydroxypropyl metaallylate (EGDMA cross-linked AHPMA polymer)

(reagent)
Glycidyl methacrylate (GMA, Wako Pure Chemicals, grade 1) was subjected to a polymerization reaction after distillation under reduced pressure (6 mmHg, 76 ° C.). Ethylene glycol dimethacrylate (EGDMA, manufactured by Wako Pure Chemicals, grade 1) was subjected to a polymerization reaction after removing the polymerization inhibitor with a 10% sodium hydroxide solution. Purified GMA and EGDMA were purged with nitrogen and stored in a refrigerator until use. Azobisisobutyronitrile (AIBN, manufactured by Wako Pure Chemicals, special grade) was used without purification.
A 50% aqueous solution of 1% by weight hydroxyethyl cellulose (made by Tokyo Chemical Industry, 4500-6000 cps) and 6 g of sodium sulfate (manufactured by Nacalai Tesque, special grade) were mixed at the time of use to make a total amount of 500 mL with deionized water. A dispersion medium was used. As other reagents, commercially available special grade or first grade products were used.

(Synthesis of EGDMA cross-linked GMA polymer)
500 mL of a dispersion medium was placed in a 1000 mL separable round bottom flask equipped with a thermometer, a stirrer, a Dimroth, and a nitrogen introduction tube. As the stirring blades, two Teflon blades (blade diameter 80 mm) were used.
After stirring for about 10 minutes at 400 min ⁻¹ under a nitrogen stream, the stirring speed was lowered to 250 min ⁻¹ , and the monomer mixed solution shown in Table 1 below in which 100 mg of AIBN was dissolved was poured into the dispersion medium.

  After confirming that the spherical monomer phase was well dispersed under an optical microscope, the contents were heated to 50 ° C. over about 1 hour and allowed to react for 2 hours. Further, the contents were heated to 80 ° C. over about 30 minutes and reacted for 1 hour. After completion of the reaction, the polymer obtained was filtered off with suction and washed three times with hot deionized water. The obtained polymer was washed with methanol and then placed in a desiccator for 12 hours at 60 ° C. and dried overnight under reduced pressure.

(Amine addition reaction to EGDMA cross-linked GMA polymer)
30 mL of ethanol was put into a pressure-resistant reaction vessel with a capacity of 200 mL sufficiently cooled in a dry ice-acetone bath, and ammonia gas was injected for about 20 minutes. 10 g of the polymer obtained above was put in a pressure vessel, shaken well, and then reacted in a water bath at 60 ° C. for 10 hours. After cooling and opening in a dry ice-acetone bath, the contents were transferred into deionized water and left in a fume hood until unreacted ammonia evaporated. The obtained polymer was transferred to a glass column tube and washed with a deionized water-methanol (1: 1) mixture until the pH of the effluent reached 6-7. After washing with methanol, it was placed in a desiccator for 12 hours at 60 ° C. and dried under reduced pressure for about 12 hours.

(Derivation of EGDMA cross-linked AHPMA polymer to hydrochloride)
Elemental analysis of the free base form EGDMA crosslinked AHPMA polymer obtained above was performed and the nitrogen content was measured. About 5 g of the polymer was put into a beaker with a capacity of 100 mL, and deionized water was added to swell sufficiently, and then 1N hydrochloric acid in an amount corresponding to 40 mol% of the polymer nitrogen content was dropped while stirring with a glass rod (5% EGDMA). 1N hydrochloric acid 7.02 mL for 4.80 g of crosslinked AHPMA polymer, 7.30 mL of 1N hydrochloric acid for 4.99 g of 10% EGDMA crosslinked AHPMA polymer). After standing at room temperature for about 12 hours, it was confirmed that the pH of the suspension supernatant was 5-6, and when 0.1 mol / L silver nitrate was added dropwise to the supernatant, it did not become cloudy.
Next, the polymer was transferred to a glass column tube, thoroughly washed with methanol, then suction filtered using a Buchner funnel, and washed with methanol. Thereafter, it was placed in a desiccator for 12 hours at 60 ° C. and dried under reduced pressure for about 24 hours. Subsequently, a polymer having a particle size of 710 μm or less was collected using a JIS standard 24 mesh sieve.

