Medicinal polymer for treating hyperkalemia and method for producing same

Abstract

The present application relates to a potassium-binding polymer prepared by a polymerization reaction of a monomer and a crosslinker, wherein the monomer is a compound of formula (V), the crosslinker is a compound of formula (VI) and / or a compound of formula (VII), and the variables are as defined herein, and the potassium-binding polymer and its use for treating or preventing hyperkalemia are provided herein. JPEG2024542898000093.jpg23150

Description

[Technical field]

[0001] Related Applications This application claims priority to patent application No. PCT / CN2021 / 131264, filed on November 17, 2021, which is incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to the field of medicinal chemistry, and in particular, the present disclosure relates to medicinal polymers for treating hyperkalemia and methods for making the same. [Background technology]

[0003] 2. Background of the Invention Potassium (K+) is the most abundant intracellular cation, and its content in the human body is approximately 35mEq / kg to 40mEq / kg. Serum potassium in the range of approximately 5.0mEq / L to 6.0mEq / L can be defined as mild hyperkalemia, which is usually not life-threatening. However, moderate to severe hyperkalemia (serum potassium levels above approximately 6.1mEq / L) can have serious consequences. Cardiac arrhythmias and distortion of the electrocardiogram waveform are both characteristic of hyperkalemia. When serum potassium levels rise to approximately 9mEq / L or higher, symptoms such as atrioventricular dissociation, ventricular tachycardia, or ventricular fibrillation may appear.

[0004] Hyperkalemia is rare in the general healthy population. However, some populations have a higher incidence of hyperkalemia. Among hospitalized patients, the incidence of hyperkalemia is approximately 1% to 10%, depending on the definition of hyperkalemia. Critically ill patients, premature infants, or elderly people are all in higher risk groups. Reduced renal function, genitourinary disease, cancer, severe diabetes, and concomitant medications may all increase a patient's risk of hyperkalemia.

[0005] Most existing treatment plans for hyperkalemia are limited to hospitalization. Ion exchange resins such as Kayexalate are not suitable for outpatient or long-term treatment because they must be used in large quantities and patients are unwilling to cooperate. Such treatments have significant side effects on the gastrointestinal (GI) tract and can introduce excess sodium, which can lead to hypernatremia and associated fluid retention and hypertension. Diuretics allow patients to remove sodium and potassium via the kidneys. Nevertheless, pre-existing nephropathy and associated diuretic resistance often limit the effectiveness of diuretics. Furthermore, diuretics are contraindicated in patients in whom a reduction in blood pressure and blood volume is undesirable. For example, patients with congestive heart failure (CHF) suffer from hypotension and are often administered a combination of an ACE inhibitor and a non-kalemic diuretic that can induce hyperkalemia, such as spironolactone.

[0006] Therefore, there is an urgent need to develop new drugs with high potassium binding capacity for treating hyperkalemia. Summary of the Invention

[0007] Description of the Invention In one embodiment, the disclosure provides a polymer.

[0008] According to one embodiment of the present disclosure, the polymer comprises repeat units obtained by polymerizing a monomer and a crosslinker in a monomer / crosslinker molar ratio ranging from 1:0.02 to 1:0.20. The monomer comprises an acidic group and a pKa lowering group adjacent to the acidic group. The acidic group is a sulfonic acid group (-SO3 - ), sulfate group (-OSO3 - ), carboxyl group (-CO2 - ), phosphonic acid group (-OPO3 2- ), phosphate group (-OPO3 2- ) and sulfamic acid group (-NHSO3 -The pKa lowering group is selected from the group consisting of nitro, cyano, carbonyl, trifluoromethyl and halogen atoms. The crosslinking agent provides the polymer with a structural moiety of formula (I): [ka] (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 [ka] and preferably, R1 is H and * represents a binding site.

[0009] Applicants have discovered that polymers according to embodiments of the present disclosure have significantly higher stability and potassium ion adsorption capacity when in an acidic state than in a salt state, and polymers according to embodiments of the present disclosure in either acid or salt form can be used as drugs for the effective treatment of hyperkalemia.

[0010] According to one embodiment of the present disclosure, the polymer may further include at least one of the following technical features:

[0011] In a preferred embodiment, the acidic group is a carboxyl group and the pKa lowering group is fluorine.

[0012] In a preferred embodiment, the reactive sites of the monomer and crosslinker are free alkenyl groups.

[0013] In a preferred embodiment, the polymer is at least one selected from the group consisting of polyvinylsulfonic acid polymers, polyvinylsulfamic acid polymers, poly(vinylsulfamic acid / vinyl sulfate) copolymers, polyvinylaminophosphonic acid polymers, N-(ethyl bisphosphonate)polyvinylamine polymers, poly(α-fluoroacrylic acid) polymers, vinylphosphonic acid / acrylic acid copolymers, vinylphosphonic acid / α-fluoroacrylic acid copolymers, polyvinyl sulfate polymers and crosslinked polyvinylsulfamic acid polymers.

[0014] According to one embodiment of the present disclosure, the present disclosure further provides a compound represented by formula (II): [ka] The present invention provides a polymer represented by the formula: (Wherein, R2 is H, or [ka] and preferably, R2 is H; m is in the range of 0.80 to 0.98, n is in the range of 0.02 to 0.20, and m+n=1; 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; The wavy bonds are [ka] represents a random combination of *teeth [ka] represents the linking sites that bind to produce a chain-extended polymer network).

[0015] The polymer may further comprise at least one of the following technical features:

[0016] In a preferred embodiment, R2 is H.

[0017] In a preferred embodiment, the polymer is represented by formula (III) or a salt thereof. [ka]

[0018] In a preferred embodiment, the salt of the polymer of formula (II) is a salt represented by formula (IV). [ka] where M is an alkaline group.

[0019] In a preferred embodiment, M is Fe, Ca, Na, Mg, lysine or a combination thereof.

[0020] In a preferred embodiment, the polymer is a mixture comprising or consisting of one or more polymers or salts thereof.

[0021] In another preferred embodiment, the polymer is represented by any of the following structural formulas, or a salt thereof: [ka] (wherein m ranges from 0.80 to 0.98, n ranges from 0.02 to 0.20, p ranges from 0.02 to 0.20, and when only the variables m and n are present, m+n=1, and when all of the variables m, n, and p are present, m+n+p=1).

[0022] Preferably, the polymer is a salt represented by any of the following structures: [ka] [ka] (wherein m ranges from 0.80 to 0.98, n ranges from 0.02 to 0.20, p ranges from 0.02 to 0.20, and m+n=1 when only the variables m and n are present, or m+n+p=1 when the variables m, n, and p are all present).

[0023] The variables m, n, and p can be any value within the above ranges, including the end values. 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, 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 m+n=1 when only the variables m and n are present, or m+n+p=1 when the variables m, n and p are all present.

[0024] In preferred embodiments, 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.

[0025] In another preferred embodiment, m is in the range of 0.85 to 0.98, n is in the range of 0.02 to 0.15, and m+n=1; more preferably, m is in the range of 0.90 to 0.98, n is in the range of 0.02 to 0.10, and m+n=1; even more preferably, m is in the range of 0.93 to 0.97, n is in the range of 0.03 to 0.07, and m+n=1.

[0026] In another preferred embodiment, m is in the range of 0.84 to 0.96, n is in the range of 0.02 to 0.14, p is in the range of 0.02 to 0.14, and m+n+p=1; more preferably, m is in the range of 0.86 to 0.94, n and p are the same and in the range of 0.03 to 0.07, and m+n+p=1; even more preferably, m is 0.90, n is 0.05, and p is 0.05.

[0027] According to one embodiment of the present disclosure, the present disclosure provides a polymer or a salt thereof, comprising a repeating unit obtained by polymerizing a monomer and a crosslinker in a monomer / crosslinker 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 crosslinker is pentaerythritol triallyl ether.

[0028] According to one embodiment of the present disclosure, the present disclosure provides a polymer or a salt thereof prepared by a polymerization reaction of a monomer with a crosslinking agent, wherein the monomer is represented by formula (V): [ka] (Wherein, R1 is H or C 1-6 Alkyl, preferably C 1-3 alkyl, more preferably methyl; The crosslinking agent is represented by formula (IV) [ka] and / or formula (VII) [ka] 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; In the polymerization reaction, the molar fraction of the monomer is in the range of 0.80-0.98, and the molar fraction of the crosslinking agent is in the range of 0.02-0.20, with the proviso that the sum of the molar fraction of the monomer and the molar fraction of the crosslinking agent is 1.

[0029] The mole fraction of monomer and the mole fraction of crosslinker in the polymerization reaction can be any value within the ranges given above, including the end values. For example, the mole fraction of monomer is 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 is 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 crosslinker is 1.

[0030] In a preferred embodiment, in the polymerization reaction, 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.

[0031] In another preferred embodiment, in the polymerization reaction, the molar fraction of the monomer is in the range of 0.85 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 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 in the range of 0.90 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 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 in the range of 0.93 to 0.97, the molar fraction of the crosslinking agent is in the range of 0.03 to 0.07, and the sum of the molar fractions of the monomer and the crosslinking agent is 1.

