Pharmaceutical polymers for the treatment of hyperkalemia and methods of making the same

Abstract

Provided herein are potassium-binding polymers prepared by a polymerization reaction of a monomer and a crosslinking agent, wherein the monomer is a compound of Formula (V), the crosslinking agent is a compound of Formula (VI) and / or a compound of Formula (VII), wherein the variables are as defined in the specification; the present application relates to their use in the treatment or prevention of hyperkalemia.

Description

[0001] Related Applications

[0002] This application claims priority to Patent Application No. PCT / CN2021 / 131264 filed on November 17, 2021, which is incorporated herein by reference.

[0003] TECHNICAL FIELD

[0004] The present disclosure relates to the field of pharmaceutical chemistry; in particular, the present disclosure relates to pharmaceutical polymers for treating hyperkalemia and methods of making the same. BACKGROUND

[0006] Potassium (K + ) is the most abundant cation in cells, with a content of about 35 mEq / kg to 40 mEq / kg in the human body. Serum potassium in the range of about 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 about 6.1 mEq / L) can lead to serious consequences. Both cardiac arrhythmias and ECG waveform distortion are characteristic of hyperkalemia. Symptoms such as atrioventricular dissociation, ventricular tachycardia, or ventricular fibrillation can occur when serum potassium levels rise to about 9 mEq / L or above.

[0007] Hyperkalemia is rare in the general healthy population. However, for certain populations, hyperkalemia has a higher incidence. In hospitalized patients, the incidence of hyperkalemia is about 1%-10%, depending on the definition of hyperkalemia. Critically ill patients, premature infants, or the elderly are all at high risk. Decreased kidney function, genitourinary diseases, cancer, severe diabetes, and combined medication can all increase the risk of hyperkalemia in patients.

[0008] Most existing hyperkalemia treatment regimens are limited to inpatient treatment. Ion exchange resins, such as Kayexalate, are not suitable for outpatients or long-term treatment because the drug must be used in large doses and patient compliance is poor. This treatment has serious side effects on the gastrointestinal (GI) tract, can lead to excessive sodium intake, which can cause hypernatremia, related fluid retention, and hypertension. Diuretics can allow patients to excrete sodium and potassium through the kidneys. However, due to the presence of kidney disease and related diuretic resistance, the efficacy of diuretics is often limited. In addition, diuretics are contraindicated for those patients who are disadvantaged by a decrease in blood pressure and blood volume. For example, congestive heart failure (CHF) patients have low blood pressure, and are usually administered a combination of ACE inhibitors and non-potassium diuretics such as spironolactone, which can cause hyperkalemia.

[0009] Therefore, there is an urgent need to develop new drugs for treating hyperkalemia with high potassium binding capacity.

[0010] SUMMARY

[0011] In one aspect, the present disclosure provides a polymer.

[0012] According to one embodiment of the present disclosure, the polymer comprises a repeating unit obtained by polymerization of a monomer and a crosslinking agent at a monomer:crosslinking agent molar ratio of 1:0.02 to 1:0.20. The monomer comprises an acidic group and a pKa-reducing group adjacent to the acidic group. The acidic group is selected from the group consisting of a sulfonic acid group (-SO3 - ), a sulfuric acid group (-OSO3 - ), a carboxylic acid group (-CO2 - ), a phosphonic acid group (-OPO3 2- ), a phosphoric acid group (-OPO3 2- ), and a sulfamic acid group (-NHSO3 - ). The pKa-reducing group is selected from the group consisting of a nitro group, a cyano group, a carbonyl group, a trifluoromethyl group, and a halogen atom. The crosslinking agent provides the polymer with a structural moiety represented by Formula (I):

[0013] ,

[0014] wherein 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 represents a binding position.

[0015] Applicants have found that the polymer of the present disclosure embodiment has better stability and potassium ion adsorption capacity in an acid state than in a salt state. The polymer of the present disclosure embodiment in acid or salt form can be used as a medicament for effectively treating hyperkalemia.

[0016] According to one embodiment of the present disclosure, the above-mentioned polymer can further comprise at least one of the following technical features.

[0017] In one preferred embodiment, the acidic group is a carboxylic acid group, and the pKa-reducing group is fluorine.

[0018] In one preferred embodiment, the reaction position of the monomer and the crosslinking agent is a free alkenyl group.

[0019] In a preferred embodiment, the polymer is at least one selected from the group consisting of polyvinyl sulfonic acid polymer, polyvinyl aminosulfonic acid polymer, poly(vinyl aminosulfonic acid / vinyl sulfuric acid) copolymer, polyvinyl aminophosphonic acid polymer, N-(bisphosphonate ethyl) polyvinyl amine polymer, poly(alpha-fluoroacrylic acid) polymer, vinyl phosphonic acid / acrylic acid copolymer, vinyl phosphonic acid / alpha-fluoroacrylic acid copolymer, polyvinyl sulfuric acid polymer, and cross-linked polyvinyl aminosulfonic acid polymer.

[0020] According to one embodiment of the present disclosure, the present disclosure also provides a polymer represented by formula (II) or a salt thereof,

[0021] ,

[0022] wherein,

[0023] R2 is H or , preferably R2 is H;

[0024] m is in the range of 0.80-0.98, n is in the range of 0.02-0.20, and m+n=1;

[0025] n1 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, 3, more preferably 1;

[0026] n2 is 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, 3, more preferably 1;

[0027] a random connection of or ;

[0028] a binding site or to which is connected to form an extended polymer network structure.

[0029] The above-mentioned polymer can further include at least one of the following technical features.

[0030] In a preferred embodiment, R2 is H.

[0031] In a preferred embodiment, the polymer is represented by formula (III) or a salt thereof:

[0032] (III).

[0033] In a preferred embodiment, the salt of the polymer of formula (II) is a salt represented by formula (IV):

[0034] (IV)

[0035] wherein M is a basic group.

[0036] In a preferred embodiment, M is Fe, Ca, Na, Mg, lysine, or a combination thereof.

[0037] In a preferred embodiment, the polymer is a mixture consisting of or comprising one or more polymers or salts thereof.

[0038] In another preferred embodiment, the polymer is represented by any one of the following structures or salts thereof:

[0039] or ,

[0040] wherein 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 are present, m+n = 1, or when variables m, n, and p are all present, m+n+p = 1.

[0041] Preferably, the polymer is a salt represented by any one of the following structures:

[0042] , ,

[0043]

[0044] ,

[0045] ,

[0046]

[0047] or

[0048] wherein 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 are present, m+n = 1, or when variables m, n, and p are all present, m+n+p = 1.

[0049] The variables m, n, and p can be any value included in the ranges defined above, including the 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, 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, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20, 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 are present, m + n = 1, or when variables m, n, and p are all present, m + n + p = 1.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] According to one embodiment of the present disclosure, the present disclosure provides a polymer or a salt thereof, wherein the polymer comprises a repeating unit obtained by polymerization of a monomer and a crosslinking agent at 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-fluoropropenoate, and the crosslinking agent is pentaerythritol triallyl ether.

[0054] According to one embodiment of the present disclosure, the present disclosure provides a polymer or a salt thereof, the polymer being prepared by a polymerization reaction of a monomer and a crosslinking agent, wherein

[0055] the monomer is a compound of formula (V) wherein R1is H or C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl;

[0056] the crosslinking agent is a compound of formula (VI) and / or a compound of formula (VII) wherein each n1independently is 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, more preferably 1; each n2independently is 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, more preferably 1; and each q independently is 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, more preferably 1, and

[0057] In the polymerization reaction, the mole fraction of the monomer is 0.80-0.98 and the mole fraction of the crosslinking agent is 0.02-0.20, provided that the sum of the mole fraction of the monomer and the mole fraction of the crosslinking agent is 1.

[0058] In the polymerization reaction, the mole fraction of the monomer and the mole fraction of the crosslinking agent can be any value included in the ranges defined above, including the 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, 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 fraction of the monomer and the mole fraction of the crosslinking agent is 1.

[0059] 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.

[0060] 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.

[0061] In a preferred embodiment, the monomer is of formula (VIII). Compounds.