(Physicochemical properties of polymers)
1. Elemental analysis The nitrogen and chlorine contents of the polymer were measured according to conventional methods.
2. Measurement of infrared absorption spectrum The infrared absorption spectrum of the polymer was measured using DR-8000 (manufactured by Shimadzu Corporation, 3FT01).
3. Measurement of specific volume About 10 g of polymer was placed in a graduated cylinder having a capacity of 50 mL, and the crude specific volume of the polymer was measured.
4). Measurement of loss on drying Using a LP16 infrared moisture meter (Metola), the change in weight of the polymer after drying at 160 ° C. for 10 minutes was measured.
5). Measurement of Water Regain Value (Water Absorption Characteristic Value) About 300 mg of polymer and about 60 mL of deionized water were placed in a 100 mL beaker and sonicated for 10 minutes. After leaving for about 2 hours, the polymer was suction filtered with a glass filter (G4) and centrifuged at 1000 rpm for 5 minutes. A part of the polymer on the filter was transferred to a weighing bottle and weighed (W ₁ ). It was dried at 120 ° C. until the sample weight became constant (W ₂ ). The Water Regin value was calculated from the following formula.
Water Regain (g / g) = (W ₁ −W ₂ ) / (W ₂ −W ₀ ) (W ₀ : Weight of weighing bottle)

  Ethylene glycol dimethacrylate crosslinked glycidyl methacrylate-triethylenetetramine copolymer (EGDMA crosslinked GMA-TTA polymer)

(reagent)
Glycidyl methacrylate (GMA, Wako Pure Chemicals, grade 1) was subjected to a polymerization reaction after distillation under reduced pressure (6 mmHg, 76 ° C.). Ethylene glycol dimethacrylate (EGDMA, manufactured by Wako Pure Chemicals, grade 1) was subjected to a polymerization reaction after removing the polymerization inhibitor with a 10% sodium hydroxide solution. Purified GMA and EGDMA were stored in a refrigerator until the inside of the container was replaced with nitrogen and used. Azobisisobutyronitrile (AIBN, manufactured by Wako Pure Chemicals, special grade) was used without purification. Triethylenetetramine (TTA, Wako Pure Chemicals, first grade) was subjected to an addition reaction after distillation under reduced pressure.
Dispersion of the polymerization reaction was carried out by mixing 50 mL of an aqueous solution of single hydroxyethyl cellulose (4500 to 6000 cps, manufactured by Tokyo Chemical Industry) and 6 g of sodium sulfate (manufactured by Nacalai Tesque, special grade), and making the total amount 500 mL with deionized water. It was used as a medium. As other reagents, commercially available special grade or first grade products were used.

(Synthesis of GMA homopolymer and EGDMA cross-linked GMA polymer)
500 mL of a dispersion medium was placed in a 1000 mL separable round bottom flask equipped with a thermometer, a stirrer, a Dimroth, and a nitrogen introduction tube. As the stirring blades, two Teflon blades (blade diameter 80 mm) were used. After stirring for about 10 minutes at 400 min ⁻¹ under a nitrogen stream, the stirring speed was lowered to 250 min ⁻¹ and the monomer mixed solution shown in Table 2 in which 100 mg of AIBN was dissolved was poured into the dispersion medium. After confirming that the spherical monomer phase was well dispersed under an optical microscope, the contents were heated to 50 ° C. over about 1 hour and allowed to react for 2 hours.
Further, the contents were heated to 80 ° C. over about 30 minutes and reacted for 1 hour, and the resulting polymer was collected by suction filtration and washed with hot deionized water three times. The polymer was washed with methanol, then placed in a desiccator for 12 hours at 60 ° C. and dried under reduced pressure overnight. JIS standards 22, 30, 42, 60, 83, 100, 140, and 200 mesh sieves were sequentially stacked, and about 30 g of the obtained polymer was placed in a 22 mesh sieve and classified by shaking for 30 minutes using a sieve shaker. . The obtained polymers having a particle size of 149 to 355 and 355 to 500 μm were subjected to the following synthesis.