[0032] In a preferred embodiment, the monomer has formula (VIII) [ka] It is a compound of the formula:

[0033] In a preferred embodiment, the crosslinker is of formula (VI) [ka] In a further preferred embodiment, the crosslinker is a compound of formula (IX): [ka] and in the polymerization reaction, the molar fraction of the monomer is in the range of 0.80 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.20, and the sum of the molar fraction of the monomer and the molar fraction of the crosslinking agent is 1; preferably, in the polymerization reaction, the molar fraction of the monomer is in the range of 0.85 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.15, and the sum of the molar fraction of the monomer and the crosslinking agent is 1; more preferably, in the polymerization reaction, the molar fraction of the monomer is in the range of 0.90 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.10, and the sum of the molar fraction of the monomer and the crosslinking agent is 1; even more preferably, in the polymerization reaction, the molar fraction of the monomer is in the range of 0.93 to 0.97, the molar fraction of the crosslinking agent is in the range of 0.03 to 0.07, and the sum of the molar fraction of the monomer and the crosslinking agent is 1. For example, in the polymerization reaction, 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.

[0034] In another preferred embodiment, the crosslinker has formula (VI) [ka] and compounds of formula (VII) [ka] It is a compound of the formula: In the formula, 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, each 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 to 0.96, and a compound represented by the formula (VI) as a crosslinking agent is The molar fraction of the compound of formula (VI) as a crosslinking agent is 0.02 to 0.14, the molar fraction of the compound of formula (VII) as a crosslinking agent is 0.02 to 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 to 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, is 0.03 to 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 the compound of formula (VI) as a crosslinking agent is 0.05, and the molar fraction of the compound of formula (VII) as a crosslinking agent is 0.05.

[0035] In a more preferred embodiment, the compound of formula (VI) has the formula (IX) [ka] and the compound of formula (VII) is a compound of formula (X) [ka] It is a compound of the formula:

[0036] It is to be understood that the polymer resulting from the polymerization reaction of the monomer with the crosslinker comprises a structural portion A provided by the monomer and a structural portion B provided by the crosslinker, where the structural portion A is represented by the formula (V): [ka] The structural portion A provided by the monomer of formula (V') [ka] and R1 is H or C 1-6 Alkyl, preferably C 1-3 is alkyl, more preferably methyl, and * represents the attachment site of structural moiety A or structural moiety B; Formula (VI) [ka] The structural portion B provided by the crosslinker of formula (VI') [ka] 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 * represents the binding site of structural moiety A or structural moiety B; Formula (VII) [ka] The structural portion B provided by the crosslinker of formula (VII') [ka] wherein each q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and * represents the binding site of structural moiety A or structural moiety B.

[0037] It is to be understood that the mole fraction of structural moiety A or structural moiety B in a polymer is the same as the mole fraction of the corresponding monomer and the corresponding crosslinker in the polymerization reaction.

[0038] In a preferred embodiment, the monomer has formula (VIII) [ka] and correspondingly, structural moiety A is a compound of formula (VIII') [ka] is a residue of

[0039] In a preferred embodiment, the crosslinker has formula (VI) [ka] and correspondingly, structural moiety B is a compound of formula (VI') [ka] 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 * represents the attachment site of structural moiety A or structural moiety B. More preferably, the crosslinker has formula (IX): [ka] and correspondingly, structural moiety B is a compound of formula (IX') [ka] In the formula, * represents a bonding site of the structural moiety A or the structural moiety B, and the molar fraction of the structural moiety A in the polymer is in the range of 0.80 to 0.98, the molar fraction of the structural moiety B in the polymer is in the range of 0.02 to 0.20, and the sum of the molar fractions of the structural moiety A and the structural moiety B is 1, preferably, the molar fraction of the structural moiety A in the polymer is in the range of 0.85 to 0.98, the molar fraction of the structural moiety B in the polymer is in the range of 0.02 to 0.15, and the sum of the molar fractions of the structural moiety A and the structural moiety B is 1. The sum of the molar fractions is 1, more preferably, the molar fraction of structural moiety A in the polymer is in the range of 0.90 to 0.98, the molar fraction of structural moiety B in the polymer is in the range of 0.02 to 0.10, and the sum of the molar fractions of structural moiety A and structural moiety B is 1, and even more preferably, the molar fraction of structural moiety A in the polymer is in the range of 0.93 to 0.97, the molar fractions of the structural moieties in the polymer are in the range of 0.03 to 0.07, and the sum of the molar fractions of structural moiety A and structural moiety B is 1. For example, the molar fraction of structural moiety A is 0.80 and the molar fraction of structural moiety B is 0.20; or the molar fraction of structural moiety A in the polymer is 0.85 and the molar fraction of structural moiety B in the polymer is 0.15; or the molar fraction of structural moiety A in the polymer is 0.89 and the molar fraction of structural moiety B in the polymer is 0.11; or the molar fraction of structural moiety A in the polymer is 0.90 and the molar fraction of structural moiety B in the polymer is 0.10; or the molar fraction of structural moiety A in the polymer is 0.95 and the molar fraction of structural moiety B in the polymer is 0.05; or the molar fraction of structural moiety A in the polymer is 0.98 and the molar fraction of structural moiety B in the polymer is 0.02.

[0040] In another preferred embodiment, the crosslinker has formula (VI) [ka] and formula (VII) [ka] and correspondingly, structural moiety B is a compound of formula (VI') [ka] and a residue of formula (VII') [ka] 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; each q is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1; and * represents a binding site for structural moiety A or structural moiety B. The molar fraction of the structural moiety A in the polymer is 0.84 to 0.96, the molar fraction of the residue of formula (VI') as the structural moiety B in the polymer is 0.02 to 0.14, the molar fraction of the residue of formula (VII') as the structural moiety B in the polymer is 0.02 to 0.14, and the sum of the molar fractions of the structural moiety A and the two structural moieties B in the polymer is 1; more preferably, the molar fraction of the structural moiety A in the polymer is 0.86 to 0.94, the molar fraction of the residue of formula (VI') as the structural moiety B in the polymer is equal to the molar fraction of the residue of formula (VII') as the structural moiety B in the polymer and is 0.03 to 0.07, and the sum of the molar fractions of the 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 residues of formula (VI') as structural moiety B in the polymer is 0.05, and the molar fraction of residues of formula (VII') as structural moiety B in the polymer is 0.05.

[0041] In a more preferred embodiment, the crosslinker has formula (IX): [ka] and a compound of formula (X) [ka] and correspondingly, structural moiety B is a compound of formula (IX') [ka] and a residue of formula (X') [ka] is a residue of

[0042] The salt of the polymer as described above is preferably a pharma-ceutically acceptable salt.For example, the polymer is in the form of sodium salt, calcium salt, iron salt, lysine salt or combination thereof.For example, the polymer is in the form of Na-Ca-Fe complex salt or Lys-Ca-Fe complex salt.

[0043] The above polymers or salts thereof are collectively referred to as "polymers according to the present invention."

[0044] The polymers of the present invention have several advantages that will become apparent to those of skill in the art in light of the disclosure of this application.

[0045] First, the polymers according to the invention have a high binding capacity for potassium cations (K+) in vitro and in vivo, and therefore can remove excess potassium cations from the animal's body. More specifically, when the potassium binding capacity of the polymers according to the invention is determined in vitro under physiological conditions simulating the gastrointestinal tract, in particular the colon, for example, when the potassium binding capacity of the polymers according to the invention is determined in vitro in a solution having a pH of about 5.5 or more, the polymers according to the invention in the acid form have a potassium binding capacity of 5 mmol / g or more, preferably 5 to 12 mmol / g, more preferably 5.5 to 10 mmol / g, even more preferably 6 mmol / g to 8 mmol / g, and the polymers according to the invention in the salt form have a potassium binding capacity of 2 to 5 mmol / g.

[0046] Second, the polymers according to the present invention do not contain aromatic groups, thus avoiding potential drug interactions caused by aromatic conjugated systems.

[0047] Thirdly, the polymer according to the invention in the salt form is elaborately designed so that the intake of calcium cations from the polymer according to the invention is significantly reduced compared to the commercial product Veltassa (Replypsa), and the intake of sodium cations from the polymer according to the invention is significantly reduced compared to the commercial product Lokelma® (AstraZenca). Thus, the polymer according to the invention in the salt form can reduce hypercalcemia caused by Veltassa® and hypernatremia caused by Lokelma®.

[0048] Fourth, the polymers according to the present invention can contain iron cations and therefore are beneficial for patients with chronic kidney disease who often suffer from ischemic anemia as a complication.

[0049] In another aspect, the present disclosure provides a method for preparing a potassium-binding polymer or a salt thereof, the method comprising the steps of: (a) mixing a monomer, a crosslinking agent and an initiator to form an oil phase, adding a dispersant and an inorganic salt to water, dissolving and dispersing them uniformly at room temperature to form an aqueous phase, mixing the oil phase and the aqueous phase, and reacting them at a high temperature for a certain period of time to obtain an ester polymer; (b) removing alkyl moieties from the ester polymer from step (a) by hydrolysis in a mixture of aqueous alkali and organic solvent to produce a carboxylate polymer; (c) acidifying the carboxylate polymer from step (b) with an acid to obtain the desired polymer in acid form; (d) optionally converting the acid form of the polymer from step (c) to a salt form of the desired polymer.