[0062] 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). of 0.02 to 0.20, and the sum of the mole fraction of the monomer and the mole fraction of the crosslinking agent is 1 ; preferably, in the polymerization reaction, the mole fraction of the monomer is 0.85 to 0.98, the mole fraction of the crosslinking agent is 0.02 to 0.15, and the sum of the mole fraction of the monomer and the mole fraction of the crosslinking agent is 1 ; more preferably, in the polymerization reaction, the mole fraction of the monomer is 0.90 to 0.98, the mole fraction of the crosslinking agent is 0.02 to 0.10, and the sum of the mole fraction of the monomer and the mole fraction of the crosslinking agent is 1 ; even more preferably, in the polymerization reaction, the mole fraction of the monomer is 0.93 to 0.97, the mole fraction of the crosslinking agent is 0.03 to 0.07, and the sum of the mole fraction of the monomer and the mole fraction of the crosslinking agent is 1. For example, in the polymerization reaction, the mole fraction of the monomer is 0.80, and the mole fraction of the crosslinking agent is 0.20; or the mole fraction of the monomer is 0.85, and the mole fraction of the crosslinking agent is 0.15; or the mole fraction of the monomer is 0.89, and the mole fraction of the crosslinking agent is 0.11 ; or the mole fraction of the monomer is 0.90, and the mole fraction of the crosslinking agent is 0.10; or the mole fraction of the monomer is 0.95, and the mole fraction of the crosslinking agent is 0.05; or the mole fraction of the monomer is 0.98, and the mole fraction of the crosslinking agent is 0.02.

[0063] In another preferred embodiment, the crosslinking agent is a compound of formula (VI) and a compound of formula (VII) 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, wherein the mole fraction of the monomer is 0.84 to 0.96, the mole fraction of the compound of formula (VI) as crosslinking agent is 0.02 to 0.14, and the mole fraction of the compound of formula (VII) as crosslinking agent is 0.02 to 0.14, and the sum of the mole fraction of the monomer and the two crosslinking agents is 1 ; more preferably, the mole fraction of the monomer is 0.86 to 0.94, the mole fraction of the compound of formula (VI) as crosslinking agent is equal to the mole fraction of the compound of formula (VII) as crosslinking agent, and is 0.03 to 0.07, and the sum of the mole fraction of the monomer and the two crosslinking agents is 1. For example, the mole fraction of the monomer is 0.90, the mole fraction of the compound of formula (VI) as crosslinking agent is 0.05, and the mole fraction of the compound of formula (VII) as crosslinking agent is 0.05.

[0064] In a more preferred embodiment, the compound of formula (VI) is of formula (IX) Compounds of formula (VII) are compounds of formula (X). Compounds.

[0065] 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...

[0066] 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;

[0067] 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;

[0068] 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.

[0069] 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.

[0070] In a preferred embodiment, the monomer is of formula (VIII). For compounds, structural moiety A is correspondingly of formula (VIII'). . residues.

[0071] 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 compounds, 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.

[0072] 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 represents the attachment position of Structural Moiety A or Structural Moiety B. The molar fraction of Structural Moiety A in the polymer is 0.84-0.96, the molar fraction of the residue of formula (VI') as Structural Moiety B in the polymer is 0.02-0.14, the molar fraction of the residue of formula (VII') as Structural Moiety B in the polymer is 0.02-0.14, and the sum of the molar fractions of Structural Moiety A and the two Structural Moieties B in the polymer is 1 ; more preferably, the molar fraction of Structural Moiety A in the polymer is 0.86-0.94, the molar fraction of the residue of formula (VI') as Structural Moiety B in the polymer is equal to the molar fraction of the residue of formula (VII') as Structural Moiety B in the polymer, and is 0.03-0.07, and the sum of the molar fractions of Structural Moiety A and the two Structural Moieties B in the polymer is 1. For example, the molar fraction of Structural Moiety A in the polymer is 0.90, the molar fraction of the residue of formula (VI') as Structural Moiety B in the polymer is 0.05, and the molar fraction of the residue of formula (VII') as Structural Moiety B in the polymer is 0.05.

[0073] In a more preferred embodiment, the crosslinking agent is a compound of formula (IX) and a compound of formula (X) and Structural Moiety B is accordingly a residue of formula (IX') and a residue of formula (X')

[0074] The salt of the polymer as described above is preferably a pharmaceutically acceptable salt. For example, the polymer is in the form of a sodium salt, a calcium salt, an iron salt, a 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.

[0075] The above-mentioned polymer or salt thereof is collectively referred to as "the polymer of the present application".

[0076] The polymer of the present application has some advantages, which are obvious to those skilled in the art in light of the disclosure of the present application.

[0077] First, the polymer of the present application has a high affinity for potassium ions (K + ​) has a high binding capacity, and thus can remove excess potassium ions from the body of an animal. More specifically, when the potassium binding capacity of the polymer of the present application is measured in vitro under physiological conditions simulating the gastrointestinal tract, in particular the colon, for example when the potassium binding capacity of the polymer of the present application is measured in vitro in a solution having a pH of about 5.5 or more, the potassium binding capacity of the acid form of the polymer of the present application is equal to or greater than 5 mmol / g, preferably 5-12 mmol / g, more preferably 5.5-10 mmol / g, further preferably 6 mmol / g-8 mmol / g; the salt form of the polymer of the present application has a potassium binding capacity of 2-5 mmol / g.

[0078] Second, the polymer of the present application does not include any aromatic group, thereby avoiding potential drug interactions caused by aromatic conjugated systems.

[0079] Third, the salt form of the polymer of the present application is carefully designed so that the calcium ion intake from the polymer of the present application is greatly reduced compared to the commercially available product Veltassa® (Replypsa), and the sodium ion intake from the polymer of the present application is greatly reduced compared to the commercially available product Lokelma ® (AstraZenca). Thus, the salt form polymer of the present application can reduce hypercalcemia caused by Veltassa® and hypernatremia caused by Lokelma ® .

[0080] Fourth, chronic kidney disease patients often suffer from iron deficiency anemia as a complication, and the polymer of the present application includes iron ions, thus being beneficial to chronic kidney disease patients.

[0081] In another aspect, the present disclosure provides a method of preparing a polymer or a salt thereof for binding potassium ions, the method comprising the steps of:

[0082] (a) mixing a monomer, a crosslinking agent, and an initiator to obtain an oil phase, adding a dispersant and an inorganic salt to water and dissolving and dispersing them uniformly at room temperature to obtain an aqueous phase, mixing the oil phase and the aqueous phase and reacting at an elevated temperature for a period of time to obtain a polymer ester,

[0083] (b) hydrolyzing the polymer ester from step (a) in a mixed solution of an aqueous base and an organic solvent to remove an alkyl moiety, to produce a polymer carboxylate salt,

[0084] (c) acidifying the polymer carboxylate salt from step (b) with an acid to obtain the desired acid form of the polymer;

[0085] (d) optionally, converting the acid form of the polymer from step (c) into the desired salt form of the polymer.

[0086] The molar ratio of monomer to crosslinker is in the range of 1 :0.02 to 1 :0.25, which means that the mole fraction of monomer is 0.80 to 0.98 and the mole fraction of crosslinker is 0.02 to 0.20, provided that the sum of the mole fraction of monomer and the mole fraction of crosslinker is 1.

[0087] The mole fraction of monomer and the mole fraction of crosslinker can be any value included in the ranges defined above, including the 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, the mole fraction of crosslinker 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 fraction of monomer and the mole fraction of crosslinker is 1.

[0088] In a preferred embodiment, the mole fraction of monomer is 0.80 and the mole fraction of crosslinker is 0.20; or the mole fraction of monomer is 0.85 and the mole fraction of crosslinker is 0.15; or the mole fraction of monomer is 0.89 and the mole fraction of crosslinker is 0.11; or the mole fraction of monomer is 0.90 and the mole fraction of crosslinker is 0.10; or the mole fraction of monomer is 0.95 and the mole fraction of crosslinker is 0.05; or the mole fraction of monomer is 0.98 and the mole fraction of crosslinker is 0.02.

