Proton-binding polymers for oral administration

文档序号：1161545 发布日期：2020-09-18 浏览：27次中文

阅读说明：本技术 用于口服施用的结合质子的聚合物 (Proton-binding polymers for oral administration ) 是由 G·克拉尔内尔 E·F·康纳 R·K·格布尔 M·J·凯德 P·H·凯尔斯泰德 J·M·布于 2014-06-05 设计创作，主要内容包括：本发明涉及用于口服施用的结合质子的聚合物、用于治疗包括人在内的动物的药物组合物和方法以及制备这类组合物的方法。所述药物组合物含有交联胺聚合物且可用于例如治疗其中从胃肠道中除去质子和/或氯离子可给包括人在内的动物提供生理学益处例如正常化血清碳酸氢根浓度和血液pH的疾病或其它代谢性病症。(The present invention relates to proton-binding polymers for oral administration, pharmaceutical compositions and methods for treating animals, including humans, and methods of making such compositions. The pharmaceutical compositions contain a crosslinked amine polymer and are useful, for example, in the treatment of diseases or other metabolic disorders in which removal of protons and/or chloride ions from the gastrointestinal tract can provide physiological benefits to animals, including humans, such as normalization of serum bicarbonate concentration and blood pH.)

1. A pharmaceutical composition comprising a proton-binding crosslinked amine polymer comprising residues of an amine of formula 1:

wherein R is₁、R₂And R₃Independently is hydrogen, hydrocarbyl or substituted hydrocarbyl, provided however that R₁、R₂And R₃At least one of which is not hydrogen, and (i) at a pH of 1.2, 37 ℃, containing 35An equilibrium proton binding capacity of at least 5mmol/g and a chloride ion binding capacity of at least 5mmol/g in an aqueous simulated gastric fluid buffer ("SGF") of mM NaCl and 63mM HCl, and (ii) an equilibrium swelling ratio in deionized water of about 2 or less.

2. A pharmaceutical composition comprising a proton-binding crosslinked amine polymer comprising residues of an amine of formula 1:

wherein R is₁、R₂And R₃Independently hydrogen, hydrocarbyl, substituted hydrocarbyl, provided that R₁、R₂And R₃Is not hydrogen, and binds at least a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, in an interfering ion buffer at 37 ℃, wherein (i) the interfering ions are phosphate ions and the interfering ion buffer is a buffer solution of 36mM chloride ions and 20mM phosphate at pH5.5, or (ii) the interfering ions are phosphate, citrate, and taurocholate ions (combined amount), and the interfering ion buffer is a buffer solution comprising 36mM chloride ions, 7mM phosphate, 1.5mM citrate, and 5mM taurocholate at pH 6.2.

3. A pharmaceutical composition comprising a proton-binding crosslinked amine polymer comprising residues of an amine of formula 2:

wherein the crosslinked amine polymer is crosslinked with a crosslinking agent useful in substitution polymerization and post-polymerization crosslinking, wherein the crosslinking agent is one or more of: dihaloalkane, di (haloalkyl) amine, tri (haloalkyl) amine, bis (halomethyl) benzene, tri (halomethyl) benzene, tetra (halomethyl) benzene, 1, 2-dibromoethane, 1, 3-dichloropropane, 1, 2-dichloroethane, 1-bromo-2-chloroethane, 1, 3-dibromopropane, bis (2-chloroethyl) amine, tri (2-chloroethyl) amine, bis (2-chloroethyl) methylamine, bis (halomethyl) benzene, bis (halomethyl) biphenyl, bis (halomethyl) naphthalene, 1, 2-bis (3-chloropropylamino) ethane, bis (3-chloropropyl) amine or 1, 3-dichloropropane, wherein

m and n are independently non-negative integers;

R₁₀、R₂₀、R₃₀and R₄₀Independently hydrogen, hydrocarbyl or substituted hydrocarbyl;

X₁is that

X₂Is a hydrocarbyl or substituted hydrocarbyl group;

X₁₁each independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy or amino; and is

z is a non-negative number and z is,

the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5mmol/g and a chloride ion binding capacity of at least 5mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing 35mM NaCl and 63mM HCl at pH1.2, 37 ℃, (ii) an equilibrium swell ratio in deionized water of about 2 or less, and (iii) a salt concentration of 36mM NaCl, 20mM NaH, buffered to pH5.5 at 37 ℃, (ii) a salt concentration of sodium chloride in a mixture of sodium chloride and sodium chloride₂PO₄And 50mM 2- (N-morpholino) ethanesulfonic acid (MES) in an aqueous simulated small intestine inorganic buffer ("SIB") having a chloride ion to phosphate ion binding molar ratio of at least 1:1, respectively.

4. The use of a composition for the manufacture of a pharmaceutical composition for the treatment of metabolic acidosis by oral administration of said pharmaceutical composition,

the composition comprises a proton-binding crosslinked amine polymer comprising residues of an amine of formula 1:

wherein R is₁、R₂And R₃Independently is hydrogen, hydrocarbyl or substituted hydrocarbyl, provided however that R₁、R₂And R₃At least one of which is not hydrogen,

the crosslinked amine polymer has an equilibrium swell ratio in deionized water of about 5 or less,

the crosslinked amine polymer binds a molar ratio of chloride ion to interfering ion of at least 0.35:1, respectively, in an interfering ion buffer at 37 ℃, wherein the interfering ion is a phosphate ion and the interfering ion buffer is a buffer solution of 36mM chloride ion and 20mM phosphate at pH 5.5.

5. Use of a composition in the manufacture of a pharmaceutical composition for the treatment of metabolic acidosis, wherein the pharmaceutical composition comprises a proton-binding crosslinked amine polymer comprising residues of an amine of formula 2b and prepared by free radical polymerization of an amine of formula 2 a:

wherein

m and n are independently non-negative integers;

R₁₂each independently is hydrogen, a substituted hydrocarbyl group, or a hydrocarbyl group;

R₂₂and R₃₂Independently hydrogen, substituted hydrocarbyl or hydrocarbyl;

R₄₂is hydrogen, hydrocarbyl or substituted hydrocarbyl;

X₁is that

X₂Is alkyl, aminoalkyl or alkanol;

X₁₃each independently is hydrogen, hydroxy, cycloaliphatic, amino, aminoalkyl, halogen,Alkyl, heteroaryl, boronic acid or aryl;

z is a non-negative number; and is

The amine of formula 2b contains at least one allyl group, and

the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5mmol/g and a chloride ion binding capacity of at least 5mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing 35mM NaCl and 63mM HCl at pH1.2, 37 ℃, (ii) an equilibrium swell ratio in deionized water of about 2 or less, and (iii) exposure of the polymer to a solution containing 36mM NaCl, 20mM NaH buffered to pH5.5 at 37 ℃, (ii) a crosslinking agent comprising a crosslinking agent selected from the group consisting of a crosslinking agent, and a crosslinking agent₂PO₄And 50mM 2- (N-morpholino) ethanesulfonic acid (MES) in SIB assay buffer after 1 hour the chloride ion binding in the SIB assay was greater than 2.0mmol/g polymer.

6. Use of a composition for the manufacture of a pharmaceutical composition for the treatment of metabolic acidosis, wherein the pharmaceutical composition comprises a proton-binding cross-linked amine polymer comprising residues of an amine of formula 2:

m and n are independently non-negative integers;

R₁₀、R₂₀、R₃₀and R₄₀Independently hydrogen, hydrocarbyl or substituted hydrocarbyl;

X₁is that

X₂Is a hydrocarbyl or substituted hydrocarbyl group;

X₁₁each independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy or amino; and is

z is a non-negative number and z is,

7. Use of a pharmaceutical composition according to claim 1,2 or 3 in the manufacture of a pharmaceutical composition for the treatment of an acid/base disorder by oral administration of the pharmaceutical composition.

8. The use of claim 7, wherein a daily dose of the pharmaceutical composition comprises less than 1g of sodium.

9. The use of claim 7, wherein the daily dose of the pharmaceutical composition is less than 10 g.

10. The use of claim 4, 5 or 6, wherein a daily dose of the pharmaceutical composition comprises less than 1g of sodium.

11. The use of claim 4, 5 or 6, wherein the daily dose of the pharmaceutical composition is less than 10 g.

12. The pharmaceutical composition of claim 1,2 or 3, or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer has a balanced chloride ion binding capacity of at least 7.5mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing 35mM NaCl and 63mM HCl at pH1.2, 37 ℃.

13. The pharmaceutical composition of claim 1,2 or 3, or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer has a balanced chloride ion binding capacity of at least 10mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing 35mM NaCl and 63mM HCl at pH1.2, 37 ℃.

14. The pharmaceutical composition of claim 2 or the use of claim 4, wherein the crosslinked amine polymer has an equilibrium swell ratio in deionized water of about 2 or less.

15. The pharmaceutical composition of claim 1 or 2 or the use of claim 4, wherein R₁、R₂And R₃Independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocycle, with the proviso that R₁、R₂And R₃Each is not hydrogen.

16. The pharmaceutical composition of claim 1 or 2 or the use of claim 4, wherein R₁、R₂And R₃Independently hydrogen, an aliphatic group or a heteroaliphatic group, provided that R₁、R₂And R₃At least one of which is not hydrogen.

17. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer is prepared by substitution polymerization of an amine with a multifunctional crosslinking agent, the multifunctional crosslinking agent further optionally comprising an amine moiety.

18. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer comprises the residue of an amine of formula 1a and the crosslinked amine polymer is prepared by free radical polymerization of an amine of formula 1 a:

wherein R is₄And R₅Independently hydrogen, hydrocarbyl or substituted hydrocarbyl.

19. The pharmaceutical composition of claim 18, wherein R₄And R₅Independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic.

20. The pharmaceutical composition of claim 18, wherein R₄And R₅Independently hydrogen, an aliphatic group or a heteroaliphatic group.

21. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer comprises the residue of an amine of formula 1b and the crosslinked amine polymer is prepared by substitution polymerization of an amine of formula 1b with a multifunctional crosslinker:

22. The pharmaceutical composition or use of claim 21, wherein R₄And R₅Independently hydrogen, saturated hydrocarbons, unsaturated aliphatic radicals, aryl radicals, heteroaryl radicals, heteroAlkyl or unsaturated heteroaliphatic groups.

23. The pharmaceutical composition or use of claim 21, wherein R₄And R₅Independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic.

24. The pharmaceutical composition or use of claim 21, wherein R₄And R₅Independently hydrogen, allyl or aminoalkyl.

25. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer comprises a residue of an amine of formula 1 c:

wherein R is₇Is hydrogen, an aliphatic or heteroaliphatic radical, and R₈Is an aliphatic group or a heteroaliphatic group.

26. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer comprises a residue of an amine of formula 2 a:

wherein

m and n are independently non-negative integers;

R₁₁each independently is hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl;

R₂₁and R₃₁Independently hydrogen or a heteroaliphatic group;

R₄₁is hydrogen, a substituted hydrocarbyl group or a hydrocarbyl group;

X₁is that

X₂Is an alkyl or substituted hydrocarbyl group;

X₁₂each independently is hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halo; and is

z is a non-negative number.

27. The pharmaceutical composition or use of claim 26, wherein m and z are independently 0-3, and n is 0 or 1.

28. The pharmaceutical composition or use of claim 26, wherein R₁₁Independently hydrogen, an aliphatic group, an aminoalkyl, a haloalkyl or a heteroaryl, R₂₁And R₃₁Independently is hydrogen or a heteroaliphatic group, and R₄₁Is hydrogen, an aliphatic group, an aryl group, a heteroaliphatic group or a heteroaryl group, or especially a pharmaceutical composition according to claim 12 or 13, wherein R is₁₁Each is hydrogen, an aliphatic group, aminoalkyl or haloalkyl, R₂₁And R₃₁Is hydrogen or aminoalkyl, and R₄₁Is hydrogen, an aliphatic group or a heteroaliphatic group.

29. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer is prepared by: (i) substitution polymerization of polyfunctional reagents, at least one of which comprises an amine moiety, (2) free radical polymerization of monomers comprising at least one amine moiety or nitrogen-containing moiety, or (3) crosslinking of an amine-containing intermediate with a crosslinking agent, the crosslinking agent optionally containing an amine moiety.

30. The pharmaceutical composition or use of claim 29, wherein the crosslinked amine polymer is a crosslinked homopolymer or a crosslinked copolymer.

31. The pharmaceutical composition or use of claim 29, wherein the crosslinked amine polymer comprises free amine moieties separated by repeating linker units of the same or different lengths.

32. The pharmaceutical composition or use of claim 29, wherein the crosslinked amine polymer is prepared by polymerizing an amine-containing monomer with a crosslinking agent in a substitution polymerization reaction.

33. The pharmaceutical composition or use of claim 32, wherein the amine-containing monomer is a linear amine having at least two reactive amine moieties that participate in a substitution polymerization reaction.