(TTA addition reaction to GMA homopolymer and EGDMA cross-linked GMA polymer)
A pressure resistant reaction vessel with a capacity of 200 mL was charged with 37.5 mL of 1,4-dioxane, 12.5 mL of TTA and 5 g of GMA homopolymer or EGDMA-crosslinked GMA polymer, and after shaking well, the mixture was reacted in an 80 ° C. water bath for 5 hours. After opening the pressure-resistant reaction vessel, the contents were transferred into deionized water, and the polymer was collected by suction filtration. Next, the obtained polymer was transferred to a glass column tube, washed successively with 0.1N HCl and 0.1N NaOH, and further washed with deionized water until the pH of the effluent reached 6-7. The polymer was filtered off with suction using a buchner funnel, washed with methanol, then placed in a desiccator for 12 hours and dried under reduced pressure for about 12 hours.

(Induction of polymer to hydrochloride)
About 2 g of the polymer was placed in a 50 mL Erlenmeyer flask, and 1N hydrochloric acid in an amount corresponding to the polymer nitrogen content was added. After standing at room temperature for about 12 hours, the polymer was filtered off with suction using a buchner funnel, washed with methanol, then placed in a desiccator for 12 hours and dried under reduced pressure for about 24 hours.

The physicochemical properties of the obtained polymer were measured as follows.
1. Elemental analysis The nitrogen and chlorine contents of the polymer were measured according to conventional methods.
2. Measurement of infrared absorption spectrum The infrared absorption spectrum of the polymer was measured using DR-8000 (manufactured by Shimadzu Corporation, 3FT01).
3. Measurement of Specific Volume The specific volume of the polymer was measured by putting about 1.5 g of the polymer into a 5 mL measuring cylinder.
4). Measurement of loss on drying Using a LP16 infrared moisture meter (Metola), the change in weight of the polymer after drying at 160 ° C. for 10 minutes was measured.
5). Measurement of Water Regain Value (Water Absorption Characteristic Value) About 300 mg of polymer and about 60 mL of deionized water were placed in a 100 mL beaker and sonicated for 10 minutes. After leaving for about 2 hours, the polymer was suction filtered with a glass filter (G4) and centrifuged at 1000 rpm for 5 minutes. A part of the polymer on the filter was transferred to a weighing bottle and weighed (W ₁ ). It was dried at 120 ° C. until the sample weight became constant (W ₂ ). The Water Regin value was calculated from the following formula.
Water Regain (g / g) = (W ₁ −W ₂ ) / (W ₂ −W ₀ ) (W ₀ : Weight of weighing bottle)

Nitylene glycol dimethacrylate crosslinked N-methylpyridylethylene hydrochloride (EGDMA-4-VP) copolymer

(reagent)
Ethylene glycol dimethacrylate (EGDMA; Wako Pure Chemical; Grade 1) was subjected to a polymerization reaction after removing the polymerization inhibitor with a 10% sodium hydroxide solution. During storage, the storage container was purged with nitrogen. 4-Vinylpyridine (4-VP; Wako Pure Chemical Industries) was used after distillation under reduced pressure. The polymerization initiator azobisisobutyronitrile (AIBN; Wako Pure Chemical; special grade) was used as it was.
(Polymerization dispersion medium)
A 0.5 w / v% hydroxyethyl cellulose aqueous solution containing 10 w / v% sodium chloride was used as a polymerization dispersion medium.

(Polymer synthesis method)
500 mL of a dispersion medium was placed in a 1000 mL separable three-necked round bottom flask equipped with a thermometer, a stirrer, a Dimroth, and an argon inlet tube. Two blades made of Teflon (blade diameter 80 mm) were used as the stirring blades. After stirring for about 10 minutes at 400 min ⁻¹ under a nitrogen stream, the stirring speed was lowered to 300 min ⁻¹ and 100 mL of 4-VP and EGDMA were mixed at a ratio of 3: 7 or 4: 6, and 100 mg of AIBN was added thereto. A monomer mixed solution in which was dissolved was injected into the dispersion medium.
After confirming that the spherical monomer phase was satisfactorily dispersed under an optical microscope, the temperature was raised to 70 ° C. over 30 to 40 minutes, and polymerization was continued for 4 hours at 70 ° C. Further, the temperature was raised to 80 ° C. and reacted for 1 hour. Then, it cooled slowly over 5 hours or more. The resulting polymer was filtered with suction and washed three times with hot deionized water. The polymer was washed with an equal volume of deionized water / methanol and dried at 60 ° C. for 12 hours. After that, it was dried for one day under reduced pressure.