[0089] In another preferred embodiment, the mole fraction of monomer is 0.85 to 0.98, the mole fraction of crosslinker is 0.02 to 0.15, and the sum of the mole fraction of monomer and the mole fraction of crosslinker is 1; more preferably, the mole fraction of monomer is 0.90 to 0.98, the mole fraction of crosslinker is 0.02 to 0.10, and the sum of the mole fraction of monomer and the mole fraction of crosslinker is 1.

[0090] The monomer is a compound of formula (V) wherein R1is H or C 1-6 alkyl, preferably C 1-3 alkyl, more preferably methyl. The compound of formula (V) wherein R1is methyl corresponds to a compound of formula (VIII) (VIII).

[0091] The crosslinker is a compound of formula (VI) (VI) and / or a compound of formula (VII) (VI) 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.

[0092] In a preferred embodiment, the crosslinker is a compound of formula (VI) (VI) 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. In a more preferred embodiment, the crosslinker is a compound of formula (IX) (VI) 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. In a more preferred embodiment, the crosslinker is a compound of formula (IX) The molar fraction of monomer is 0.80-0.98, the molar fraction of crosslinker is 0.02-0.20, and the sum of the molar fraction of monomer and the molar fraction of crosslinker is 1; preferably, the molar fraction of monomer is 0.85-0.98, the molar fraction of crosslinker is 0.02-0.15, and the sum of the molar fraction of monomer and the molar fraction of crosslinker is 1; more preferably, the molar fraction of monomer is 0.90-0.98, the molar fraction of crosslinker is 0.02-0.10, and the sum of the molar fraction of monomer and the molar fraction of crosslinker is 1; even more preferably, the molar fraction of monomer is 0.93-0.97, the molar fraction of crosslinker is 0.03-0.07, and the sum of the molar fraction of monomer and the molar fraction of crosslinker is 1. For example, the molar fraction of monomer is 0.80, and the molar fraction of crosslinker is 0.20; or the molar fraction of monomer is 0.85, and the molar fraction of crosslinker is 0.15; or the molar fraction of monomer is 0.89, and the molar fraction of crosslinker is 0.11; or the molar fraction of monomer is 0.90, and the molar fraction of crosslinker is 0.10; or the molar fraction of monomer is 0.95, and the molar fraction of crosslinker is 0.05; or the molar fraction of monomer is 0.98, and the molar fraction of crosslinker is 0.02.

[0093] In another preferred embodiment, the crosslinker is a compound of formula (VI) (VI) 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. (VI) 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. The mole fraction of the monomer is 0.84-0.96, the mole fraction of the compound of formula (VI) as a crosslinking agent is 0.02-0.14, the mole fraction of the compound of formula (VII) as a crosslinking agent is 0.02-0.14, and the sum of the mole fractions of the monomer and the two crosslinking agents is 1; more preferably, the mole fraction of the monomer is 0.86-0.94, the mole fraction of the compound of formula (VI) as a crosslinking agent is equal to the mole fraction of the compound of formula (VII) as a crosslinking agent, and is 0.03-0.07, and the sum of the mole fractions of the monomer and the two crosslinking agents is 1. For example, the mole fraction of the monomer is 0.90, the mole fraction of the compound of formula (VI) as a crosslinking agent is 0.05, and the mole fraction of the compound of formula (VII) as a crosslinking agent is 0.05.

[0094] In a more preferred embodiment, the compound of formula (VI) is a compound of formula (IX) and the compound of formula (VII) is a compound of formula (X) .

[0095] In the above method, the initiator can be a water-soluble radical initiator or an oil-soluble radical initiator or a mixture of two or more initiators. The water-soluble initiator includes, but is not limited to, potassium persulfate, ammonium persulfate, 2,2'-azobis(2-methylpropionamidine) dihydrochloride (V50), 2,2'-azobis(2-imidazoline) dihydrochloride (VA044), and the like. The oil-soluble initiator includes, but is not limited to, 2,2'-azobis(2-methylpropionitrile), 2,2'-azobis-(2,4-dimethylvaleronitrile), 2,2-azobis(2-methylbutyronitrile), 1,1'-azobis(cyclohexane-1-carbonitrile), dimethyl 2,2'-azobis(2-methylpropionate), benzoyl peroxide (BPO), lauroyl peroxide, cumene hydroperoxide, and the like. The amount of these initiators used in the method of the present disclosure is the same as that conventionally used in the art. For example, the amount of BPO used in the method of the present disclosure can be 0.1 ‰-10.0 ‰, preferably 1.0 ‰-5.0 ‰, in moles, of the monomer.

[0096] The polymerization in the present disclosure is suspension polymerization as shown in step (a) of the above process. The dispersing agents used in the above process are intended to prevent the particles from aggregating during the suspension polymerization. The dispersing agents suitable 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, diatomite, 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 amount of these dispersing agents used in the process of the present disclosure is the same as that conventionally used in the art. For example, the amount of PVA used in the process of the present disclosure can be 0.1% to 2.0% (w / w), preferably 0.3% to 1.0% (w / w) of the aqueous phase.

[0097] It has been found that the aggregation of the particles can be reduced by adding an inorganic salt to the aqueous phase in step (a) of the above process. The inorganic salt suitable for this purpose includes various salts capable of dissolving in the aqueous phase. For example, it can be selected from the group consisting of potassium chloride, sodium chloride, ammonium chloride, calcium chloride, magnesium chloride, and any mixture thereof. The amount of the inorganic salt to be added is 0.1% to 10% w / w, preferably 1% to 5% w / w, more preferably 3% to 4% w / w, for example 2% w / w, based on the total weight of the aqueous phase.

[0098] The elevated temperature of the polymerization in step (a) of the above process refers to a temperature equal to or higher than 60°C, for example 60°C to 85°C.

[0099] The hydrolysis in step (b) of the above process should be carried out in a mixed solution of an aqueous base and an organic solvent. The inventors have found that the hydrolysis is incomplete in an aqueous base without an organic solvent or in the presence of an acid, or produces colored impurities if the temperature is elevated to facilitate the hydrolysis. The organic solvent used for the hydrolysis is selected from the group consisting of ethanol, methanol, isopropanol, toluene, acetonitrile, ethers such as 2-methyltetrahydrofuran and tetrahydrofuran, and any mixture thereof. The base used for the hydrolysis includes, but is not limited to, potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, and any mixture thereof.

[0100] The acid used in step (c) of the above process includes, but is not limited to, sulfuric acid, hydrochloric acid, nitric acid, or any mixture thereof.

[0101] The conversion in step (d) of the above process can be carried out in a conventional manner suitable for salification. For example, it can be carried out by using a suitable aqueous base or salt solution. The suitable base or salt can be selected from the group consisting of ferric chloride hexahydrate, ferric chloride, calcium hydroxide, sodium hydroxide, iron hydroxide, calcium carbonate, sodium carbonate, and any mixture thereof.

[0102] In another aspect, the present disclosure provides a polymer prepared by the above-mentioned method.

[0103] In another aspect, the present disclosure also provides a pharmaceutical composition comprising one or more polymers or salts thereof as described above and a pharmaceutically acceptable excipient.

[0104] The pharmaceutical composition is used as a potassium-binding agent for reducing the level of potassium ions in the body and for preventing and treating hyperkalemia.

[0105] The pharmaceutical composition can be formulated into a solid preparation (including but not limited to a capsule, a tablet, a pill, a granule, a powder, a solid dispersion) or a liquid preparation (including but not limited to a suspension) for oral administration according to a conventional method.

[0106] The pharmaceutical composition can comprise 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 can be present in an amount 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, 100 g in a unit dosage form.

[0107] The pharmaceutically acceptable excipient used in the pharmaceutical composition can be selected from one or more of the following:

[0108] a) diluents, such as lactose, sucrose, sorbitol, mannitol, starch, microcrystalline cellulose, dextrin, etc.;

[0109] b) disintegrants, such as croscarmellose sodium, crospovidone, starch (e.g., starch, sodium starch glycolate, hydroxypropyl starch), etc.;

[0110] c) binders, such as starch paste, polyvinylpyrrolidone (PVP), methylcellulose, ethylcellulose, etc.;

[0111] d) glidants, such as silicon dioxide, magnesium stearate, etc.;

[0112] e) colorants;

[0113] f) flavoring agents;

[0114] h) suspending agents.