34. The pharmaceutical composition or use of claim 32, wherein the amine-containing monomer is 1, 3-bis [ bis (2-aminoethyl) amino ] propane, 3-amino-1- { [2- (bis {2- [ bis (3-aminopropyl) amino ] ethyl } amino) ethyl ] (3-aminopropyl) amino } propane, 2- [ bis (2-aminoethyl) amino ] ethylamine, tris (3-aminopropyl) amine, 1, 4-bis [ bis (3-aminopropyl) amino ] butane, 1, 2-ethylenediamine, 2-amino-1- (2-aminoethylamino) ethane, 1, 2-bis (2-aminoethylamino) ethane, 1, 3-propylenediamine, 3' -diaminodipropylamine, a, 2, 2-dimethyl-1, 3-propanediamine, 2-methyl-1, 3-propanediamine, N ' -dimethyl-1, 3-propanediamine, N-methyl-1, 3-diaminopropane, 3' -diamino-N-methyldipropylamine, 1, 3-diaminopentane, 1, 2-diamino-2-methylpropane, 2-methyl-1, 5-diaminopentane, 1, 2-diaminopropane, 1, 10-diaminodecane, 1, 8-diaminooctane, 1, 9-diaminooctane, 1, 7-diaminoheptane, 1, 6-diaminohexane, 1, 5-diaminopentane, 3-bromopropylamine hydrobromide, N ' -dimethyl-1, 3-propanediamine, N-methyl-1, 3-diaminopropane, 3-diamino-1, 3-, N, 2-dimethyl-1, 3-propanediamine, N-isopropyl-1, 3-diaminopropane, N '-bis (2-aminoethyl) -1, 3-propanediamine, N' -bis (3-aminopropyl) ethylenediamine, N '-bis (3-aminopropyl) -1, 4-butanediamine tetrahydrate salt, 1, 3-diamino-2-propanol, N-ethylethylenediamine, 2' -diamino-N-methyldiethylamine, N '-diethylethylenediamine, N-isopropylethylenediamine, N-methylethylenediamine, N' -di-tert-butylethylenediamine, N '-diisopropylethylenediamine, N' -dimethylethylenediamine, N '-diaminotoluene, N' -dimethylethylenediamine, N, n-butylethylenediamine, 2- (2-aminoethylamino) ethanol, 1,4,7,10,13, 16-hexaazacyclooctadecane, 1,4,7, 10-tetraazacyclododecane, 1,4, 7-triazacyclononane, N' -bis (2-hydroxyethyl) ethylenediamine, piperazine, bis (hexamethylene) triamine, N- (3-hydroxypropyl) ethylenediamine, N- (2-aminoethyl) piperazine, 2-methylpiperazine, homopiperazine, 1,4,8, 11-tetraazacyclotetradecane, 1,4,8, 12-tetraazacyclopentadecane, 2- (aminomethyl) piperidine or 3- (methylamino) pyrrolidino.

35. The pharmaceutical composition or use of claim 29, wherein the cross-linking agent is selected from the group consisting of dihaloalkanes, haloalkyl oxiranes, alkyl oxiranesulfonates, di (haloalkyl) amines, tri (haloalkyl) amines, diepoxides, triepoxides, tetracyclics, bis (halomethyl) benzenes, tri (halomethyl) benzenes, tetra (halomethyl) benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin, poly (epichlorohydrin), (iodomethyl) oxiranes, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1, 2-epoxybutane, bromo-1, 2-epoxybutane, 1, 2-dibromoethane, 1, 3-dichloropropane, 1, 2-dichloroethane, 1-bromo-2-chloroethane, 1, 3-dibromopropane, bis (2-chloroethyl) amine, tris (2-chloroethyl) amine and bis (2-chloroethyl) methylamine, 1, 3-butadiene diepoxide, 1, 5-hexadiene diepoxide, diglycidyl ether, 1,2,7, 8-diepoxyoctane, 1,2,9, 10-diepoxydedecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1, 4-butanediol diglycidyl ether, 1, 2-ethylene glycol diglycidyl ether, glycerol diglycidyl ether, 1, 3-diglycidyl ether glycerol, N-diglycidyl aniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1, 4-bis (glycidyloxy) benzene, resorcinol diglycidyl ether, resorcinol, ethylene glycol diglycidyl ether, glycerol, ethylene glycol diglycidyl ether, ethylene glycol, propylene glycol, ethylene glycol, propylene, 1, 6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1, 4-cyclohexanedimethanol diglycidyl ether, 1, 3-bis- (2, 3-epoxypropyloxy) -2- (2, 3-dihydroxypropyloxy) propane, 1, 2-cyclohexanedicarboxylic acid diglycidyl ester, 2' -bis (glycidyloxy) diphenylmethane, bisphenol F diglycidyl ether, 1, 4-bis (2',3' epoxypropyl) perfluoron-butane, 2, 6-bis (oxiran-2-ylmethyl) -1,2,3,5,6, 7-hexahydropyrrolo [3,4-F ] isoindol-1, 3,5, 7-tetraone, bisphenol A diglycidyl ether, 5-hydroxy-6, 8-bis (oxiran-2-ylmethyl) -4-oxo-4-h-chromene-2-carboxylic acid ethyl ester, bis [4- (2, 3-epoxypropylthio) phenyl ] -sulfide, 1, 3-bis (3-glycidoxypropyl) tetramethyldisiloxane, 9-bis [4- (glycidyloxy) phenyl ] fluoro, triepoxylisocyanate, glycerol triglycidyl ether, N-diglycidyl-4-glycidyloxyaniline, (S, S, S) -triglycidyl isocyanurate, (R, R, R) -triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, 1, 3-bis (3-glycidoxypropyl) tetramethyldisiloxane, Glycerol propoxytrigidylether, trishydroxyphenylmethane triglycidylether, 3,7, 14-tris [ [3- (glycidoxy) propyl ] dimethylsilyloxy ] -1,3,5,7,9,11, 14-heptacyclopentyltricyclo [7,3,3,15,11] heptasiloxane, 4' -methylenebis (N, N-diglycidylaniline), bis (halomethyl) benzene, bis (halomethyl) biphenyl and bis (halomethyl) naphthalene, toluene diisocyanate, acryloyl chloride, methyl acrylate, ethylenebisacrylamide, pyromellitic dianhydride, succinyl chloride, dimethyl succinate, 3-chloro-1- (3-chloropropylamino-2-propanol, 1, 2-bis (3-chloropropylamino) ethane, bis (3-chloropropyl) amine, 1, 3-dichloro-2-propanol, 1, 3-dichloropropane, 1-chloro-2, 3-epoxypropane, tris [ (2-oxiranyl) methyl ] amine, and combinations thereof.

36. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the preparation of the crosslinked amine polymer comprises free radical polymerization of an amine monomer comprising at least one amine moiety or nitrogen-containing moiety.

37. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer has an equilibrium swell ratio of about 1.5 or less in deionized water.

38. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the cross-linked amine polymer is at 37 ℃ CBuffered to pH5.5 containing 36mM NaCl, 20mM NaH₂PO₄And 50mM 2- (N-morpholino) ethanesulfonic acid (MES) in an aqueous simulated small intestine inorganic buffer ("SIB") having a chloride ion to phosphate ion binding molar ratio of at least 0.5:1, respectively.

39. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer contains 36mM NaCl, 20mM NaH buffered to pH5.5 at 37 ℃₂PO₄And 50mM 2- (N-morpholino) ethanesulfonic acid (MES) in an aqueous simulated small intestine inorganic buffer ("SIB") having a chloride ion to phosphate ion binding molar ratio of at least 1:1, respectively.

40. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer contains 36mM NaCl, 20mM NaH buffered to pH5.5 at 37 ℃₂PO₄And 50mM 2- (N-morpholino) ethanesulfonic acid (MES) in an aqueous simulated small intestine inorganic buffer ("SIB") having a chloride ion to phosphate ion binding molar ratio of at least 2:1, respectively.

41. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the crosslinked amine polymer has a proton binding capacity of at least 10mmol/g and a chloride ion binding capacity of at least 10mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing 35mM NaCl and 63mM HCl at 37 ℃, pH 1.2.

42. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the cross-linked amine polymer is a gel or bead having an average particle size of 40-180 microns.

43. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the cross-linked amine polymer is a gel or bead having an average particle size of 80-140 microns.

44. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein less than about 0.5% by volume of the particles have a diameter of less than about 10 microns.

45. The pharmaceutical composition of claim 1,2 or 3 or the use of claim 4, 5 or 6, wherein the pharmaceutical composition is in unit dosage form.

46. The pharmaceutical composition or use of claim 45, wherein the unit dosage form is a capsule, tablet or sachet dosage form.

47. A process for preparing a pharmaceutical composition according to claim 1,2 or 3, wherein the crosslinked amine polymer is prepared by: (i) substitution polymerization of polyfunctional reagents, at least one of which comprises an amine moiety, (2) free radical polymerization of monomers comprising at least one amine moiety or nitrogen-containing moiety, or (3) crosslinking of an amine-containing intermediate with a crosslinking agent, the crosslinking agent optionally containing an amine moiety.

Technical Field

The present invention relates generally to proton-binding polymers for oral administration, which may be used to treat metabolic acidosis.

Background

Metabolic acidosis is the result of metabolic and dietary processes that produce accumulation of non-volatile acids in the body leading to a net increase in protons (H +) or bicarbonate radicals (HCO) in various disease states₃ ^-) A loss condition. When the body accumulates the acid produced by metabolic and dietary processes and the excess acid is not completely removed from the body by the kidneysMetabolic acidosis. Chronic kidney disease is often accompanied by metabolic acidosis, due to secondary failure to recover filtered bicarbonate (HCO)₃ ^-) The ability of the kidneys to excrete hydrogen ions decreases, as well as the synthesis of ammonia (ammonia production) and excretion of the increasable acid. Clinical practice guidelines recommend that alkaline therapy be initiated in patients with dialysis-independent Chronic Kidney Disease (CKD) to prevent or treat complications of metabolic acidosis when serum bicarbonate levels are < 22 mEq/L. (Clinical practice guidelines for nutrition in chronic renal failure), K/DOQI, National kit Foundation, am.J.Kidney Dis.2000; 35: S1-140; Raphael, KL, Zhang, Y, Wei, G et al 2013, NHANES III adult Serum bicarbonate and morbidity (Serum bicarbonate and reporting in NHANES III), Nephrol.Dial.Transplant 28: 1207-. These complications include malnutrition and growth retardation in children, worsening of bone disease, increased muscle degradation, decreased albumin synthesis and increased inflammation. (Leman, J, Litzow, JR, Lennon, EJ.1966. Long term acid compliance in Normal Male further evidence of bone mineral involvement in combating Chronic metabolic acidosis (The effects of Chronic acid loads in normal Man: human being: theoretical evidence for The involvement of The differentiation of bone mineral in The systemic metabolic acidosis), J.Clin.Invest.45: 1608-1614; FranchHA, Mitch WE, 1998, effects of catabolic acidosis in uremia: The effects of metabolic acidosis (Catalogenetic in human being: The metabolic acidosis), J.Am.Soc.Nephrol.9: S78-81; Batahoma, PE, Syngnan, Hurlan, health, human being healthy, human being, health, serum balance of human being, clinical anion of interest: 1. Chondritic albumin, 1. Biotic, Ab.9: S78-81; see negative metabolic acidosis in human being, serum albumin, 9: 1. Ab.1. C., Bicarbonate and biomarkers (Serum anion gap, biochanates and biomarkers of inflammation in chemotherapy in biological summary), CMAJ 182: 137-141). When estimated kidneyThe filtration rate of the pellets is lower than 30ml/min/1.73m²At times, there is significant metabolic acidosis in a significant proportion of patients. (KDOQI bone minerals: American Journal of Kidney Diseases (2003) 42: S1-S201 (supplement), Widmerb, Gerhardt RE, Harrington JT, Cohen JJ, Serum electrolyte and acid base composition: Effect of The grade degree of chronic renal failure (Serum electrolyte and acid base composition: The fluorescence of Serum renal failure), Arch Intern Med 139: 1099-, 2010).

Regardless of the cause, metabolic acidosis lowers bicarbonate in extracellular fluid and thus lowers extracellular pH. The relationship between serum pH and serum bicarbonate is described by Henderson-Hasselbalch equation:

pH＝pK’+log[HCO3-]/[(0.03X Paco2)]

wherein 0.03 is CO₂Coefficient of physical solubility, [ HCO ]₃ ^-]And PaCO₂The bicarbonate concentration and the carbon dioxide partial pressure, respectively.

There are several laboratory tests that can be used to define metabolic acidosis. These assays measure primarily bicarbonate (HCO) in different biological samples including venous or arterial blood₃ ^-) Or proton (H)⁺) And (4) concentration.

The most useful measurement for determining acidosis depends on intravenous plasma bicarbonate (or total carbon dioxide [ tCO ]₂]) Serum electrolyte Cl^-、K⁺And Na⁺And determination of anion gap. In the clinical laboratory, venous plasma orMeasurement of serum electrolytes included evaluation of tCO 2. The measurement reflects circulating CO₂Total of [ i.e. from bicarbonate (HCO)₃ ^-) Carbonic acid, (H)₂CO₃) And dissolved CO₂(0.03X Pco₂) Total CO of₂]. the tCO2 may also be combined with HCO by using a simplified and standardized form of the Hendeson-Hasel Barch equation₃ ^-Establishing a relation: tCO2 ═ HCO₃ ^-+0.03PCO₂Wherein PCO₂Is measured CO₂Partial pressure. Due to HCO₃ ^-Concentration greater than 90% of tCO2, and small amount of H₂CO₃Therefore, the vein tCO2 is generally used as a venous HCO in blood₃A reasonable approximation of the concentration. Abnormal plasma HCO of < 24-26mEq/L, especially during chronic kidney disease₃ ^-Values generally indicate metabolic acidosis.

