Pharmaceutical polymers for treating hyperkalemia and their preparation methods

Abstract

This disclosure pertains to the field of medicinal chemistry and relates to pharmaceutical polymers for the treatment of hyperkalemia and methods for their preparation. Specifically, this document provides potassium-binding polymers prepared by polymerization of monomers and crosslinking agents, wherein the monomers are compounds of formula (V), and the crosslinking agents are compounds of formula (VI) and / or formula (VII), wherein the variables are as defined in this specification; this application relates to their use in the treatment or prevention of hyperkalemia.

Description

[0001] Related applications

[0002] This application is a divisional application. The parent application is the application filed on November 4, 2022, with application number 202280014150.0 and invention title "Pharmaceutical polymer for treating hyperkalemia and preparation method thereof".

[0003] This application claims priority to patent application No. PCT / CN2021 / 131264, filed on November 17, 2021, which is incorporated herein by reference.

[0004] Invention Field

[0005] This disclosure relates to the field of medicinal chemistry; specifically, this disclosure relates to pharmaceutical polymers for the treatment of hyperkalemia and methods for their preparation. Background of the Invention

[0007] Potassium (K) + Potassium (HbA1c) is the most abundant cation in cells, with a concentration in the human body ranging from approximately 35 mEq / kg to 40 mEq / kg. Serum potassium levels in the range of approximately 5.0 mEq / L to 6.0 mEq / L can be defined as mild hyperkalemia, which is usually not life-threatening. However, moderate to severe hyperkalemia (serum potassium greater than approximately 6.1 mEq / L) can lead to serious consequences. Cardiac arrhythmias and ECG waveform distortions are characteristic of hyperkalemia. When serum potassium levels rise to approximately 9 mEq / L or higher, symptoms such as atrioventricular dissociation, ventricular tachycardia, or ventricular fibrillation may occur.

[0008] Hyperkalemia is rare in the general healthy population. However, it has a higher incidence in certain groups. The incidence of hyperkalemia in hospitalized patients is approximately 1%–10%, depending on the definition of hyperkalemia. Critically ill patients, premature infants, and the elderly are considered high-risk groups. Decreased kidney function, genitourinary disorders, cancer, severe diabetes, and combined medication use can all increase the risk of hyperkalemia.

[0009] Most existing treatments for hyperkalemia are limited to inpatient care. Ion exchange resins, such as Kayexalate, are not suitable for outpatients or long-term treatment because they must be administered in high doses and patient compliance is poor. This treatment has serious gastrointestinal (GI) side effects, leading to excessive sodium intake, which can result in hypernatremia, associated fluid retention, and hypertension. Diuretics allow patients to excrete sodium and potassium through the kidneys. However, the efficacy of diuretics is often limited due to nephropathy and associated diuretic resistance. Furthermore, diuretics are contraindicated in patients whose blood pressure and blood volume decline are adversely affected. For example, patients with congestive heart failure (CHF) have hypotension and are often treated with a combination of ACE inhibitors and non-potassium diuretics such as spironolactone, which may cause hyperkalemia.

[0010] Therefore, there is an urgent need to develop new drugs with high potassium binding capacity for the treatment of hyperkalemia.

[0011] Invention Description

[0012] In one aspect, this disclosure provides polymers.

[0013] According to one embodiment of this disclosure, the polymer comprises repeating units obtained by polymerization of monomers and crosslinking agents at a monomer:crosslinking agent molar ratio of 1:0.02 to 1:0.20. The monomers comprise an acidic group and a pKa-lowering group adjacent to the acidic group. The acidic group is selected from sulfonic acid groups (-SO3). - ), sulfate group (-OSO3) - ), carboxylic acid group (-CO2) - ), phosphonic acid group (-OPO3) 2- ), phosphate group (-OPO3) 2- ) and aminosulfonic acid group (-NHSO3) - The pKa lowering group is selected from nitro, cyano, carbonyl, trifluoromethyl, and halogen atoms. The crosslinking agent provides the polymer with a structural moiety represented by formula (I):

[0014] ,

[0015] Where n1 is 0, 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3, more preferably 1; n2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2, 3, more preferably 1; R1 is H or Preferably, R1 is H; and Indicates the position of combination.

[0016] The applicant has discovered that the polymers of this disclosure exhibit better stability and potassium ion adsorption capacity in their acidic state than in their salt state. The polymers of this disclosure, in either acidic or salt form, can be used as a drug for the effective treatment of hyperkalemia.

[0017] According to one embodiment of this disclosure, the polymer may further include at least one of the following technical features.

[0018] In a preferred embodiment, the acidic group is a carboxylic acid group, and the pKa-lowering group is fluorine.

[0019] In a preferred embodiment, the reaction sites of the monomer and the crosslinking agent are free alkenyl groups.

[0020] In a preferred embodiment, the polymer is selected from at least one of the following: polyethylene sulfonic acid polymer, polyethylene aminosulfonic acid polymer, poly(vinylaminosulfonic acid / vinyl sulfuric acid) copolymer, polyethylene aminophosphonic acid polymer, N-(ethyl bisphosphonate) polyethyleneamine polymer, poly(α-fluoroacrylic acid) polymer, vinylphosphonic acid / acrylic acid copolymer, vinylphosphonic acid / α-fluoroacrylic acid copolymer, polyethylene sulfuric acid polymer, and cross-linked polyethylene aminosulfonic acid polymer.

[0021] According to one embodiment of this disclosure, this disclosure also provides a polymer or a salt thereof represented by formula (II).

[0022] (II),

[0023] in,

[0024] R2 is H or R2 is preferably H;

[0025] m is in the range of 0.80-0.98, n is in the range of 0.02-0.20, and m+n=1;

[0026] n1 can be 0, 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, and more preferably 1;

[0027] n2 can be 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, and more preferably 1;

[0028] Waveform key representation or Random connections;

[0029] express or The bonding sites that connect with it to form an extended polymer network structure.

[0030] The polymer described above may further include at least one of the following technical features.

[0031] In a preferred embodiment, R2 is H.

[0032] In a preferred embodiment, the polymer is represented by formula (III) or a salt thereof:

[0033] (III).

[0034] In a preferred embodiment, the salt of the polymer of formula (II) is the salt represented by formula (IV):

[0035] (IV)

[0036] M is a basic group.

[0037] In a preferred embodiment, M is Fe, Ca, Na, Mg, lysine, or a combination thereof.

[0038] In a preferred embodiment, the polymer is composed of one or more polymers or their salts, or a mixture containing one or more polymers or their salts.

[0039] In another preferred embodiment, the polymer is represented by any one of the following structures or a salt thereof:

[0040] or ,

[0041] Where m is in the range of 0.80-0.98; n is in the range of 0.02-0.20; p is in the range of 0.02-0.20; and when only variables m and n exist, m+n=1, or when variables m, n and p all exist, m+n+p=1.

[0042] Preferably, the polymer is a salt represented by any of the following structures:

[0043] , ,

[0044]

[0045] ,

[0046] ,

[0047]

[0048] or

[0049] Where m is in the range of 0.80-0.98; n is in the range of 0.02-0.20; p is in the range of 0.02-0.20; and when only variables m and n exist, m+n=1, or when variables m, n and p all exist, m+n+p=1.

[0050] Variables m, n, and p can be any value within the range defined above, including endpoints. For example, m can be 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, or 0.98, and n can be 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, or 0.14. The 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20, and p can be 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20; and when only variables m and n exist, m+n=1, or when variables m, n, and p all exist, m+n+p=1.

[0051] In a preferred embodiment, m is 0.80 and n is 0.20; or m is 0.85 and n is 0.15; or m is 0.89 and n is 0.11; or m is 0.90 and n is 0.10; or m is 0.95 and n is 0.05; or m is 0.98 and n is 0.02.

[0052] In another preferred embodiment, m is in the range of 0.85-0.98, n is in the range of 0.02-0.15, and m+n=1; more preferably, m is in the range of 0.90-0.98, n is in the range of 0.02-0.10, and m+n=1; even more preferably, m is in the range of 0.93-0.97, n is in the range of 0.03-0.07, and m+n=1.

[0053] In another preferred embodiment, m is in the range of 0.84-0.96, n is in the range of 0.02-0.14, p is in the range of 0.02-0.14, and m+n+p=1; more preferably, m is in the range of 0.86-0.94, n and p are the same and in the range of 0.03-0.07, and m+n+p=1; even more preferably, m is 0.90, n is 0.05, and p is 0.05.

[0054] According to one embodiment of this disclosure, this disclosure provides a polymer or a salt thereof, wherein the polymer comprises repeating units obtained by polymerization of a monomer and a crosslinking agent in a monomer:crosslinking agent molar ratio of 1:0.02 to 1:0.25, for example 1:0.02, 1:0.05, 1:0.12 or 1:0.25, wherein the monomer is methyl 2-fluoroacrylate and the crosslinking agent is pentaerythritol triallyl ether.

[0055] According to one embodiment of this disclosure, this disclosure provides a polymer or a salt thereof, said polymer being prepared by a polymerization reaction of a monomer and a crosslinking agent, wherein...

[0056] The monomer is of formula (V) Compounds in which R1 is H or C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl;

[0057] The crosslinking agent is of formula (VI). Compounds and / or formula (VII) The compound, wherein n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and

[0058] In the polymerization reaction, the molar fraction of monomer is 0.80-0.98 and the molar fraction of crosslinking agent is 0.02-0.20, provided that the sum of the molar fractions of monomer and crosslinking agent is 1.

[0059] In the polymerization reaction, the mole fractions of monomer and crosslinking agent can be any values ​​within the range defined above, including end values. For example, the mole fraction of monomer can be 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, or 0.98, and the mole fraction of crosslinking agent can be 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20, and the sum of the mole fractions of monomer and crosslinking agent is 1.

[0060] In a preferred embodiment, during the polymerization reaction, the molar fraction of the monomer is 0.80 and the molar fraction of the crosslinking agent is 0.20; or the molar fraction of the monomer is 0.85 and the molar fraction of the crosslinking agent is 0.15; or the molar fraction of the monomer is 0.89 and the molar fraction of the crosslinking agent is 0.11; or the molar fraction of the monomer is 0.90 and the molar fraction of the crosslinking agent is 0.10; or the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinking agent is 0.05; or the molar fraction of the monomer is 0.98 and the molar fraction of the crosslinking agent is 0.02.

[0061] In another preferred embodiment, in the polymerization reaction, the molar fraction of the monomer is 0.85-0.98, the molar fraction of the crosslinking agent is 0.02-0.15, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; more preferably, in the polymerization reaction, the molar fraction of the monomer is 0.90-0.98, the molar fraction of the crosslinking agent is 0.02-0.10, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; even more preferably, in the polymerization reaction, the molar fraction of the monomer is 0.93-0.97, the molar fraction of the crosslinking agent is 0.03-0.07, and the sum of the molar fractions of the monomer and the crosslinking agent is 1.

[0062] In a preferred embodiment, the monomer is of formula (VIII). Compounds.