(Quaternary ammonium)
After injecting bromomethane, the reaction was followed by quaternary ammoniumation by washing with deionized water / methanol (1: 1) and drying.

(Polymer hydrochloride)
Elemental analysis of the free base polymer obtained above was performed to measure the nitrogen content. The polymer was put into a beaker and deionized water was added to swell sufficiently, and then 1N hydrochloric acid corresponding to 40 mol% of the polymer nitrogen content was added while stirring with a glass rod. After standing at room temperature for one night or longer, it was confirmed that the pH of the suspension supernatant was 5 to 6 and that it did not become cloudy even when 0.1 M silver nitrate was added dropwise to the supernatant. Wash with deionized water / methanol (1: 1), dry thoroughly and chlorinate.

(Synthesis and coating of 2-hydroxyethyl methacrylate (HEMA) polymer)
As the reagent, 2-hydroxyethyl methacrylate (HEMA) (first grade reagent of Wako Pure Chemical Industries, Ltd.), GEMA (Nippon Seika Co., Ltd.), glycidyl methacrylate (GMA) (Nacalai Tesque Co., Ltd.) was used. . Since these reagents contain hydroxymonomethyl ether which is a polymerization inhibitor, each was subjected to synthesis after removal by distillation under reduced pressure.
Add 12 mL of HEMA to 50 mL of ethanol, add 60 μL of GMA, and further add 400 mg of α, α′-azobizisobutyronitrile (polymerization initiator; Nacalai Tesque) and polymerize at 60 ° C. for 10 hours. I let you. The obtained GMA-HEMA copolymer was dropped into acetone to obtain a bead-shaped HEMA polymer.
The poly-HEMA obtained above was filtered, vacuum dried, and further pulverized with a pulverizer. Thereafter, poly-HEMA was dissolved in dimethyl sulfoxide (DMSO). The resin to be coated was put into this and sufficiently immersed, then filtered, air dried, and dried in a 120 ° C. vacuum dryer to obtain a coated HEMA polymer.

(Synthesis and coating of glycoside ethyl methacrylate (GEMA) polymer)
By simply replacing the above HEMA with GEMA, the other steps were the same, and a beaded GEMA polymer was obtained.
The obtained poly GEMA was filtered, vacuum-dried, and further pulverized with a pulverizer. Thereafter, poly-HEMA was dissolved in water. The resin to be coated was put into this and sufficiently immersed, followed by filtration, air drying, and drying in a vacuum dryer at 120 ° C. to obtain a coated GEMA polymer.

(Production of chelate resin of formula [VI])
Glycidyl methacrylate (GMA) (Nacalai Tesque) was subjected to synthesis after removing hydroxymonomethyl ether, which is a polymerization inhibitor contained by distillation under reduced pressure.
Α, α′-Azobizisobutyronitrile (polymerization initiator; Nacalai Tesque) was added to this GMA to synthesize GMA beads. The 5 g GMA beads were dissolved in 100 mL water to which 3.3 g iminodiacetic acid (IDA: Nacalai Tesque) was added. Thereafter, the pH was adjusted to 11 and reacted at 50 ° C. for 24 hours. Thereafter, the resin beads were filtered, washed with 2 mol dm ^-3 hydrochloric acid, washed with water, and vacuum-dried.