[0115] In some embodiments, the diluent can be present in an amount of 35-90% w / w of the composition. In some embodiments, the disintegrant can be present in an amount of 0.5-10% w / w of the composition. In some embodiments, the binder can be present in an amount of 0.5-5% w / w of the composition. In some embodiments, the glidant can be present in an amount of 0.1-5% w / w of the composition. In some embodiments, the coloring agent, flavoring agent, and suspending agent can each be present in an amount of 0.05-5% w / w of the composition.

[0116] In another aspect, the present disclosure further provides use of the polymer as described above or a salt thereof or the pharmaceutical composition as described above in the manufacture of a medicament for adsorbing potassium ions or reducing potassium ion levels in vivo.

[0117] In yet another aspect of the present disclosure, the present disclosure further provides use of the polymer as described above or a salt thereof or the pharmaceutical composition as described above in the manufacture of a medicament for preventing or treating hyperkalemia.

[0118] According to one embodiment of the present disclosure, the hyperkalemia is caused by administration of a drug that causes potassium retention.

[0119] The drug that causes potassium retention includes, but is 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, mosypril, perindopril, quinapril, ramipril, trandolapril, candesartan, eprosartan, irbesartan, losartan, valsartan, telmisartan, acebutolol, atenolol, betaloc, bisoprolol, carteolol, nadolol, propranolol, sotalol, timolol, canrenone, aliskiren, aldosterone synthesis inhibitors, VAP antagonists, amiloride, triamterene, potassium supplements, heparin, non-steroidal anti-inflammatory drugs, ketoconazole, trimethoprim, pentamidine, potassium-sparing diuretics, amiloride, aminophylline, doxorubicin, and combinations thereof.

[0120] In another aspect, the present disclosure further provides a method for reducing potassium ion levels in vivo or for preventing or treating hyperkalemia in an animal, the method comprising administering an effective amount of one or more of the polymers or salts thereof described above.

[0121] In another aspect, the present disclosure also provides a method for determining the potassium ion adsorption of a polymer, the method comprising the following steps: detecting the potassium binding capacity of the polymer by ion chromatography with the following conditions.

[0122] Chromatographic column: IonPac CS17 Analytic Column (4 x 250 mm)

[0123] Guard column: IonPac CG17 Guard Column (4 x 50 mm)

[0124] Flow rate: 1.0 ml / min

[0125] Detector: Conductivity detector

[0126] Column temperature: 30 °C

[0127] Injection volume: 10 μl

[0128] Eluent: 6 mM Methanesulfonic acid solution

[0129] Run time: 20 min.

[0130] Definitions and explanations

[0131] It will be appreciated by those skilled in the art that the symbol represents a binding site which can be further linked to a moiety contributed by a monomer or by the same or a different crosslinking agent.

[0132] The terms "potassium", "potassium ion" and "potassium cation" are used interchangeably herein to mean K + , unless the context indicates otherwise.

[0133] The term "animal" as used herein includes humans and other mammals, such as primates, cows, sheep, goats, horses, dogs, cats, rabbits, and the like, preferably humans. The present disclosure specifically provides a polymer composition for eliminating potassium ions from the body of an animal. Preferably, the composition can be used for eliminating potassium ions from the gastrointestinal tract of an animal.

[0134] The terms "potassium binding", "potassium ion adsorption", and "potassium adsorption" are used interchangeably herein. The potassium binding polymers of the present application have a high potassium binding capacity. The potassium binding capacity of the polymers of the present application can be determined in vitro. Preferably, the in vitro determination of the potassium binding capacity of the polymers of the present application is performed under physiological conditions simulating the gastrointestinal tract, in particular 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 having a pH of about 5.5 or above, for example, pH 6-8. In different embodiments, the potassium binding capacity of the polymers of the present application in acid form, as determined in a solution having a pH of about 5.5 or above, for example, pH 6-8, 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, the potassium binding capacity of the polymers of the present application in acid form, as determined in a solution having a pH of about 5.5 or above, is in the range of 5 mmol / g to 12 mmol / g, preferably 5.5 mmol / g to 10 mmol / g, more preferably 6 mmol / g to 8 mmol / g. The in vivo potassium binding capacity of the polymers of the present application was found to be directly proportional to the in vitro potassium binding capacity of the polymers in acid form, whether administered to an animal in acid form or in salt form.

[0135] The term "effective amount" or "effective dose" as used herein refers to an amount of the polymers of the present application that, when administered to an animal, will significantly reduce the potassium ion level in the animal, such that a disease associated with high potassium ion levels or one or more symptoms of the disease can be prevented, alleviated, or cured, or the onset or progression of the disease or one or more symptoms thereof can be delayed. The higher the potassium binding capacity of the polymers of the present application, the lower the dose. Typically, the effective therapeutic and prophylactic dose of the polymers of the present application ranges from about 1 g / day to about 100 g / day. A preferred dose ranges from about 5 g / day to about 60 g / day. A more preferred dose ranges from about 15 g / day to about 50 g / day. The daily dose can be administered in a single dose or in multiple divided doses. For example, the daily dose can be taken three times a day or once a day.

[0136] The polymer of the present application or a composition comprising the polymer can retain a substantial amount of bound potassium, the polymer binds potassium in the gastrointestinal tract, and the polymer does not release the bound potassium prior to excretion in the feces. By "substantial" is not meant the ability to retain all of the bound potassium. Preferably, at least a portion of the bound potassium is retained to achieve a therapeutic and / or prophylactic 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 a period of time sufficient to effectively treat and / or prevent hyperkalemia.

[0137] The potassium-binding polymer of the present application is preferably not absorbed by the gastrointestinal tract. The expression "not absorbed by" and its grammatical synonyms do not mean that none of the administered polymer is 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.

[0138] In some embodiments, the potassium-binding polymer of the present application can contain a protic or ionic acidic group, such as a sulfonic acid group (-SO3 - ), a sulfuric acid group (-OSO3 - ), a carboxylic acid group (-CO2 - ), a phosphonic acid group (-OPO3 2- ), a phosphoric acid group (-OPO3 2- ), and a sulfamic acid group (-NHSO3 - ).

[0139] Suitable phosphonic acid monomers that provide a phosphonic acid group (-OPO3 2- ) or a phosphoric acid group (-OPO3 2- ) to the polymer include vinyl phosphonic acid, ethylene-1,1-diphosphonic acid, ethylene derivatives of phosphonocarboxylic acid esters, oligo(methylene phosphonic acid), and hydroxyethane-1,1-diphosphonic acid. Methods of synthesis of these monomers are known.

[0140] The preferred monomer used herein is 2-fluoroacrylate, most preferably 2-fluoroacrylic acid methyl ester. These monomers are commercially available, for example, from Waterstone Pharmaceuticals (Hubei) Co., Ltd., or can also be prepared by known methods, for example, by the methods disclosed in European Patent EP 415214.

[0141] The word "about" used in connection with a numerical value, as used herein, extends the numerical value by ±20% of the stated value. For example, about 5% means a range of 4-6%. Preferably, the word "about" used in connection with a numerical value extends the numerical value by ±10% or ±5% of the stated value.

[0142] The expression "w / w" as used herein means that the ratio or percentage associated with this expression is expressed in weight.

[0143] The term "alkyl" as used herein means a straight-chain or branched-chain saturated hydrocarbon group having 1-6 carbon atoms (C 1-6 alkyl), preferably 1-3 carbon atoms (C 1-3 alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl, n-pentyl, n-hexyl.

[0144] The term "mole fraction" means the molar ratio of a compound or moiety relative to a specified basis. For example, the expression "the mole fraction of monomer is 0.85-0.98, the mole fraction of crosslinker is 0.02-0.15, and the sum of the mole fractions of monomer and crosslinker is 1" means that the specified basis for calculating the mole fraction is the sum of the moles of monomer and crosslinker, the mole fraction of monomer means the ratio of the moles of monomer to the sum of the moles of monomer and crosslinker and ranges from 0.85-0.98; similarly, the mole fraction of crosslinker means the ratio of the moles of crosslinker to the sum of the moles of monomer and crosslinker and ranges from 0.02-0.15.