Serum Cl^-Changes in concentration may provide additional insight into the study of possible disorders of acid-base balance, particularly when they interact with serum Na⁺When the change in concentration is not proportional. When this occurs, serum Cl^-Changes in concentration are typically correlated with reciprocal changes in serum bicarbonate. Thus, in metabolic acidosis with normal anion space, serum Cl-increases by > 105mEq/L when serum bicarbonate is reduced by < 24-26 mEq/L.

Anion space [ defined as serum Na ]⁺-(Cl^-+HCO₃ ^-)]Is an important aspect of diagnosing metabolic acidosis. Metabolic acidosis may occur with normal or elevated anion space. However, serum HCO is not critical₃ ^-Whether altered, an increased anion gap is generally indicative of metabolic acidosis. Anion gaps greater than 20mEq/L (normal anion gaps are 8-12mEq/L) are typical features of metabolic acidosis.

Arterial blood gas is used to identify the type of acid-base balance disorder and to determine the presence or absence of mixed disorders. Generally, the results of arterial blood gas determinations should be coordinated with the above listed medical history, physical examination and routine laboratory data. Arterial blood-qiMeasurement of arterial carbon dioxide tension (P)_aCO₂) Acidity (pH) and oxygen tension (P)_aO₂). According to pH and Paco₂Calculating HCO₃ ^-And (4) concentration. The metabolic acidosis is marked by pH < 7.35, P_aCO₂Less than 35mm Hg and HCO₃ ^-＜22mEq/L。P_aO₂Values (normal values 80-95mmHg) are not used to make a diagnosis of metabolic acidosis, but may help to determine the cause. Acid-base imbalance disorders are first classified as respiratory or metabolic. The respiratory disorder is caused by CO₂Production of CO in extracellular fluid caused by abnormal lung elimination₂(carbon dioxide) excess (acidosis) or deficiency (alkalosis). In respiratory acid-base disorders, serum bicarbonate (HCO)₃ ^-) Initially Pco₂Direct result of the change, Pco₂More increase in (b) resulted in HCO₃ ^-Increases (Adrogue HJ, Madias NE, 2003, Respiratory acidosis, Respiratory alkalosis and mixed disorders (Respiratory acidosis), Johnson RJ, Feehally J (eds): comprehensive clinical Newrole, London, CV Mosby, pp.167-182). Metabolic disorders are those caused by excessive uptake or metabolic production or loss of non-volatile acids or bases in the extracellular fluid. These changes are reflected in the bicarbonate anion (HCO) in the blood₃ ^-) A change in concentration; adaptation in this context includes buffering (immediate), respiration (hours to days) and renal (days) mechanisms (DuBose TD, MacDonald GA: crude tubular acids, 2002, DuBose TD, Hamm LL (eds.: Acid-base and electrolyte disorders: A compositions to Brenners and Rector's the Kidney, Philadelphia, WB Saunders, pp.189-206).

Total hydrogen ion concentration in blood was defined as serum HCO₃ ^-Content (regulated by the kidney) and P_CO2The ratio of the two quantities of content (modulated by the lungs) is expressed as follows:

[H⁺]∝(P_CO2/[HCO₃ ^-])

the result of the increase in total hydrogen ion concentration is the major extracellular buffer carbonic acidHydrogen radicals decrease. The normal blood pH is 7.38-7.42, corresponding to hydrogen ion (H)⁺) The concentration was 42-38nmol/L (Goldberg M: appliach to Acid-base Disorders.2005 Greenberg A, Cheung AK (eds.) Primer on Kidney Disases, national Kidney Foundation, Philadelphia, Elsevier-Saunders, pp.104-109.). Bicarbonate radical (HCO)₃ ^-) Is an anion that buffers in vivo pH disorders, and normal levels of plasma bicarbonate are 22-26mEq/L (SzerlipHM: metabolic acidiosis, 2005, Greenberg A, Cheung AK (eds.) Primer on Kidney diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pp.74-89.). Acidosis is a process leading to a drop in blood pH (acidemia) and reflects hydrogen ions (H)⁺) Accumulation and subsequent use of bicarbonate ions (HCO)₃ ^-) Buffering, resulting in a reduction in serum carbonate. Metabolic acidosis may be expressed as follows:

(clinical practice guidelines for nutrition of chronic renal failure. K/DOQI, National Kidney Foundation. am. J. Kidney Dis.2000; 35: S1-140). Using this equilibrium equation, one HCO was deleted₃ ^-Corresponding to the addition of one H⁺On the contrary, one HCO is added₃Equivalent to the loss of one H⁺. Thus, the change in the pH of the blood, in particular H⁺Can be increased by increasing serum HCO (lower pH, acidosis)₃ ^-Or equivalently by reducing serum H⁺And (6) correcting.

In order to maintain the extracellular pH within the normal range, the acid produced daily must be excreted from the body. Acid production in the body is caused by the metabolism of dietary carbohydrates, fats and amino acids. Complete oxidation of these metabolic substrates produces water and CO₂. Carbon dioxide produced by this oxidation (-20,000 mmol/day) is efficiently exhaled by the lungs, representing the volatile acid component of the acid-base equilibrium.

In contrast, non-volatile acids (. about.50-100 mEq/day) are passed through sulfate and phosphate containing amino acidsAnd metabolic production of nucleic acids. Additional non-volatile acids (lactic acid, butyric acid, acetic acid, other organic acids) are produced by incomplete oxidation of fats and carbohydrates and carbohydrate metabolism in the colon, where bacteria residing in the lumen of the colon convert substrates into small organic acids which are then absorbed into the bloodstream. The effect of short chain fatty acids on acidosis is to some extent anabolized (e.g., anabolized long chain fatty acids) or catabolized to water and CO₂To a minimum.

The kidneys maintain pH balance in the blood by two mechanisms: recovery of filtered HCO₃ ^-To prevent complete depletion of bicarbonate and to eliminate non-volatile acids in the urine. Both mechanisms are necessary to prevent bicarbonate depletion and acidosis.

In the first mechanism, the kidneys recover HCO filtered by the glomeruli₃ ^-. This mechanism occurs in the proximal tubule, accounting for the recovered HCO₃ ^-4500 mEq/day. This mechanism prevents HCO₃ ^-Is lost in the urine and thus prevents metabolic acidosis. In the second mechanism, the kidney eliminates enough H⁺Equivalent to the non-volatile acids produced daily by the metabolism and oxidation of proteins, fats and carbohydrates. Elimination of this acid load is via two distinct pathways in the kidney, including H⁺Efficient secretion of ions and ammonia production. The net result of these two interconnected processes is the elimination of the non-volatile acids produced by the normal metabolism of 50-100 mEq/day.

Therefore, maintaining acid-base balance requires normal renal function. In the course of chronic kidney disease, HCO₃ ^-Is impaired by the production and secretion of ammonia. These defects rapidly lead to chronic metabolic acidosis, which is itself a potent precursor to end-stage renal disease. As metabolism continues to produce acid, the reduction of acid elimination will destroy H⁺/HCO₃ ^-Equilibrating so that the blood pH drops below the normal pH of 7.38-7.42.

Treatment of metabolic acidosis with alkaline therapy is generally manifested by raising and maintaining plasma pH to greater than 7.20. Sodium bicarbonate (NaHCO)₃) Is the most commonly used drug for correcting metabolic acidosis. NaHCO may be administered intravenously₃So as to raise HCO in serum sufficiently₃ ^-To increase the pH to greater than 7.20. The additional correction depends on the individual situation, and is not applicable if the underlying procedure is treatable or the patient is asymptomatic. This is especially true in certain forms of metabolic acidosis. For example, in high Anion Gap (AG) acidosis secondary to the accumulation of organic acids lactic acid and ketones, the homologous anion is eventually metabolized to HCO₃ ^-. When the underlying disorder is treated, serum pH is calibrated; therefore, care should be taken in these patients when providing base to raise the pH well above 7.20 to prevent the bicarbonate from increasing above the normal range (> 26 mEq/L).

Citrate in the form of potassium or sodium salt is a suitable base therapy for oral or IV administration as it is metabolized by the liver and results in the formation of 3 moles of bicarbonate per mole of citrate. IV administered potassium citrate should be used with caution in the presence of renal injury and should be closely monitored to avoid hyperkalemia.

Intravenous sodium bicarbonate (NaHCO) may be administered if metabolic acidosis is severe or if correction is not possible without exogenous base administration₃) And (3) solution. Oral base administration is the preferred treatment route in humans with chronic metabolic acidosis. The most commonly used base form for oral therapy includes NaHCO₃Tablet, in which 1g NaHCO₃Equal to 11.9mEq HCO₃ ^-. However, NaHCO₃Is not approved for medical use, and the package instructions for intravenous sodium bicarbonate solutions include the following contraindications, warnings and precautions (Hospira label of NDC 0409-:

contraindications: sodium bicarbonate injection USP is contraindicated in patients who have lost chloride ions (chloride) due to vomiting or continuous gastrointestinal aspiration and in patients receiving diuretics known to produce hypochloro alkalosis.

Warning: great care is taken if sodium ion containing solutions are used in patients with congestive heart failure, severe renal insufficiency and in clinical states where edema with sodium retention is present. In patients with reduced renal function, administration of a solution containing sodium ions may result in sodium retention. Intravenous administration of these solutions can result in fluid and/or solute overload, resulting in diluted serum electrolyte concentrations, excessive body water, congestive states, or pulmonary edema.

Note that: [.. ] the potentially large load of sodium given with bicarbonate requires careful use of sodium bicarbonate in patients with congestive heart failure or other edematous or sodium-retaining states, as well as in patients with little or no urine.

Acid-base disorders are common in patients with chronic kidney disease and heart failure. Chronic renal disease (CKD) progressively impairs the renal excretion of hydrogen ions produced in healthy adults at about 1mmol/kg body weight (Yaqoob, MM.2010, Acidosis and progression of chronic kidney disease (acidity and progression of chronic kidney disease), Curr, Opin, Nephrol, hyperten.19: 489-. From the body acid (H)⁺) Accumulation or base (HCO)₃ ^-) Metabolic acidosis due to depletion is a common complication in patients with CKD, especially when glomerular filtration rate (GFR, a measure of renal function) is below 30ml/min/1.73m²Then (c) is performed. Metabolic acidosis has profound long-term effects on protein and muscle metabolism, bone turnover and renal osteodystrophy. In addition, metabolic acidosis affects various paracrine and endocrine functions, with long-term consequences such as increased inflammatory mediators, decreased leptin, insulin resistance, and increased production of corticosteroids and parathyroid hormone (Mitch WE, 1997, the effect of metabolic acidosis on nutrition (allergy of metabolic acidosis on nutrition), am.J.Kidney Dis.29: 46-48.). The net effects of persistent metabolic acidosis in CKD patients are loss of bone and muscle mass, negative nitrogen balance, and accelerated chronic renal failure due to hormonal and cellular abnormalities (De Brito-Ashurst I, varaugam M, rafter MJ et al, 2009, Bicarbonate supplementation slowing CKD progression and improving nutritional status (fertility progress of CKD and improved nutritional status), j.am.soc.nephrol.20: 2075-. In contrast, potential concerns with alkaline therapy in CKD patients include the expansion of extracellular fluid volume associated with sodium intake (which leads to the development or exacerbation of hypertension), the promotion of vascular calcification, and decompensation of existing heart failure. Moderate (GFR 20-25% of normal) CKD patients first develop hyperchloremic acidosis with normal anion gaps due to the inability to recover filtered bicarbonate and to excrete protons and ammonium cations. As they progress toward late stage CKD, the anion gap increases, reflecting a continuous decrease in the ability of the kidney to excrete anions bound to unexpired protons. Serum bicarbonate is rarely below 15mmol/L in these patients, with a maximum elevated anion gap of about 20 mmol/L. The nonmetabolizable anions accumulated in CKD are buffered by alkali salts from Bone (Lemann JJJR, Bushinsky DA, Hamm LL human acid and alkali Bone buffering (Bone buffering of acid and base inhamans). Am.J.physiol Renal physiol.2003, 11 months, 285 (5): F811-32).

Most patients with chronic kidney disease have underlying diabetes (diabetic nephropathy) and hypertension, which leads to a deterioration of kidney function. In almost all hypertensive patients, high sodium intake will worsen hypertension. Therefore, renal, heart Failure, diabetes and hypertension guidelines severely limit sodium intake in these patients to less than 1.5g or 65mEq per day (HFSA 2010 guidelines, Lindenfeld 2010, J heart Failure V16 No 6P 475). Chronic antihypertensive therapy often induces sodium excretion (diuretics) or alters the ability of the kidneys to excrete sodium and water (e.g., "RAASi" drugs that inhibit the renin angiotensin aldosterone system). However, as kidney function deteriorates, diuretics become less effective because of the inability of the tubules to respond. RAASi drugs induce life-threatening hyperkalemia as they inhibit renal potassium excretion. Given the additional sodium load, it is not a reasonable practice to treat metabolic acidosis patients chronically with sodium-containing bases in amounts that often exceed the total daily recommended sodium intake. As a result, oral sodium bicarbonate is not usually prescribed for a long period of time in these diabetic nephropathy patients. Potassium bicarbonate is also unacceptable because patients with CKD cannot readily excrete potassium, resulting in severe hyperkalemia.