(In vitro phosphoric acid adsorption experiment on the anion exchange polymer of the present invention)
[Method]
This experiment was performed by partially modifying the method of Sheikh et al. (J Clin Invest 83 (1989) 66-73).
0.234 g or 0.702 g of NaH ₂ PO ₄ .2H ₂ O was dissolved in ultrapure water (17 MΩcm or more), and a test substance was added thereto to finally make a 300 mL test solution. The pH of the aqueous phosphoric acid solution in which the test substance and calcium carbonate (Nacalai Tesque) were suspended was adjusted to 3, 5, 7, and 9 using HCl or NaOH. The pH after the start of the experiment was readjusted every 30 minutes. The flask containing the sample solution was shaken 30 times / min in a constant temperature bath at 37 ° C. A sample for phosphorus measurement was collected after a specified time and centrifuged at 3000 rpm for 30 minutes. The supernatant was further filtered with filter paper (# 4, Whatman) and a 0.2 μm filter, and the residual phosphorus concentration of the solution was determined by the method of Fiske and Subbarow (J Biol Chem 66 (1925) 375-400). The phosphate adsorption amount at each pH of the test substance was defined as the final phosphate adsorption amount when the incubation time exceeded 24 hours and the phosphate adsorption amount did not increase by 3% or more from the previous measurement point.

[result]
In an adsorption experiment using 5 mol dm ^-3 phosphoric acid, calcium carbonate showed about twice the phosphate adsorption capacity at pH 7 and pH 9 compared to the coated EGDMA-4VP (FIG. 1). On the other hand, at pH 3 and 5, the phosphate adsorption of calcium carbonate was greatly reduced, but the adsorption of the coated EGDMA-4VP was only slightly reduced. In addition, similar results were obtained in an adsorption experiment using 15 mol dm ^-3 phosphoric acid (Fig. 2), and the coated EGDMA-4VP had a phosphate adsorption capacity in the neutral range as compared with that of calcium carbonate. Although it was inferior, it became clear that the adsorption ability was maintained in a wide pH range. This indicates that the coated EGDMA-4VP can maintain the ability to adsorb phosphoric acid even in the stomach at pH 3 or lower, and phosphoric acid is absorbed before reaching the upper part of the small intestine where the phosphoric acid is absorbed. This suggests the possibility of acid adsorption.

(Adsorption experiment of phosphate, total bile acid, and total bilirubin on anion exchange polymer in intestinal fluid)
[Method]
The rats were bred for 3 days under free eating and drinking (Claire CA-1), and on the 4th day, the rats were sacrificed, and then the gastrocardia region to the ileocecal region were excised. The intestine was incised, the contents were taken out, and the weight was measured. Next, the intestinal tract was washed out using 3 times the amount of pure water, and the contents and the washing solution were pooled. The pooled liquid was sufficiently stirred and then centrifuged (3000 rpm, 10 min). After centrifugation, the supernatant was stocked (Sample A). To 100 mL of Sample A, 1.0 g of a test substance (calcium carbonate, uncoated EGDMA-4VP, and coated EGDMA-4VP) was added and shaken at 37 ° C. for 18 hours. After 18 hours, the liquid was centrifuged (3000 rpm, 10 min), and the supernatant was taken out (Sample B). For samples A and B, phosphoric acid content (molybdenum blue method; Phospha C-Test Wako for inorganic phosphorus measurement, Wako Pure Chemical Industries), total bile acid content (enzymatic colorimetric method; total bile acid / test wako, Wako Pure Chemical Industries) ), And the amount of bilirubin (alkali azobilirubin method; bilirubin BII / Test Wako, Wako Pure Chemical Industries).
The phosphorus concentration, bile acid concentration, and total bilirubin concentration adsorbed on the test substance were all determined as the amount adsorbed on the test substance by calculating the difference between the initial solution concentration and the solution residual concentration after the end of the experiment. The unit of adsorption amount was expressed as the amount of phosphorus adsorbed per unit mass (g) of the test substance (mg), the total amount of bile acids (mmol), and the total amount of bilirubin (mg).