[0145] Terms not defined herein have their ordinary meaning in the art. BRIEF DESCRIPTION OF DRAWINGS

[0147] The above and / or additional aspects and advantages of the present disclosure will become apparent and be readily appreciated from the description of the embodiments, taken in conjunction with the following drawings:

[0148] Figure 1A is a SEM spectrum of the MFA-APE-Na-Ca-Fe salt polymer of Example 3, Figure 1B is the XPS results of the MFA-APE-Na-Ca-Fe salt polymer of Example 3.

[0149] Figure 2 is a graph produced in Example 14 showing that Lokelma and the MFA-APE sodium salt polymer (MFA-APE-Na) prepared in Example 3 reduced serum K + in normal SD rats, and that the serum potassium lowering effect of the MFA-APE-Na polymer was superior to the two positive controls, Lokelma and Veltassa.

[0150] Figure 3is a graph produced in Example 15 showing Lokelma and MFA-APE sodium salt polymer (MFA-APE-Na) prepared in Example 3 reduced KCl-induced serum K + increased.

[0151] Figure 4 is a graph produced in Example 16 showing Lokelma and MFA-APE complex salt polymer (MFA-APE-Na-Ca-Fe) prepared in Example 3 reduced serum K in a 5 / 6 nephrectomized hyperkalemic rat model + .

[0152] Figure 5 is a graph produced in Example 17 showing Lokelma and MFA-APE complex salt polymer (MFA-APE-lysine-Ca-Fe) prepared in Example 5 reduced serum K in a 5 / 6 nephrectomized hyperkalemic rat model + and the serum potassium lowering effect of the MFA-APE-lysine-Ca-Fe polymer was significantly better than the positive control (Lokelma) at day 14 post-dosing.

[0153] Example

[0154] The present disclosure is described below with reference to specific implementations. It should be noted that these implementations are merely descriptive, and do not limit the present disclosure in any way.

[0155] The following abbreviations are used throughout the present disclosure:

[0156]

[0157] The crosslinking agents used in the Examples have the structures shown in Table 1.

[0158] [Table 1]

[0159]

[0160] Example 1

[0161]

[0162] Pure water (550 mL), NaCI (11.0 g) and PVA (3.4 g) were added to a reaction flask and stirred at 20-30 °C until complete dissolution to get a clear solution. MFA solution was prepared by stirring and complete dissolution of 104.0 g MFA (1.0 mol), 12.8 g APE (0.05 mol) and 0.73 g BPO (0.003 mol) to get a clear solution, which was kept ready for use. The prepared MFA solution was added to the solution in the reaction flask. The temperature of the contents in the reaction flask was gradually increased to 70-80 °C, after which the temperature was maintained and stirred for 15 hours. Gas chromatography monitoring showed that the reaction was complete. After the temperature was reduced to 20-30 °C, suction filtration was performed. The filter cake was slurried and washed with water and ethanol. The resulting wet product was dried at 50 °C under vacuum to obtain 97.3 g of white solid, which was MFA-APE ester polymer. The MFA-APE ester product was characterized by infrared spectroscopy using a SHIMADZU IRSpirit-T Fourier Transform Infrared Spectrometer (FTIR) (Chinese Pharmacopoeia 2020 Volume IV, General Chapter 0402). No characteristic absorption peak of C=C bond was observed on the Fourier Transform Infrared Spectroscopy (FTIR) of the MFA-APE ester polymer.

[0163] 400 mL of water, 130 mL of EtOH and 48.0 g of sodium hydroxide were added to a reaction flask, followed by the above MFA-APE ester polymer under stirring. The temperature was increased to 50-60 °C, then stirred and maintained at this temperature for 15 hours. The temperature was reduced to 20-30 °C, then filtered, the filter cake was slurried and washed with water and ethanol, and filtered to obtain wet MFA-APE sodium salt polymer.

[0164] 500 mL of water and 100 mL of concentrated hydrochloric acid were added to a reaction flask, followed by the above wet MFA-APE sodium salt polymer, then stirred at 20-30 °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 dried at 50 °C under vacuum for 8 hours to obtain 84.6 g of white dry product, which was pulverized and sieved through a 120 mesh sieve to obtain MFA-APE acid polymer (m = 0.95, n = 0.05) (MFA-APE-H).

[0165] The K + The adsorption capacity was 7.2 mmol / g, as determined in Example 13.

[0166] MFA-APE acid polymer was determined by differential scanning calorimeter (DSC). Instrument model: METTLER TOLEDO DSC3 differential scanning calorimeter. Analytical method: Chinese Pharmacopoeia 2020 edition, general section 0661 thermal analysis method. Nitrogen condition: 50 mL / min. Scanning operation: 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, temperature was increased to 150 °C again at a rate of 10 °C / min, and the second heating curve was recorded. All reagent trays were aluminum. The obtained DSC curve showed that the glass transition temperature (Tg) of the acid polymer was 139.75 °C.

[0167] MFA-APE acid polymer was determined by thermal gravimetric analyzer (TGA). Instrument model: TGA 2 differential scanning calorimeter. Analytical method: Chinese Pharmacopoeia 2020 edition, general section 0661 thermal analysis method. Nitrogen condition: 50 mL / min. Scanning operation: temperature was increased from 30 °C to 800 °C at a rate of 10 °C / min. The decomposition temperature value of MFA-APE acid polymer was calculated based on the curve. All reagent trays were platinum. The obtained TGA curve showed that the decomposition temperature of the final polymer was 208.90 °C.

[0168] Example 2

[0169]

[0170] Pure water (550 mL), NaCl (11.0 g), and PVA (3.4 g) were added to a reaction flask, stirred at 20 °C-30 °C until completely dissolved, to obtain a clear solution. The MFA solution was prepared as follows: 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) were stirred and completely dissolved to obtain a clear solution, ready for use. The prepared MFA solution was added to the clear solution in the reaction flask. The temperature of the materials in the reaction flask was gradually increased to 70 °C-80 °C, then the temperature was maintained and stirred for 15 hours. Gas chromatography monitoring showed that the reaction was complete. After the temperature was reduced to 20 °C-30 °C, suction filtration was performed. The filter cake was slurried with water and washed 3 times. The obtained wet product was dried to obtain 115.2 g of white solid, which was MFA-TAIC-APE ester polymer. The MFA-TAIC-APE ester polymer was dried and characterized by FTIR as described in Example 1. For MFA-TAIC-APE ester polymer, no characteristic absorption peak of C=C bond was observed on the Fourier transform spectrometer (FTIR).

[0171] Into a reaction flask was added 400 mL of water, 130 mL of EtOH and 48.0 g of sodium hydroxide, followed by the addition of the above MFA-TAIC-APE ester polymer under stirring. The temperature was increased to 50°C-60°C, followed by stirring and maintaining the temperature for 15 hours. The temperature was decreased to 20°C-30°C and then filtered. The filter cake was slurried with water and washed 3 times. The filtered wet product was MFA-TAIC-APE sodium salt polymer (MFA-TAIC-APE-Na).

[0172] Into a reaction flask was added 500 mL of water and 100 mL of concentrated hydrochloric acid, followed by the addition of the above wet MFA-TAIC-APE sodium salt polymer under stirring for 15 hours at 20°C-30°C. After filtration, the filter cake was washed repeatedly with 4 L of water. The filtered wet product was slurried once with 500 mL of ethanol. The filtered wet product was dried under vacuum at 50°C for 8 hours to obtain 85.7 g of white dry product, which was pulverized and sieved through a 120 mesh sieve to obtain MFA-TAIC-APE acid polymer (m = 0.90, n = 0.05, p = 0.05) (MFA-TAIC-APE-H).

[0173] The K + The adsorption capacity was 6.6 mmol / g, as determined in Example 13.

[0174] The MFA-TAIC-APE acid polymer was tested by DSC and TGA as described in Example 1. The DSC curve obtained showed that the glass transition temperature of the MFA-TAIC-APE acid polymer was 137.90°C. The TGA curve obtained showed that the decomposition temperature of the MFA-TAIC-APE acid polymer was 192.97°C.