[0050] The monomer / crosslinker ratio is in the range of 1:0.02-1:0.25, which means that the molar fraction of monomer is in the range of 0.80-0.98, and the molar fraction of crosslinker is in the range of 0.02-0.20, provided that the sum of the molar fraction of monomer and the molar fraction of crosslinker is 1.

[0051] The mole fractions of monomer and crosslinker may be any value within the above ranges, including the end values, for example, the mole fraction of monomer is 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 is 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 crosslinker is 1.

[0052] 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.

[0053] In another preferred embodiment, the molar fraction of the monomer is in the range of 0.85 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 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 in the range of 0.90 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.10, and the sum of the molar fractions of the monomer and the crosslinking agent is 1.

[0054] The monomer has the formula (V) [ka] wherein R1 is H or C 1-6 Alkyl, preferably C 1-3R1 is preferably alkyl, more preferably methyl. The compound of formula (V) in which R1 is methyl is represented by the formula (VIII) [ka] Corresponds to.

[0055] The crosslinking agent is represented by formula (VI) [ka] and / or a compound of formula (VII) [ka] 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.

[0056] In a preferred embodiment, the crosslinker has formula (VI) [ka] wherein each n1 is independently 1, 2, 3, 4, 5, 6 or 7, preferably 1, 2 or 3, more preferably 1, and 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): [ka] The molar fraction of the monomer is in the range of 0.80 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.20, and the sum of the molar fraction of the monomer and the molar fraction of the crosslinking agent is 1, preferably, the molar fraction of the monomer is in the range of 0.85 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.15, and the sum of the molar fraction of the monomer and the crosslinking agent is 1, more preferably, the molar fraction of the monomer is in the range of 0.90 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.10, and the sum of the molar fraction of the monomer and the crosslinking agent is 1, and even more preferably, the molar fraction of the monomer is in the range of 0.93 to 0.97, the molar fraction of the crosslinking agent is in the range of 0.03 to 0.07, and the sum of the molar fraction of the monomer and the crosslinking agent is 1. 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.

[0057] In another preferred embodiment, the crosslinker has the formula (VI) [ka] and compounds of formula (VII) [ka] 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 molar fraction of the monomer is 0.84 to 0.96, the molar fraction of the compound of formula (VI) as a crosslinking agent is 0.02 to 0.14, the molar fraction of the compound of formula (VII) as a crosslinking agent is 0.02 to 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 to 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, which is 0.03 to 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 the compound of formula (VI) as a crosslinking agent is 0.05, and the molar fraction of the compound of formula (VII) as a crosslinking agent is 0.05.

[0058] In a more preferred embodiment, the compound of formula (VI) is represented by formula (IX) [ka] and the compound of formula (VII) is a compound of formula (X) [ka] It is a compound of the formula:

[0059] In the above method, 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-methylpropionamidine) 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-dimethylvaleronitrile), 2,2-azodi(2-methylbutyronitrile), 1,1'-azobis(cyclohexane-1-carbonitrile), dimethyl 2,2'-azobis(2-methylpropionate), benzoyl peroxide (BPO), lauroyl peroxide, cumene hydroperoxide, etc. The amounts of these initiators used in the method of the present disclosure are the same as those conventionally used in the art. For example, the amount of BPO used in the method of the present disclosure can range from 0.1 to 10.0 mole percent (%) of the monomer, preferably from 1.0 to 5.0 mole percent.

[0060] The polymerization reaction in the present disclosure is a suspension polymerization, as shown in step (a) of the above method. The dispersant used in the above method is intended to prevent particle aggregation during suspension polymerization. Dispersants suitable for this purpose include, but are not limited to, gelatin, polyvinyl alcohol (PVA), sodium carboxymethylcellulose, hydroxymethylcellulose, sodium polyacrylate, calcium carbonate, magnesium carbonate, barium sulfate, diatomaceous earth, talc powder, 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 dispersants used in the method of the present disclosure is the same as that conventionally used in the art. For example, the amount of PVA used in the method of the present disclosure can range from 0.1% to 2.0% (w / w) of the aqueous phase, preferably from 0.3% to 1.0% (w / w).

[0061] It has been found that the addition of an inorganic salt to the aqueous phase in step (a) of the above method can reduce particle aggregation. Inorganic salts suitable for this purpose include various salts 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 in the range of 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 mass of the entire aqueous phase.

[0062] The high temperature of the polymerization reaction in step (a) of the above method refers to a temperature of 60°C or higher, for example, 60°C to 85°C.

[0063] The hydrolysis in step (b) of the above process should be carried out in a mixed solution of aqueous alkali and organic solvent. The inventors have found that hydrolysis in aqueous alkali without organic solvent or in the presence of acid is incomplete or produces colored impurities when the temperature is increased to accelerate the hydrolysis. The organic solvent used for hydrolysis is selected from ethanol, methanol, isopropanol, toluene, acetonitrile, ethers such as 2-methyltetrahydrofuran, tetrahydrofuran, and any mixture 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 mixture thereof.

[0064] 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.

[0065] The conversion in step (d) of the above process can be carried out in a suitable conversion manner to form a salt. For example, it can be achieved using a suitable aqueous base or salt solution. The suitable base or salt can be selected from ferric chloride hexahydrate, ferric chloride, calcium hydroxide, sodium hydroxide, ferric hydroxide, calcium carbonate, sodium carbonate, and any mixture thereof.

[0066] In another aspect, the present disclosure provides a polymer prepared by the above method.

[0067] In yet another aspect, the present disclosure further provides a pharmaceutical composition comprising one or more polymers or salts thereof as described above and a pharma- ceutically acceptable excipient.

[0068] The pharmaceutical composition is used as a potassium binder to reduce potassium cation levels in vivo and to prevent and treat hyperkalemia.

[0069] The pharmaceutical compositions may be formulated into solid dosage forms (including but not limited to capsules, tablets, pills, granules, powders, solid dispersions) or liquid dosage forms (including but not limited to suspensions) for conventional oral administration.

[0070] The pharmaceutical composition comprises one or more of the above polymers or salts thereof in an amount between 1% and 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 one or more of the above polymers or salts thereof may be present in a unit dosage form 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.

[0071] Pharmaceutically acceptable excipients used in the pharmaceutical compositions may be selected from one or more of the following substances: a) diluents, such as lactose, sucrose, sorbitol, mannitol, starch, microcrystalline cellulose, dextrin, etc. b) disintegrants, such as croscarmellose sodium, crospovidone, starches (e.g., starch, sodium starch glycolate, hydroxypropyl starch), etc. c) Binders, such as starch slurry, polyvinylpyrrolidone (PVP), methylcellulose, ethylcellulose, etc. d) glidants, such as silicon dioxide, magnesium stearate, etc. e) colorants, f) flavouring agents; h) Suspending agents.

[0072] In some embodiments, the diluent may be present in an amount of 35% to 90% w / w of the composition. In some embodiments, the disintegrant may be present in an amount of 0.5% to 10% w / w of the composition. In some embodiments, the binder may be present in an amount of 0.5% to 5% w / w of the composition. In some embodiments, the glidant may be present in an amount of 0.1% to 5% w / w of the composition. In some embodiments, the colorant, flavoring agent, and suspending agent may each be present in an amount of 0.05% to 5% w / w of the composition.

[0073] In yet another aspect, the present disclosure further provides the use of a polymer or a salt thereof as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for adsorbing potassium cations or reducing potassium cation levels in vivo.

[0074] In yet another aspect of the present disclosure, the present disclosure further provides the use of a polymer or a salt thereof as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for preventing or treating hyperkalemia.

[0075] According to one embodiment of the present disclosure, hyperkalemia is caused by administration of an agent that causes potassium retention.

[0076] Drugs that cause potassium retention include, but are not limited to, spironolactone, fluoxetine, metoprolol, quinine, loperamide, chlorpheniramine, chlorpromazine, ephedrine, amitriptyline, imipramine, loxapine, cinnarizine, amiodarone, nortriptyline, mineralocorticosteroids, propofol, digitalis, succinylcholine, eplerenone, alpha-adrenergic agonists, RAAS inhibitors, ACE inhibitors, angiotensin II receptor blockers, beta blockers, aldosterone antagonists, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, Perindopril, quinapril, ramipril, trandolapril, candesartan, eprosartan, irbesartan, losartan, valsartan, telmisartan, acebutolol, atenolol, betaxolol, bisoprolol, carteolol, nadolol, propranolol, sotalol, timolol, canrenone, aliskiren, aldosterone synthesis inhibitors, VAP antagonists, amiloride, triamterine, potassium supplements, heparin, nonsteroidal anti-inflammatory drugs, ketoconazole, trimethoprim, pentamide, potassium sparing diuretics, amiloride, triamterene, adriamycin and combinations thereof.