[0063] In a preferred embodiment, the crosslinking agent is of formula (VI). The compound, wherein each of n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and each of n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1. In a further preferred embodiment, the crosslinking agent is of formula (IX). The compound, wherein in the polymerization reaction, the molar fraction of the monomer is 0.80-0.98, the molar fraction of the crosslinking agent is 0.02-0.20, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; preferably, in the polymerization reaction, the molar fraction of the monomer is 0.85-0.98, the molar fraction of the crosslinking agent is 0.02-0.15, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; more preferably, in the polymerization reaction, the molar fraction of the monomer is 0.90-0.98, the molar fraction of the crosslinking agent is 0.02-0.10, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; even more preferably, in the polymerization reaction, the molar fraction of the monomer is 0.93-0.97, the molar fraction of the crosslinking agent is 0.03-0.07, and the sum of the molar fractions of the monomer and the crosslinking agent is 1. For example, in the polymerization reaction, the molar fraction of monomer is 0.80 and the molar fraction of crosslinking agent is 0.20; or the molar fraction of monomer is 0.85 and the molar fraction of crosslinking agent is 0.15; or the molar fraction of monomer is 0.89 and the molar fraction of crosslinking agent is 0.11; or the molar fraction of monomer is 0.90 and the molar fraction of crosslinking agent is 0.10; or the molar fraction of monomer is 0.95 and the molar fraction of crosslinking agent is 0.05; or the molar fraction of monomer is 0.98 and the molar fraction of crosslinking agent is 0.02.

[0064] In another preferred embodiment, the crosslinking agent is of formula (VI). The compounds and formula (VII) The compound, wherein n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, wherein the molar fraction of the monomer is 0.84-0.96, the molar fraction of the compound of formula (VI) as a crosslinking agent is 0.02-0.14, and the molar fraction of the compound of formula (VII) as a crosslinking agent is 0.02-0.14, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1; more preferably, the molar fraction of the monomer is 0.86-0.94, the molar fraction of the compound of formula (VI) as a crosslinking agent is equal to the molar fraction of the compound of formula (VII) as a crosslinking agent, and is 0.03-0.07, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1. For example, the molar fraction of the monomer is 0.90, the molar fraction of compound (VI) as a crosslinking agent is 0.05, and the molar fraction of compound (VII) as a crosslinking agent is 0.05.

[0065] In a more preferred embodiment, the compound of formula (VI) is of formula (IX). Compounds of formula (VII) are compounds of formula (X). Compounds.

[0066] It should be understood that the polymer obtained by the polymerization reaction of monomers and crosslinking agents comprises structural moiety A contributed by the monomers and structural moiety B contributed by the crosslinking agents, wherein...

[0067] From equation (V) The structural component A contributed by the monomer is represented by equation (V'). residues, wherein R1 is H or C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl; and Indicates the connection position of structural part A or structural part B;

[0068] From formula (VI) The structural part B contributed by the crosslinking agent is formula (VI'). The residues, wherein n1 are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and Indicates the connection position of structural part A or structural part B;

[0069] From equation (VII) The structural part B contributed by the crosslinking agent is represented by formula (VII'). The residues, wherein q are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and Indicates the connection position of structural part A or structural part B.

[0070] It should be understood that the molar fraction of structural moiety A or structural moiety B in the polymer is the same as the molar fraction of the corresponding monomer and the corresponding crosslinking agent in the polymerization reaction.

[0071] In a preferred embodiment, the monomer is of formula (VIII). For compounds, structural moiety A is correspondingly of formula (VIII'). . residues.

[0072] In a preferred embodiment, the crosslinking agent is of formula (VI). For compounds, structural moiety B is correspondingly of formula (VI'). The residues, wherein n1 are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and This indicates the connection location of structural part A or structural part B. More preferably, the crosslinking agent is of formula (IX). For the compound, structural part B is correspondingly of formula (IX'). residues, of which This indicates the connection position of structural part A or structural part B, wherein the mole fraction of structural part A in the polymer is 0.80-0.98, the mole fraction of structural part B in the polymer is 0.02-0.20, and the sum of the mole fractions of structural part A and structural part B is 1; preferably, the mole fraction of structural part A in the polymer is 0.85-0.98, the mole fraction of structural part B in the polymer is 0.02-0.15, and the sum of the mole fractions of structural part A and structural part B is 1; more preferably, the mole fraction of structural part A in the polymer is 0.90-0.98, the mole fraction of structural part B in the polymer is 0.02-0.10, and the sum of the mole fractions of structural part A and structural part B is 1; even more preferably, the mole fraction of structural part A in the polymer is 0.93-0.97, the mole fraction of structural part B in the polymer is 0.03-0.07, and the sum of the mole fractions of structural part A and structural part B is 1. For example, structural mole A has a mole fraction of 0.80 and structural mole B has a mole fraction of 0.20; or structural mole A in the polymer has a mole fraction of 0.85 and structural mole B in the polymer has a mole fraction of 0.15; or structural mole A in the polymer has a mole fraction of 0.89 and structural mole B in the polymer has a mole fraction of 0.11; or structural mole A in the polymer has a mole fraction of 0.90 and structural mole B in the polymer has a mole fraction of 0.10; or structural mole A in the polymer has a mole fraction of 0.95 and structural mole B in the polymer has a mole fraction of 0.05; or structural mole A in the polymer has a mole fraction of 0.98 and structural mole B in the polymer has a mole fraction of 0.02.

[0073] In another preferred embodiment, the crosslinking agent is of formula (VI). The compounds and formula (VII) The compound, and correspondingly the structural part B is of formula (VI'). The residues and formula (VII') The residues, wherein n1 are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and q are each independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and This indicates the connection position of structural part A or structural part B. The molar fraction of structural part A in the polymer is 0.84-0.96, the molar fraction of residues of formula (VI') as structural part B in the polymer is 0.02-0.14, the molar fraction of residues of formula (VII') as structural part B in the polymer is 0.02-0.14, and the sum of the molar fractions of structural part A and the two structural parts B in the polymer is 1; more preferably, the molar fraction of structural part A in the polymer is 0.86-0.94, the molar fraction of residues of formula (VI') as structural part B in the polymer is equal to the molar fraction of residues of formula (VII') as structural part B in the polymer, and is 0.03-0.07, and the sum of the molar fractions of structural part A and the two structural parts B in the polymer is 1. For example, the mole fraction of structural moiety A in the polymer is 0.90, the mole fraction of residues of formula (VI') which is structural moiety B in the polymer is 0.05, and the mole fraction of residues of formula (VII') which is structural moiety B in the polymer is 0.05.

[0074] In a more preferred embodiment, the crosslinking agent is of formula (IX). The compound and formula (X) The compound, and structural moiety B is correspondingly of formula (IX'). The residues and formula (X') . residues.

[0075] The salts of the polymers described above are preferably pharmaceutically acceptable salts. For example, the polymers are in the form of sodium salts, calcium salts, iron salts, lysine salts, or combinations thereof. For example, the polymers are in the form of Na-Ca-Fe complex salts or Lys-Ca-Fe complex salts.

[0076] The polymers mentioned above or their salts are collectively referred to as "polymers of the present invention".

[0077] The polymers of the present invention have several advantages that will be apparent to those skilled in the art based on the disclosure of this application.

[0078] First, the polymer of the present invention exhibits good adhesion to potassium ions (K+) both in vitro and in vivo. +It has a high potassium-binding capacity, and therefore can remove excess potassium ions from animals. More specifically, when the potassium-binding capacity of the polymers of the present invention is determined in vitro under physiological conditions simulating the gastrointestinal tract, particularly the colon, for example, when the potassium-binding capacity of the polymers of the present invention is determined in vitro in a solution with a pH of about 5.5 or higher, the potassium-binding capacity of the polymers of the present invention in acid form is equal to or greater than 5 mmol / g, preferably 5-12 mmol / g, more preferably 5.5-10 mmol / g, and even more preferably 6 mmol / g-8 mmol / g; the potassium-binding capacity of the polymers of the present invention in salt form is 2-5 mmol / g.

[0079] Secondly, the polymers of the present invention do not contain any aromatic groups, thereby avoiding potential drug interactions caused by aromatic conjugated systems.

[0080] Third, the salt-form polymers of the present invention are carefully designed to significantly reduce calcium ion intake compared to commercially available products such as Veltassa® (Replypsa), and sodium ion intake compared to commercially available products such as Lokelma. ® (AstraZenca) is significantly reduced. Therefore, the salt form polymer of the present invention can reduce hypercalcemia caused by Veltassa® and that caused by Lokelma. ® This can cause hypernatremia.

[0081] Fourth, patients with chronic kidney disease often suffer from iron deficiency anemia as a complication, and the polymer of the present invention contains iron ions, thus benefiting patients with chronic kidney disease.

[0082] In another aspect, this disclosure provides a method for preparing a polymer or a salt thereof for binding potassium ions, the method comprising the following steps:

[0083] (a) A monomer, crosslinking agent, and initiator are mixed to obtain an oil phase. A dispersant and inorganic salt are added to water and dissolved and dispersed uniformly at room temperature to obtain an aqueous phase. The oil phase and aqueous phase are mixed and reacted at elevated temperature for a period of time to obtain a polymer ester.

[0084] (b) The polymer ester from step (a) is hydrolyzed in a mixed solution of an alkaline aqueous solution and an organic solvent to remove the alkyl moiety, yielding a polymeric carboxylate.

[0085] (c) Acidify the polymer carboxylate from step (b) to obtain the desired acid form of the polymer;

[0086] (d) Optionally, the polymer in acid form from step (c) is converted into the desired polymer in salt form.

[0087] The molar ratio of monomer to crosslinker is in the range of 1:0.02-1:0.25, which means that the molar fraction of monomer is 0.80-0.98 and the molar fraction of crosslinker is 0.02-0.20, provided that the sum of the molar fractions of monomer and crosslinker is 1.

[0088] The mole fractions of the monomer and the crosslinking agent can be any values ​​within the range defined above, including end values. For example, the mole fraction of the monomer can be 0.80, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, or 0.98, and the mole fraction of the crosslinking agent can be 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20, and the sum of the mole fractions of the monomer and the crosslinking agent is 1.

[0089] In a preferred embodiment, the molar fraction of the monomer is 0.80 and the molar fraction of the crosslinking agent is 0.20; or the molar fraction of the monomer is 0.85 and the molar fraction of the crosslinking agent is 0.15; or the molar fraction of the monomer is 0.89 and the molar fraction of the crosslinking agent is 0.11; or the molar fraction of the monomer is 0.90 and the molar fraction of the crosslinking agent is 0.10; or the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinking agent is 0.05; or the molar fraction of the monomer is 0.98 and the molar fraction of the crosslinking agent is 0.02.

[0090] In another preferred embodiment, the molar fraction of the monomer is 0.85-0.98, the molar fraction of the crosslinking agent is 0.02-0.15, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; more preferably, the molar fraction of the monomer is 0.90-0.98, the molar fraction of the crosslinking agent is 0.02-0.10, and the sum of the molar fractions of the monomer and the crosslinking agent is 1.

[0091] The monomer is of formula (V). Compounds in which R1 is H or C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl. Compounds of formula (V), where R1 is methyl, are equivalent to formula (VIII). Compounds.

[0092] The crosslinking agent is of formula (VI). Compounds and / or formula (VII) The compound wherein each n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; each n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and each q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1.