[result]
In the phosphate adsorption experiment using intestinal fluid, calcium carbonate did not show the original phosphate adsorption ability (FIG. 3). This is probably because calcium carbonate was hardly dissociated because there was no prior exposure to acid. On the other hand, EGDMA-4VP with coating showed higher phosphate adsorption (23.7% increase) than EGDMA-4VP without coating. This result seems to be because the adsorption of bile acid (Fig. 4) or bilirubin (Fig. 5), which is normally adsorbed to an anion exchange resin competitively with phosphoric acid, was inhibited by the coating of the hydrophilic resin. It is. Conventionally, it is known that bile acids and bilirubin prefer a hydrophobic environment and are adsorbed in the resin even if no anion exchange group is introduced. In the present invention, the effect is expressed by utilizing a hydrophilic barrier.

(Linmouth balance experiment on coating resin using rats)
[Method]
This experiment was performed by the 2 × 2 crossover method. Rats subjected to the experiment (SD; 6 weeks old; male) were housed in individual cages in a room with controlled temperature (23 ± 2 ° C.) and humidity (55 ± 10%). Rats were bred and bred for 1 week under free feeding / free feeding with a powdered feed for rats (CA-1; CLEA Japan) prepared to be 2.0 g-inorganic phosphorus / 100 g-feed. Grouping was performed so that there were 8 animals in the group. After that, for 3 days, a group to which 6.0% of the test substance per weight of the feed was added and a group to which a normal feed was administered were prepared, and half of each group had a histamine H ₂ receptor antagonist. Certain famotidine (Sigma) was administered at a dose of 10 mg / kg body weight, and the other half was given physiological saline 3 times / day. In the next 48 hours, feces and urine excreted from the test rats were collected using an individual metabolic cage. Then, after raising for 1 week with the feed which does not contain a test drug, the feed contrary to the last time was given, and feces and urine were collected similarly. During the experiment, food intake and water intake were measured every day, and feces / urine volume and body weight were measured every two days.
The collected feces were weighed, freeze-dried and powdered, further ashed in a 600 ° C. oven, and then 2 mol dm ⁻³ hydrochloric acid was added to dissolve phosphoric acid. After measuring volume and weight, urine was thoroughly stirred and diluted with 2 mol dm ^-3 hydrochloric acid and deionized water. The phosphorus concentration was determined by the method described above ⁵ ).
The measured value was expressed by mean ± standard error, the difference was tested by ANOVA, and the case where the P value was smaller than 0.05 was considered significant. The overall assay followed the method of Bland and Altman (Lancet 1 (1986) 307-310).

[result]
By administering phosphate excretion stimulants, dietary phosphate is adsorbed to the phosphate excretion enhancers, increasing the amount of phosphate excreted in the feces and consequently reducing the amount of phosphate absorbed by the body. As a result, the amount of phosphorus in the urine that overflows from the body decreases.
As shown in FIG. 5, administration of calcium carbonate significantly increased the amount of phosphorus in feces (P <0.01). On the other hand, the coated EGDMA-4VP obtained in the above example also increased the amount of phosphorus in feces (P <0.05), but the increase was less than that of calcium carbonate. In contrast, when a histamine H ₂ receptor antagonist, which is said to be taken by 40% of dialysis patients, was administered, the amount of phosphorus in the feces due to calcium carbonate decreased (compared to when the antagonist was not administered). P <0.05). However, EGDMA-4VP obtained in the above example had no influence of the antagonist.
On the other hand, as shown in FIG. 6, the amount of urinary phosphorus was significantly reduced by adding test substances (calcium carbonate and coated EGDMA-4VP) (P <0.01). In particular, in the case of calcium carbonate, the amount decreased to 37% when no test substance was added. On the other hand, the decrease of the coated EGDMA-4VP obtained in the above example was 60% (P <0.01). When a histamine H ₂ receptor antagonist was administered, the amount of urinary phosphorus was increased in the case of calcium carbonate as in the case of fecal phosphorus (P <0.05 compared to when the antagonist was not administered). . However, even in the case of urine, EGDMA-4VP obtained in the above example had no influence of the antagonist.
From the above, it has been clarified that calcium carbonate and coated EGDMA-4VP are effective in a phosphorus balance test using rats. It was also revealed that the coated EGDMA-4VP was not affected by the histamine H ₂ receptor antagonist, unlike calcium carbonate.