[0077] In yet another aspect, the present disclosure further provides a method for reducing potassium cation levels in vivo or for preventing or treating hyperkalemia in an animal, comprising administering an effective amount of one or more of the above-described polymers or salts thereof.

[0078] In yet another aspect, the present disclosure further provides a method for measuring the amount of potassium ion adsorption of a polymer, comprising the step of detecting the potassium binding ability of the polymer by ion chromatography under the following conditions: Chromatography column: IonPac CS17 analytical column (4 x 250 mm) Guard column: IonPac CG17 guard column (4 x 50 mm) Flow rate: 1.0 ml / min Detector: Electrical conductivity detector Column temperature: 30℃ Injection volume: 10μl Eluent: 6mM methanesulfonic acid solution Driving time: 20 minutes

[0079] Definitions and Explanations One skilled in the art can understand that the symbol * represents a bond site that can further bond to a monomer or a structural moiety provided by the same or a different cross-linking agent.

[0080] As used herein, the terms "potassium," "potassium ion," and "potassium cation" may be used interchangeably and refer to K+, unless the context indicates otherwise.

[0081] The term "animal" as used herein includes humans and other mammals, such as primates, cows, sheep, goats, horses, dogs, cats, rabbits, etc., preferably humans. The present disclosure specifically provides a polymeric composition for removing potassium ions from the body of an animal. Preferably, the composition can be used to remove potassium ions from the gastrointestinal tract of an animal.

[0082] The terms "potassium binding", "potassium ion absorption" and "potassium absorption" are used interchangeably as used herein. The potassium-binding polymer according to the present invention has a high potassium-binding capacity. The potassium-binding capacity of the polymer according to the present invention can be measured in vitro. Preferably, the in vitro measurement of the potassium-binding capacity of the polymer according to the present invention is performed under physiological conditions simulating the gastrointestinal tract, particularly the colon. In certain embodiments, the in vitro measurement of the potassium-binding capacity of the polymer of the present disclosure is performed in a solution having a pH of about 5.5 or more, for example a pH of 6-8. In various embodiments, the potassium-binding capacity of the polymer according to the present invention in the acid form, measured in a solution having a pH of about 5.5 or more, for example a pH of 6-8, is 5 mmol / g or more, preferably 5.5 mmol / g or more, more preferably 6 mmol / g or more. Preferably, the in vitro potassium binding capacity of the polymers according to the invention in the acid form, measured in a solution having a pH of about 5.5 or more, is between 5 mmol / g and 12 mmol / g, preferably between 5.5 mmol / g and 10 mmol / g, more preferably between 6 mmol / g and 8 mmol / g. The in vivo potassium binding capacity of the polymers according to the invention is found to be proportional to the in vitro potassium binding capacity of the polymers in the acid form, regardless of whether they are administered to the animal in the acid form or in the salt form.

[0083] The term "effective amount" or "effective dose" as used herein refers to an amount of a polymer according to the present invention that, when administered to an animal, can substantially reduce the potassium ion level of the animal, thereby preventing, alleviating or curing a disease or one or more symptoms of a disease associated with high levels of potassium ions, or delaying the onset or progression of a disease or one or more symptoms thereof. The higher the potassium binding capacity of the polymer according to the present invention, the lower the dose. In general, effective therapeutic and prophylactic doses of the polymer according to the present invention range from about 1 g / day to about 100 g / day. A preferred dose range is from about 5 g / day to about 60 g / day. A more preferred dose range is from about 15 g / day to about 50 g / day. The daily dose may be administered in a single dose or in several divided doses. For example, the daily dose may be taken three times a day or once a day.

[0084] The polymer according to the present invention or a composition comprising the same can retain a large amount of bound potassium. The polymer binds potassium in the gastrointestinal tract and does not release the bound potassium before the polymer is excreted in the feces. The term "large amount" does not mean that all of the bound potassium can be retained. 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. Optimally, the period of retention of the bound potassium is sufficient for effective treatment and / or prevention of hyperkalemia.

[0085] The potassium-binding polymers of the present invention are preferably not absorbed by the gastrointestinal tract. The phrase "not absorbed by" and its grammatical equivalents do not mean that an administered polymer is not completely absorbed. It is desirable that a certain amount of the polymer is not absorbed. Preferably, at least about 90% of the polymer is not absorbed. More preferably, at least about 95% of the polymer is not absorbed. More preferably, at least about 97% of the polymer is not absorbed. Most preferably, at least about 98% of the polymer is not absorbed.

[0086] In some embodiments, the potassium-binding polymer according to the present invention has protic or ionic acidic groups, such as sulfonic acid groups (-SO - ), sulfate group (-OSO3 - ), carboxyl group (-CO2 - ), phosphonic acid group (-OPO3 2- ), phosphate group (-OPO3 2- ), sulfamic acid group (-NHSO3 - ).

[0087] The polymer contains phosphonic acid groups (-OPO3 2- ) or phosphate group (-OPO3 2- Suitable phosphonic acid monomers which provide the above-mentioned phosphonic acid include vinyl phosphonic acid, ethylene-1,1-bisphosphonic acid, ethylene derivatives of phosphonic acid carboxylates, oligo(methylene phosphonic acid), and hydroxyethane-1,1-bisphosphonic acid. Methods for the synthesis of these monomers are known.

[0088] The preferred monomers used herein are 2-fluoroacrylates, most preferably methyl 2-fluoroacrylate. These monomers are commercially available, for example from Waterstone Pharmaceuticals (Hubei) Co., Ltd., or can be prepared by known methods, for example the methods disclosed in European Patent No. EP415214.

[0089] The term "about" when used in conjunction with a value herein extends to a range of ±20% of that value. For example, about 5% means a range of 4% to 6%. Preferably, the word "about" in conjunction with a value extends that value to a range of ±10% or ±5% of that value.

[0090] The expression "w / w" as used herein means that the ratio or percentage with which it is associated is expressed on a weight basis.

[0091] The term "alkyl" as used herein means an alkyl group having 1 to 6 carbon atoms (C 1-6 alkyl), preferably having 1 to 3 carbon atoms (C 1-3 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having the substituents (alkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl, n-pentyl, and n-hexyl.

[0092] The term "molar fraction" refers to the molar ratio of a compound or structural part relative to a specific standard. For example, the expression "molar fraction of monomer is 0.85-0.98, molar fraction of crosslinker is 0.02-0.15, and the sum of the molar fractions of monomer and crosslinker is 1" means that the standard specified for calculating the molar fraction is the sum of the moles of monomer and crosslinker, and the molar fraction of monomer refers to the ratio of the moles of monomer to the sum of the moles of monomer and crosslinker, which ranges from 0.85 to 0.98; similarly, the molar fraction of crosslinker refers to the ratio of the moles of crosslinker to the sum of the moles of monomer and crosslinker, which ranges from 0.02 to 0.15.

[0093] Terms not defined herein have their ordinary meaning in the art. [Brief description of the drawings]

[0094] BRIEF DESCRIPTION OF THE DRAWINGS The above and / or additional aspects and advantages of the present disclosure will become apparent and readily understood from a reading of the following description of the embodiments in conjunction with the drawings, in which:

[0095] [Figure 1] FIG. 1A is an SEM spectrum of the MFA-APE-Na—Ca—Fe salt polymer of Example 3, and FIG. 1B is an XPS result of the MFA-APE-Na—Ca—Fe salt polymer of Example 3.

[0096] [Diagram 2] FIG. 2 is a diagram prepared in Example 14, and shows that Lokelma and MFA-APE sodium salt polymer (MFA-APE-Na) prepared in Example 3 reduced serum K+ in normal SD rats, and the serum potassium reducing effect of the MFA-APE-Na polymer was superior to that of the two positive controls, Lokelma and Veltassa.

[0097] [Diagram 3] FIG. 3 was produced in Example 15 and shows that Lokelma and MFA-APE sodium salt polymer (MFA-APE-Na) prepared in Example 3 reduced the increase in serum K+ induced by KCl.

[0098] [Figure 4] FIG. 4 is a diagram prepared in Example 16, which shows that 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.

[0099] [Diagram 5]FIG. 5 is a diagram prepared in Example 17, and shows that 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 that the serum potassium reducing effect of the MFA-APE-lysine-Ca-Fe polymer was significantly superior to that of the positive control (Lokelma) on day 14 after administration. EXAMPLES

[0100] example The present disclosure is described below with reference to specific embodiments. It should be noted that these embodiments are merely illustrative and are not intended to limit the present disclosure in any way.