[0093] In a preferred embodiment, the crosslinking agent is of formula (VI). The compound, wherein n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1. In a more preferred embodiment, the crosslinking agent is of formula (IX). The compound has a monomer molar fraction of 0.80-0.98, a crosslinking agent molar fraction of 0.02-0.20, and the sum of the monomer molar fraction and the crosslinking agent molar fraction is 1; preferably, the monomer molar fraction is 0.85-0.98, the crosslinking agent molar fraction is 0.02-0.15, and the sum of the monomer molar fraction and the crosslinking agent molar fraction is 1; more preferably, the monomer molar fraction is 0.90-0.98, the crosslinking agent molar fraction is 0.02-0.10, and the sum of the monomer molar fraction and the crosslinking agent molar fraction is 1; even more preferably, the monomer molar fraction is 0.93-0.97, the crosslinking agent molar fraction is 0.03-0.07, and the sum of the monomer molar fraction and the crosslinking agent molar fraction is 1. For example, the molar fraction of the monomer is 0.80 and the molar fraction of the crosslinking agent is 0.20; or the molar fraction of the monomer is 0.85 and the molar fraction of the crosslinking agent is 0.15; or the molar fraction of the monomer is 0.89 and the molar fraction of the crosslinking agent is 0.11; or the molar fraction of the monomer is 0.90 and the molar fraction of the crosslinking agent is 0.10; or the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinking agent is 0.05; or the molar fraction of the monomer is 0.98 and the molar fraction of the crosslinking agent is 0.02.

[0094] In another preferred embodiment, the crosslinking agent is of formula (VI). The compounds and formula (VII) The compound, wherein n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1. The molar fraction of the monomer is 0.84-0.96, the molar fraction of the compound of formula (VI) as a crosslinking agent is 0.02-0.14, the molar fraction of the compound of formula (VII) as a crosslinking agent is 0.02-0.14, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1; more preferably, the molar fraction of the monomer is 0.86-0.94, the molar fraction of the compound of formula (VI) as a crosslinking agent is equal to the molar fraction of the compound of formula (VII) as a crosslinking agent, and is 0.03-0.07, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1. For example, the molar fraction of the monomer is 0.90, the molar fraction of compound (VI) as a crosslinking agent is 0.05, and the molar fraction of compound (VII) as a crosslinking agent is 0.05.

[0095] In a more preferred embodiment, the compound of formula (VI) is of formula (IX). Compounds of formula (VII) are compounds of formula (X). Compounds.

[0096] In the above methods, the initiator can be a water-soluble free radical initiator, an oil-soluble free radical initiator, or a mixture of two or more initiators. Water-soluble initiators include, but are not limited to, potassium persulfate, ammonium persulfate, 2,2'-azobis(2-methylpropanediamine) dihydrochloride (V50), 2,2'-azabis(2-imidazoline) dihydrochloride (VA044), etc. Oil-soluble initiators include, but are not limited to, 2,2'-azobis(2-methylpropionitrile), 2,2'-azobis-(2,4-dimethylpentanonitrile), 2,2-azobis(2-methylbutanonitrile), 1,1'-azobis(cyclohexane-1-carboxynitrile), dimethyl 2,2'-azobis(2-methylpropionic acid), benzoyl peroxide (BPO), lauroyl peroxide, cumene hydroperoxide, etc. The amounts of these initiators used in the methods of this disclosure are the same as those conventionally used in the art. For example, the amount of BPO used in the method of this disclosure may be 0.1‰-10.0‰, preferably 1.0‰-5.0‰, of the monomer in molar terms.

[0097] The polymerization reaction in this disclosure is suspension polymerization, as shown in step (a) of the method described above. The dispersant used in the method described above is intended to prevent particle aggregation during suspension polymerization. Suitable dispersants for this purpose include, but are not limited to, gelatin, polyvinyl alcohol (PVA), sodium carboxymethyl cellulose, hydroxymethyl cellulose, sodium polyacrylate, calcium carbonate, magnesium carbonate, barium sulfate, diatomaceous earth, talc, Tween 20, Tween 40, Tween 80, Tween 85, Span 20, Span 40, Span 60, Span 65, Span 80, Span 85, or any mixture thereof. The amounts of these dispersants used in the method of this disclosure are the same as those conventionally used in the art. For example, the amount of PVA used in the method of this disclosure may be 0.1%-2.0% (w / w), preferably 0.3%-1.0% (w / w), of the aqueous phase.

[0098] It has been found that adding an inorganic salt to the aqueous phase in step (a) of the above method can reduce particle aggregation. Suitable inorganic salts for this purpose include various salts that are soluble in the aqueous phase. For example, it can be selected from potassium chloride, sodium chloride, ammonium chloride, calcium chloride, magnesium chloride, and any mixture thereof. The amount of inorganic salt added is 0.1%-10% w / w, preferably 1%-5% w / w, more preferably 3%-4% w / w, for example 2% w / w, based on the total weight of the aqueous phase.

[0099] The elevation temperature of the polymerization reaction in step (a) of the above method refers to a temperature equal to or higher than 60°C, for example, 60°C-85°C.

[0100] The hydrolysis in step (b) of the above method should be carried out in a mixed solution of an alkaline aqueous solution and an organic solvent. The inventors have found that hydrolysis in an alkaline aqueous solution without organic solvent or in the presence of acid is incomplete, or colored impurities are produced if the temperature is increased to promote hydrolysis. The organic solvent used for hydrolysis is selected from ethanol, methanol, isopropanol, toluene, acetonitrile, ethers such as 2-methyltetrahydrofuran and tetrahydrofuran, and any mixtures thereof. The alkali used for hydrolysis includes, but is not limited to, potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, and any mixtures thereof.

[0101] The acids used in step (c) of the above method include, but are not limited to, sulfuric acid, hydrochloric acid, nitric acid, or any mixture thereof.

[0102] The conversion in step (d) of the above method can be carried out in a conventional manner suitable for salt formation. For example, it can be carried out by using a suitable aqueous alkali or salt solution. The suitable alkali or salt can be selected from ferric chloride hexahydrate, ferric chloride, calcium hydroxide, sodium hydroxide, iron hydroxide, calcium carbonate, sodium carbonate, and any mixture thereof.

[0103] In another aspect, this disclosure provides polymers prepared by the above-described method.

[0104] In another aspect, this disclosure also provides pharmaceutical compositions comprising one or more polymers as described above or salts thereof, and pharmaceutically acceptable excipients.

[0105] The pharmaceutical composition is used as a potassium binder to lower potassium ion levels in the body and to prevent and treat hyperkalemia.

[0106] The pharmaceutical composition can be formulated into solid dosage forms (including but not limited to capsules, tablets, pills, granules, powders, and solid dispersions) or liquid dosage forms (including but not limited to suspensions) for oral administration using conventional methods.

[0107] The pharmaceutical composition may contain one or more polymers or salts thereof as described above, in an amount of 1%-100% w / w of the composition, for example 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% w / w. Alternatively, the above-mentioned one or more polymers or salts thereof may be present in unit dosage forms in amounts of 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 12 g, 16 g, 18 g, 20 g, 24 g, 30 g, 40 g, 50 g, 60 g, 70 g, 80 g, 90 g, or 100 g.

[0108] The pharmaceutically acceptable excipients used in the pharmaceutical composition may be selected from one or more of the following substances:

[0109] a) Diluents, such as lactose, sucrose, sorbitol, mannitol, starch, microcrystalline cellulose, dextrin, etc.;

[0110] b) Disintegrants, such as croscarmellose sodium, croscarmellose, starch (e.g., starch, sodium glycolate starch, hydroxypropyl starch), etc.

[0111] c) Adhesives, such as starch paste, polyvinylpyrrolidone (PVP), methylcellulose, ethylcellulose, etc.;

[0112] d) Glide aids, such as silica, magnesium stearate, etc.;

[0113] e) Coloring agents;

[0114] f) Flavoring agents;

[0115] h) Suspension agents.

[0116] In some embodiments, the diluent may be present at an amount of 35%-90% w / w of the composition. In some embodiments, the disintegrant may be present at an amount of 0.5%-10% w / w of the composition. In some embodiments, the binder may be present at an amount of 0.5%-5% w / w of the composition. In some embodiments, the gliding agent may be present at an amount of 0.1%-5% w / w of the composition. In some embodiments, the colorant, flavoring agent, and suspending agent may each be present at an amount of 0.05%-5% w / w of the composition.

[0117] In another aspect, this disclosure further provides the use of the polymer as described above or a salt thereof or a pharmaceutical composition as described above in the preparation of a medicament for adsorbing or reducing potassium ion levels in vivo.

[0118] In another aspect of this disclosure, the use of the polymer as described above or a salt thereof or a pharmaceutical composition as described above in the preparation of a medicament for the prevention or treatment of hyperkalemia is further provided.

[0119] According to one embodiment of this disclosure, hyperkalemia is caused by the administration of drugs that cause potassium retention.

[0120] Drugs that can cause potassium retention include, but are not limited to, spironolactone, fluoxetine, metoprolol, quinine, loperamide, chlorpheniramine, chlorpromazine, ephedrine, amitriptyline, imipramine, loxapine, cinnarizine, amiodarone, nortriptyline, mineralocorticoids, propofol, digitalis, succinylcholine, eplerenone, alpha-adrenergic agonists, RAAS inhibitors, ACE inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone antagonists, benazepril, captopril, enalapril, fosinopril, lisinopril, and moxipril. Perindopril, quinapril, ramipril, quindopril, candesartan, eprosartan, irbesartan, losartan, valsartan, telmisartan, acebutolol, atenolol, betalolol, bisoprolol, carteolol, nadolol, propranolol, sotalolol, timolol, canrenone, aliskiren, aldosterone synthesis inhibitors, VAP antagonists, amiloride, triamterene, potassium supplements, heparin, nonsteroidal anti-inflammatory drugs, ketoconazole, trimethoprim, pentamivir, potassium-sparing diuretics, amiloride, triamterene, doxorubicin and combinations thereof.

[0121] In another aspect, this disclosure further provides a method for reducing potassium ion levels in vivo or for preventing or treating hyperkalemia in animals, the method comprising administering an effective amount of one or more of the above polymers or salts thereof.

[0122] In another aspect, this disclosure also provides a method for determining the potassium ion adsorption of a polymer, the method comprising the steps of detecting the potassium binding capacity of the polymer by ion chromatography under the following conditions.

[0123] Chromatographic column: IonPac CS17 Analytic Column (4 x 250 mm)

[0124] Guard column: IonPac CG17 Guard Column (4 x 50 mm)

[0125] Flow rate: 1.0 ml / min

[0126] Detector: Conductivity detector

[0127] Column temperature: 30°C

[0128] Injection volume: 10 μl

[0129] Eluent: 6mM mesylate solution

[0130] Running time: 20 minutes.

[0131] Definitions and Explanations

[0132] As will be understood by those skilled in the art, symbols This indicates a binding site that can be further connected to structural portions contributed by monomers or by the same or different crosslinking agents.

[0133] The terms "potassium," "potassium ion," and "potassium cation" used in this article are interchangeable and refer to K. + Unless the context contradicts this.

[0134] As used herein, the term "animal" includes humans and other mammals, such as primates, cattle, sheep, goats, horses, dogs, cats, rabbits, etc., preferably humans. This disclosure specifically provides polymer compositions for eliminating potassium ions from the body of animals. Preferably, the composition can be used to eliminate potassium ions from the gastrointestinal tract of animals.