Despite these drawbacks, the effect of oral sodium bicarbonate has been studied in a small fraction of non-hypertensive CKD patient populations. As part of the Kidney Research National Dialogue, alkaline therapy was identified as having the potential to slow CKD progression and correct metabolic acidosis. In normal individuals, the annual age-related decrease in Glomerular Filtration Rate (GFR) after age 40 is 0.75-1.0ml/min/1.73m². In patients with rapidly progressing CKD, > 4ml/min/1.73m per year can be observed²Faster decrease of (c).

In one outcome study, De Brito-Ashurst et al demonstrated that bicarbonate supplementation in CKD maintained renal function (De Brito-Ashurst I, Varagunam M, Raftery MJ et al, 2009, bicarbonate supplementation slowed CKD progression and improved nutritional status, J.Am.Soc.Nephrol.20: 2075-. The study will have CKD (creatinine clearance [ CrCl ]) at position 134]15-30ml/min/1.73m²) And 16-20mmol/L serum bicarbonate were randomly assigned to supplement oral sodium bicarbonate or monitored for up to 2 years. The average dose of bicarbonate in this study was 1.82 g/day, which provided 22mEq of bicarbonate per day. The main endpoints are the rate of decrease of CrCl, with a rapid decrease of CrCl (> 3ml/min/1.73 m)²/yr) and end-stage renal disease ("ESRD") (CrCl < 10 ml/min). The decrease in bicarbonate supplementation CrCl was slower compared to the control group (decrease of 1.88ml/min/1.73m in patients receiving bicarbonate²While the control group decreased by 5.93ml/min/1.73m²(ii) a P is less than 0.0001). Patients supplemented with bicarbonate were significantly less likely to experience rapid progression (9% vs 45%; relative risk 0.15; 95% confidence interval 0.06-0.40; P < 0.0001). Similarly, bicarbonate supplemented patients rarely develop ESRD (6.5% vs 33%; relative risk 0.13; 95% confidence interval 0.04-0.40; P < 0.001).

Hyperphosphatemia is a common co-morbid condition in patients with CKD, particularly those with advanced or end stage renal disease. Sevelamer hydrochloride is a commonly used ion exchange resin to reduce serum phosphate concentrations. However, the reported drawbacks of this drug include metabolic acidosis, apparently due to the net absorption of HCl during phosphate binding in the small intestine. Several studies in patients with CKD and hyperphosphatemia who received hemodialysis or peritoneal dialysis found that the use of sevelamer hydrochloride reduced serum bicarbonate concentrations (Brezina, 2004Kidney int.v66S 90(2004) S39-S45; Fan, 2009Nephrol Dial Transplant (2009) 24: 3794).

Thus, in various aspects of the invention, compositions and methods for treating animals, including humans, and methods of making the compositions may be noted. The compositions comprise crosslinked amine polymers and may be used, for example, in the treatment of diseases or other metabolic disorders where removal of protons and/or chloride ions from the gastrointestinal tract would provide a physiological benefit. For example, the polymers described herein are useful for modulating acid-base related diseases in animals, including humans. In one such embodiment, the polymers described herein are useful for normalizing (normolize) serum bicarbonate concentration and blood pH in animals, including humans. As another example, the polymers described herein may be used to treat acidosis. There are a number of different physiological conditions that describe this imbalance, each of which can be treated with polymers that bind and remove HCl.

Metabolic acidosis resulting from a net increase in acid includes processes that increase endogenous hydrogen ion production, such as ketoacidosis, L-lactic acidosis, D-lactic acidosis, and salicylate acidosis (salicylate oxygenation). Metabolism of ingested toxins such as methanol, ethylene glycol, and side aldehydes also increases hydrogen ion concentrations. The reduced renal excretion of hydrogen ions in uremic acidosis and remote (type I) renal tubular acidosis is another cause of the increased in vivo acid net resulting in metabolic acidosis. Metabolic acidosis due to bicarbonate loss is a hallmark of proximal (type II) renal tubule acidosis. Furthermore, gastrointestinal loss of bicarbonate in acute or chronic diarrhea also leads to metabolic acidosis. Primary or secondary aldosteronism is a common disorder leading to hyperkalemia and metabolic acidosis and forms the basis of the classification of renal tubular acidosis type IV. Hyporenin hypoaldosteronism (hyponephrogenic hypoaldosteronism) is the most frequently encountered category of disorders.

Another way to describe metabolic acidosis is in terms of anion space. Causes of high anionic interstitial acidosis include diabetic ketoacidosis, L-lactic acidosis, D-lactic acidosis, alcoholic ketoacidosis (alcoholic ketoacidosis), hunger ketoacidosis, uremic acidosis associated with end-stage renal failure (stage CKD 4-5), salicylate acidosis, and toxin exposure due to ingestion including a selection of methanol, ethylene, propylene glycol, and side-aldehydes. Causes of normal anionic interstitial acidosis include early renal failure (CKD stage 1-3), gastrointestinal loss of bicarbonate due to acute or chronic diarrhea, distal (type I) renal tubular acidosis, proximal (type II) renal tubular acidosis, type IV renal tubular acidosis, dilute acidosis associated with large volume intravenous fluid administration, and treatment of diabetic ketoacidosis due to ketone loss in urine.

With respect to lactic acidosis, hypoxic lactic acidosis is caused by an imbalance between oxygen balance and oxygen supply and is associated with tissue ischemia, seizures, extreme exercise (extreme exercise), shock, cardiac arrest, low cardiac output and congestive heart failure, severe anemia, severe hypoxemia and carbon monoxide poisoning, vitamin deficiency and sepsis. In other types of lactic acidosis, oxygen delivery is normal, but oxidative phosphorylation is impaired, often as a result of defects in the mitochondria of the cell. This is often seen in congenital metabolic errors or caused by drug or toxin intake. Alternative sugars (e.g., fructose, sorbitol) used for gavage or as irrigants (irrigant) during surgery also lead to metabolism that triggers lactic acidosis.

There are three major types of tubular acidosis, each with a different etiology, with several subtypes. Remote (type I) renal tubular acidosis may be caused by genetic and genomic changes, in particular HCO₃ ^-/Cl^-Exchanger (AE1) or H⁺Mutations in/ATPase. Examples of acquired distal (type I) renal tubular acidosis include hyperparathyroidism, Sjogren's syndrome, medullary sponge kidney, cryoglobulinemia, systemicLupus erythematosus, renal transplant rejection, chronic tubulointerstitial disease (chronic tubulointerstitial disease), and exposure to various drugs including amphotericin B, lithium, ifosfamide, foscarnet, toluene, and vanadium. A special classification of distal (type IV) renal tubular acidosis with hyperkalemia is found in lupus nephritis, obstructive renal disease (obstructive nephropathy), sickle cell anemia and voltage defects. Genetic examples include pseudoaldosteronism type I and pseudoaldosteronism type II (Gordon's disease) and exposure to certain drugs (amiloride, triamterene, trimethoprim and pentamidine) also leads to distal (type IV) renal tubular acidosis with hyperkalemia. Proximal (type II) renal tubular acidosis may also be caused by genetic or acquired causes. Hereditary causes include wilson's disease and rockwell's syndrome (Lowe ' ssyndrome). Acquired causes include cystinosis, galactosemia, multiple myeloma, light chain disease (Lightchain disease), amyloidosis, vitamin D deficiency, lead and mercury intake, and exposure to certain drugs including ifosfamide, cidofovir, aminoglycosides, and acetazolamide. Separation defects in bicarbonate reabsorption can be responsible for proximal (type II) renal tubular acidosis; examples of such defects include exposure to carbonic anhydrase inhibitors, acetazolamide, topiramate, sulfamylon, and carbonic anhydrase deficiencies. Combined proximal and distal tubular acidosis (type III) is uncommon, resulting from defects in proximal bicarbonate reabsorption and distal proton secretion. Mutations in the gene for cystolic carbonic anhydrase and certain drugs including ifosfamide can cause defects. Renal tubular acidosis type IV with hyperkalemia is the cause of metabolic acidosis. The main etiology behind this type of acidosis is aldosterone deficiency; aldosterone deficiency is caused by primary adrenal failure, the hyporeninemic hypoaldosteronism syndrome (RTA type IV) common in elderly individuals, addison's disease and pseudoaldosterone deficiency type I due to mineralocorticoid resistance. Chronic interstitial nephritis due to analgesic nephropathy, chronic pyelonephritis, obstructive nephropathy and sickle cell diseaseAcidosis with hyperkalemia can also occur. Finally, drugs such as amiloride, spironolactone, triamterene, trimethoprim, heparin therapy, NSAIDs, angiotensin receptor blockers and angiotensin converting enzyme inhibitors can induce metabolic acidosis accompanied by hyperkalemia.

All of the above causes and etiologies of metabolic acidosis can be treated with polymers designed to bind and remove HCl in the gastrointestinal tract.

Disclosure of Invention

The method of treatment generally comprises administering a therapeutically effective amount of a crosslinked amine polymer having the ability to remove protons and chloride ions from the gastrointestinal tract of an animal, including a human. In general, such crosslinked amine polymers have two or more of the following properties: lower swelling, higher proton and chloride ion binding, and/or lower binding of interfering anions such as phosphate, citrate, short chain fatty acids, and bile acids. In the examples and embodiments below, unless otherwise indicated, the crosslinked amine polymers are used in the free amine form and protonation of the amine is required for binding the anion. As such, many assays report anion binding, and due to the necessary low degree of amine quaternization, it is assumed that anion binding approximates the amount of proton binding. For example, in one embodiment, the crosslinked amine polymer has two or more of the following properties: (i) a proton binding capacity and a chloride ion binding capacity of at least about 5mmol/g in simulated gastric fluid ("SGF"); (ii) a swelling ratio of less than about 5; (iii) chlorine examples in simulated small intestine inorganic buffer ("SIB") of at least about 0.35:1, respectively: phosphate ion binding ratio; (iv) selectivity for chloride ions over other anions in simulated small intestine organic and inorganic buffers ("SOB"); (v) an average particle size of about 80-120 microns; (vi) more than about 50% retention of bound HCl when performing the chloride ion retention assay ("CRA", defined below); (vii) no more than about 40% of the quaternized amine groups prior to administration to animals, including humans, as measured in the quaternized amine assay ("QAA") in order to ensure proton binding that constitutes the primary therapeutic effect of the polymer; (viii) in "SOB" of at least about 0.35:1 chloride ion: interfering with the anion binding ratio; (ix) molecular weight/nitrogen of 50-170 daltons; and/or (x)25 to 90% by weight of a cross-linking agent. For example, in one such embodiment, the crosslinked amine polymer has at least two of the properties "(i)" - "(x)" defined in this paragraph. As another example, in one such embodiment, the crosslinked amine polymer has at least three of the properties "(i)" - "(x)" defined in this paragraph. As another example, in one such embodiment, the crosslinked amine polymer has at least four of the properties "(i)" - "6 (x)" defined in this paragraph. As another example, in one such embodiment, the crosslinked amine polymer has at least five of the properties "(i)" - "(x)" defined in this paragraph. As another example, in one such embodiment, the crosslinked amine polymer has at least six of the properties "(i)" - "(x)" defined in this paragraph. As another example, in one such embodiment, the crosslinked amine polymer has at least seven of the properties "(i)" - "(x)" defined in this paragraph. As another example, in one such embodiment, the crosslinked amine polymer has at least eight of the properties "(i)" - "(x)" defined in this paragraph.

In one embodiment, the crosslinked amine polymer is administered in the form of a pharmaceutical composition comprising the crosslinked amine polymer, and optionally a pharmaceutically acceptable carrier, diluent or excipient, or a combination thereof, that does not significantly interfere with the proton and/or chloride ion binding properties of the crosslinked amine polymer in vivo. Optionally, the pharmaceutical composition may further comprise another therapeutic agent.

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer having (i) at least 0.35:1 chloride ions in simulated small intestine inorganic buffer ("SIB"), respectively: phosphate ion binding ratio; and (ii) a swelling ratio of no more than about 5.

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer that has (i) selectivity for chloride ions over other anions in a simulated small intestine organic and inorganic buffer ("SOB"); and (ii) a swelling ratio of no more than about 5.

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer having: (i) a proton binding capacity and a chloride ion binding capacity of at least 5mmol/g in simulated gastric fluid; and (ii) a swelling ratio of no more than about 2.

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity of at least 5mmol/g in simulated gastric fluid; (ii) a swelling ratio of less than 5; and (iii) a chloride to phosphate ion binding ratio of at least 0.35:1, respectively, in a simulated small intestine inorganic buffer ("SIB").

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer having (i) a proton binding capacity and a chloride ion binding capacity of at least 5mmol/g in simulated gastric fluid; (ii) a swelling ratio of less than 5; and (iii) selectivity for chloride ions over other anions in simulated small intestine organic and inorganic buffers ("SOBs").

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer having i) a chloride ion binding capacity of > 2mmol/g in a simulated organic/inorganic buffer (SOB) and ii) a bound chloride ion of > 50% retention when determined in a chloride ion retention assay (CRA).

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer having i) a chloride ion binding capacity of > 5mmol/g in Simulated Gastric Fluid (SGF) and ii) no more than 40% quaternized amine groups as measured in a Quaternized Amine Assay (QAA).

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer comprising an amine residue of formula 1,

wherein R is₁、R₂And R₃Independently is hydrogen, hydrocarbyl or substituted hydrocarbyl, provided however that R₁、R₂And R₃Is other than hydrogen, and the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5mmol/g and a chloride ion binding capacity of at least 5mmol/g in an aqueous simulated gastric fluid buffer ("SGF") containing 35mM NaCl and 63mM HCl at pH1.2, 37 ℃, and (ii) an equilibrium swelling ratio in deionized water of about 2 or less.