[0101] The following abbreviations are used throughout this disclosure: [Table 1]

[0102] The crosslinkers used in the examples have the structures shown in Table 1. [Table 2]

[0103] Example 1 [ka] Purified water (550 mL), NaCl (11.0 g) and PVA (3.4 g) were added to the reaction flask and dissolved by stirring at 20°C-30°C until completely dissolved and a clear solution was obtained. 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 to provide a clear solution for later use. The prepared MFA solution was added to the solution in the reaction flask. The temperature of the material in the reaction flask was gradually increased to 70°C-80°C, and then the temperature was maintained and stirred for 15 hours. Monitoring by gas chromatography showed that the reaction was complete. After lowering the temperature to 20°C-30°C, suction filtration was performed. The filter cake was slurried and washed with water and ethanol. The resulting wet product was dried under vacuum at 50°C to obtain 97.3 g of a white solid, i.e., MFA-APE ester polymer. The MFA-APE ester product was characterized by infrared spectroscopy (Chinese Pharmacopoeia 2020 Vol. IV General Provisions 0402) using a SHIMADZU IRSpirit-T Fourier transform infrared spectrometer (FTIR). No characteristic absorption peaks of C=C bonds were observed in the Fourier transform infrared spectrometer (FTIR) of the MFA-APE ester polymer.

[0104] 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide were added to the reaction flask, followed by the addition of the above MFA-APE ester polymer with stirring. The temperature was increased to 50°C-60°C, followed by stirring and holding the temperature for 15 hours. The temperature was reduced to 20°C-30°C, followed by filtration, and the filter cake was slurried, washed with water and ethanol, and filtered to provide the wet MFA-APE sodium salt polymer.

[0105] 500mL of water and 100mL of concentrated hydrochloric acid were added to the reaction flask, and the above wet MFA-APE sodium salt polymer was added, followed by stirring at 20°C to 30°C for 15 hours. After filtration, the filter cake was repeatedly washed with 4L of water. The wet product obtained after filtration was slurried once with 500mL of ethanol. The wet product obtained after filtration was vacuum dried at 50°C for 8 hours to obtain 84.6g of white dry product, which was crushed and sieved through a 120 mesh sieve to obtain MFA-APE acid polymer (m=0.95, n=0.05) (MFA-APE-H).

[0106] The K+ adsorption capacity of this MFA-APE acid polymer was measured in Example 13 and was 7.2 mmol / g.

[0107] The MFA-APE acid polymer was measured by differential scanning calorimetry (DSC). Instrument model: METTLER TOLEDO DSC3 differential scanning calorimeter. Analysis method: Chinese Pharmacopoeia 2020 edition, General Provision 0661 Thermal Analysis. Nitrogen conditions: 50mL / min. Scan procedure: Heat up from 30°C to 140°C at 10°C / min, then the temperature was reduced to 30°C at 20°C / min. Then, the temperature was increased again to 150°C at 10°C / min, and the second heating curve was recorded. All reagent trays are aluminum. The obtained DSC profile showed that the glass transition temperature (Tg) of the acid polymer was 139.75°C.

[0108] The MFA-APE acid polymer was measured by thermogravimetric analyzer (TGA). Instrument model: TGA 2 differential scanning calorimeter. Analysis method: Chinese Pharmacopoeia 2020, General Provision 0661 Thermal Analysis. Nitrogen condition: 50mL / min. Scan procedure: 30℃ to 800℃ at 10℃ / min. Based on this curve, the decomposition temperature value of MFA-APE acid polymer was calculated. All reagent trays are platinum. The obtained TGA profile showed that the decomposition temperature of the final polymer was 208.90℃.

[0109] Example 2 [ka] Purified water (550 mL), NaCl (11.0 g) and PVA (3.4 g) were added to the reaction flask and stirred at 20-30 °C until completely dissolved to provide a clear solution. 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 provide a clear solution for later use. The prepared MFA solution was added to the clear solution in the reaction flask. The temperature of the material in the reaction flask was gradually increased to 70 °C-80 °C, and then the temperature was maintained and stirred for 15 hours. Monitoring by gas chromatography showed that the reaction was complete. After lowering the temperature to 20 °C-30 °C, suction filtration was performed. The filter cake was slurried and washed with water three times. The resulting wet product was dried to obtain 115.2 g of a white solid, i.e., 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 C=C bonds were observed in the Fourier transform infrared spectrometer (FTIR) of the MFA-TAIC-APE ester polymer.

[0110] 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide were added to the reaction flask, followed by the addition of the above MFA-TAIC-APE ester polymer with stirring. The temperature was raised to 50°C-60°C, followed by stirring and holding the temperature for 15 hours. The temperature was lowered to 20°C-30°C, followed by filtration, and the filter cake was slurried and washed with water three times. The filtered wet product was MFA-TAIC-APE sodium salt polymer (MFA-TAIC-APE-Na).

[0111] 500mL of water and 100mL of concentrated hydrochloric acid were added to the reaction flask, and the above wet MFA-TAIC-APE sodium salt polymer was added, followed by stirring at 20°C to 30°C for 15 hours. After filtration, the filter cake was repeatedly washed with 4L of water. The wet product obtained after filtration was slurried once with 500mL of ethanol. The wet product obtained after filtration was vacuum dried at 50°C for 8 hours to obtain 85.7g of white dry product, which was crushed 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).

[0112] As measured in Example 13, the K+ adsorption capacity of this MFA-TAIC-APE acid polymer was 6.6 mmol / g.

[0113] The MFA-TAIC-APE acid polymer was characterized by DSC and TGA as described in Example 1. The obtained DSC profile showed that the glass transition temperature of the MFA-TAIC-APE acid polymer was 137.90° C. The obtained TGA profile showed that the decomposition temperature of the MFA-TAIC-APE acid polymer was 192.97° C.

[0114] Example 3 [ka] The MFA-APE ester polymer was prepared using a procedure similar to that of 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 C=C bonds were observed in the Fourier transform infrared spectrometer (FTIR) of the MFA-APE ester polymer.

[0115] A reaction flask was charged with 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide, and the above MFA-APE ester polymer was added with stirring. The temperature was raised to 50°C-60°C, followed by stirring and holding the temperature for 15 hours. The temperature was lowered to 20°C-30°C, and then filtration was performed, and the filter cake was slurried, washed with water and ethanol, and filtered to provide wet MFA-APE sodium salt polymer (MFA-APE-Na). The MFA-APE sodium salt polymer was sampled and dried for potassium binding measurements as described in Example 13, which showed that the K+ adsorption capacity of this MFA-APE sodium salt polymer was 4.2 mmol / g.

[0116] 500 mL of water and 100 mL of concentrated hydrochloric acid were added to the reaction flask, and the above wet MFA-APE sodium salt polymer was added, and then stirred for 15 hours at 20° C.-30° C. After filtration, the filter cake was repeatedly washed with 4 L of water and filtered to provide wet MFA-APE acid polymer (MFA-APE-H).

[0117] The MFA-APE acidic polymer was sampled and dried for potassium binding measurements as described in Example 13, and the K+ adsorption capacity of the MFA-APE acidic polymer was shown to be 7.4 mmol / g.

[0118] 240 mL of water was added to the above acid polymer and stirred at 10-30°C. FeCl3 (0.7 g), Ca(OH)2 (18.0 g) and NaOH (9.6 g) were slowly added to the mixture, and the internal temperature was controlled in the range of 10-30°C. The mixture was stirred for 2-5 hours, and then the mixture was filtered to obtain a wet solid. The wet solid was slurried with 2 L of water. After filtration, the obtained wet cake was vacuum dried at 50°C for 8 hours to obtain 99.0 g of a yellow dry product. It was crushed and sieved through a 120 mesh sieve to obtain MFA-APE Na-Ca-Fe complex salt polymer (m=0.95, n=0.05) (MFA-APE-Na-Ca-Fe).

[0119] As measured in Example 13, the K+ adsorption capacity of this MFA-APE-Na-Ca-Fe polymer was 2.39 mmol / g.

[0120] The MFA-APE-Na-Ca-Fe polymer was characterized by DSC and TGA as described in Example 1. The DSC profile obtained showed that the glass transition temperature of the final polymer was 130.82° C. The TGA profile obtained showed that the decomposition temperature of the final polymer was 193.06° C.

[0121] The MFA-APE-Na-Ca-Fe polymer was detected by scanning electron microscope (SEM). Analytical instrument model: Quanta 400 thermal field emission scanning electron microscope. Analytical procedure: JY / T 0584-2020 General Provisions of Scanning Electron Microscopy Analytical Procedure. The SEM result is shown in Figure 1A. The SEM photograph showed that the MFA-APE-Na-Ca-Fe polymer had a regular spherical structure.

[0122] The MFA-APE-Na-Ca-Fe polymer was detected by X-ray photoelectron spectroscopy (XPS). Analysis method: GB / T 19500-2004 General Provisions for X-ray Photoelectron Spectroscopy. The XPS result was shown in Figure 1B. The result showed that carbon, oxygen, fluorine, calcium, and sodium existed in the MFA-APE-Na-Ca-Fe polymer. The MFA-APE-Na-Ca-Fe polymer was acidified with sulfuric acid solution, the supernatant was taken, and the potassium thiocyanate test solution was added, which showed a positive reaction, indicating the presence of iron ions in the MFA-APE-Na-Ca-Fe polymer.

[0123] Example 4 [ka] The MFA-TAIC-APE ester polymer was prepared using the same procedure as in Example 2. Gas chromatography monitoring showed that the reaction was complete. The MFA-TAIC-APE ester polymer was characterized by FTIR as described in Example 1. No characteristic absorption peaks of C=C bonds were observed in the Fourier transform infrared spectrometer (FTIR) of the MFA-TAIC-APE ester polymer.