[0135] The terms “potassium binding,” “potassium ion adsorption,” and “potassium adsorption” used herein are interchangeable. The potassium-binding polymers of the present invention exhibit high potassium-binding capacity. The potassium-binding capacity of the polymers of the present invention can be determined in vitro. Preferably, the in vitro determination of the potassium-binding capacity of the polymers of the present invention is performed under physiological conditions simulating the gastrointestinal tract, particularly the colon. In some embodiments, the in vitro determination of the potassium-binding capacity of the polymers of the present disclosure is performed in a solution with a pH of about 5.5 or higher, for example, pH 6-8. In various embodiments, such as when determined in a solution with a pH of about 5.5 or higher, for example, pH 6-8, the potassium-binding capacity of the polymers of the present invention in acidic form is equal to or greater than 5 mmol / g, preferably equal to or greater than 5.5 mmol / g, more preferably equal to or greater than 6 mmol / g. Preferably, such as when determined in a solution with a pH of about 5.5 or higher, the potassium-binding capacity of the polymers of the present invention in acidic form is 5 mmol / g-12 mmol / g, preferably 5.5 mmol / g-10 mmol / g, more preferably 6 mmol / g-8 mmol / g. It was found that the in vivo potassium-binding capacity of the polymer of the present invention is proportional to the in vitro potassium-binding capacity of the polymer in acid form, regardless of whether it is applied to animals in acid or salt form.

[0136] As used herein, the terms "effective amount" or "effective dose" refer to an amount of the polymer of the present invention that, when administered to animals, significantly reduces potassium levels, thereby preventing, alleviating, or curing diseases associated with high potassium levels or one or more symptoms of such diseases, or delaying the onset or progression of such diseases or one or more symptoms. The higher the potassium-binding capacity of the polymer of the present invention, the lower its dosage. Typically, the effective therapeutic and preventative dosage range of the polymer of the present invention is from about 1 g / day to about 100 g / day. A preferred dosage range is from about 5 g / day to about 60 g / day. A more preferred dosage range is from about 15 g / day to about 50 g / day. The daily dose can be administered as a single dose or multiple separate doses. For example, the daily dose can be taken three times a day or once a day.

[0137] The polymer of the present invention, or a composition comprising the polymer, can retain a significant amount of bound potassium, the polymer binding potassium in the gastrointestinal tract and not releasing the bound potassium before excretion in feces. "Significant amount" as used herein does not refer to the ability to retain all bound potassium. Preferably, at least a portion of the bound potassium is retained to achieve a therapeutic and / or preventative effect. It is desirable to retain about 5% to about 100% of the bound potassium; preferably, the polymer composition can retain about 25% of the bound potassium. More preferably, about 50% of the bound potassium can be retained. More preferably, about 75% of the bound potassium can be retained. Most preferably, about 100% of the bound potassium can be retained. Optionally, the retention period of the bound potassium is sufficient to effectively treat and / or prevent hyperkalemia.

[0138] The potassium-bound polymer of the present invention is preferably not absorbed by the gastrointestinal tract. The expression "not absorbed" and its grammatical synonyms do not imply that the applied polymer is absolutely not absorbed. It is desirable that a certain amount of the polymer is not absorbed. Preferably, about 90% or more of the polymer is not absorbed. More preferably, about 95% or more of the polymer is not absorbed. More preferably, about 97% or more of the polymer is not absorbed. Most preferably, about 98% or more of the polymer is not absorbed.

[0139] In some embodiments, the potassium-bound polymer of the present invention may contain protonated or ionic acid groups, such as sulfonic acid groups (-SO3). - ), sulfate group (-OSO3) - ), carboxylic acid group (-CO2) - ), phosphonic acid group (-OPO3) 2- ), phosphate group (-OPO3) 2- ) and aminosulfonic acid group (-NHSO3) - ).

[0140] Provide phosphonic acid groups (-OPO3) to the polymer 2- ) or phosphate group (-OPO3) 2- Suitable phosphonic acid monomers include vinylphosphonic acid, ethylene-1,1-diphosphonic acid, ethylene derivatives of phosphonic acid carboxylates, oligo(methylenephosphonic acid), and hydroxyethane-1,1-diphosphonic acid. Methods for synthesizing these monomers are known.

[0141] The preferred monomers used in this article are 2-fluoroacrylates, with methyl 2-fluoroacrylate being the most preferred. These monomers are commercially available, for example from Waterstone Pharmaceuticals (Hubei) Co., Ltd., or can be prepared by known methods, such as those disclosed in European Patent EP 415214.

[0142] As used herein, the numerical term "about" extends to a range of ±20% of the value. For example, about 5% refers to a range of 4%-6%. Preferably, the numerical term "about" extends to a range of ±10% or ±5% of the value.

[0143] As used in this article, “w / w” means that the proportion or percentage associated with the expression is expressed in weight.

[0144] As used in this article, the term "alkyl" refers to an alkyl group having 1-6 carbon atoms (C6H ... 1-6 Alkyl groups, preferably 1-3 carbon atoms (C 1-3 Alkyl groups are straight-chain or branched saturated hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, n-pentyl, and n-hexyl.

[0145] The term "mole fraction" refers to the molar ratio of a compound or structural moiety relative to a specified basis. For example, the statement "the mole fraction of the monomer is 0.85-0.98, the mole fraction of the crosslinker is 0.02-0.15, and the sum of the mole fractions of the monomer and the crosslinker is 1" means that the specified basis used to calculate the mole fraction is the sum of the moles of the monomer and the crosslinker. The mole fraction of the monomer refers to the ratio of the number of moles of the monomer to the sum of the moles of the monomer and the crosslinker, and its range is 0.85-0.98. Similarly, the mole fraction of the crosslinker refers to the ratio of the number of moles of the crosslinker to the sum of the moles of the monomer and the crosslinker, and its range is 0.02-0.15.

[0146] Terms not defined herein have their usual meaning in the art.

[0147] Implementation Plan

[0148] Implementation Scheme 1. A polymer comprising repeating units obtained by polymerization of a monomer and a crosslinking agent, wherein the molar ratio of monomer to crosslinking agent is in the range of 1:0.02-1:0.20, and the monomer comprises an acidic group and a pKa-lowering group adjacent to the acidic group, wherein the acidic group is selected from sulfonic acid groups (-SO3). - ), sulfate group (-OSO3) - ), carboxylic acid group (-CO2) - ), phosphonic acid group (-OPO3) 2- ), phosphate group (-OPO3) 2- ) and aminosulfonic acid group (-NHSO3) - The pKa-lowering group is selected from nitro, cyano, carbonyl, trifluoromethyl, and halogen atoms; and the crosslinking agent contributes a structural portion represented by formula (I) to the polymer:

[0149] (I),

[0150] Where n1 is 0, 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, where n2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and R1 is H or H is preferred.

[0151] Implementation Scheme 2. The polymer of Implementation Scheme 1, wherein the acidic group is a carboxylic acid group and the pKa-lowering group is fluorine.

[0152] Implementation Scheme 3. The polymer of Implementation Scheme 1, wherein the reaction position is a free alkenyl group.

[0153] Implementation Scheme 4. The polymer of Implementation Scheme 1, wherein the polymer is selected from at least one of the following: polyethylene sulfonic acid polymer, polyethylene aminosulfonic acid polymer, poly(vinylaminosulfonic acid / vinyl sulfuric acid) copolymer, polyethylene aminophosphonic acid polymer, N-(bisphosphonate ethyl ester) polyethyleneamine polymer, poly(α-fluoroacrylic acid) polymer, vinylphosphonic acid / acrylic acid copolymer, vinylphosphonic acid / α-fluoroacrylic acid copolymer, polyethylene sulfuric acid polymer, and cross-linked polyethylene aminosulfonic acid polymer.

[0154] Implementation Scheme 5. A polymer having formula (II) or a pharmaceutically acceptable salt thereof:

[0155] (II),

[0156] Where n1 is 0, 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 is 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and R2 is H or H is preferred;

[0157] m is in the range of 0.80-0.98, n is in the range of 0.02-0.20, and m+n=1;

[0158] and Indicates the position of combination.

[0159] Implementation Scheme 6. The polymer of Implementation Scheme 5, wherein R2 is H.

[0160] Implementation Scheme 7. The polymer of Implementation Scheme 5, wherein the polymer has a structure represented by formula (III) or is a salt of a structure represented by formula (III):

[0161] (III).

[0162] Implementation Scheme 8. The polymer of Implementation Scheme 5, wherein its salt has formula (IV).

[0163] (IV),

[0164] M is a basic group.

[0165] Implementation Scheme 9. The polymer of Implementation Scheme 8, wherein M is Fe, Ca, Na, Mg or lysine.

[0166] Implementation Scheme 10. The polymer of any one of Implementation Schemes 5-9, wherein the polymer comprises at least one polymer or a salt thereof.

[0167] Implementation Scheme 11. A polymer having any of the following structures or being a salt of any of the following structures:

[0168] or

[0169] ,

[0170] Where m is in the range of 0.80-0.98; n is in the range of 0.02-0.20; p is in the range of 0.02-0.20; and m+n=1 or m+n+p=1.

[0171] Implementation Scheme 12. The polymer of Implementation Scheme 11, wherein its salt has any one of the following structures.

[0172] , , , , , or .

[0173] Implementation Scheme 13. A polymer or a salt thereof, the polymer being prepared by polymerization of a monomer and a crosslinking agent, wherein...

[0174] The monomer is of formula (V). Compounds in which R1 is H or C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl;

[0175] The crosslinking agent is of formula (VI). Compounds and / or formula (VII) The compound, wherein n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and

[0176] In the polymerization reaction, the molar fraction of monomer is 0.80-0.98 and the molar fraction of crosslinking agent is 0.02-0.20, provided that the sum of the molar fractions of monomer and crosslinking agent is 1.

[0177] Implementation Scheme 14. The polymer or a salt thereof according to Implementation Scheme 13, wherein the monomer is of formula (VIII). Compounds.

[0178] Implementation Scheme 15. The polymer or a salt thereof according to Implementation Scheme 13 or 14, wherein the crosslinking agent is of formula (VI). The compound, wherein each of n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and each of n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; preferably, the crosslinking agent is of formula (IX). Compounds; and

[0179] In the polymerization reaction, the molar fraction of the monomer is 0.80-0.98, and the molar fraction of the crosslinking agent is 0.02-0.20, provided that the sum of the molar fractions of the monomer and the crosslinking agent is 1; preferably, in the polymerization reaction, the molar fraction of the monomer is 0.85-0.98, the molar fraction of the crosslinking agent is 0.02-0.15, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; more preferably, in the polymerization reaction, the molar fraction of the monomer is 0.90-0.98, the molar fraction of the crosslinking agent is 0.02-0.10, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; even more preferably, in the polymerization reaction, the molar fraction of the monomer is 0.93-0.97, the molar fraction of the crosslinking agent is 0.03-0.07, and the sum of the molar fractions of the monomer and the crosslinking agent is 1; most preferably, the molar fraction of the monomer is 0.95, and the molar fraction of the crosslinking agent is 0.05.

[0180] Implementation Scheme 16. The polymer or a salt thereof according to Implementation Scheme 13 or 14, wherein the crosslinking agent is of formula (VI). The compounds and formula (VII) The compound, wherein each of n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; each of n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and each of q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and

[0181] The monomer has a molar fraction of 0.84-0.96, the crosslinking agent (VI) compound has a molar fraction of 0.02-0.14, and the crosslinking agent (VII) compound has a molar fraction of 0.02-0.14, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1; preferably, the monomer has a molar fraction of 0.86-0.94, the crosslinking agent (VI) compound has a molar fraction equal to the crosslinking agent (VII) compound, and is 0.03-0.07, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1; more preferably, the monomer has a molar fraction of 0.90, the crosslinking agent (VI) compound has a molar fraction of 0.05, and the crosslinking agent (VII) compound has a molar fraction of 0.05.

[0182] Implementation Scheme 17. The polymer of claim 16 or a salt thereof, wherein the compound of formula (VI) is of formula (IX). Compounds of formula (VII) are compounds of formula (X). Compounds.