In some embodiments, the pharmaceutical composition comprises a crosslinked amine polymer comprising an amine residue of formula 1,

wherein R is₁、R₂And R₃Independently hydrogen, hydrocarbyl, substituted hydrocarbyl, provided that R₁、R₂And R₃Is not hydrogen, and binds chloride to interfering ions in a molar ratio of at least 0.35:1, respectively, in an interfering ion buffer at 37 ℃, wherein (i) the interfering ions are phosphate ions and the interfering ion buffer is a buffer solution of 36mM chloride and 20mM phosphate at pH5.5, or (ii) the interfering ions are phosphate, citrate, and taurocholate ions and the interfering ion buffer is a buffer solution comprising 36mM chloride, 7mM phosphate, 1.5mM citrate, and 5mM taurocholate at pH 6.2. Stated differently, in embodiments where the interfering ion buffer is a buffer solution of 36mM chloride and 20mM phosphate at pH5.5, the chloride to interfering ion ratio is the chloride to phosphate ratio, and in embodiments where the interfering ion buffer is a buffer solution comprising 36mM chloride, 7mM phosphate, 1.5mM citrate, and 5mM taurocholate at pH 6.2, the chloride to interfering ion ratio isRatio of chloride ions to the combined (total) amount of phosphate, citrate and taurocholate ions.

In some embodiments, the crosslinked amine polymer is derived from the polymerization of an amine of formula 2,

wherein

m and n are independently non-negative integers;

R₁₀、R₂₀、R₃₀and R₄₀Independently hydrogen, a hydrocarbyl group or a substituted hydrocarbyl group,

X₁is that

X₂Is a hydrocarbyl or substituted hydrocarbyl group;

X₁₁each independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, amino, boronic acid or halo (halo); and is

z is a non-negative number.

Another aspect of the present application is a method of crosslinking a proton-binding intermediate with a multifunctional crosslinking agent (polyfunctionalalsinker) to obtain one or more of the following characteristics: lower swelling, higher proton and chloride ion binding, and/or lower interference from interfering ions. The proton-binding intermediate may be, for example, an oligomer or polymer containing an amine moiety, which is prepared by (i) substitution polymerization, (ii) addition polymerization, or (iii) post-polymerization crosslinking of the intermediate.

Other aspects and features will be in part apparent and in part pointed out hereinafter.

Brief description of the drawings

Fig. 1A-1C are flow charts illustrating the mechanism of action of a polymer as it passes through the gastrointestinal tract of an individual from oral ingestion/stomach (fig. 1A) to the upper gastrointestinal tract (fig. 1B) to the lower gastrointestinal tract/colon (fig. 1C).

FIG. 2 is a graph of swelling ratio of the polymer of the present application versus chloride to phosphate binding ratio in SIB.

Abbreviations and Definitions

The following definitions and methods are provided to better define the invention and to guide those skilled in the art in the practice of the invention. Unless otherwise indicated, the terms should be understood by those of ordinary skill in the relevant art in light of the conventional usage.

The term "acrylamide" denotes a compound of formula H₂A moiety of C ═ CH-C (o) NR- ＊, where ＊ represents the point of attachment of the moiety to the rest of the molecule, and R is hydrogen, hydrocarbyl, or substituted hydrocarbyl.

The term "acrylic acid" denotes a compound of formula H₂C-CH-C (O) O- ＊, wherein ＊ represents the point of attachment of the moiety to the rest of the molecule.

The terms "alicyclic", "cycloaliphatic", "alicyclic group" or "alicyclic group" mean a saturated monocyclic group of 3 to 8 carbon atoms, including cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The terms "aliphatic", "aliphatic group" and "aliphatic" refer to saturated and non-aromatic unsaturated hydrocarbon moieties having, for example, from 1 to about 20 carbon atoms, or in specific embodiments, from 1 to about 12 carbon atoms, from 1 to about 10 carbon atoms, from 1 to about 8 carbon atoms, or even from 1 to about 4 carbon atoms. Aliphatic groups include, for example: alkyl moieties such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like, and alkenyl moieties of corresponding chain length.

The term "alkanol" denotes an alkyl moiety which has been substituted by at least one hydroxyl group. In some embodiments, the alkanol group is a "lower alkanol" group containing 1 to 6 carbon atoms, one of which is attached to an oxygen atom. In other embodiments, the lower alkanol group contains 1 to 3 carbon atoms.

The term "alkenyl" includes straight or branched chain carbon residues having at least one carbon-carbon double bond. The term "alkenyl" may include conjugated or unconjugated carbon-carbon double bonds or combinations thereof. Alkenyl groups may include, for example, but are not limited to, 2 to about 20 carbon atoms, or in one particular embodiment, 2 to about 12 carbon atoms. In some embodiments, alkenyl is "lower alkenyl" having 2 to about 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, vinyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" include groups having either a "cis" or "trans" orientation or an "E" or "Z" orientation.

"alkyl", used alone or in other terms such as "haloalkyl", "aminoalkyl" and "alkylamino", includes saturated straight or branched chain carbon residues having, for example, from 1 to about 20 carbon atoms, or in particular embodiments from 1 to about 12 carbon atoms. In other embodiments, alkyl is "lower alkyl" having from 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. In a more specific embodiment, the lower alkyl group has 1 to 4 carbon atoms.

The term "alkylamino" refers to an amino group that is directly attached to the rest of the molecule through the nitrogen atom of the amino group, and wherein the nitrogen atom of the alkylamino group is substituted with 1 or 2 alkyl groups. In some embodiments, alkylamino is a "lower alkylamino" group having 1 or 2 alkyl groups of 1 to 6 carbon atoms attached to the nitrogen atom. In other embodiments, lower alkylamino has 1 to 3 carbon atoms. Suitable "alkylamino" groups can be monoalkylamino or dialkylamino groups such as N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, piperidine (pentamethylenamine), and the like.

The term "allyl" denotes a compound of formula H₂C＝CH-CH₂-_＊Wherein ＊ represents the point of attachment of the moiety to the rest of the molecule and the point of attachment is to a heteroatom or aromatic moiety.

The term "allylamine" denotes a compound having the formula H₂C＝CH-CH₂N(X₈)(X₉) Wherein X is₈And X₉Independently is hydrogen, hydrocarbyl or substituted hydrocarbyl, or X₈And X₉Together form a substituted or unsubstituted cycloaliphatic, aryl, or heterocyclic group, each as defined for that term, typically having from 3 to 8 atoms in the ring.

The term "amine" or "amino" used alone or as part of another group denotes the formula-N (X)₈)(X₉) In which X is₈And X₉Independently is hydrogen, hydrocarbyl or substituted hydrocarbyl, heteroaryl or heterocyclyl, or X₈And X₉Together form a substituted or unsubstituted cycloaliphatic, aryl, or heterocyclic group, each as defined for that term, typically having from 3 to 8 atoms in the ring.

The term "aminoalkyl" includes straight or branched chain alkyl groups having from 1 to about 10 carbon atoms, any of which may be substituted with one or more amino groups, attached directly to the remainder of the molecule through an atom other than the nitrogen of the amino group. In some embodiments, aminoalkyl is a "lower aminoalkyl" having 1 to 6 carbon atoms and one or more amino groups. Examples of the group include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

The term "aromatic group" or "aryl group" refers to an aromatic group having one or more rings, wherein the rings may be linked to each other in a pendant manner or may be fused. In particular embodiments, the aromatic group is 1,2, or 3 rings. Monocyclic aromatic groups can contain 5 to 10 carbon atoms, typically 5 to 8 carbon atoms, more typically 5 to 6 carbon atoms in the ring. Typical polycyclic aromatic groups have 2 or 3 rings. Polycyclic aromatic groups having 2 rings typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms, in the 2 rings. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl, or acenaphthenyl (acenaphthyl).

The term "bead" is used to describe a crosslinked polymer that is substantially spherical.

As used herein, the term "bound" in relation to a polymer and one or more ions, i.e., cations (e.g., "proton-binding" polymers) and anions, is "ion-binding" polymer and/or when bound to an ion, although generally not necessarily non-covalently bound, has sufficient binding capacity that at least a portion of the ion remains bound under in vitro or in vivo conditions, wherein the polymer is used for a sufficient period of time to effect removal of the ion from solution or from the body.

The term "chloride retention assay" or "CRA" refers to an assay in which the retention of chloride or other anions by the free amine test polymer and the retention of chloride and other anions by the free amine sevelamer and bisxamethylene (bixalomer) control polymer are evaluated by exposing them to typical competitive anion concentrations in the lumen of the colon. The anions released from the polymer and the anions retained by the polymer under these conditions were determined. The first step in this retention assay is to perform a specific organic/inorganic buffer assay (SOB screen) as described in the other sections herein. A blank tube without polymer was included throughout the retention screen and treated in the same manner. Instead of discarding the polymer and SOB matrix in the assay tube, the contents were transferred to a Solid Phase Extraction (SPE) tube equipped with a 20 micron pore frit. Excess SOB matrix was removed by applying negative pressure to the bottom of the SPE tube or positive pressure to the top. The SOB assay tubes were rinsed 2 times with deionized water and the contents transferred to SPE tubes to ensure that as much polymer as possible was recovered. The retention assay matrix was then added to the SPE tube. The retention assay matrix contained 50mM 2- (N-morpholino) ethanesulfonic acid (MES), 100mM sodium acetate, 5mM sodium phosphate, 15mM sulfate, adjusted to pH 6.2. The concentration of potentially competing anions reflects the typical late colon lumen concentration (Wrong, O et al 1965]Clinical Science 28, 357- & 375). Chloride ions are omitted because the goal is to determine chloride retention and bicarbonate is omitted because it is converted to water and CO₂And is unstable. Retention buffer was added to reach a final poly of 2.5mg/mlCompound concentration (assuming no polymer loss, as weighed into the SOB assay tube in the original amount). The SPE tubes were capped and sealed and incubated at 37 ℃ for about 40 hours. A 600 microliter sample was removed, filtered, and if necessary diluted, and the anion content determined as described above for SOB. For each polymer tested, the following calculations were used to calculate the chloride, citrate and taurocholate release from the polymer in the retention matrix:

where [ Ion ] ret is the Ion concentration in the retention matrix at the end of the 48 hour incubation, [ Ion ] rebblank is the value of the specific Ion in the retention matrix of the blank SPE tube, the dilution factor is the dilution factor if necessary, and 2.5 is the polymer concentration in mg/ml. Excess retained matrix was removed by applying negative pressure to the bottom of the SPE tube or positive pressure to the top. The SPE cartridge was briefly washed with 10ml of deionized water to remove excess water. The ions specifically bound to the polymer were eluted by adding 0.2M NaOH to the SPE tubes to reach a final polymer concentration of 2.5mg/ml (assuming no polymer loss, as weighed into the SOB assay tubes in the original amount) and incubating at 37 ℃ for 16-20 hours. A 600 microliter sample was removed, filtered, and if necessary diluted, and the anion content determined as described above for SOB. For each polymer tested, the following calculations were used to calculate the chloride, phosphate, citrate and taurocholate released from the polymer in the retention matrix:

where [ Ion ] elu is the Ion concentration in the 0.2M NaOH elution matrix at the end of the 16-20 hour incubation, [ Ion ] elulank is the value of the specific Ion in the elution matrix of the blank SPE tube, dilution factor is the dilution factor if necessary, and 2.5 is the polymer concentration in mg/ml.

The term "crosslink density" refers to the average number of amine containing repeat units attached to the rest of the polymer. The number of connections may be 2,3, 4 and more. The repeating units in the linear non-crosslinked polymer are combined by 2 linkages. To form an insoluble gel, the number of linkages should be greater than 2. Low crosslink density materials such as sevelamer have an average of about 2.1 linkages between repeat units. More crosslinking systems, for example, have an average of about 4.6 linkages between amine-containing repeat units than do salomones. "crosslink density" means the semi-quantitative measurement based on the ratio of the starting materials used. Limitations include the fact that it cannot explain different crosslinking and polymerization methods. For example, small molecule amine systems require higher amounts of crosslinking agents because the crosslinking agents also act as monomers to form the polymer backbone, whereas for free radical polymerization, the polymer chains are formed independently of the linking reaction. This results in an inherently higher crosslink density of the substituted polymeric/small molecule amines under this definition compared to free radical polymeric crosslinked materials.

The term "crosslinker", used alone or applied within other terms, includes hydrocarbyl or substituted hydrocarbyl groups, straight or branched chain molecules capable of reacting more than once with any of the monomers or infinite polymer networks described in formula 1. Reactive groups in the crosslinking agent include, but are not limited to, alkyl halides, epoxides, phosgene, anhydrides, urethanes, carbonates, isocyanates, isothiocyanates, esters, activated esters, carboxylic acids and derivatives thereof, sulfonates and derivatives thereof, acid halides, aziridines, α, β -unsaturated carbonyls, ketones, aldehydes, pentafluoroaryl, vinyl, allyl, acrylate, methacrylate, acryl, methacrylamide, styrene (styrenic), acrylonitrile, and combinations thereof. In an exemplary embodiment, the reactive group of the crosslinking agent includes alkyl halides, epoxides, anhydrides, isocyanates, allyl groups, vinyl groups, acrylamides, and combinations thereof. In one such embodiment, the reactive group of the crosslinking agent is an alkyl halide, epoxide, or allyl group.