[0124] 400 mL of water, 130 mL of EtOH, and 48.0 g of sodium hydroxide were added to the reaction flask, followed by the addition of the MFA-TAIC-APE ester polymer with stirring. The temperature was raised to 50°C-60°C, followed by stirring and holding the temperature for 15 hours. The temperature was lowered to 20°C-30°C, followed by filtration, and the filter cake was slurried and washed three times with water. The filtered wet solid was the MFA-TAIC-APE sodium salt polymer (MFA-TAIC-APE-Na).

[0125] 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 and stirred for 15 hours at 20° C. to 30° C. After filtration, the filter cake was repeatedly washed with 4 L of water and filtered to provide MFA-TAIC-APE acid polymer (MFA-TAIC-APE-H).

[0126] The resulting wet MFA-TAIC-APE acid polymer was added with 240 mL of water 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 with the internal temperature ranging from 10-30°C. The mixture was stirred for 2-5 hours and then filtered to provide a wet solid. The wet solid was slurried with 2 L of water. After filtration, the resulting wet cake was dried under vacuum at 50°C for 8 hours to obtain 102.5 g of a yellow dried product, which was crushed and sieved through a 120 mesh sieve 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).

[0127] Example 5 [ka] The MFA-APE acid polymer was prepared using a procedure 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 C=C bonds were observed in the Fourier transform infrared spectrometer (FTIR) of the MFA-APE acid polymer.

[0128] 240 mL of water was added to the wet MFA-APE acid polymer and stirred at 10-30°C. FeCl3 (0.7 g), Ca(OH)2 (15.0 g) and L-lysine (23.7 g) were added slowly to the mixture with the internal temperature ranging from 10-30°C. The mixture was stirred for 2-5 hours and then filtered to provide a wet solid. The wet solid was slurried with 2 L of water. After filtration, the resulting wet cake was dried under vacuum at 50°C for 8 hours to obtain 109.3 g of a pale red dried product, which was crushed and sieved through a 120 mesh sieve to obtain MFA-APE Lys-Ca-Fe complex salt polymer (m=0.95, n=0.05) (MFA-APE-Lys-Ca-Fe).

[0129] The K+ adsorption capacity of this MFA-APE-Lys-Ca-Fe salt polymer was 2.95 mmol / g as measured in Example 13.

[0130] The MFA-APE-Lys-Ca-Fe salt polymer was characterized by DSC and TGA as described in Example 1. The DSC profile obtained showed that the glass transition temperature of the polymer was 144.52° C. The TGA profile obtained showed that the decomposition temperature of the polymer was 194.38° C.

[0131] Examples 6-9 Examples 6-9 were carried out in a similar manner to Example 1 to provide MFA-APE acid polymers. Salt polymers were then prepared using a similar procedure to Example 3. No characteristic absorption peaks of C=C bonds were observed in the Fourier transform infrared spectroscopy (FTIR) of these MFA-APE acid polymers.

[0132] In Example 6, the amounts of MFA and APE were 1.0 mole and 0.25 mole, corresponding to a mole fraction of MFA and APE of 0.80:0.20 (m:n=0.80:0.20). The K+ adsorption capacity of the MFA-APE acid polymer was 5.5 mmol / g as measured in Example 13. The MFA-APE acid polymer was detected by DSC and TGA as described in Example 1. The DSC profile obtained showed that the glass transition temperature of the MFA-APE acid polymer was 164.25°C. The TGA profile obtained showed that the decomposition temperature of the MFA-APE acid polymer was 196.51°C. The K+ adsorption capacity of the MFA-APE-Na-Ca-Fe salt polymer was 2.6 mmol / g as measured in Example 13. The MFA-APE-Na-Ca-Fe salt polymer was detected by DSC and TGA as described in Example 1. The DSC profile obtained showed that the glass transition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 166.65° C. The TGA profile obtained showed that the decomposition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 181.09° C.

[0133] In Example 7, the amounts of MFA and APE were 1.0 mole and 0.12 mole, corresponding to a mole fraction of MFA and APE of 0.89:0.11 (m:n=0.89:0.11). As measured in Example 13, the K+ adsorption capacity of the MFA-APE acid polymer was 6.6 mmol / g. The MFA-APE acid polymer was analyzed by DSC and TGA as described in Example 1. The DSC profile obtained showed that the glass transition temperature of the acid polymer was 134.94°C. The TGA profile obtained showed that the decomposition temperature of the polymer was 211.67°C. As measured in Example 13, the K+ adsorption capacity of the MFA-APE-Na-Ca-Fe salt polymer was 2.8 mmol / g. The MFA-APE-Na-Ca-Fe salt polymer was analyzed by DSC and TGA as described in Example 1. The DSC profile obtained showed that the glass transition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 146.51° C. The TGA profile obtained showed that the decomposition temperature of the MFA-APE-Na-Ca-Fe salt polymer was 191.81° C.

[0134] In Example 8, the amounts of MFA and APE were 1.0 mole and 0.02 mole, corresponding to a mole fraction of MFAAPE of 0.98:0.02 (m:n=0.98:0.02). As measured in Example 13, the K+ adsorption amount of the MFA-APE acid polymer was 7.6 mmol / g. The MFA-APE acid polymer was detected by DSC and TGA as described in Example 1. The obtained DSC profile showed that the glass transition temperature of the MFA-APE acid polymer was 140.17°C. The obtained TGA profile showed that the decomposition temperature of the MFA-APE acid polymer was 209.85°C.

[0135] In Example 9, the amount of MFA and APE was 0.5 mole and 0.5 mole, which corresponds to a molar fraction of MFA and APE of 0.50:0.50 (m:n=0.50:0.50). As measured in Example 13, the K+ adsorption capacity of the MFA-APE acid polymer was 3.2 mmol / g. The final product was detected by DSC and TGA as described in Example 1. The obtained DSC profile showed that the glass transition temperature of the MFA-APE acid polymer was 106.01°C. The obtained TGA profile showed that the decomposition temperature of the MFA-APE acid polymer was 198.09°C.

[0136] Example 10 Purified water (550 mL), PEG600 (4.6 g) and NaCl (11.0 g) were added to the 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 for later 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. Bulk solids were formed in the flask. After filtration of the reaction mixture, 123 g of wet cake was obtained and dried at 50°C to obtain 90.4 g of white solid. This MFA-APE ester polymer was inhomogeneous, hard, irregular and clumpy.

[0137] Example 11 Purified water (550 mL), NaCl (11.0 g), and PVA (4.6 g) were added to the reaction flask and the mixture was stirred at 50-60°C until it 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 for later 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 solids precipitated. An additional amount of BPO (0.73 g, 0.003 mol) was charged to the reaction mixture and the temperature was increased above 60°C, resulting in the precipitation of some white solids. The temperature was maintained and the mixture was stirred for 15-20 hours. The reaction was filtered and the resulting solid was slurried with water and EtOH to provide 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 peaks of C=C bonds were observed in the Fourier transform infrared spectrometer (FTIR) of this MFA-APE ester polymer.

[0138] Water (270 mL), EtOH (90 mL) and 71 g of the prepared wet MFA-APE ester polymer were added to the flask. 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 reduced to 20-30° C. and the mixture was filtered and washed with water to provide the MFA-APE-Na salt polymer.

[0139] The MFA-APE-Na salt polymer was stirred in concentrated HCl, diluted 2-fold with water, filtered, and washed with water to give 120 g of wet MFA-APE acid polymer, which was dried at 50-60° C. to give 46.7 g of MFA-APE acid polymer.

[0140] As measured in Example 13, the K+ adsorption capacity of the MFA-APE acid polymer was 7.2 mmol / g. The MFA-APE acid polymer was detected by DSC and TGA as described in Example 1. The obtained DSC profile showed that the glass transition temperature of the MFA-APE acid polymer was 138.64°C. The obtained TGA profile showed that the decomposition temperature of the MFA-APE acid polymer was 210.32°C.

[0141] Example 12 [ka]

[0142] Purified water (570 mL), NaCl (11.4 g) and PVA (4.6 g) were added to the reaction flask and stirred at 50°C-60°C until completely dissolved. The MFA solution was prepared as follows: MFA (104.1 g, 1.0 mol), TMPTA (14.8 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 of the materials in the reaction flask was gradually increased to 70°C-75°C. The mixture was stirred at 70-75°C for 15 hours. The temperature was reduced to 20-30°C and the reaction mixture was filtered. The filter cake was successively slurried twice with water and once with EtOH. Filtration provided 85.6 g of white solid wet cake, which is MFA-TMPTA ester polymer.

[0143] Water (270 mL), EtOH (90 mL) and 66.0 g of wet MFA-TMPTA ester polymer were added to the reaction flask. Sodium hydroxide (40 g) was added to the flask. The reaction mixture was stirred at 60-65° C. for 20 h. The temperature was reduced to 20-30° C. and then filtration was performed. The resulting filter cake was gel-like. Detection by GCMS showed the presence of decomposition product trimethylolpropane. It dissolved when the cake was washed with water. The mixture was concentrated and EtOH was added, resulting in the precipitation of a yellow solid. The precipitate was filtered off, washed with EtOH, and dried to provide 23.0 g of a yellow layered solid. The solubility of the solid in water was >1 mg / mL.