(Suppression of lanthanum accumulation by chelate resin and phosphate discharge experiment)
[Method]
Rats (SD; male) subjected to this animal experiment had 7/8 kidneys removed at 4 weeks of age and one week later, only 7/8 kidneys were removed. Thereafter, they were reared in individual cages in a room in which temperature (23 ± 2 ° C.) and humidity (55 ± 10%) were controlled. Rats were divided into two groups. From 6 weeks of age, one group had a solid diet (oriental yeast custom-made) with 3% lanthanum carbonate added to a calcium-free diet, and the other group Gave a solid diet (oriental yeast special order) in which 3% by weight lanthanum carbonate and 3% by weight chelating resin (compound VI) were added to a diet not containing calcium. Thereafter, the animals were reared under the same conditions for 3 months, and after 3 months, the urinary phosphorus content of each rat and the lanthanum content in the liver, which is said to have the largest lanthanum accumulation, were measured by plasma emission spectrometry. .

[result]
The administration of the chelate resin is intended to reduce the organ accumulation of the polyvalent cation used in the administration of a phosphate excretion promoter using a polyvalent cation such as lanthanum or aluminum.
In order to demonstrate this effect, experiments with 7/8 nephrectomized rats were performed. As a result, by using the chelate resin (Compound VI), the urinary phosphorus excretion increased by 31.5% compared to the case where the chelate resin was not mixed and administered (FIG. 8). This indicates that the phosphate excretion action was attenuated by the lanthanum chelate. On the other hand, as a result of administration of lanthanum over a long period of 3 months, 5.3 μg of lanthanum accumulated per 1 g of dried liver in the rat liver (FIG. 9). However, when a chelating resin (compound VI) is used in combination with this, the accumulation is extremely reduced to 1.2 μg of lanthanum per 1 g of dried liver. This indicates that although the chelate resin of the present invention slightly attenuates its phosphate excretion action, the organ accumulation property of polyvalent cation is remarkably attenuated and can be made into a safe phosphorus excretion promoter.

(Oxalic acid adsorption effect)
[Method]
Rats purchased at 4 weeks of age (SD; male) were bred in a room with controlled temperature (23 ± 2 ° C.) and humidity (55 ± 10%). One week later, 5/6 of the kidney on one side was removed under breath anesthesia. Thereafter, the animals were reared in the same environment for one week, and the other kidney was removed 5/6. Thereafter, the animals were further bred for 1 week, and it was confirmed that renal function was reduced using creatinine clearance as an index.
Then, it switched to individual breeding, and the feed (oriental yeast) which does not contain calcium was given, and breeding was performed for another week. Thereafter, the rats were divided into two groups (5 animals per group), and in one group, sodium oxalate was added to a diet containing no calcium and added to 1% by weight, and the pellet was formed into pellets (food A). Oriental yeast), and the other group was further fed with 3% by weight of EGDMA-4VP to feed A and fed into pellets (feed B; oriental yeast) and reared.
After breeding, changes in body weight every week were recorded, and the average number of days of survival was observed. When the patient died, the remaining kidney was removed and fixed with a 10% formalin solution to prepare a pathological specimen.

[result]
Administration of diets A and B started at 7 weeks of age, but in the diet A (containing only oxalic acid) group, body weight began to decrease from the following week, and by 8 weeks after administration, body weight decreased by about 100 g. (FIG. 10), the first death was observed. On the other hand, in the diet B in which EGDMA-4VP was added to oxalic acid, a steady increase in body weight was observed even after administration (FIG. 10). As a result, in the diet A administration group, the average life span was only 10 weeks after administration, that is, 17 weeks of age. On the other hand, in the diet B administration group, all animals survived even after 40 weeks of age (FIG. 11). In the diet A administration group, a pathological specimen of the remaining kidney was prepared immediately after the death was confirmed. As a result, many calcium oxalate monohydrate (COM) crystals were inserted into the renal tubule. It was confirmed.