The term "diallylamine" denotes an amino moiety having 2 allyl groups.

The term "ether" denotes the formula ＊ -H_xC-O-CH_x- ＊, wherein ＊ represents the point of attachment of the moiety to the remainder, and x is independently equal to 0,1, 2, or 3.

The term "gel" is used to describe a crosslinked polymer having an irregular shape.

The term "halo" means a halogen, such as a fluorine, chlorine, bromine or iodine atom.

The term "haloalkyl" includes groups wherein any one or more of the alkyl carbon atoms is substituted by halo as defined above. Specifically included are monohaloalkyl, dihaloalkyl, and polyhaloalkyl groups, including perhaloalkyl groups. The monohaloalkyl group may have, for example, an iodine, bromine, chlorine or fluorine atom within the group. The dihalo-and polyhaloalkyl groups may have two or more of the same halo atom or a combination of different halo groups. "lower haloalkyl" includes groups having 1 to 6 carbon atoms. In some embodiments, lower haloalkyl has 1 to 3 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The terms "heteroaliphatic", "heteroalicyclic" describe chains of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms, which may be saturated or unsaturated (but not aromatic), containing one or more heteroatoms, such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron. The heteroatom may be linked to an atomic chain (e.g. - -CH (OH) - - - -CH (NH)₂) -, where the carbon atom is a member of a chain of atoms), or it may be one of the chain atoms (e.g., -ROR-or-RNHR-, where each R is an aliphatic group). Heteroaliphatic groups include heteroalkyl and heterocyclic groups, but exclude heteroaryl groups.

The term "heteroalkyl" describes a fully saturated heteroaliphatic group.

The term "heteroaryl" means 5-A monocyclic or bicyclic aromatic residue of 10 ring atoms, wherein one or more (in one embodiment, 1,2 or 3) ring atoms is a heteroatom selected from N, O or S, the remaining ring atoms being carbon, unless otherwise specified. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, imidazolyl, furyl, indolyl, and the like,

Azolyl radical, isoAzolyl, benzothiazolyl, benzoOxazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. The terms "heteroaryl" and "aryl" are defined herein independently of each other. "heteroarylene" means a divalent heteroaryl residue.

The term "heteroatom" means an atom other than carbon and hydrogen. Typically, the heteroatoms are selected from halogen, sulfur, phosphorus, nitrogen, boron, and oxygen atoms, but are not limited thereto. Groups containing more than one heteroatom may contain different heteroatoms.

The term "heterocycle", "heterocyclic group" or "heterocyclyl" means a saturated or unsaturated group of 4 to 8 ring atoms in which one or two ring atoms are heteroatoms such as N, O, B, P and S (O)_nWherein n is an integer from 0 to 2 and the remaining ring atoms are carbon. In addition, 1 or 2 ring carbon atoms in the heterocyclyl ring may optionally be replaced by a-C (O) -group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidino (pyrrolidino), piperidino, homopiperidino (homoperidino), 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino (piperazino), tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it may contain 1 or 2 ring double bonds, provided that the ring is not aromatic. When a heterocyclyl contains at least one nitrogen atom, it is also referred to hereinAre referred to as heterocyclic amino (heterocycloamino) and are a subset of heterocyclic groups.

The term "hydrocarbon group" or "hydrocarbyl group" means a chain of 1-25 carbon atoms, typically 1-12 carbon atoms, more typically 1-10 carbon atoms, most typically 1-8 carbon atoms. The hydrocarbon group may have a linear or branched structure. Typical hydrocarbyl groups have 1 or 2 branches, typically 1 branch. Typically, the hydrocarbyl group is saturated. The unsaturated hydrocarbyl group can have one or more double bonds, one or more triple bonds, or a combination thereof. Typical unsaturated hydrocarbon groups have 1 or 2 double bonds or 1 triple bond; more typically, the unsaturated hydrocarbyl group has 1 double bond.

An "initiator" is used to describe an agent that initiates polymerization.

The term "molecular weight/nitrogen" or "MW/N" refers to the calculated molecular weight/nitrogen atom of the polymer. It represents the average molecular weight of the amine functionality within the crosslinked polymer. It is calculated by dividing the mass of the polymer sample by the moles of nitrogen present in the sample. "MW/N" is the reciprocal of theoretical capacity, and calculations are based on feed ratios, while assuming complete reaction of the crosslinker and monomer. The lower the molecular weight/nitrogen, the higher the theoretical capacity of the crosslinked polymer.

"optional," "optional," or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl may, but need not, be present, and that the description includes embodiments in which heterocyclyl is substituted with alkyl and embodiments in which heterocyclyl is not substituted with alkyl.

"pharmaceutically acceptable" when used in conjunction with a carrier, diluent or excipient, respectively, means a carrier, diluent or excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and has no biologically or otherwise undesirable properties for veterinary use and/or human pharmaceutical use.

The term "post-polymerization crosslinking" is a term describing a reaction to an already formed bead or gel, wherein more crosslinking is introduced into the already formed bead or gel, thereby generating a bead or gel with an increased amount of crosslinking.

The term "post-polymerization modification" is a term describing the modification of an already formed bead or gel, wherein the reaction or treatment introduces additional functional groups. The functional group may be covalently or non-covalently attached to the already formed bead.

The term "quaternized amine assay" ("QAA") describes a method for assessing the amount of quaternary amine present in a given sample of crosslinked polymer. This assay measures chloride ion binding of crosslinked amine polymers at pH 11.5. At this pH, the primary, secondary and tertiary amines are not substantially protonated and do not substantially contribute to chloride ion binding. Thus, any binding observed under these conditions can be attributed to the presence of the permanently charged quaternary amine. The test solution for the QAA assay is 100mM sodium chloride pH 11.5. The concentration of chloride ions was similar to that in the SGF assay used to evaluate the total binding capacity of the crosslinked amine polymer. The quaternary amine content as a percentage of total amine present was calculated as follows:

for the QAA assay, the free-amine polymer to be tested is prepared at a concentration of 2.5mg/mL (e.g., 25mg dry mass) in 10mL QAA buffer. The mixture was incubated at 37 ℃ for-16 hours while stirring on a rotisserie mixer. After incubation and mixing, 600 microliters of supernatant was removed and filtered using an 800 microliter, 0.45 micron pore size 96-well polypropylene filter plate. With the sample lined up in the filter plate and bottom-mounted collection plate, the device was centrifuged at 1000Xg for 1 minute to filter the sample. After filtration into a collection plate, each filtrate was diluted appropriately and then the chloride ion content was determined. The IC method (e.g., ICS-2100Ion Chromatography, Thermo Fisher Scientific) used to analyze the chloride Ion content of the filtrate consisted of a 15mM KOH mobile phase, a 5 microliter sample volume with a run time of 3 minutes, a 1000 microliter wash/rinse volume, and a flow rate of 1.25 mL/min. To determine the chloride ion bound to the polymer, the following calculations were done:

is shown asWhere Clstart is the initial concentration of chloride ions in QAA buffer, Cl eq is the equilibrium value of chloride ions in the filtrate determined after exposure to the test polymer, and 2.5 is the polymer concentration in mg/ml.

The "simulated gastric fluid" or "SGF" assay describes an assay to determine the total chloride binding capacity of a test polymer using a defined buffer that simulates the contents of gastric fluid as follows: simulated Gastric Fluid (SGF) consisted of 35mM NaCl, 63mM HCl, pH 1.2. For the present assay, the free-amine polymer to be tested was prepared at a concentration of 2.5mg/mL (25mg dry mass) in 10mL SGF buffer. The mixture was incubated at 37 ℃ for-12-16 hours while stirring on a rotisserie mixer. After incubation and mixing, the tube containing the polymer was centrifuged at 500-1000Xg for 2 minutes to pellet the test sample. Approximately 750 microliters of supernatant was removed and filtered using a suitable filter, such as a 0.45 micron pore size syringe filter or an 800 microliter 1 micron pore size 96-well glass filter plate that had been mounted on a 96-well 2ml collection plate. With the latter arrangement, multiple samples tested in SGF buffer can be prepared for analysis, including a standard control of the free amine sevelamer, free amine bistalom, and a control tube containing blank buffer to perform all assay steps. With the sample lined up in the filter plate and bottom-mounted collection plate, the device was centrifuged at 1000Xg for 1 minute to filter the sample. In the case of a small sample set, a syringe filter may be used instead of a filter pad to recover-2-4 mL of filtrate into a 15mL container. After filtration, each filtrate was diluted 4X with water and the chloride ion content of the filtrate was determined by Ion Chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermoscientific) consisted of an AS11 column and 15mM KOH mobile phase, 5 microliter sample volume with 3 min run time, 1000 microliter wash/rinse volume, and a flow rate of 1.25 mL/min. To determine the chloride ion bound to the polymer, the following calculations were done:

expressed as the binding capacity in mmol chloride ions per g polymer: where Cl start is the initial concentration of chloride ions in SGF buffer, Cl eq is the equilibrium value of chloride ions in the measured filtrate diluted after exposure to the test polymer, 4 is the dilution factor, and 2.5 is the polymer concentration in mg/ml.

"simulated small intestine inorganic buffer" or "SIB" is an assay to determine the chloride and phosphate binding capacity of free amine test polymers in a selective specific interference buffer assay (SIB). The chloride and phosphate binding capacities of the free amine test polymers and the chloride and phosphate binding capacities of the free amine sevelamer and bisaxamethylene control polymers were determined using the selective specific interference buffer assay (SIB) as follows: the buffer used for the SIB assay contained 36mM NaCl, 20mM NaH buffered to pH5.5₂PO₄50mM 2- (N-morpholino) ethanesulfonic acid (MES). SIB buffer containing chloride ions, phosphate concentration and pH present in the human duodenum and upper Gastrointestinal tract (Stevens T, Conwell DL, Zuccaro G, VanLente F, Khadwala F, Purich E et al, Electrolyte composition of endoscopically collected duodenal drainage fluid after synthesis of porcine pancreatic stimulation in healthy individuals (Electrolyte composition of endoscopic tissue drainage fluid) gastric and intestinal tissue viscosity index samples 2004; 60(3) 351-5, Fordtran J, Locklar T. after feeding stomach and small intestinal fluids and osmotic pressure (Ionic connectivity and osmotic pressure) binding of phosphate ions to phosphate ions was measured and compared to 21. 11. 21. 2. 3. calcium chloride binding was effective. To perform the assay, the free amine polymer to be tested was prepared at a concentration of 2.5mg/mL (25mg dry mass) in 10mL of SIB buffer. The mixture was incubated at 37 ℃ for 1 hour while stirring on a rotisserie mixer. After incubation and mixing, the tube containing the polymer was centrifuged at 1000Xg for 2 minutes to pellet the test sample. 750 microliters of supernatant was removed and 800 microliters of 1 micron wells were usedFiltering with a 96-well glass filter plate, which has been mounted on a 96-well 2mL collection plate; with this arrangement, multiple samples tested in SIB buffer can be prepared for analysis, including a standard control of the free amine sevelamer, free amine bistalomer, and a control tube containing blank buffer to perform all assay steps. With the sample lined up in the filter plate and bottom-mounted collection plate, the device was centrifuged at 1000Xg for 1 minute to filter the sample. In the case of a small sample set, a syringe filter (0.45 micron) may be used instead of a filter plate to recover-2-4 mL of filtrate into a 15mL vial. After filtration into a collection plate, each filtrate was diluted and then the chloride or phosphate content was determined. To determine chloride and phosphate, the filtrate to be analyzed was diluted 4X with water. The chloride and phosphate content of the filtrate was determined by Ion Chromatography (IC). The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consisted of an AS24A column, 45mM KOH mobile phase, 5 microliter sample volume with about 10 minutes run time, 1000 microliter wash/rinse volume, and a flow rate of 0.3 mL/min. To determine the chloride ion bound to the polymer, the following calculations were done:

is shown asWherein Cl is_startIs the initial concentration of chloride ions, Cl, in the SIB buffer_finalIs the final value of chloride ion in the diluted filtrate determined after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml. To determine the phosphate bound to the polymer, the following calculations were done:

is shown as

Wherein P is_startIs the initial concentration of phosphate in the SIB buffer, Cl_finalIs the final value of phosphate in the diluted filtrate determined after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml.