[0144] Example 13 Potassium buffer: Potassium buffer consisted of 150 mmol / L potassium and 200 mmol / L 2-[morpholino]ethanesulfonic acid, with a pH of 6.0–8.0.

[0145] Standard graph: Five 100 ml volumetric flasks are identified with numbers 1, 2, 3, 4 and 5. In that order, 1, 3, 6, 8 and 10 mL of potassium buffer are pipetted into the flasks, diluted to volume with water and mixed. Ion chromatographic detection is performed on volumetric flasks 1, 2, 3, 4 and 5 and the potassium ion peak areas are recorded. On a lined coordinate paper, the observed peak areas are plotted as the ordinate and the concentration of potassium (in mmol / L) as the abscissa.

[0146] Test sample solution: take about 1.6g of polymer, put it into a 250ml Erlenmeyer flask, add 100ml of potassium buffer solution, put it into a water bath at 37℃±2℃, stir with a magnet for 24 hours, shake evenly, take a sample (15 minutes, 3 hours, 5 hours or 24 hours as recommended), filter, pipette 1.0ml of the filtrate into a 100ml measuring flask accurately, and dilute to the mark with water.

[0147] Analyze the test sample solution by ion chromatography, record the peak area of ​​potassium ions, and determine the potassium concentration in millimoles / liter by interpolation from the standard graph. Calculate the amount of potassium ions adsorbed on the resin (mmol / g) using the following formula: Amount of potassium ions adsorbed by polymer = (X-2.5Y) / W (where X is the weight (mmol) of potassium in 100 mL of potassium solution before exchange, Y is the weight (mmol) of potassium per liter interpolated from the standard graph, and W is the weight (g) of polymer collected on an anhydrous basis.

[0148] The chromatographic conditions are shown in Table 2 below. [Table 3]

[0149] Results and Analysis The potassium absorption capacity of the polymers in the examples is shown in Table 3 below. [Table 4-1] [Table 4-2]

[0150] Example 14 Twenty-four normal male SD rats (6-8 weeks, 190-210g, Hubei Provincial Laboratory Animal Research Center) were adapted and raised for 3-5 days, and then randomly divided into four groups, namely, blank control group, positive control group 1 (Lokelma), positive control group 2 (Veltassa), and test article group (MFA-APE-Na prepared in Example 3), each group containing 6 rats. The animals in each group were orally administered with vehicle or drug in a single dose according to a volume of 10ml / kg. More specifically, the animals in the blank control group were treated with 10ml / kg saline, the positive control group 1 was treated with 1.8g / kg Lokelma in the same volume of saline, the positive control group 2 was treated with 3.5g / kg Veltassa in the same volume of saline, and the test article group was treated with 1.8g / kg MFA-APE-Na in the same volume of saline. Six hours after administration, blood was collected from the jugular vein, centrifuged, and the supernatant was collected to detect serum potassium concentration.

[0151] The results showed that: As shown in Figure 2, (1) compared with the blank control group, the serum K+ level of the test product group (MFA-APE-Na) was significantly decreased 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) the change in serum K+ level from baseline in the test product group was significantly lower (P<0.05), and (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).

[0152] Example 15 Eighteen normal male SD rats (6-8 weeks, 190-210g, Hubei Provincial Laboratory Animal Research Center) were adapted and fed for 3-5 days, then randomly divided into three groups, namely, model group, positive control group (Lokelma), and test article group (MFA-APE-Na prepared in Example 3), each group containing 6 rats. The animals in each group were orally administered with vehicle or drug in a single dose according to a volume of 10ml / kg. The rats in the model group were treated with saline in a volume of 10ml / kg. The rats in the positive control group were treated with Lokelma at 1.8g / kg in the same volume of saline. The rats in the test article group were treated with MFA-APE-Na at 1.8g / kg in the same volume of saline. 10% KCl solution was intraperitoneally injected 3 hours after administration, followed by 5% KCl solution at 4, 5 and 6 hours after administration. The intraperitoneal injection volume of 10% and 5% KCl solutions was 4 ml / kg. Blood samples were collected from the jugular vein before administration (0 h) and 3.5 h, 4.5 h, and 6.5 h after administration. The blood samples were centrifuged and the supernatant was collected to detect serum potassium concentration.

[0153] The results showed that, as shown in Figure 3, at 4.5 hours and 6.5 hours after administration, the serum potassium concentration in the test product group (MFA-APE-Na prepared in Example 3) and the positive control group (Lokelma) was decreased compared with the model group, with a statistically significant difference (P<0.05).

[0154] Example 16 Twenty-four normal male SD rats (6-8 weeks old, 200-250g, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.) were adapted and raised for 3-5 days, then randomly divided into five groups, namely, normal group, model group, positive control group (Lokelma), and test article group (MFA-APE-Na-Ca-Fe prepared in Example 3), each group containing six 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 and lower kidneys) were removed, and one week later, the entire right kidney was removed to obtain a 5 / 6 nephrectomized rat model. After two weeks of conventional diet, they were given a single intravenous injection of adriamycin (3.5mg / kg), followed immediately by trimethoprim (300mg / kg intragastrically, four times a day) and quinapril (30mg / L, added to water). Animals in each group were orally administered vehicle or drug in a single dose according to a volume of 20ml / kg. Rats in normal and model groups were treated with vehicle (0.1% xanthan gum) in a volume of 20ml / kg, positive control was treated with Lokelma in the same volume of vehicle at 2g / kg, and test article group was treated with MFA-APE-Na-Ca-Fe of Example 3 in the same volume of vehicle at 2g / kg. Oral administration was performed once a day for 2 weeks. Blood of all rats was collected from the jugular vein 5 days before adriamycin injection, and 7 and 14 days after adriamycin injection. Blood samples were centrifuged and the supernatant was collected to detect serum potassium concentration.

[0155] The results showed that, compared with the model group, the serum potassium concentration of the test product group (MFA-APE-Na-Ca-Fe prepared in Example 3) was significantly decreased on the 7th and 14th days after administration (P<0.001, P<0.01, respectively), as shown in Figure 4.

[0156] Example 17 Twenty-four normal male SD rats (6-8 weeks, 200-250 g, Zhejiang Vital River Institute Animal Technology Co., Ltd.) were adapted and fed for 3-5 days, then randomly divided into four groups, normal group, model group, positive control group (Lokelma), and test article group (MFA-APE-Lysine-Ca-Fe prepared in Example 5), each group contained 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 and lower kidneys) were removed, and 11 weeks later, the entire right kidney was removed to obtain a 5 / 6 nephrectomized rat model. After 2 weeks of conventional diet, adriamycin was injected intravenously (3.5 mg / kg), and trimethoprim (300 mg / kg intragastrically) and quinapril (30 mg / L, added in water) were immediately administered. The animals in each group were orally administered with vehicle or drug in a single dose according to a volume of 20 ml / kg. Normal and model rats were treated with vehicle (0.1% xanthan gum) at a volume of 20ml / kg, positive control group was treated with Lokelma at 2g / kg in the same volume of vehicle, and test article group was treated with MFA-APE-Lysine-Ca-Fe of Example 5 at 2g / kg in the same volume of vehicle. Oral administration was performed once a day for two weeks. Blood of all rats was collected from the jugular vein 5 days before adriamycin injection, and 7 and 14 days after adriamycin injection. Blood samples were centrifuged and the supernatant was collected to detect serum potassium concentration.

[0157] The results showed that, as shown in Figure 5, compared with the model group on the 7th and 14th days after administration, the serum potassium concentrations of the test product group (MFA-APE-lysine-Ca-Fe) and the positive control group (Lokelma) were significantly decreased (P<0.01 or P<0.001), and the potassium-lowering effect of the test product (MFA-APE-lysine-Ca-Fe) on the 14th day after administration was significantly better than that of the positive control (Lokelma).

[0158] In this specification, a description referring to terms such as "embodiments," "some embodiments," "examples," "specific examples," or "some examples" means that a particular feature, structure, material, or characteristic described with respect to an embodiment or example is included in at least one embodiment or example of the present disclosure. In this specification, the above terms are exemplary and do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described can be combined in any suitable manner in any one or more embodiments or examples. Furthermore, a person skilled in the art can combine different embodiments or examples and features of different embodiments or examples described herein without mutual inconsistency.

[0159] Although the embodiments of the present disclosure have been illustrated and described above, it should be understood that the above-described embodiments are illustrative and should not be construed as limiting the present disclosure. Those skilled in the art may make changes, modifications, substitutions and variations to the above-described embodiments within the scope of the present disclosure.