[0183] Implementation Scheme 18. A polymer or a salt thereof, prepared by a method comprising the following steps:

[0184] (a) A monomer, crosslinking agent, and initiator are mixed to obtain an oil phase. A dispersant and inorganic salt are added to water and dissolved and dispersed uniformly at room temperature to obtain an aqueous phase. The oil phase and aqueous phase are mixed and reacted at elevated temperature for a period of time to obtain an ester polymer.

[0185] (b) The alkyl moiety is removed from the ester polymer from step (a) by hydrolysis in a mixed solution of an alkaline aqueous solution and an organic solvent to generate a carboxylate polymer.

[0186] (c) Acidify the carboxylate polymer from step (b) to obtain the desired acid form of the polymer;

[0187] (d) Optionally, the polymer in acid form from step (c) is converted into the desired polymer in salt form;

[0188] The monomer is of formula (V). Compounds in which R1 is H or C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl;

[0189] The crosslinking agent is of formula (VI). Compounds and / or formula (VII) The compound wherein each n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; each n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and each q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1;

[0190] In the polymerization reaction, the molar fraction of monomer is 0.80-0.98 and the molar fraction of crosslinking agent is 0.02-0.20, provided that the sum of the molar fractions of monomer and crosslinking agent is 1.

[0191] The elevation temperature of the polymerization reaction refers to a temperature equal to or greater than 60°C, for example, 60°C-85°C;

[0192] The dispersant is selected from gelatin, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxymethyl cellulose, sodium polyacrylate, calcium carbonate, magnesium carbonate, barium sulfate, diatomaceous earth, talc, Tween 20, Tween 40, Tween 80, Tween 85, Span 20, Span 40, Span 60, Span 65, Span 80, Span 85, and any mixture thereof.

[0193] Implementation Scheme 19. The polymer or a salt thereof according to Implementation Scheme 18, wherein the monomer is of formula (VIII). Compounds.

[0194] Implementation Scheme 20. The polymer or a salt thereof according to Implementation Scheme 18 or 19, wherein the crosslinking agent is of formula (VI). The compound, wherein each of n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and each of n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; preferably, the crosslinking agent is of formula (IX). Compounds; and

[0195] In the polymerization reaction, the molar fraction of monomer is 0.80-0.98, the molar fraction of crosslinking agent is 0.02-0.20, and the sum of the molar fractions of monomer and crosslinking agent is 1; preferably, in the polymerization reaction, the molar fraction of monomer is 0.85-0.98, the molar fraction of crosslinking agent is 0.02-0.15, and the sum of the molar fractions of monomer and crosslinking agent is 1; more preferably, in the polymerization reaction, the molar fraction of monomer is 0.90-0.98, the molar fraction of crosslinking agent is 0.02-0.10, and the sum of the molar fractions of monomer and crosslinking agent is 1; even more preferably, in the polymerization reaction, the molar fraction of monomer is 0.93-0.97, the molar fraction of crosslinking agent is 0.03-0.07, and the sum of the molar fractions of monomer and crosslinking agent is 1; most preferably, the molar fraction of monomer is 0.95, and the molar fraction of crosslinking agent is 0.05.

[0196] Implementation Scheme 21. The polymer or a salt thereof according to Implementation Scheme 18 or 19, wherein the crosslinking agent is of formula (VI). The compounds and formula (VII) The compound, wherein each of n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; each of n2 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and each of q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and

[0197] The monomer has a molar fraction of 0.84-0.96, the crosslinking agent (VI) compound has a molar fraction of 0.02-0.14, and the crosslinking agent (VII) compound has a molar fraction of 0.02-0.14, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1; preferably, the monomer has a molar fraction of 0.86-0.94, the crosslinking agent (VI) compound has a molar fraction equal to the crosslinking agent (VII) compound, and is 0.03-0.07, and the sum of the molar fractions of the monomer and the two crosslinking agents is 1; more preferably, the monomer has a molar fraction of 0.90, the crosslinking agent (VI) compound has a molar fraction of 0.05, and the crosslinking agent (VII) compound has a molar fraction of 0.05.

[0198] Implementation Scheme 22. The polymer or a salt thereof according to Implementation Scheme 21, wherein the compound of formula (VI) is of formula (IX). Compounds of formula (VII) are compounds of formula (X). Compounds.

[0199] Implementation Scheme 23. The polymer or a salt thereof according to any one of Implementation Schemes 18-22, wherein the initiator is selected from potassium persulfate, ammonium persulfate, 2,2'-azobis(2-methylpropanediamine) dihydrochloride (V50), 2,2'-azabis(2-imidazoline) dihydrochloride (VA044), 2,2'-azobis(2-methylpropionitrile), 2,2'-azobis-(2,4-dimethylpentanonitrile), 2,2-azobis(2-methylbutanonitrile), 1,1'-azobis(cyclohexane-1-carboxynitrile), dimethyl 2,2'-azobis(2-methylpropionic acid), benzoyl peroxide (BPO), lauroyl peroxide, cumene hydroperoxide, and any mixture thereof.

[0200] Implementation Scheme 24. A polymer or a salt thereof according to any one of Implementation Schemes 18-23, wherein the inorganic salt is selected from potassium chloride, sodium chloride, ammonium chloride, calcium chloride, magnesium chloride and any mixture thereof.

[0201] Implementation Scheme 25. A polymer or a salt thereof according to any one of Implementation Schemes 18-24, wherein the organic solvent in step (b) is selected from ethanol, methanol, isopropanol, toluene, acetonitrile, ethers such as 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, dimethoxyethane, ethylene glycol diethyl ether, and any mixture thereof, and the base in step (b) is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, and any mixture thereof.

[0202] Implementation Scheme 26. A polymer or a salt thereof according to any one of Implementation Schemes 18-25, wherein the acid used in step (c) is selected from sulfuric acid, hydrochloric acid, nitric acid and any mixture thereof.

[0203] Implementation Scheme 27. A polymer or a salt thereof according to any one of Implementation Schemes 18-26, wherein the polymer is in the form of a sodium salt, calcium salt, iron salt, lysine salt or a combination thereof, for example, the polymer is in the form of a Na-Ca-Fe complex salt or a Lys-Ca-Fe complex salt.

[0204] Implementation Scheme 28. A pharmaceutical composition comprising the polymer of any one of embodiments 1-27 or a salt thereof and a pharmaceutically acceptable excipient.

[0205] Implementation Scheme 29. A polymer or a salt thereof according to any one of Implementation Schemes 1-27, used to reduce potassium levels in animals or to treat or prevent hyperkalemia.

[0206] Implementation Scheme 30. A method for reducing potassium levels in animals or for treating or preventing hyperkalemia, the method comprising administering an effective amount of the polymer or a salt thereof of any one of Implementation Schemes 1-27.

[0207] Implementation Plan 31. The method according to Implementation Plan 30, wherein hyperkalemia is caused by the administration of drugs that cause potassium retention. Attached Figure Description

[0209] The above and / or other aspects and advantages of this disclosure will become clear and readily understood from the description of the embodiments in conjunction with the following figures:

[0210] Figure 1A This is the SEM spectrum of the MFA-APE-Na-Ca-Fe salt polymer from Example 3. Figure 1B The XPS results are for the MFA-APE-Na-Ca-Fe salt polymer of Example 3.

[0211] Figure 2 The figure produced in Example 14 shows that Lokelma and the MFA-APE sodium salt polymer (MFA-APE-Na) prepared in Example 3 reduced serum potassium in normal SD rats. + Furthermore, the MFA-APE-Na polymer was superior to the two positive controls, Lokelma and Veltassa, in lowering serum potassium.

[0212] Figure 3 The graph from Example 15 shows that Lokelma and the MFA-APE sodium salt polymer (MFA-APE-Na) prepared in Example 3 reduce KCl-induced serum K+ levels. + Increase.

[0213] Figure 4 The figure produced in Example 16 shows that Lokelma and the MFA-APE complex salt polymer (MFA-APE-Na-Ca-Fe) prepared in Example 3 reduced serum potassium in a hyperkalemic rat model after 5 / 6 nephrectomy. + .

[0214] Figure 5 The figure produced in Example 17 shows that Lokelma and the MFA-APE complex salt polymer (MFA-APE-lysine-Ca-Fe) prepared in Example 5 reduced serum potassium in a hyperkalemic rat model after 5 / 6 nephrectomy. + Furthermore, on day 14 after administration, the MFA-APE-lysine-Ca-Fe polymer showed a significantly better effect on reducing serum potassium than the positive control (Lokelma).

[0215] Example

[0216] This disclosure is described below with reference to specific embodiments. It should be noted that these embodiments are descriptive only and do not limit this disclosure in any way.

[0217] The following abbreviations are used throughout this publication:

[0218]

[0219] The crosslinking agents used in the examples have the structures shown in Table 1.

[0220] [Table 1]

[0221]

[0222] Example 1

[0223]

[0224] Pure water (550 mL), NaCl (11.0 g), and PVA (3.4 g) were added to a reaction flask and stirred at 20°C-30°C until completely dissolved, yielding a clear solution. The MFA solution was prepared as follows: 104.0 g MFA (1.0 mol), 12.8 g APE (0.05 mol), and 0.73 g BPO (0.003 mol) were stirred and completely dissolved, yielding a clear solution. The prepared MFA solution was added to the solution in the reaction flask. The temperature of the substances in the reaction flask was gradually increased to 70°C-80°C, and then maintained at this temperature with stirring for 15 hours. Gas chromatography monitoring showed that the reaction was complete. After cooling to 20°C-30°C, the mixture was filtered. The filter cake was slurried with water and ethanol and washed. The resulting wet product was dried under vacuum at 50°C to obtain 97.3 g of a white solid, namely the MFA-APE ester polymer. The MFA-APE ester product (Chinese Pharmacopoeia 2020, Volume IV, General Chapter 0402) was characterized by infrared spectroscopy using a SHIMADZU IRSpirit-T Fourier transform infrared spectrometer (FTIR). No characteristic absorption peaks of the C=C bond were observed in the Fourier transform infrared (FTIR) spectrum of the MFA-APE ester polymer.

[0225] 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide were added to a reaction flask, followed by the addition of the above-mentioned MFA-APE ester polymer while stirring. The temperature was increased to 50°C-60°C, and then stirred and maintained at this temperature for 15 hours. The temperature was then lowered to 20°C-30°C, and the mixture was filtered. The filter cake was slurried with water and ethanol, washed, and filtered again to obtain wet MFA-APE sodium salt polymer.

[0226] Add 500 mL of water and 100 mL of concentrated hydrochloric acid to a reaction flask, then add the above-mentioned wet MFA-APE sodium salt polymer, and stir at 20°C-30°C for 15 hours. After filtration, wash the filter cake repeatedly with 4 L of water. Pulverize the filtered wet product once with 500 mL of ethanol. Dry the filtered wet product under vacuum at 50°C for 8 hours to obtain 84.6 g of white dry product, which is then pulverized and sieved through a 120-mesh sieve to obtain the MFA-APE acid polymer (m=0.95, n=0.05) (MFA-APE-H).

[0227] The K of the MFA-APE acid polymer + The adsorption capacity was 7.2 mmol / g, as determined in Example 13.

[0228] The MFA-APE acid polymer was determined by differential scanning calorimetry (DSC). Instrument model: METTLER TOLEDODSC3 differential scanning calorimeter. Analytical method: Chinese Pharmacopoeia 2020 Edition, General Chapter 0661 Thermal Analysis. Nitrogen conditions: 50 mL / min. Scanning operation: The temperature was increased from 30°C to 140°C at a rate of 10°C / min, then decreased to 30°C at a rate of 20°C / min. Next, the temperature was increased again to 150°C at a rate of 10°C / min, and the second heating curve was recorded. All reagent trays were made of aluminum. The obtained DSC curves showed that the glass transition temperature (Tg) of the acid polymer was 139.75°C.