The ion-exchange resinous phosphate adsorbent according to the present invention suppresses the adsorption of bilirubin and bile acids that favor adsorption in a hydrophobic environment by coating the surface of the ion-exchange resin with a hydrophilic polymer, and thereby adsorbs ions. A major advantage is that the occurrence of high gastrointestinal side effects in clinical trials of existing drugs can be suppressed by reducing the influence of the swelling of the ion exchange resin and the effect of surface charges on the gastrointestinal epithelium together with the gel. There is.
Moreover, the ion exchange resinous phosphate adsorbent according to the present invention can adsorb oxalic acid in addition to adsorption of phosphoric acid, and produce calcium oxalate monohydrate causing urinary calculus. Can be suppressed.

  Furthermore, among the phosphate adsorbents according to the present invention, the chelate resin can also suppress organ accumulation of lanthanum ions and aluminum ions that exhibit toxicity.

Graph showing the results of an in vitro adsorption test using phosphoric acid (5 mmol dm ^-3 Graph showing the in vitro adsorption test results using phosphoric acid (15 mmol ^{dm -3)}   Graph showing the phosphate adsorption capacity test results using intestinal fluid   Graph showing the total bile acid adsorption ability test results using intestinal fluid   Graph showing the results of total bilirubin adsorption ability using intestinal fluid   Graph showing the amount of phosphorus in feces   Graph showing urinary phosphorus excretion   Graph showing urinary phosphorus excretion   Graph showing the amount of lanthanum accumulated in the liver   Effect of EGDMA-4VP on oxalic acid administration (weight change)   Graph showing the effect (average life) of EGDMA-4VP on oxalic acid administration

Claims (11)

Formula [I]:

{In the formula, Z represents the general formula [II]:

[Wherein Y1 represents a biridyl group or a general formula [III]:
ANR1R2R3 [III]
(In the formula, A means a single bond, a carbonyl group, an alkylene group having 1 to 8 carbon atoms, an arylene group or an aralkylene group;
R1, R2 and R3 all represent a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, and when bonded to a nitrogen atom (N) to form a quaternary ammonium group May have a counter ion, but R1, R2, and R3 are not simultaneously hydrogen atoms)
Means a nitrogen-containing group represented by
A substituted methylene group represented by
Or general formula [IV]:

(Wherein Y2 has the same meaning as in general formula [III])
Or a phenyl-substituted ethylene group represented by the general formula [V]:

(Wherein R4 means an alkyl group having 1 to 4 carbon atoms)
A pyridyl-substituted ethylene group represented by:
x and y mean a ratio of 0.1: 99.9 to 15:85 (x: y ratio). }
Or a functional group represented by the formula [VI]:

Resin containing the component represented by these. The resin according to claim 1 is the above general formula [I], formula [VI] or formula [VII]:

A resin for adsorbing phosphoric acid, which is a resin for adsorbing phosphoric acid represented by   The resin for adsorbing phosphoric acid according to claim 1 or 2, wherein the resin is a cross-linked anion exchange resin represented by the general formula [I].   The resin for adsorbing phosphoric acid according to claim 1 or 2, wherein the resin is a chelate resin represented by the formula [VI] or the formula [VII].   The resin for adsorbing phosphoric acid according to any one of claims 2 to 4, further capable of adsorbing oxalic acid.   The resin for adsorbing phosphoric acid according to claim 4, further adsorbing lanthanum ions or aluminum ions.   A phosphate adsorption method comprising adsorbing phosphate in blood using a resin represented by the above general formula [I], formula [VI] or formula [VII].   8. The phosphoric acid adsorption method according to claim 7, further comprising adsorbing oxalic acid.   The phosphate adsorption method according to claim 7 or 8, further comprising adsorbing lanthanum ions or aluminum ions using a chelate resin represented by formula [VI] or formula [VII]. Method.   A method for removing phosphoric acid, lanthanum ions and / or oxalic acid in blood using a resin represented by the above general formula [I], general formula [V] or general formula [VI].   Use of the phosphate adsorption resin according to any one of claims 4 to 8 and / or the phosphate adsorption method according to any one of claims 9 to 14 to produce phosphate and lanthanum ions in blood. And / or removing oxalic acid.

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