Claims

1. A polymer comprising repeating units obtained by polymerizing a monomer and a crosslinker in a monomer / crosslinker molar ratio ranging from 1:0.02 to 1:0.20, wherein the monomer comprises an acidic group and a pKa-reducing group adjacent to the acidic group, the acidic group being a sulfonic acid group (—SO ３ － ), sulfate group (-OSO ３ － ), carboxyl group (-CO ２ － ), a phosphonic acid group (—OPO ３ ２－ ), phosphate group (-OPO ３ ２－ ) and sulfamic acid group (-NHSO ３ － ), wherein the pKa lowering group is selected from the group consisting of nitro, cyano, carbonyl, trifluoromethyl, and halogen atoms, and the crosslinker provides the polymer with a compound of formula (I): 【Chemistry 1】 (wherein n1 is 0, 1, 2, 3, 4, 5, 6, or 7, n2 is 1, 2, 3, 4, 5, 6, or 7, and R １ is H or 【Chemistry 2】 A polymer that provides a structural portion represented by the formula (I).

2. A polymer described in claim 1, wherein in the formula, n1 is 1, 2 or 3 and n2 is 1, 2 or 3.

3. 2. The polymer of claim 1, wherein the acidic group is a carboxyl group and the pKa-lowering group is fluorine.

4. The polymer of claim 1 , wherein the reactive sites are free alkenyl groups.

5. Formula (II) 【Transformation 3】 wherein n1 is 0, 1, 2, 3, 4, 5, 6, or 7, n2 is 1, 2, 3, 4, 5, 6, or 7, and R ２ is H, or 【Chemistry 4】 and m is in the range of 0.80 to 0.98, n is in the range of 0.02 to 0.20, and m+n=1; * represents a binding site), or a pharmaceutically acceptable salt thereof.

6. The polymer or pharmaceutically acceptable salt thereof according to claim 5, wherein in the formula, n1 is 1, 2 or 3, or n2 is 1, 2 or 3.

7. R ２ The polymer of claim 5, wherein is H, or a pharmaceutically acceptable salt thereof.

8. 6. The polymer of claim 5, or a pharmaceutically acceptable salt thereof, wherein the polymer has a structure represented by formula (III) or is a salt of a structure represented by formula (III), wherein m, n, and * are as defined in claim 5. 【Transformation 5】

9. The salt of the polymer is represented by formula (IV): 【Transformation 6】 wherein M is Fe, Ca, Na, Mg, or lysine; and m, n, n1, n2, R ２ 6. The polymer or a pharmaceutically acceptable salt thereof according to claim 5, wherein and * are as defined in claim 5.

10. The polymer or pharmaceutically acceptable salt thereof of claim 5 , wherein the polymer comprises one or more polymers or salts thereof.

11. A polymer having any of the following structures, or a salt of any of the following structures, or a pharmaceutically acceptable salt thereof. 【Transformation 7】 (wherein m is in the range of 0.80 to 0.98, n is in the range of 0.02 to 0.20, p is in the range of 0.02 to 0.20, and m+n=1 or m+n+p=1)

12. 12. The polymer of claim 11, or a pharmaceutically acceptable salt thereof, wherein the salt of the polymer has any of the following structures: 【Transformation 8】

13. A polymer or a salt thereof prepared by a polymerization reaction of a monomer with a crosslinking agent, the monomer being represented by formula (V): 【Chemistry 9】 (In the formula, R １ is H or C １－６ is a compound of The crosslinking agent is represented by formula (IV): 【Chemistry 10】 Compounds of wherein each n1 is independently 1, 2, 3, 4, 5, 6, or 7; each n2 is independently 1, 2, 3, 4, 5, 6, or 7; and each q is independently 1, 2, 3, 4, 5, 6, or 7; In the polymerization reaction, the molar fraction of the monomer is in the range of 0.80 to 0.98, and the molar fraction of the crosslinking agent is in the range of 0.02 to 0.20, provided that the sum of the molar fraction of the monomer and the molar fraction of the crosslinking agent is 1.

14. The monomer has formula (VIII) 【Chemistry 11】 The polymer or salt thereof according to claim 13, which is a compound represented by the formula:

15. The crosslinking agent is represented by formula (IX): 【Chemistry 12】 The polymer or salt thereof according to claim 13, which is a compound represented by the formula:

16. A polymer or salt thereof described in claim 13, wherein in the polymerization reaction, the molar fraction of the monomer is in the range of 0.85 to 0.98, the molar fraction of the crosslinking agent is in the range of 0.02 to 0.15, and the sum of the molar fractions of the monomer and the crosslinking agent is 1.

17. The polymer or salt thereof of claim 13, wherein the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinker is 0.

05.

18. The following steps: (a) mixing a monomer, a crosslinking agent, and an initiator to form an oil phase, adding a dispersant and an inorganic salt to water, dissolving and dispersing them uniformly at room temperature to form an aqueous phase, mixing the oil phase and the aqueous phase, and reacting them at a high temperature for a certain period of time to obtain an ester polymer; (b) removing alkyl moieties from the ester polymer from step (a) by hydrolysis in a mixture of aqueous alkaline and organic solvent to form a carboxylate polymer; (c) acidifying the carboxylate polymer from step (b) with an acid to obtain the desired polymer in acid form; (d) optionally converting the acid form of the polymer from step (c) to the salt form of the desired polymer; prepared by a method comprising: The monomer has formula (V) 【Chemistry 13】 wherein R １ is H or C １－６ alkyl), The crosslinking agent is represented by formula (VI) 【Chemistry 14】 wherein each n1 is independently 1, 2, 3, 4, 5, 6, or 7, and each n2 is independently 1, 2, 3, 4, 5, 6, or 7; In the polymerization reaction, the mole fraction of the monomer is in the range of 0.80 to 0.98, and the mole fraction of the crosslinking agent is in the range of 0.02 to 0.20, provided that the sum of the mole fraction of the monomer and the mole fraction of the crosslinking agent is 1; The elevated temperature of the polymerization reaction is a temperature of 60°C or higher, The dispersing agent is a polymer or a salt thereof selected from gelatin, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxymethylcellulose, sodium polyacrylate, calcium carbonate, magnesium carbonate, barium sulfate, diatomaceous earth, talc powder, Tween 20, Tween 40, Tween 80, Tween 85, Span 20, Span 40, Span 60, Span 65, Span 80, Span 85, or any mixture thereof.

19. The monomer has formula (VIII) 【Chemistry 15】 19. The polymer or salt thereof according to claim 18, which is a compound of the formula:

20. The crosslinking agent has the formula (VI) 【Chemistry 16】 19. The polymer or salt thereof of claim 18, which is a compound of the formula: (wherein each n1 is independently 1, 2, or 3, and each n2 is independently 1, 2, or 3).

21. The crosslinking agent is represented by formula (IX): 【Chemistry 17】 21. The polymer of claim 20, which is a compound of the formula:

22. A polymer as described in claim 18, wherein in the polymerization reaction, the molar fraction of the monomer is in the range of 0.85 to 0.98, the molar fraction of the crosslinker is in the range of 0.02 to 0.15, and the sum of the molar fractions of the monomer and the crosslinker is 1.

23. The polymer of claim 18, wherein the molar fraction of the monomer is 0.95 and the molar fraction of the crosslinker is 0.

05.

24. The polymer or salt thereof according to claim 18, wherein the initiator is selected from potassium persulfate, ammonium persulfate, 2,2'-azobis(2-methylpropionamidine) dihydrochloride (V50), 2,2'-azabis(2-imidazoline) dihydrochloride (VA044), 2,2'-azobis(2-methylpropionitrile), 2,2'-azobis-(2,4-dimethylvaleronitrile), 2,2-azodi(2-methylbutyronitrile), 1,1'-azobis(cyclohexane-1-carbonitrile), dimethyl 2,2'-azobis(2-methylpropionate), benzoyl peroxide (BPO), lauroyl peroxide, cumene hydroperoxide, and any mixture thereof.

25. 19. The polymer or salt thereof according to claim 18, wherein the inorganic salt is selected from potassium chloride, sodium chloride, ammonium chloride, calcium chloride, magnesium chloride, and any mixture thereof.

26. 19. The polymer according to claim 18, wherein the organic solvent in step (b) is selected from ethanol, methanol, isopropanol, toluene, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, methyl tert-butyl ether, dimethoxyethane, ethylene glycol diethyl ether, and other ethers, and any mixture thereof; and the alkali in step (b) is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, and any mixture thereof.

27. 19. The polymer or salt thereof according to claim 18, wherein the acid used in step (c) is selected from sulfuric acid, hydrochloric acid, nitric acid, or any mixture thereof.

28. 20. The polymer or salt thereof of claim 18, wherein the polymer is in the form of a sodium salt, a calcium salt, an iron salt, a lysine salt, or a combination thereof.

29. The polymer or salt thereof of claim 18, wherein the polymer is in the form of a Na-Ca-Fe complex salt or a Lys-Ca-Fe complex salt.

30. A pharmaceutical composition comprising the polymer or salt thereof according to any one of claims 1 to 29 and a pharmaceutically acceptable excipient.

31. 31. The pharmaceutical composition of claim 30 for lowering potassium levels or for treating or preventing hyperkalemia in an animal.

32. 32. The pharmaceutical composition of claim 31, wherein the hyperkalemia is caused by administration of a drug that causes potassium retention.

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