"simulated small intestine organic and inorganic buffers" or "SOBs" are assays for determining chloride binding capacity, which is determined in the presence of organic and inorganic interferents commonly found in the gastrointestinal tract. The chloride binding capacity and other anion binding capacity of the free amine test polymer as well as the amine sevelamer and bisaxamethylene control polymer were determined as follows in the presence of specific organic interferents common in the gastrointestinal tract: to simulate the conditions of the gastrointestinal lumen, the free amine polymer was tested for chloride binding capacity upon exposure to chloride in the presence of other potentially competing anions such as bile acids, fatty acids, phosphates, acetates, and citrates using the SOB screen. The test buffer used for the SOB assay contained 50mM 2- (N-morpholino) ethanesulfonic acid (MES), 50mM sodium acetate, 36mM sodium chloride, 7mM sodium phosphate, 1.5mM sodium citrate, 30mM oleic acid, and 5mM sodium taurocholate buffered to pH 6.2. The concentration of potentially competing anions reflects the typical gastrointestinal lumen concentration found at different points in the gastrointestinal tract, and the pH is the average of the representative pH values encountered in the duodenum and large intestine. The chloride ion concentration used was the same as used in SIB screening. For the present determination, the free amine polymer to be tested was weighed accurately into a 16x100mm glass tube with a liquid-tight screw cap. The appropriate amount of SOB buffer was added to the test tube to a final polymer concentration of 2.5 mg/ml. The mixture was incubated at 37 ℃ for 2 hours while stirring on a rotisserie mixer. After incubation and mixing, 600 microliters of supernatant was removed and filtered using a 96-well glass filter plate. With the sample lined up in the filter plate and bottom-mounted collection plate, the device was centrifuged at 1000Xg for 1 minute to filter the sample. In the case of the small sample set, a syringe filter was used instead of the filter plate to recover-2-4 mL of filtrate into a 15mL vial. After filtration into a collection plate, each filtrate was diluted appropriately and then the anion content was determined. The IC method (e.g., Dionex ICS-2100, Thermo Scientific) consisted of an AS24A column, a 20mM-100mM KOH gradient, a 5 microliter sample volume with 30 min run time, a 1000 microliter wash/rinse volume, and a flow rate of 0.3 mL/min. The method is suitable for quantifying chloride ions, phosphate radicals and taurocholate radicals. Other suitable methods may be substituted. To determine the ions bound to the polymer, the following calculations were performed:

is shown asWherein [ Ion]_startIs the initial concentration of ions in the SOB buffer, [ Ion]_finalIs the final value of the specific ion in the filtrate determined after exposure to the test polymer, the dilution factor is the dilution factor, and 2.5 is the polymer concentration in mg/ml.

The term "substituted hydrocarbyl", "substituted alkyl", "substituted alkenyl", "substituted aryl", "substituted heterocyclyl" or "substituted heteroaryl" as used herein denotes a hydrocarbyl, alkyl, alkenyl, aryl, heterocyclyl or heteroaryl group substituted with at least one atom other than carbon and hydrogen, including groups in which carbon chain atoms are substituted with heteroatoms such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur or halogen atoms. These substituents include halogen, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, sulfhydryl, ketal, acetal, ester and ether.

"swelling ratio" or similar "swelling" describes the amount of water absorbed by a given amount of polymer divided by the weight of an aliquot of the polymer. The swelling ratio is expressed as: swell ═ g swollen polymer-g dry polymer)/g dry polymer. The method for determining the swelling ratio of any given polymer comprises the steps of:

a. 50-100mg of dry (water content below 5 wt%) polymer was placed in 11mL of sealable tube (with screw cap) of known weight (tube weight: weight a).

b. Deionized water (10mL) was added to the tube containing the polymer, the tube was sealed and inverted at room temperature for 16 hours (overnight). After incubation, the tubes were centrifuged at 3000Xg for 3 minutes and the supernatant carefully removed by vacuum aspiration. For polymers that form very loose precipitates, another centrifugation step is performed.

c. After step (B), the weight of swollen polymer + tube (weight B) was recorded.

d. Freezing at-40 deg.C for 30 min. And (5) freeze-drying for 48 h. The dried polymer and test tube were weighed (recorded as weight C).

e. Calculate g water absorbed/g polymer, defined as: [ (weight B-weight A) - (weight C-weight A) ]/(weight C-weight A).

"target ion" is a polymer-bound ion, generally referring to the primary ion bound by the polymer, or an ion whose binding to the polymer is believed to produce the therapeutic effect of the polymer (e.g., a combination of protons and chloride ions resulting in net removal of HCl).

The term "theoretical capacity" means the expected hydrochloric acid binding calculated in the "SGF" assay, expressed in mmol/g. The theoretical capacity is based on the assumption that 100% of the amines from the monomers and the crosslinking agent are incorporated into the crosslinked polymer in their respective feed ratios. The theoretical capacity is therefore equal to the concentration of amine functions in the polymer (mmol/g). Theoretical capacity assumes that each amine can be utilized for binding the respective anion and cation and no adjustment is required for the type of amine formed (e.g., it does not subtract out the capacity of quaternary amines that are not available for binding protons).

By "therapeutically effective amount" is meant an amount of proton-binding cross-linked polymer that, when administered to a patient for the treatment of a disease, is sufficient to effect treatment of such disease. The amount constituting a "therapeutically effective amount" will vary depending on the polymer, the severity of the disease, and the age, weight, etc., of the mammal to be treated.

"treating" a disease or "treatment" of a disease includes: (i) inhibiting a disease, i.e., arresting or reducing the development of a disease or its clinical symptoms; or (ii) ameliorating the disease, i.e., causing regression of the disease or its symptoms. Inhibiting a disease includes, for example, prophylaxis.

The term "triallylamine" refers to an amino moiety having 3 allyl groups.

The term "vinyl" denotes a compound of formula R_xH_yA moiety of C ═ CH- ＊, wherein ＊ represents the point of attachment of the moiety to the rest of the molecule, wherein the point of attachment is a heteroatom or an aryl group, X and Y are independently 0,1 or 2, such that X + Y ═ 2, and R is a hydrocarbyl or substituted hydrocarbyl group.

The term "weight percent crosslinker" refers to the calculated percentage of the polymer sample by mass that is derived from the crosslinker. The feed ratio of the polymerization was used to calculate the weight percent crosslinker assuming complete conversion of the monomers and crosslinker. The mass attributed to the crosslinker is equal to the expected increase in molecular weight in the infinite polymer network after reaction (e.g. 1,3, -dichloropropane is 113amu, but only 42amu is added to the polymer network after crosslinking with DCP, since the chlorine atom as a leaving group is not incorporated into the polymer network).

When introducing elements of the present invention or the preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and not exclusive (i.e., there may be additional elements other than the listed elements).

Detailed description of the preferred embodiments

As previously explained, in various aspects of the present application, a method of treatment using a composition comprising a nonabsorbent crosslinked polymer containing free amine moieties may be noted. In one embodiment, the crosslinked amine polymer has the capacity to remove a clinically significant amount of protons and chloride ions from the gastrointestinal tract of an animal, including, for example, a human, when a therapeutically effective amount (i.e., an effective dose) of the crosslinked amine polymer is administered to achieve a therapeutic or prophylactic benefit.

The therapeutically effective dose of the crosslinked amine polymers disclosed herein will depend, at least in part, on the condition to be treated, the capacity of the crosslinked free amine polymer, and the desired effect. In one embodiment, the daily dose of the crosslinked free amine polymer is sufficient to slow the rate of decrease in serum bicarbonate levels over an extended period of time. In another embodiment, the daily dose of the crosslinked free amine polymer is sufficient to maintain serum bicarbonate levels for an extended period of time. In another embodiment, the daily dose of the crosslinked free amine polymer is sufficient to increase serum bicarbonate levels over an extended period of time. For example, in one embodiment, the daily dose of the crosslinked free amine polymer is sufficient to achieve or maintain a serum bicarbonate level of at least about 20mEq/L over an extended period of time. As another example, in one such embodiment, the daily dose is sufficient to achieve or maintain a serum bicarbonate level of at least about 21mEq/L over an extended period of time. As another example, in one such embodiment, the daily dose is sufficient to achieve or maintain a serum bicarbonate level of at least about 22mEq/L over an extended period of time. In another embodiment, the daily dose is sufficient to achieve or maintain a serum bicarbonate level of at least about 24mEq/L over an extended period of time. In each of the above embodiments, the extended period of time is a period of at least 1 month, such as at least 2 months, at least 3 months, or even at least several months.

Generally, dosage levels of the crosslinked amine polymers for therapeutic and/or prophylactic use can range from about 0.5 g/day to about 20 g/day. In order to facilitate patient compliance, a dosage in the range of about 1 g/day to about 10 g/day is generally preferred. For example, in one such embodiment, the dose is from about 2 g/day to about 7 g/day. As another example, in one such embodiment, the dose is from about 3 g/day to about 6 g/day. As another example, in one such embodiment, the dose is from about 4 g/day to about 5 g/day. Optionally, the daily dose may be administered during the day in a single dose (i.e. 1 time per day) or divided into multiple doses (e.g. 2,3 or more doses). Typically, the crosslinked amine polymers for therapeutic and/or prophylactic use are administered in a fixed daily dose or are titrated up (titrate) according to the serum bicarbonate value or other indicator of acidosis of a patient in need of treatment. The escalating doses may occur at the beginning of the treatment or throughout the treatment as required, and the initial and maintenance dose levels may vary from patient to patient depending on the severity of the underlying disease.

As graphically depicted in fig. 1A-1C, and according to one embodiment, the nonabsorbent free amine polymers of the present application are orally ingested to treat metabolic acidosis in mammals by binding HCl in the gastrointestinal ("GI") tract and removing HCl through feces (feces) (including by increasing serum bicarbonate and normal bicarbonate levels)To digest blood pH for treatment). The free amine polymer was orally ingested at a dose that enhanced compliance (fig. 1A), with the goal of long-term binding of sufficient HCl to enable a clinically meaningful increase in serum bicarbonate of 3 mEq/L. In the stomach (FIG. 1B), the free amine binds H⁺Is protonated. The positive charge on the polymer can then be utilized to bind Cl-; by controlling access to the binding sites by cross-linking and hydrophilic/hydrophobic properties, other larger organic anions (e.g., acetate, propionate, butyrate, etc., depicted as X^-And Y^-) To a lesser extent (if any). Thus, the net effect is binding to HCI. In the lower gastrointestinal tract/colon (FIG. 1C), Cl is not released^-HCl is removed from the body by regular bowel movements and fecal excretion, resulting in a net alkalization in the serum. Cl bound in this way^-For the passage of Cl^-/HCO3^-The exchange of the antiporter system is not available.

In one embodiment, the polymer is designed to simultaneously maximize efficacy (net HCl binding and excretion) and minimize gastrointestinal side effects (through low swelling particle design and particle size distribution). Optimal HCl binding can be achieved by carefully balancing the following: capacity (number of amine binding sites), selectivity (preferential binding of chloride ions compared to other anions, particularly organic anions in the colon) and retention (no significant amount of chloride ions is released in the lower gastrointestinal tract to avoid Cl in the colon and intestine^-/HCO3^-Exchanger [ antiporter protein]Activity of (a); cl if chloride ions are not tightly bound to the polymer^-/HCO3^-The exchanger mediates the interconversion of chloride uptake from the intestinal lumen and bicarbonate from the serum, thereby effectively reducing serum bicarbonate.

The competing anion to displace the chloride ion results in a net bicarbonate reduction by the following mechanism. First, the replacement of chloride ions from the polymer in the gastrointestinal lumen, particularly the colon lumen, provides a convenient exchange with bicarbonate in the serum. The colon has an anion exchanger (chloride/bicarbonate antiporter) that removes chloride ions from the luminal side, exchanging secreted bicarbonate. When free chloride ions are released from the polymer in the gastrointestinal tract, it exchanges out bicarbonate, which is then lost in the feces and leads to a reduction in total extracellular bicarbonate (Davis, 1983; D' Agostino, 1953). The binding of Short Chain Fatty Acids (SCFA) that exchange chloride ions bound on the polymer results in depletion of extracellular HCO 3-reserves. Short chain fatty acids are bacterial metabolites of complex carbohydrates that are not catabolized by normal digestive processes (Chemlarova, 2007). Short chain fatty acids that reach the colon are absorbed and distributed to various tissues, a common metabolic fate being the production of H2O and CO2, which are converted to bicarbonate equivalents. Therefore, binding of SCFA neutralizing proton charge to the polymer is detrimental to the overall bicarbonate reserve and buffering capacity, necessitating the design of chemical and physical features in the polymer that limit SCFA exchange. Finally, phosphate binding to the polymer should also be limited, as phosphate represents an additional source of buffering capacity in cases where ammonia production and/or hydrogen ion secretion is impaired in chronic kidney disease.

For each binding of protons, it is preferred to bind anions, since positive charges seek to leave the human body in the form of neutral polymers. The "binding" of ions is greater than the minimum binding, i.e., at least about 0.2mmol ions/gm polymer, in some embodiments at least about 1mmol ions/gm polymer, in some embodiments at least about 1.5mmol ions/gm polymer, in some embodiments at least about 3mmol ions/gm polymer. In one embodiment, the polymer is characterized by its high proton binding capacity while at the same time providing selectivity for anions; selectivity for chloride is achieved by reducing the binding of interfering anions including, but not limited to, phosphate, citrate, acetate, bile acids, and fatty acids. For example, in some embodiments, the polymers of the present application bind phosphate with a binding capacity of less than about 5mmol/gm, less than about 4mmol/gm, less than about 3mmol/gm, less than about 2mmol/gm, or even less than about 1 mmol/gm. In some embodiments, the polymers of the present invention bind to bile and fatty acids with a binding capacity of less than about 5mmol/g, less than about 4mmol/g, less than about 3mmol/g, less than about 2mmol/gm, in some embodiments less than about 1mmol/gm, in some embodiments less than about 0.5mmol/gm, in some embodiments less than about 0.3mmol/gm, in some embodiments less than about 0.1 mmol/gm.