[0229] The MFA-APE acid polymer was determined by thermogravimetric analysis (TGA). Instrument model: TGA 2 differential scanning calorimeter. Analytical method: Chinese Pharmacopoeia 2020 edition, General Chapter 0661 Thermal Analysis. Nitrogen conditions: 50 mL / min. Scanning operation: The temperature was increased from 30°C to 800°C at a rate of 10°C / min. The decomposition temperature of the MFA-APE acid polymer was calculated based on the curve. All reagent trays were platinum. The obtained TGA curve showed that the final decomposition temperature of the polymer was 208.90°C.

[0230] Example 2

[0231]

[0232] Add pure water (550 mL), NaCl (11.0 g), and PVA (3.4 g) to a reaction flask and stir at 20°C-30°C until completely dissolved to obtain a clear solution. Prepare the MFA solution as follows: Stir and completely dissolve 104.0 g MFA (1.0 mol), 14.0 g TAIC (0.056 mol), 12.8 g APE (0.05 mol), and 0.73 g BPO (0.003 mol) to obtain a clear solution. Add the prepared MFA solution to the clear solution in the reaction flask. Gradually increase the temperature of the substances in the reaction flask to 70°C-80°C, then maintain this temperature and stir for 15 hours. Gas chromatography monitoring showed that the reaction was complete. After the temperature dropped to 20°C-30°C, filter. Pulverize the filter cake with water and wash it three times. Dry the resulting wet product to obtain 115.2 g of white solid, namely the MFA-TAIC-APE ester polymer. The MFA-TAIC-APE ester polymer was dried and characterized by FTIR as described in Example 1. No characteristic absorption peaks of the C=C bond were observed on Fourier transform spectroscopy (FTIR) for the MFA-TAIC-APE ester polymer.

[0233] 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide were added to a reaction flask, followed by the addition of the aforementioned MFA-TAIC-APE ester polymer with stirring. The temperature was increased to 50°C-60°C, then stirred and maintained at this temperature for 15 hours. The temperature was then lowered to 20°C-30°C, followed by filtration. The filter cake was slurried with water and washed three times. The filtered wet product was the sodium salt polymer of MFA-TAIC-APE (MFA-TAIC-APE-Na).

[0234] 500 mL of water and 100 mL of concentrated hydrochloric acid were added to a reaction flask, followed by the addition of the aforementioned wet MFA-TAIC-APE sodium salt polymer. The mixture was then stirred at 20°C-30°C for 15 hours. After filtration, the filter cake was repeatedly washed with 4 L of water. The wet product obtained after filtration was slurried once with 500 mL of ethanol. The wet product obtained after filtration was vacuum dried at 50°C for 8 hours to obtain 85.7 g of white dry product. This product was pulverized and sieved through a 120-mesh sieve to obtain the MFA-TAIC-APE acid polymer (m=0.90, n=0.05, p=0.05) (MFA-TAIC-APE-H).

[0235] The K of the MFA-TAIC-APE acid polymer + The adsorption capacity was 6.6 mmol / g, as determined in Example 13.

[0236] The MFA-TAIC-APE acid polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the MFA-TAIC-APE acid polymer was 137.90°C. The obtained TGA curve showed that the decomposition temperature of the MFA-TAIC-APE acid polymer was 192.97°C.

[0237] Example 3

[0238]

[0239] The MFA-APE ester polymer was prepared using a procedure similar to that in Example 1. The MFA-APE ester polymer was characterized by FTIR as described in Example 1. Gas chromatography monitoring showed that the reaction was complete. No characteristic absorption peaks of the C=C bond were observed in the Fourier transform infrared (FTIR) spectrum of the MFA-APE ester polymer.

[0240] 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide were added to a reaction flask, followed by the addition of the above-mentioned MFA-APE ester polymer with stirring. The temperature was increased to 50°C-60°C, and then stirred and maintained at this temperature for 15 hours. The temperature was then reduced to 20°C-30°C, and the mixture was filtered. The filter cake was slurried with water and ethanol, washed, and filtered again to obtain wet MFA-APE sodium salt polymer (MFA-APE-Na). The MFA-APE sodium salt polymer was sampled and dried for potassium binding determination as described in Example 13, showing the K of the MFA-APE sodium salt polymer. + The adsorption capacity was 4.2 mmol / g.

[0241] Add 500 mL of water and 100 mL of concentrated hydrochloric acid to a reaction flask, then add the above wet MFA-APE sodium salt polymer, and stir at 20°C-30°C for 15 hours. After filtration, wash the filter cake repeatedly with 4 L of water, filter again, and obtain the wet MFA-APE acid polymer (MFA-APE-H).

[0242] The MFA-APE acid polymer was sampled and dried for potassium binding determination as described in Example 13, showing the K of the MFA-APE acid polymer. + The adsorption capacity was 7.4 mmol / g.

[0243] Add 240 mL of water to the above acid polymer and stir at 10-30°C. Slowly add FeCl3 (0.7 g), Ca(OH)2 (18.0 g), and NaOH (9.6 g) to the mixture, controlling the internal temperature at 10-30°C. Stir the mixture for 2-5 hours, then filter the mixture to obtain a wet solid. Slurry the wet solid with 2 L of water. After filtration, vacuum dry the resulting wet filter cake at 50°C for 8 hours to obtain 99.0 g of yellow dry product. Crush the product and sieve it through a 120 mesh sieve to obtain the MFA-APE Na-Ca-Fe composite salt polymer (m=0.95, n=0.05) (MFA-APE-Na-Ca-Fe).

[0244] The K of the MFA-APE-Na-Ca-Fe polymer + The adsorption capacity was 2.39 mmol / g, as determined in Example 13.

[0245] The MFA-APE-Na-Ca-Fe polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the final polymer was 130.82°C. The obtained TGA curve showed that the decomposition temperature of the final polymer was 193.06°C.

[0246] The MFA-APE-Na-Ca-Fe polymer was examined using scanning electron microscopy (SEM). The analytical instrument was a Quanta 400 thermal field emission scanning electron microscope. The analytical method was the general rule JY / T 0584-2020 for scanning electron microscopy examination. The SEM results are as follows: Figure 1A As shown in the image, the SEM image reveals that the MFA-APE-Na-Ca-Fe polymer has a regular spherical structure.

[0247] The MFA-APE-Na-Ca-Fe polymer was analyzed by X-ray photoelectron spectroscopy (XPS). Analytical method: General rules for X-ray photoelectron spectroscopy examination as per GB / T 19500-2004. XPS results are as follows. Figure 1B As shown in the figure. The results show that carbon, oxygen, fluorine, calcium, and sodium are present in the MFA-APE-Na-Ca-Fe polymer. The MFA-APE-Na-Ca-Fe polymer was acidified with sulfuric acid solution, and the supernatant was taken. Potassium thiocyanate test solution was added, which showed a positive reaction, proving the presence of iron ions in the MFA-APE-Na-Ca-Fe polymer.

[0248] Example 4

[0249]

[0250] The MFA-TAIC-APE ester polymer was prepared using a method similar to that of Example 2. Gas chromatography was used to monitor the completeness of the reaction. The MFA-TAIC-APE ester polymer was characterized by FTIR as described in Example 1. No characteristic absorption peaks of the C=C bond were observed in the Fourier transform infrared (FTIR) spectrum of the MFA-TAIC-APE ester polymer.

[0251] Add 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide to a reaction flask, then add the MFA-TAIC-APE ester polymer while stirring. Increase the temperature to 50°C-60°C, then stir and maintain this temperature for 15 hours. Reduce the temperature to 20°C-30°C, then filter. Pulverize the filter cake with water and wash three times. The filtered wet solid is the MFA-TAIC-APE sodium salt polymer (MFA-TAIC-APE-Na).

[0252] Add 500 mL of water and 100 mL of concentrated hydrochloric acid to a reaction flask, then add the above-mentioned MFA-TAIC-APE sodium salt polymer, and stir at 20°C-30°C for 15 hours. After filtration, wash the filter cake repeatedly with 4 L of water, and filter again to obtain the MFA-TAIC-APE acid polymer (MFA-TAIC-APE-H).

[0253] 240 mL of water was added to the obtained wet MFA-TAIC-APE acid polymer and stirred at 10-30°C. 0.7 g FeCl3, 18.0 g Ca(OH)2, and 9.6 g NaOH were slowly added to the mixture while maintaining the internal temperature at 10-30°C. The mixture was stirred for 2-5 hours and then filtered to obtain a wet solid. The wet solid was slurried with 2 L of water. After filtration, the resulting wet filter cake was vacuum dried at 50°C for 8 hours to obtain 102.5 g of yellow dry product. This product was pulverized and sieved through a 120-mesh sieve to obtain the MFA-TAIC-APE Na-Ca-Fe composite salt polymer (m=0.90, n=0.05, p=0.05) (MFA-TAIC-APE-Na-Ca-Fe).

[0254] Example 5

[0255]

[0256] The MFA-APE acid polymer was prepared using a method similar to that of Example 1. The MFA-APE acid polymer was characterized by FTIR as described in Example 1. No characteristic absorption peaks of the C=C bond were observed in the Fourier transform infrared (FTIR) spectrum of the MFA-APE acid polymer.

[0257] Add 240 mL of water to the wet MFA-APE acid polymer and stir at 10-30°C. Slowly add FeCl3 (0.7 g), Ca(OH)2 (15.0 g), and L-lysine (23.7 g) to the mixture, controlling the internal temperature at 10-30°C. Stir the mixture for 2-5 hours, then filter to obtain a wet solid. Slurry the wet solid with 2 L of water. After filtration, vacuum dry the resulting wet filter cake at 50°C for 8 hours to obtain 109.3 g of bright red dried product. Crush the dried product and sieve it through a 120-mesh sieve to obtain the MFA-APE Lys-Ca-Fe composite salt polymer (m=0.95, n=0.05) (MFA-APE-Lys-Ca-Fe).

[0258] The K of the MFA-APE-Lys-Ca-Fe salt polymer + The adsorption capacity was 2.95 mmol / g, as determined in Example 13.

[0259] The MFA-APE-Lys-Ca-Fe salt polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the polymer was 144.52°C. The obtained TGA curve showed that the decomposition temperature of the polymer was 194.38°C.

[0260] Examples 6-9

[0261] Examples 6-9 were performed using a method similar to that of Example 1 to obtain MFA-APE acid polymers. Salt polymers were then prepared using a method similar to that of Example 3. No characteristic absorption peaks of the C=C bond were observed in the Fourier transform infrared (FTIR) spectra of these MFA-APE acid polymers.

[0262] In Example 6, the amounts of MFA and APE were 1.0 mol and 0.25 mol, respectively, corresponding to a mole fraction of MFA:0.20 (m:n=0.80:0.20). This MFA-APE acid polymer K... + The adsorption capacity was 5.5 mmol / g, as determined in Example 13. The MFA-APE acid polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the MFA-APE acid polymer was 164.25°C. The obtained TGA curve showed that the decomposition temperature of the MFA-APE acid polymer was 196.51°C. The K0 of the MFA-APE-Na-Ca-Fe salt polymer... +The adsorption capacity was 2.6 mmol / g, as determined in Example 13. The MFA-APE-Na-Ca-Fe salt polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 166.65°C. The obtained TGA curve showed that the decomposition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 181.09°C.