[0175] Example 3

[0176]

[0177] MFA-APE ester polymer was prepared using similar procedures as 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 peak of C=C bond was observed on the Fourier transform infrared spectrum (FTIR) of the MFA-APE ester polymer.

[0178] To a reaction flask was added 400 mL of water, 130 mL of EtOH and 48.0 g of sodium hydroxide, followed by the addition of the above MFA-APE ester polymer under stirring. The temperature was increased to 50°C-60°C, then stirred and maintained at this temperature for 15 hours. The temperature was decreased to 20°C-30°C, then filtered, the filter cake was slurried and washed with water and ethanol, filtered to obtain the wet MFA-APE sodium salt polymer (MFA-APE-Na). A sample of the MFA-APE sodium salt polymer was taken and dried for potassium binding capacity determination as described in Example 13, which showed the K + The adsorption capacity was 4.2 mmol / g.

[0179] To a reaction flask was added 500 mL of water and 100 mL of concentrated hydrochloric acid, followed by the addition of the above wet MFA-APE sodium salt polymer, followed by stirring at 20°C-30°C for 15 hours. After filtration, the filter cake was washed repeatedly with 4 L of water, filtered to obtain the wet MFA-APE acid polymer (MFA-APE-H).

[0180] A sample of the MFA-APE acid polymer was taken and dried for potassium binding capacity determination as described in Example 13, which showed the K + The adsorption capacity was 7.4 mmol / g.

[0181] To the above acid polymer was added 240 mL of water under stirring at 10-30°C. To this mixture was slowly added FeCl3(0.7 g), Ca(OH)2(18.0 g) and NaOH (9.6 g) while controlling the internal temperature at 10-30°C. The mixture was stirred for 2-5 hours, then the mixture was 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 99.0 g of a yellow dry product, which was pulverized and sieved through a 120 mesh sieve to obtain the MFA-APE Na-Ca-Fe complex salt polymer (m=0.95, n=0.05) (MFA-APE-Na-Ca-Fe).

[0182] The K + The adsorption capacity was 2.39 mmol / g, as determined in Example 13.

[0183] The MFA-APE-Na-Ca-Fe polymer was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the final polymer was 130.82°C. The resulting TGA curve showed that the decomposition temperature of the final polymer was 193.06°C.

[0184] The MFA-APE-Na-Ca-Fe polymer was detected by scanning electron microscopy (SEM). Analysis instrument model: Quanta 400 hot field emission scanning electron microscope. Analysis method: JY / T 0584-2020 General Rules for Scanning Electron Microscope Examination Analysis Method. The SEM results are shown in Figure 1A FIG. 6. The SEM photos show that the MFA-APE-Na-Ca-Fe polymer has a regular spherical structure.

[0185] The MFA-APE-Na-Ca-Fe polymer was detected by X-ray photoelectron spectroscopy (XPS). Analysis method: GB / T 19500-2004 General Rules for X-ray Photoelectron Spectroscopy Examination. The XPS results are shown in Figure 1B FIG. 7. The results show that carbon, oxygen, fluorine, calcium, and sodium exist in the MFA-APE-Na-Ca-Fe polymer. The MFA-APE-Na-Ca-Fe polymer was acidified with a sulfuric acid solution, the supernatant was taken, and potassium thiocyanate test solution was added, which showed a positive reaction, proving that iron ions exist in the MFA-APE-Na-Ca-Fe polymer.

[0186] Example 4

[0187]

[0188] A MFA-TAIC-APE ester polymer was prepared using a method similar to that of Example 2. The reaction was monitored by gas chromatography. The MFA-TAIC-APE ester polymer was characterized by FTIR as described in Example 1. No characteristic absorption peak of C=C bond was observed on the Fourier transform infrared spectrum (FTIR) of the MFA-TAIC-APE ester polymer.

[0189] 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide were added to a reaction flask, and then the MFA-TAIC-APE ester polymer was added under stirring. The temperature was increased to 50°C-60°C, and then stirring was maintained at this temperature for 15 hours. The temperature was reduced to 20°C-30°C, and then filtration was performed, the filter cake was slurried with water and washed 3 times. The filtered wet solid was a MFA-TAIC-APE sodium salt polymer (MFA-TAIC-APE-Na).

[0190] 500 mL of water and 100 mL of concentrated hydrochloric acid were added to a reaction flask, and the above MFA-TAIC-APE sodium salt polymer was added, followed by stirring at 20°C-30°C for 15 hours. After filtration, the filter cake was repeatedly washed with 4 L of water, and filtration was performed to obtain a MFA-TAIC-APE acid polymer (MFA-TAIC-APE-H).

[0191] To the resulting wet MFA-TAIC-APE acid polymer, 240 mL of water was added and stirred at 10-30 °C. To this mixture, 0.7 g of FeCl3, 18.0 g of Ca(OH)2, and 9.6 g of NaOH were slowly added while the internal temperature was controlled 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 cake was dried at 50 °C under vacuum for 8 hours to obtain 102.5 g of a yellow dry product, which was pulverized and sieved through a 120 mesh screen to obtain MFA-TAIC-APE Na-Ca-Fe complex salt polymer (m = 0.90, n = 0.05, p = 0.05) (MFA-TAIC-APE-Na-Ca-Fe).

[0192] Example 5

[0193]

[0194] MFA-APE acid polymer was prepared using a method similar to Example 1. The MFA-APE acid polymer was characterized by FTIR as described in Example 1. No characteristic absorption peak of C=C bond was observed on the Fourier transform infrared spectrum (FTIR) of the MFA-APE acid polymer.

[0195] To the MFA-APE acid polymer wet product, 240 mL of water was added and stirred at 10-30 °C. To this mixture, FeCl3 (0.7 g), Ca(OH)2 (15.0 g), and L-lysine (23.7 g) were slowly added while the internal temperature was controlled 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 cake was dried at 50 °C under vacuum for 8 hours to obtain 109.3 g of a bright red dry product, which was pulverized and sieved through a 120 mesh screen to obtain MFA-APE Lys-Ca-Fe complex salt polymer (m = 0.95, n = 0.05) (MFA-APE-Lys-Ca-Fe).

[0196] The K of this MFA-APE-Lys-Ca-Fe salt polymer was determined to be 0.95. + The adsorption capacity was 2.95 mmol / g, as determined in Example 13.

[0197] This MFA-APE-Lys-Ca-Fe salt polymer was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the polymer was 144.52 °C. The resulting TGA curve showed that the decomposition temperature of the polymer was 194.38 °C.

[0198] Examples 6-9

[0199] Examples 6-9 were carried out in a similar manner to Example 1 to obtain MFA-APE acid polymers. Salt polymers were then prepared using a similar method to Example 3. No characteristic absorption peak of C=C bond was observed on the Fourier transform infrared spectroscopy (FTIR) of these MFA-APE acid polymers.

[0200] In Example 6, the amounts of MFA and APE were 1.0 mol and 0.25 mol, corresponding to the mole fraction of MFA and APE of 0.80:0.20 (m:n=0.80:0.20). The MFA-APE acid polymer K + The adsorption capacity was 5.5 mmol / g, as determined in Example 13. The MFA-APE acid polymer was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the MFA-APE acid polymer was 164.25 °C. The resulting TGA curve showed that the decomposition temperature of the MFA-APE acid polymer was 196.51 °C. The K + The adsorption capacity was 2.6 mmol / g, as determined in Example 13. The MFA-APE-Na-Ca-Fe salt polymer was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 166.65 °C. The resulting TGA curve showed that the decomposition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 181.09 °C.

[0201] In Example 7, the amounts of MFA and APE were 1.0 mol and 0.12 mol, corresponding to the mole fraction of MFA and APE of 0.89:0.11 (m:n=0.89:0.11). The K + The adsorption capacity was 6.6 mmol / g, as determined in Example 13. The MFA-APE acid polymer was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the acid polymer was 134.94 °C. The resulting TGA curve showed that the decomposition temperature of the polymer was 211.67 °C. The K +The adsorption capacity was 2.8 mmol / g, as determined in Example 13. The MFA-APE-Na-Ca-Fe salt polymer was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 146.51 °C. The resulting TGA curve showed that the decomposition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 191.81 °C.