[0263] In Example 7, the amounts of MFA and APE were 1.0 mol and 0.12 mol, respectively, corresponding to a mole fraction of MFA:0.11 (m:n=0.89:0.11). The Ka of the MFA-APE acid polymer... + The adsorption capacity was 6.6 mmol / g, as determined in Example 13. The MFA-APE acid polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the acid polymer was 134.94°C. The obtained TGA curve showed that the decomposition temperature of the polymer was 211.67°C. The K0 of the MFA-APE-Na-Ca-Fe salt polymer... + The adsorption capacity was 2.8 mmol / g, as determined in Example 13. The MFA-APE-Na-Ca-Fe salt polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 146.51°C. The obtained TGA curve showed that the decomposition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 191.81°C.

[0264] In Example 8, the amounts of MFA and APE were 1.0 mol and 0.02 mol, respectively, corresponding to a mole fraction of MFA:0.02 (m:n=0.98:0.02). The Ka of the MFA-APE acid polymer... + The adsorption capacity was 7.6 mmol / g, as determined in Example 13. The MFA-APE acid polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the MFA-APE acid polymer was 140.17°C. The obtained TGA curve showed that the decomposition temperature of the MFA-APE acid polymer was 209.85°C.

[0265] In Example 9, the amounts of MFA and APE were 0.5 mol and 0.5 mol, respectively, corresponding to a mole fraction of MFA:0.50 (m:n=0.50:0.50). The Ka of the MFA-APE acid polymer... +The adsorption capacity was 3.2 mmol / g, as determined in Example 13. The final product was detected by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the MFA-APE acid polymer was 106.01°C. The obtained TGA curve showed that the decomposition temperature of the MFA-APE acid polymer was 198.09°C.

[0266] Example 10

[0267] Pure water (550 mL), PEG600 (4.6 g), and NaCl (11.0 g) were added to a reaction flask and stirred at 20°C-30°C until the mixture was completely dissolved. The MFA solution was prepared as follows: MFA (104.0 g, 1.0 mol), APE (12.8 g, 0.05 mol), and BPO (0.73 g, 0.003 mol) were stirred and completely dissolved. The prepared MFA solution was added to the reaction flask. The temperature was gradually increased to 70-75°C, and the reaction mixture was stirred for 15 hours. A large amount of solid formed in the flask. After filtering the reaction mixture, 123 g of wet filter cake was obtained, which was dried at 50°C to obtain 90.4 g of white solid. This MFA-APE ester polymer was a heterogeneous, rigid, irregular block.

[0268] Example 11

[0269] Add 550 mL of pure water, 11.0 g of NaCl, and 4.6 g of PVA to a reaction flask and stir at 50°C-60°C until the mixture is completely dissolved. Prepare the MFA solution as follows: Stir and completely dissolve MFA (104.0 g, 1.0 mol), APE (12.8 g, 0.05 mol), and BPO (0.73 g, 0.003 mol). Add the prepared MFA solution to the reaction flask. Gradually increase the temperature to 55-59°C and stir the mixture at 55-59°C for 15-20 hours. No solid precipitate forms. Add another portion of BPO (0.73 g, 0.003 mol) to the reaction mixture and increase the temperature above 60°C. Some white solid precipitates. Maintain this temperature and stir the mixture for 15-20 hours. The reactants were filtered, and the resulting solid was slurried with water and EtOH to obtain 88.5 g of wet MFA-APE ester polymer. The MFA-APE ester polymer was characterized by FTIR as described in Example 1. No characteristic absorption peak of the C=C bond was observed in the Fourier transform infrared (FTIR) spectrum of this MFA-APE ester polymer.

[0270] Water (270 mL), EtOH (90 mL), and 71 g of the prepared wet MFA-APE ester polymer were added to a flask. Sodium hydroxide (40 g) was added to the reaction flask, and the temperature was raised to 60-65°C. The mixture was stirred at 60-65°C for 20-24 hours. The temperature was then lowered to 20-30°C, the mixture was filtered, and washed with water to obtain the MFA-APE-Na salt polymer.

[0271] The MFA-APE-Na salt polymer was stirred in concentrated HCl, diluted twice with water, filtered, and washed with water to obtain 120g of wet MFA-APE acid polymer. It was then dried at 50-60°C to obtain 46.7g of MFA-APE acid polymer.

[0272] K of MFA-APE acid polymer + The adsorption capacity was 7.2 mmol / g, as determined in Example 13. The MFA-APE acid polymer was analyzed by DSC and TGA as described in Example 1. The obtained DSC curve showed that the glass transition temperature of the MFA-APE acid polymer was 138.64°C. The obtained TGA curve showed that the decomposition temperature of the MFA-APE acid polymer was 210.32°C.

[0273] Example 12

[0274]

[0275] Add pure water (570 mL), NaCl (11.4 g), and PVA (4.6 g) to a reaction flask and stir at 50°C-60°C until completely dissolved. Prepare the MFA solution as follows: Stir and completely dissolve MFA (104.1 g, 1.0 mol), TMPTA (14.8 g, 0.05 mol), and BPO (0.73 g, 0.003 mol). Add the prepared MFA solution to the reaction flask. Gradually increase the temperature of the mixture in the reaction flask to 70°C-75°C. Stir the mixture at 70-75°C for 15 hours. Cool the temperature to 20-30°C and filter the reaction mixture. Pulverize the filter cake twice with water and once with EtOH. Filter to obtain 85.6 g of white solid wet filter cake, which is an MFA-TMPTA ester polymer.

[0276] Water (270 mL), EtOH (90 mL), and 66.0 g of wet MFA-TMPTA ester polymer were added to a reaction flask. Sodium hydroxide (40 g) was added to the flask. The reaction mixture was stirred at 60-65°C for 20 hours. The temperature was lowered to 20-30°C, and then the mixture was filtered. The resulting filter cake was a gel. GC-MS analysis showed the presence of the degradation product trimethylolpropane. This product dissolved when the filter cake was washed with water. The mixture was concentrated, and EtOH was added, precipitating a yellow solid. The precipitate was filtered off, washed with EtOH, and dried to give 23.0 g of a yellow flake-like solid. The solubility of this solid in water was >1 mg / mL.

[0277] Example 13

[0278] Potassium buffer: The potassium buffer consists of 150 mmol / L potassium and 200 mmol / L 2-[morpholino]ethanesulfonic acid, with a pH of 6.0-8.0.

[0279] Standard curve: Label five 100 mL volumetric flasks with the numbers 1, 2, 3, 4, and 5. Add 1, 3, 6, 8, and 10 mL of potassium buffer solution to the flasks in that order, dilute to volume with water, and mix. Perform ion chromatography on flasks 1, 2, 3, 4, and 5, and record the peak area of ​​potassium ions. Plot a graph on regular graph paper with the observed peak area on the ordinate and potassium concentration in mmol / L on the x-axis.

[0280] Test sample solution: Take about 1.6g of polymer and place it in a 250ml Erlenmeyer flask. Add 100ml of potassium buffer solution and stir magnetically for 24 hours in a water bath at 37°C±2°C. Shake well and take a sample (as recommended at 15min, 3h, 5h or 24h). Filter and accurately pipette 1.0ml of the filtrate into a 100ml volumetric flask. Dilute with water to the mark.

[0281] The sample solution was analyzed using ion chromatography, and the peak area of ​​potassium ions was recorded. The potassium concentration was determined by extrapolation from the standard curve, in mmol / L. The amount of potassium ions adsorbed on the resin was calculated using the following formula, in mmol / g:

[0282] The potassium ion adsorption capacity of the polymer = (X - 2.5Y) / W

[0283] Where X is the weight of potassium in 100 mL potassium solution before exchange, in mmol; Y is the weight of potassium in mmol / L extrapolated from the standard curve; and W is the weight of the polymer taken in g on an anhydrous basis.

[0284] The chromatographic conditions are listed in Table 2 below.

[0285] [Table 2]

[0286]

[0287] Results and Analysis

[0288] The potassium ion adsorption capacity of the polymers in the examples is shown in Table 3 below.

[0289] [Table 3]

[0290]

[0291] ※ Note: The Veltassa acid sample was obtained as follows: 3.2 g of Veltassa was acidified overnight with 4N HCl at 37°C. The heart was cleaned, the supernatant was discarded, and the heart was washed five times with water, filtered, and dried to obtain the test sample.

[0292] Example 14

[0293] Twenty-four normal male SD rats (6-8 weeks old, 190-210g, Hubei Experimental Animal Research Center) were acclimatized for 3-5 days and then randomly divided into four groups: a blank control group, a positive control group 1 (Lokelma), a positive control group 2 (Veltassa), and a test sample group (MFA-APE-Na prepared in Example 3), with six rats in each group. Animals in each group were orally administered the solvent or drug once at a volume of 10 ml / kg. More specifically, the blank control group received physiological saline at a volume of 10 ml / kg, positive control group 1 received 1.8 g / kg of Lokelma in the same volume of physiological saline, positive control group 2 received 3.5 g / kg of Veltassa in the same volume of physiological saline, and the test sample group received 1.8 g / kg of MFA-APE-Na in the same volume of physiological saline. Six hours after administration, blood was collected from the jugular vein. The blood samples were centrifuged, and the supernatant was used to determine serum potassium concentration.

[0294] The results showed that: (1) compared with the blank control group, the serum K in the test sample group (MFA-APE-Na) was significantly higher. + (1) The potassium level decreased significantly 6 hours after administration (P < 0.01); (2) The potassium-lowering effect of the test sample (MFA-APE-Na prepared in Example 3) was significantly better than that of Lokelma (P < 0.01) and Veltassa (P < 0.001); (3) Compared with the baseline before administration, the serum potassium level in the test sample group was significantly lower. + The level change was significantly reduced (P < 0.05), (4) the potassium-reducing effect of the test sample (MFA-APE-Na prepared in Example 3) was significantly better than that of Lokelma (P < 0.05) and Veltassa (P < 0.05), such as Figure 2 As shown.

[0295] Example 15

[0296] Eighteen normal male SD rats (6-8 weeks old, 190-210g, Hubei Experimental Animal Research Center) were acclimatized for 3-5 days and then randomly divided into three groups: a model group, a positive control group (Lokelma), and a test sample group (MFA-APE-Na prepared in Example 3), with 6 rats in each group. Animals in each group were administered the solvent or drug orally in a single dose of 10 ml / kg. Rats in the model group were given physiological saline at a dose of 10 ml / kg. Rats in the positive control group were given 1.8 g / kg of Lokelma in the same volume of physiological saline. Rats in the test sample group were given 1.8 g / kg of MFA-APE-Na in the same volume of physiological saline. Three hours after administration, a 10% KCl solution was injected intraperitoneally, followed by intraperitoneal injections of a 5% KCl solution at 4, 5, and 6 hours after administration. The intraperitoneal injection volume of the 10% and 5% KCl solutions was 4 ml / kg. Blood samples were collected from the jugular vein before administration (0 hours) and at 3.5, 4.5, and 6.5 hours after administration. The blood samples were centrifuged, and the supernatant was used to determine serum potassium concentration.

[0297] The results showed that, compared with the model group, the serum potassium concentrations in the test sample group (MFA-APE-Na prepared in Example 3) and the positive control group (Lokelma) were decreased, with statistically significant differences at 4.5 hours and 6.5 hours after administration (p<0.05). Figure 3 As shown in the image.