[0202] In Example 8, the amounts of MFA and APE were 1.0 mol and 0.02 mol, corresponding to a mole fraction of MFA and APE of 0.98:0.02 (m:n = 0.98:0.02). The K + The adsorption capacity was 7.6 mmol / g, as determined in Example 13. The MFA-APE acid polymer was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the MFA-APE acid polymer was 140.17 °C. The resulting TGA curve showed that the decomposition temperature of the MFA-APE acid polymer was 209.85 °C.

[0203] In Example 9, the amounts of MFA and APE were 0.5 mol and 0.5 mol, corresponding to a mole fraction of MFA and APE of 0.50:0.50 (m:n = 0.50:0.50). The K + The adsorption capacity was 3.2 mmol / g, as determined in Example 13. The end product was tested by DSC and TGA as described in Example 1. The resulting DSC curve showed that the glass transition temperature of the MFA-APE acid polymer was 106.01 °C. The resulting TGA curve showed that the decomposition temperature of the MFA-APE acid polymer was 198.09 °C.

[0204] Example 10

[0205] Pure water (550 mL), PEG600 (4.6 g) and NaCl (11.0 g) were added to a reaction flask and stirred at 20-30 °C until the mixture was completely dissolved. A MFA solution was prepared by stirring and completely dissolving MFA (104.0 g, 1.0 mol), APE (12.8 g, 0.05 mol) and BPO (0.73 g, 0.003 mol) and ready for use. The prepared MFA solution was added to the reaction flask. The temperature was gradually increased to 70-75 °C and the reaction was stirred for 15 hours. A large amount of solid was formed in the flask. After filtering the reaction mixture, 123 g of wet cake was obtained and dried at 50 °C to obtain 90.4 g of white solid. The MFA-APE ester polymer was inhomogeneous, hard and irregular lumps.

[0206] Example 11

[0207] Pure water (550 mL), NaCl (11.0 g) and PVA (4.6 g) were added to a reaction flask and stirred at 50-60 °C until the mixture was completely dissolved. A MFA solution was prepared by stirring and completely dissolving MFA (104.0 g, 1.0 mol), APE (12.8 g, 0.05 mol) and BPO (0.73 g, 0.003 mol) and ready for use. The prepared MFA solution was added to the reaction flask. The temperature was gradually increased to 55-59 °C and the mixture was stirred at 55-59 °C for 15-20 hours. No solid was precipitated. Another portion of BPO (0.73 g, 0.003 mol) was added to the reaction mixture and the temperature was increased to above 60 °C and some white solid was precipitated. The temperature was maintained and the mixture was stirred for 15-20 hours. The reaction was filtered and the obtained solid was slurried with water and EtOH to obtain 88.5 g of MFA-APE ester polymer wet product. The MFA-APE ester polymer was characterized by FTIR as described in Example 1. No characteristic absorption peak of C=C bond was observed on the Fourier transform infrared spectrum (FTIR) of the MFA-APE ester polymer.

[0208] Water (270 mL), EtOH (90 mL) and 71 g of prepared MFA-APE ester polymer wet product were added to a flask and sodium hydroxide (40 g) was added to the reaction flask and the temperature was increased to 60-65 °C. The mixture was stirred at 60-65 °C for 20-24 hours. The temperature was decreased to 20-30 °C and the mixture was filtered and washed with water to obtain MFA-APE-Na salt polymer.

[0209] 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.

[0210] 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.

[0211] Example 12

[0212]

[0213] 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.

[0214] 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.

[0215] Example 13

[0216] 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.

[0217] Standard curve: Five 100 ml volumetric flasks are identified with the numbers 1, 2, 3, 4 and 5. Add 1, 3, 6, 8 and 10 mL of potassium buffer to the flasks in that order, dilute to volume with water and mix. Perform ion chromatography on the 1, 2, 3, 4 and 5 volumetric flasks and record the peak area for potassium ions. Plot the observed peak areas as the ordinate and the potassium concentration in mmol / liter as the abscissa on a regular coordinate paper.

[0218] Test sample solution: Take about 1.6 g of polymer and place it in a 250 ml conical flask. Add 100 ml of potassium buffer and place the flask in a 37°C ± 2°C water bath with magnetic stirring for 24 hours. Shake well and take a sample (as recommended at 15 min, 3 h, 5 h or 24 h), filter and accurately pipette 1.0 ml of the filtrate into a 100 ml volumetric flask. Dilute to the mark with water.

[0219] Analyze the test sample solution by ion chromatography and record the peak area for potassium ions. Determine the potassium concentration in mmol / liter by extrapolation from the standard curve. Calculate the amount of potassium ions adsorbed on the resin in mmol / g by the following formula:

[0220] Potassium ion adsorption capacity of the polymer = (X - 2.5Y) / W

[0221] where X is the weight of potassium in the 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.

[0222] The chromatographic conditions are listed in Table 2 below.

[0223] [Table 2]

[0224]

[0225] Results and analysis

[0226] The potassium ion adsorption capacity of the polymers in the examples is shown in Table 3 below.

[0227] [Table 3]

[0228]

[0229] ※ Note: Veltassa acid sample was obtained as follows: 3.2 g of Veltassa was acidified with 4N HC1 at 37°C overnight, centrifuged, the supernatant was discarded, washed with water 5 times, filtered, dried to obtain the test sample. Figure 2

[0230] Example 14

[0231] Twenty-four normal male SD rats (6-8 weeks, 190~210g, Hubei Experimental Animal Research Center) were adaptively fed for 3-5 days, and then randomly divided into 4 groups, namely, blank control group, positive control group 1 (Lokelma), positive control group 2 (Veltassa), and test product group (MFA-APE-Na prepared in Example 3), 6 rats in each group. The animals in each group were orally administered with solvent or drug in a single dose at a volume of 10 ml / kg. More specifically, the animals in the blank control group were administered with normal saline at a volume of 10 ml / kg, the positive control group 1 was administered with 1.8 g / kg of Lokelma in the same volume of normal saline, the positive control group 2 was administered with 3.5 g / kg of Veltassa in the same volume of normal saline, and the test product group was administered with 1.8 g / kg of MFA-APE-Na in the same volume of normal saline. At 6 hours after administration, blood was taken from the jugular vein. The blood sample was centrifuged, and the supernatant was taken for detection of serum potassium concentration.

[0232] The results showed that: (1) compared with the blank control group, the serum K + level in the test product group (MFA-APE-Na) was significantly reduced at 6 hours after administration (P < 0.01), (2) the potassium-lowering effect of the test product (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 change in serum K + level in the test product group was significantly reduced (P < 0.05), (4) the potassium-lowering effect of the test product (MFA-APE-Na prepared in Example 3) was significantly better than that of Lokelma (P < 0.05) and Veltassa (P < 0.05), as shown in the table. Figure 3

[0233] Example 15

[0234] ​Eighteen normal male SD rats (6-8 weeks, 190~210g, Hubei Experimental Animal Research Center) were acclimated for 3-5 days, and then randomly divided into 3 groups, i.e. model group, positive control group (Lokelma), and test product group (MFA-APE-Na prepared in Example 3), each group including 6 rats. The animals in each group were orally administered with a single dose of solvent or drug at a volume of 10 ml / kg. The rats in the model group were administered with normal saline at a volume of 10 ml / kg. The rats in the positive control group were administered with 1.8 g / kg of Lokelma in the same volume of normal saline. The rats in the test product group were administered with 1.8 g / kg of MFA-APE-Na in the same volume of normal saline. At 3 hours after administration, 10% KCl solution was intraperitoneally injected, and then 5% KCl solution was intraperitoneally injected at 4, 5 and 6 hours after administration. The intraperitoneal injection volume of 10% and 5% KCl solution was 4 ml / kg. Blood was taken from the jugular vein before administration (0 hour) and at 3.5, 4.5 and 6.5 hours after administration. The blood samples were centrifuged, and the supernatant was detected for serum potassium concentration.

[0235] The results showed that, compared with the model group, the serum potassium concentration of the test product group (MFA-APE-Na prepared in Example 3) and the positive control group (Lokelma) was reduced, and there was a statistically significant difference (p<0.05) at 4.5 and 6.5 hours after administration, as shown in Table 2. Figure 4

[0236] Example 16

[0237] ​Twenty-four normal male SD rats (6-8 weeks, 200-250 g, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were adaptively fed for 3-5 days, and then randomly divided into 5 groups, namely normal group, model group, positive control group (Lokelma), test product group (MFA-APE-Na-Ca-Fe prepared in Example 3), each group including 6 rats. Except for the normal group, the other animals were modeled as follows: first, two-thirds of the left kidney (one-third of the upper kidney and one-third of the lower kidney) was removed, and one week later, the entire right kidney was removed, to obtain a 5 / 6 nephrectomy rat model. After 2 weeks of regular diet, a single intravenous injection of adriamycin (3.5 mg / kg) was performed, and immediately methicillin (300 mg / kg intragastrically, qd) and quinapril (30 mg / L, added to water) were administered. The animals in each group were orally administered with a single dose of solvents or drugs in a volume of 20 ml / kg. The rats in the normal group and the model group were treated with solvents (0.1% xanthan gum) in a volume of 20 ml / kg, the positive control group was treated with 2 g / kg of Lokelma in the same volume of solvent, and the test product group was treated with 2 g / kg of MFA-APE-Na-Ca-Fe of Example 3 in the same volume of solvent. Oral administration was performed once a day for 2 weeks. All rats were bled from the jugular vein 5 days before adriamycin injection and 7 and 14 days after adriamycin injection. The blood samples were centrifuged, and the supernatant was used to detect the serum potassium concentration.

[0238] The results showed that compared with the model group, the serum potassium concentration in the test product group (MFA-APE-Na-Ca-Fe prepared in Example 3) was significantly reduced (P<0.001, P<0.01, respectively) on the 7th day and the 14th day after administration, as shown in Figure 5 .

[0239] Example 17

[0240] Twenty-four normal male SD rats (6-8 weeks, 200-250 g, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were adaptively fed for 3-5 days, and then randomly divided into 4 groups, namely normal group, model group, positive control group (Lokelma), and test product group (MFA-APE-lysine-Ca-Fe prepared in Example 5), each group including 6 rats. Except for the normal group, the other animals were modeled as follows: first, two-thirds of the left kidney (one-third of the upper kidney and one-third of the lower kidney) was removed, and one week later, the entire right kidney was removed, to obtain a 5 / 6 nephrectomy rat model. After 2 weeks of regular diet, intravenous injection of adriamycin (3.5 mg / kg) was performed, and immediately, trimethoprim (300 mg / kg by gavage) and quinapril (30 mg / L, added to water) were administered. The animals in each group were orally administered with a single dose of solvent or drug in a volume of 20 ml / kg. The rats in the normal group and the model group were administered with solvent (0.1% xanthan gum) in a volume of 20 ml / kg, the positive control group was administered with 2 g / kg of Lokelma in the same volume of solvent, and the test product group was administered with 2 g / kg of MFA-APE-lysine-Ca-Fe of Example 5 in the same volume of solvent. Oral administration was performed once a day for 2 weeks. All rats were bled from the jugular vein 5 days before adriamycin injection and 7 and 14 days after adriamycin injection. The blood samples were centrifuged, and the supernatant was taken for detection of serum potassium concentration.

[0241] The results show that, compared with the model group, the serum potassium concentration in the test product group (MFA-APE-lysine-Ca-Fe prepared in Example 5) and the positive control group (Lokelma) was significantly reduced (P<0.01 or P<0.001) on the 7th day and the 14th day after administration, and the potassium-lowering effect of the test product (MFA-APE-lysine-Ca-Fe) was significantly better than that of the positive control (Lokelma) on the 14th day after administration, as shown in Table 2. ​

[0242] In the present specification, the description involving the terms “embodiment”, “some embodiments”, “example”, “specific example”, “some examples”, “embodiment”, “specific embodiment”, or “some embodiments” or the like means that the specific features, structures, materials or characteristics described in connection with the embodiment, example or embodiment are included in at least one embodiment or example or embodiment of the present disclosure. In the present specification, the above terms are illustrative, and do not necessarily refer to the same embodiment or example or embodiment. In addition, the specific features, structures, materials or characteristics described can be incorporated in any one or more embodiments or examples or embodiments in a suitable manner. In addition, a person skilled in the art can incorporate different embodiments or examples or embodiments described in the present specification, and the features of different embodiments or examples or embodiments, without contradiction with each other.

[0243] ​While the foregoing examples and description of the embodiments of the present disclosure, it is to be understood that the above-described embodiments are illustrative and not to be construed as limiting, and that changes, modifications, substitutions and alterations can be suggested to one skilled in the art, all of which are intended to be embraced within the scope of the present disclosure.

Claims

1. A polymer having the structure of formula (II) or a pharmaceutically acceptable salt thereof: (II), Where n1 is 1, 2 or 3, n2 is 1, 2 or 3, and 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 polymer according to claim 1, wherein the polymer has the structure of formula (III) or a pharmaceutically acceptable salt thereof: (III)。 3. The polymer according to claim 1, wherein the polymer has the structure of formula (IV): (IV), M is a basic group.

4. The polymer according to claim 3, wherein M is Fe, Ca, Na, Mg, lysine, or a combination thereof.

5. The polymer according to claim 4, wherein n1 is 1, n2 is 1, and R2 is H.

6. A 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.

7. A 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.

8. The polymer 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; The crosslinking agent is of formula (VI). Compounds, wherein n1 is independently 1, 2, or 3; n2 is independently 1, 2, or 3, 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.

9. The polymer according to claim 8, wherein R1 is C 1-3 alkyl.

10. The polymer according to claim 8, wherein the monomer is of formula (VIII). Compounds.

11. The polymer according to any one of claims 8-10, wherein the crosslinking agent is of formula (IX). Compounds; 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.

12. The polymer according to claim 11, wherein 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.

13. The polymer according to claim 11, wherein 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.

14. The polymer according to claim 11, wherein 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.

15. The polymer according to claim 11, wherein in the polymerization reaction, the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinking agent is 0.

05.

16. The polymer 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; The crosslinking agent is of formula (VI). The compounds, wherein n1 is independently 1, 2 or 3; n2 is independently 1, 2 or 3; 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. The polymerization reaction temperature rise refers to a temperature equal to or greater than 60°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.

17. The polymer according to claim 16, wherein the elevation temperature of the polymerization reaction refers to 60°C-85°C.

18. The polymer according to claim 16, wherein R1 is C 1-3 alkyl.

19. The polymer according to claim 16, wherein the monomer is of formula (VIII). Compounds.

20. The polymer according to claim 16, wherein the crosslinking agent is of formula (IX). Compounds; and 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.

21. The polymer according to claim 20, wherein 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.

22. The polymer according to claim 20, wherein 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.

23. The polymer according to claim 20, wherein 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.

24. The polymer according to claim 20, wherein in the polymerization reaction, the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinking agent is 0.

05.

25. The polymer according to any one of claims 16-24, 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.

26. The polymer according to any one of claims 16-24, wherein the inorganic salt is selected from potassium chloride, sodium chloride, ammonium chloride, calcium chloride, magnesium chloride, and any mixture thereof.

27. The polymer according to any one of claims 16-24, 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.

28. The polymer of claim 27, wherein the ether is selected from 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, dimethoxyethane, and ethylene glycol diethyl ether.

29. The polymer according to any one of claims 16-24, wherein the acid used in step (c) is selected from sulfuric acid, hydrochloric acid, nitric acid, and any mixture thereof.

30. The polymer according to any one of claims 16-24, wherein the polymer is in the form of a sodium salt, calcium salt, iron salt, lysine salt, or a combination thereof.

31. The polymer according to any one of claims 16-24, wherein the polymer is in the form of a Na-Ca-Fe complex salt or a Lys-Ca-Fe complex salt.

32. A pharmaceutical composition comprising the polymer of any one of claims 1-31 and a pharmaceutically acceptable excipient.

33. Use of the polymer of any one of claims 1-31 in the preparation of a medicament for the treatment or prevention of hyperkalemia.

34. The use according to claim 33, wherein the hyperkalemia is caused by the administration of a drug that causes potassium retention.

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