[0298] Example 16

[0299] Twenty-four normal male SD rats (6-8 weeks old, 200-250g, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were acclimatized for 3-5 days and then randomly divided into 5 groups: normal group, model group, positive control group (Lokelma), and test sample group (MFA-APE-Na-Ca-Fe prepared in Example 3), with 6 rats in each group. Except for the normal group, the other animals underwent the following modeling procedure: first, two-thirds of the left kidney (one-third of the upper and lower kidneys) was removed, and one week later, the entire right kidney was removed, obtaining a 5 / 6 nephrectomy rat model. After 2 weeks of normal diet, a single intravenous injection of doxorubicin (3.5 mg / kg) was administered, followed immediately by administration of trimethoprim (300 mg / kg intragastric, qd) and quinapril (30 mg / L, added to water). Animals in each group were orally administered the solvent or drug at a single dose of 20 ml / kg. Rats in the normal and model groups were treated with 20 ml / kg of solvent (0.1% xanthan gum), the positive control group was treated with 2 g / kg of Lokelma in the same volume of solvent, and the test sample group was treated with 2 g / kg of MFA-APE-Na-Ca-Fe from Example 3 in the same volume of solvent. The treatment was administered orally once daily for 2 weeks. Blood was collected from the jugular vein of all rats 5 days before and 7 and 14 days after doxorubicin injection. The blood samples were centrifuged, and the supernatant was used to determine serum potassium concentration.

[0300] The results showed that, compared with the model group, the serum potassium concentration in the test sample group (MFA-APE-Na-Ca-Fe prepared in Example 3) was significantly lower on days 7 and 14 after application (P<0.001 and P<0.01, respectively). Figure 4 As shown in the image.

[0301] Example 17

[0302] Twenty-four normal male SD rats (6-8 weeks old, 200-250g, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were acclimatized for 3-5 days and then randomly divided into four groups: normal group, model group, positive control group (Lokelma), and test sample group (MFA-APE-lysine-Ca-Fe prepared in Example 5), with 6 rats in each group. Except for the normal group, the other animals underwent the following modeling procedure: first, two-thirds of the left kidney (one-third of the upper and lower kidneys) was removed, and one week later, the entire right kidney was removed to obtain a 5 / 6 nephrectomy rat model. After two weeks of normal diet, doxorubicin (3.5 mg / kg) was injected intravenously, followed immediately by trimethoprim (300 mg / kg by gavage) and quinapril (30 mg / L, added to water). Animals in each group were orally administered the solvent or drug at a single dose of 20 ml / kg. Rats in the normal and model groups were administered the solvent (0.1% xanthan gum) at a volume of 20 ml / kg. The positive control group was administered Lokelma at a volume of 2 g / kg in the same solvent, and the test sample group was administered MFA-APE-lysine-Ca-Fe from Example 5 at a volume of 2 g / kg in the same solvent. The administration was once daily orally for 2 weeks. Blood samples were collected from the jugular vein of all rats 5 days before doxorubicin injection and 7 and 14 days after doxorubicin injection. The blood samples were centrifuged, and the supernatant was used to determine serum potassium concentration.

[0303] The results showed that, compared with the model group, serum potassium concentrations in the test sample group (MFA-APE-lysine-Ca-Fe prepared in Example 5) and the positive control group (Lokelma) were significantly reduced on days 7 and 14 after administration (P<0.01 or P<0.001). On day 14 after administration, the potassium-lowering effect of the test sample (MFA-APE-lysine-Ca-Fe) was significantly better than that of the positive control (Lokelma). Figure 5 As shown in the image.

[0304] In this specification, the terms "implementation," "some implementations," "example," "specific example," "some examples," "embodiment," "specific embodiment," or "some embodiments," etc., refer to specific features, structures, materials, or characteristics described in connection with an implementation, example, or embodiment, which are included in at least one implementation, example, or embodiment of this disclosure. In this specification, the above terms are descriptive and do not necessarily refer to the same implementation, example, or embodiment. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more implementations, examples, or embodiments. Moreover, those skilled in the art can combine different implementations, examples, or embodiments described in this specification, as well as features of different implementations, examples, or embodiments, without contradiction.

[0305] Although embodiments of this disclosure have been exemplified and described above, it is to be understood that the above embodiments are illustrative and should not be construed as limiting the present disclosure. Those skilled in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of this disclosure.

Claims

1. Use of a polymer in the preparation of a medicament for reducing potassium levels in animals, said polymer having the structure of formula (II) or a pharmaceutically acceptable salt thereof: (II), Where n1 is 1, 2 or 3, preferably n1 is 1; n2 is 1, 2 or 3, preferably n2 is 1; R2 is H; m is in the range of 0.80-0.98, n is in the range of 0.02-0.20, and m+n=1; and Indicates the position of combination.

2. The use according to claim 1, wherein the polymer has the structure of formula (III) or a pharmaceutically acceptable salt thereof: (III)。 3. The use according to claim 1, wherein the polymer has the structure of formula (IV): (IV), Where M is Fe, Ca, Na, Mg, lysine, or a combination thereof.

4. The use according to claim 3, wherein n1 is 1, n2 is 1, and R2 is H.

5. Use of the polymer in the preparation of a medicament for reducing potassium levels in animals, said polymer having any of the following structures: , , , , or , Where m is in the range of 0.80-0.98; n is in the range of 0.02-0.20; and m+n=1.

6. Use of a polymer in the preparation of a medicament for lowering potassium levels in animals, said polymer having the following structure, in, m is 0.80 and n is 0.20; or m is 0.85 and n is 0.15; or m is 0.89 and n is 0.11; or m is 0.90 and n is 0.10; or m is 0.95 and n is 0.05; or m is 0.98 and n is 0.02; preferably, m is 0.95 and n is 0.

05.

7. The use according to claim 1, wherein the polymer is prepared by polymerization of monomers and a crosslinking agent, wherein... The monomer is of formula (V). Compounds in which R1 is C 1-6 Alkyl group, preferably R1 is C 1-3 Alkyl group; more preferably, wherein the monomer is of formula (VIII). Compounds; The crosslinking agent is of formula (VI). The compound, wherein n1 is independently 1, 2 or 3; n2 is independently 1, 2 or 3, preferably, the crosslinking agent is of formula (IX). The compound, and In the polymerization reaction, the molar fraction of monomer is 0.80-0.98 and the molar fraction of crosslinking agent is 0.02-0.20, provided that the sum of the molar fractions of monomer and crosslinking agent is 1; or In the polymerization reaction, the molar fraction of monomer is 0.85-0.98, the molar fraction of crosslinking agent is 0.02-0.15, and the sum of the molar fractions of monomer and crosslinking agent is 1; or In the polymerization reaction, the molar fraction of monomer is 0.90-0.98, the molar fraction of crosslinking agent is 0.02-0.10, and the sum of the molar fractions of monomer and crosslinking agent is 1; or In the polymerization reaction, the molar fraction of monomer is 0.93-0.97, the molar fraction of crosslinking agent is 0.03-0.07, and the sum of the molar fractions of monomer and crosslinking agent is 1; or In the polymerization reaction, the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinking agent is 0.

05.

8. The use according to claim 1, obtained by a method comprising the following steps: (a) A monomer, crosslinking agent, and initiator are mixed to obtain an oil phase. A dispersant and inorganic salt are added to water and dissolved and dispersed uniformly at room temperature to obtain an aqueous phase. The oil phase and aqueous phase are mixed and polymerized at elevated temperature for a period of time to obtain an ester polymer. (b) The alkyl moiety is removed from the ester polymer from step (a) by hydrolysis in a mixed solution of an alkaline aqueous solution and an organic solvent to generate a carboxylate polymer. (c) Acidify the carboxylate polymer from step (b) to obtain the desired acid form of the polymer; (d) Optionally, the polymer in acid form from step (c) is converted into the desired polymer in salt form; The monomer is of formula (V). Compounds in which R1 is C 1-6 Alkyl group, preferably R1 is C 1-3 Alkyl group; more preferably, wherein the monomer is of formula (VIII). compounds, The crosslinking agent is of formula (VI). The compound, wherein n1 is independently 1, 2 or 3; n2 is independently 1, 2 or 3, preferably, wherein the crosslinking agent is of formula (IX). Compounds; In the polymerization reaction, the molar fraction of monomer is 0.80-0.98 and the molar fraction of crosslinking agent is 0.02-0.20, provided that the sum of the molar fractions of monomer and crosslinking agent is 1; or, in the polymerization reaction, the molar fraction of monomer is 0.80-0.98 and the molar fraction of crosslinking agent is 0.02-0.20, and the sum of the molar fractions of monomer and crosslinking agent is 1; or, in the polymerization reaction, the molar fraction of monomer is 0.85-0.98 and the molar fraction of crosslinking agent is 0.02-0.

1. 5, and the sum of the molar fractions of monomer and crosslinking agent is 1; or, in the polymerization reaction, the molar fraction of monomer is 0.90-0.98, the molar fraction of crosslinking agent is 0.02-0.10, and the sum of the molar fractions of monomer and crosslinking agent is 1; or, in the polymerization reaction, the molar fraction of monomer is 0.93-0.97, the molar fraction of crosslinking agent is 0.03-0.07, and the sum of the molar fractions of monomer and crosslinking agent is 1; or, in the polymerization reaction, the molar fraction of monomer is 0.95, and the molar fraction of crosslinking agent is 0.

05. The elevation temperature of the polymerization reaction refers to a temperature equal to or greater than 60°C, preferably, the elevation temperature of the polymerization reaction refers to 60°C-85°C; The dispersant is selected from gelatin, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxymethyl cellulose, sodium polyacrylate, calcium carbonate, magnesium carbonate, barium sulfate, diatomaceous earth, talc, Tween 20, Tween 40, Tween 80, Tween 85, Span 20, Span 40, Span 60, Span 65, Span 80, Span 85, and any mixture thereof.

9. The use according to claim 8, wherein the initiator is selected from potassium persulfate, ammonium persulfate, 2,2'-azobis(2-methylpropanediamine) dihydrochloride, 2,2'-azabis(2-imidazoline) dihydrochloride, 2,2'-azobis(2-methylpropionitrile), 2,2'-azobis-(2,4-dimethylpentanonitrile), 2,2-azobis(2-methylbutanonitrile), 1,1'-azobis(cyclohexane-1-carboxynitrile), dimethyl 2,2'-azobis(2-methylpropionic acid), benzoyl peroxide (BPO), lauroyl peroxide, cumene hydroperoxide, and any mixtures thereof.

10. The use according to any one of claims 8-9, wherein the inorganic salt is selected from potassium chloride, sodium chloride, ammonium chloride, calcium chloride, magnesium chloride, and any mixture thereof.

11. The use according to any one of claims 8-10, wherein the organic solvent in step (b) is selected from ethanol, methanol, isopropanol, toluene, acetonitrile, ether and any mixture thereof, and the base in step (b) is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate and any mixture thereof.

12. The use according to claim 11, wherein the ether is selected from 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, dimethoxyethane, and ethylene glycol diethyl ether.

13. The use according to any one of claims 8-12, wherein the acid used in step (c) is selected from sulfuric acid, hydrochloric acid, nitric acid, and any mixture thereof.

14. The use of the polymer according to any one of claims 8-13, wherein the polymer is in the form of a sodium salt, calcium salt, iron salt, lysine salt or a combination thereof, preferably, the polymer is in the form of a Na-Ca-Fe complex salt or a Lys-Ca-Fe complex salt.

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