The effectiveness of the polymer can be established in animal models or in human volunteers and patients. In addition, in vitro, ex vivo and in vivo methods can be used to establish HCl binding. In vitro binding solutions can be used to determine binding capacity for protons, chloride ions and other ions at different pH. Ex vivo extracts from human volunteers or from model animals, such as gastrointestinal lumen contents, may be used for similar purposes. The selectivity of binding and/or retaining certain ions preferentially over other ions can also be demonstrated in such in vitro and ex vivo solutions. An in vivo model of metabolic acidosis can be used to test the effectiveness of the polymers in normalizing the acid/base balance invention-for example, 5/6 nephrectomized rats fed casein-containing animal food (e.g., Phisitkul S, Hacker C, Simoni J, Tran RM, Wesson DE. Dietary protein leads to metabolic acidosis and a decrease in the rate of glomerular filtration of endothelin receptor-mediated residual kidneys (metabolic protein a declaine in the renal filtration rate of the remnant Kidney mediated by metabolic acidosis and endonexin receptors). Kidney International 2008; 73 (2): 192-9).

In one embodiment, animals including humans are provided with the polymers described herein 1,2 or 3 times per day, most preferably at a daily dose of no more than 5g or less per day) to treat metabolic acidosis and achieve a clinically significant and sustained increase in serum bicarbonate of about 3mEq/L at these daily doses. The amount of HCl binding achieved by oral administration of the polymer is determined by the binding capacity of the polymer, which is generally in the range of 5-25mEq HCl/1g of polymer. In addition, the polymer is preferably selective in being bound with anions bound with counter protons, with chloride being the preferred anion. Anions other than chloride that are bound to neutralize the positive proton charge include phosphate, short chain fatty acids, long chain fatty acids, bile acids, or other organic or inorganic anions. The binding of anions other than these chloride ions affects the overall bicarbonate stores in the intracellular and extracellular compartments.

In one embodiment, the mechanism of action of the HCl polymer binder (binder) includes the following. In the stomach or other parts of the gastrointestinal tract, the free amine polymer binds protons (H)⁺) Becomes protonated. The positive charge formed as a result of this binding is then available for chloride anion binding. After leaving the stomach, the polymer sequentially encounters different gastrointestinal environments, in the order duodenum, jejunum, ileum, and colon, each with different organic and inorganic anion supplements. The physical and chemical properties of the polymer are designed to control access of the protonated binding sites to the set of anions. The physical barrier includes cross-linking (size exclusion to prevent anion binding) and chemical moieties (rejection of larger organic anions such as acetate, propionate, butyrate or other short chain fatty acids commonly found in the colon) and a combination of these two properties to limit phosphate, bile acid and fatty acid binding. By tailoring the bead cross-linking and the chemistry of the amine binding site, chloride ions can be tightly bound so as to reduce or eliminate exchange of other anions and release in the lower gastrointestinal tract. Without being bound by theory, by incorporating these properties into HCl-binding polymers, anions having larger ionic and/or hydration radii than chloride ions can be excluded or their binding reduced. For example, chloride ions in either the hydrated or non-hydrated form have ionic radii less than the corresponding phosphate and other anions commonly found in the lumen of the gastrointestinal tract (superior molecular Chemistry, Steed, JW (2009) John Wiley and Sons, page 226; Kielland, J (1937), J.Am.chem.Soc.59: 1675-. To selectively bind smaller ions, polymers typically exhibit a high crosslink density in order to create preferential access to the polymer binding sites. However, high crosslink density materials are typically characterized by low swelling ratios. The swelling ratio can be influenced by the following composition and process variables: 1) molar ratio of amine monomer (or polymer) to crosslinker, 2) ratio of monomer + crosslinker to solvent in the crosslinking reaction, 3) net charge of the polymer (at the physiological pH and environmental tension at which it is used), 4) backbone polyThe hydrophilic/hydrophobic balance of the compound, and/or 5) post-crosslinking (post-crosslinking) of existing materials.

In general, the crosslinked amine polymers of the present application are typically characterized by a low swelling ratio. In one embodiment, the SIB binds to chloride ions: phosphate binding ratio is an indicator of the selectivity of the crosslinked polymers herein for chloride ions compared to larger anions. Swelling ratio of certain polymers of the present application versus chloride ion in SIB: the relationship between phosphate binding ratios is shown in figure 2. For example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 0.35: phosphate binding ratio and swelling ratio of less than or equal to 2g water/g dry polymer. As another example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 0.5: phosphate binding ratio and swelling ratio of less than or equal to 2g water/g dry polymer. As another example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 1: phosphate binding ratio and swelling ratio of less than or equal to 2g water/g dry polymer. As another example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 2: phosphate binding ratio and swelling ratio of less than or equal to 2g water/g dry polymer. As another example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 0.35: phosphate binding ratio and swelling ratio of less than or equal to 1g water/g dry polymer. As another example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 0.5: phosphate binding ratio and swelling ratio of less than or equal to 1g water/g dry polymer. As another example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 1: phosphate binding ratio and swelling ratio of less than or equal to 1g water/g dry polymer. As another example, in one embodiment, the polymer of the present application has a chloride ion in SIB ≧ 2: phosphate binding ratio and swelling ratio of less than or equal to 1g water/g dry polymer.

In some embodiments, the crosslinked amine polymers of the present application are polymerized with chloride ions in SIB: the relationship of phosphate binding ratios is shown in figure 2. For example, in one embodiment, the polymers of the present application have a chloride ion binding capacity of ≥ 10mmol/g in SGF and a swelling ratio ≤ 2g water/g dry polymer. As another example, in one embodiment, the polymer herein has a chloride ion binding capacity of ≥ 12mmol/g in SGF and a swelling ratio ≤ 2g water/g dry polymer. As another example, in one embodiment, the polymer herein has a chloride ion binding capacity of 14mmol/g or more in SGF and a swell ratio of 2g or less water/g dry polymer. As another example, in one embodiment, the polymer herein has a chloride ion binding capacity of ≥ 10mmol/g in SGF and a swelling ratio ≤ 1.5g water/g dry polymer. As another example, in one embodiment, the polymer herein has a chloride ion binding capacity of ≥ 12mmol/g in SGF and a swelling ratio ≤ 1.5g water/g dry polymer. As another example, in one embodiment, the polymer herein has a chloride ion binding capacity of 14mmol/g or more in SGF and a swell ratio of 1.5g or less water/g dry polymer.

In some embodiments, the theoretical chloride ion binding capacity of the polymers of the present application can range from about 1mmol/g to about 25 mmol/g. In one embodiment, the theoretical chloride ion binding capacity of the polymer is from about 3mmol/g to about 25 mmol/g. In another embodiment, the theoretical chloride ion binding capacity of the polymer is from about 6mmol/g to about 20 mmol/g. In another embodiment, the theoretical chloride ion binding capacity of the polymer is from about 9mmol/g to about 17 mmol/g.

In some embodiments, the molecular weight/nitrogen of the polymers of the present application may be in the range of about 40 to about 1000 daltons. In one embodiment, the polymer has a molecular weight/nitrogen of from about 40 to about 500 daltons. In another embodiment, the polymer has a molecular weight/nitrogen of from about 50 to about 170 daltons. In another embodiment, the polymer has a molecular weight/nitrogen of from about 60 to about 110 daltons.

In some embodiments, the wt% crosslinker ranges from about 10 to 90 wt% of the crosslinked amine polymer. For example, in some embodiments, the wt% crosslinker ranges from about 15 wt% to about 90 wt% of the crosslinked amine polymer, or even from about 25 wt% to about 90 wt% of the crosslinked amine polymer.

The crosslinked amine polymers can be prepared using a range of chemical methods including, for example, (i) substitution polymerization of polyfunctional reagents, at least one of which comprises an amine moiety; (2) free radical polymerization of a monomer comprising at least one amine moiety or nitrogen-containing moiety; and (3) crosslinking the amine-containing intermediate with a multifunctional crosslinking agent that optionally contains an amine moiety. The crosslinked polymer thus obtained may be, for example, a crosslinked homopolymer or a crosslinked copolymer. As another example, the resulting crosslinked polymer typically has repeating units comprising free amine moieties separated by repeating linker (or insertion) units of the same or different lengths. In some embodiments, the polymer comprises a repeat unit comprising an amine moiety and an intervening linker unit. In other embodiments, a plurality of amine-containing repeat units are separated by one or more linker units. Additionally, the multifunctional crosslinker may comprise HCl-binding functional groups, such as amines ("active crosslinkers") or may lack HCl-binding functional groups, such as amines ("passive crosslinkers").

In some embodiments, the amine-containing monomer is polymerized and the polymer is simultaneously crosslinked in a substitution polymerization reaction. For substitution polymerization, the amine reactant (monomer) in the simultaneous polymerization and crosslinking reaction may react more than once. In one such embodiment, the amine monomer is a linear amine having at least two reactive amine moieties that participate in the substitution polymerization reaction. In another embodiment, the amine monomer is a branched amine having at least two reactive amine moieties that participate in the substitution polymerization reaction. Crosslinkers for simultaneous substitution polymerization and crosslinking typically have at least two amine-reactive moieties such as alkyl chlorides and alkyl epoxides. For incorporation into the polymer, the primary amine is reacted at least once with the crosslinking agent and can react up to 3 times with the crosslinking agent, the secondary amine can react up to 2 times with the crosslinking agent, and the tertiary amine can react only 1 time with the crosslinking agent. However, in general and according to one aspect of the present application, the formation of significant amounts of quaternary nitrogen/amine is generally not preferred because quaternary amines are not capable of binding protons.

Exemplary amines that can be used in the substitution polymerization reactions described herein include 1, 3-bis [ bis (2-aminoethyl) amino ] propane, 3-amino-1- { [2- (bis {2- [ bis (3-aminopropyl) amino ] ethyl } amino) ethyl ] (3-aminopropyl) amino } propane, 2- [ bis (2-aminoethyl) amino ] ethylamine, tris (3-aminopropyl) amine, 1, 4-bis [ bis (3-aminopropyl) amino ] butane, 1, 2-ethylenediamine, 2-amino-1- (2-aminoethylamino) ethane, 1, 2-bis (2-aminoethylamino) ethane, 1, 3-propanediamine, 3' -diaminodipropylamine, N-propylaniline, N-methyl-ethyl-2-methyl-2-amino-ethyl-1, 2-amino-1, 2-bis (2-aminoethylamino) ethane, 1, 3-propanediamine, 2, 2-dimethyl-1, 3-propanediamine, 2-methyl-1, 3-propanediamine, N ' -dimethyl-1, 3-propanediamine, N-methyl-1, 3-diaminopropane, 3' -diamino-N-methyldipropylamine, 1, 3-diaminopentane, 1, 2-diamino-2-methylpropane, 2-methyl-1, 5-diaminopentane, 1, 2-diaminopropane, 1, 10-diaminodecane, 1, 8-diaminooctane, 1, 9-diaminooctane, 1, 7-diaminoheptane, 1, 6-diaminohexane, 1, 5-diaminopentane, 3-bromopropylamine hydrobromide, N ' -dimethyl-1, 3-propanediamine, N-methyl-1, 3-diaminopropane, 3-diamino-1, 3-, N, 2-dimethyl-1, 3-propanediamine, N-isopropyl-1, 3-diaminopropane, N '-bis (2-aminoethyl) -1, 3-propanediamine, N' -bis (3-aminopropyl) ethylenediamine, N '-bis (3-aminopropyl) -1, 4-butanediamine tetrahydrate salt, 1, 3-diamino-2-propanol, N-ethylethylenediamine, 2' -diamino-N-methyldiethylamine, N '-diethylethylenediamine, N-isopropylethylenediamine, N-methylethylenediamine, N' -di-tert-butylethylenediamine, N '-diisopropylethylenediamine, N' -dimethylethylenediamine, N '-diaminotoluene, N' -dimethylethylenediamine, N, n-butylethylenediamine, 2- (2-aminoethylamino) ethanol, 1,4,7,10,13, 16-hexaazacyclooctadecane, 1,4,7, 10-tetraazacyclododecane, 1,4, 7-triazacyclononane, N' -bis (2-hydroxyethyl) ethylenediamine, piperazine, bis (hexamethylene) triamine, N- (3-hydroxypropyl) ethylenediamine, N- (2-aminoethyl) piperazine, 2-methylpiperazine, homopiperazine (homopiperazine), 1,4,8, 11-tetraazacyclotetradecane, 1,4,8, 12-tetraazacyclopentadecane, 2- (aminomethyl) piperidine, 3- (methylamino) pyrrolidine.

Exemplary crosslinking agents that can be used in the displacement polymerization reaction and the post-polymerization crosslinking reaction include, but are not limited to, one or more multifunctional crosslinking agents, such as: dihaloalkanes, haloalkylethylenes, alkyloxirane sulfonates (alkyloxiranes) di (haloalkyl) amines, tri (haloalkyl) amines, diepoxides (diopoxides), triepoxides (triepoxides), tetracyclooxides (tetraepoxides), bis (halomethyl) benzenes, tris (halomethyl) benzenes, tetrakis (halomethyl) benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin, poly (epichlorohydrin), (iodomethyl) oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1, 2-butylene oxide (epoxyoxetane), bromo-1, 2-butylene oxide, 1, 2-dibromoethane, 1, 3-dichloropropane, 1, 2-dichloroethane, 1-bromo-2-chloroethane, 1, 3-dibromopropane, 1, 2-dibromoethane, 1-bromo-2-chloroethane, 1, 3-dibromopropane, tris (bromopropane), bis (halomethyl) amines, tris (epihalohydrin) alcohols, Bis (2-chloroethyl) amine, tris (2-chloroethyl) amine and bis (2-chloroethyl) methylamine, 1, 3-butadiene diepoxide, 1, 5-hexadiene diepoxide, diglycidyl ether, 1,2,7, 8-diepoxyoctane, 1,2,9, 10-diepoxydedecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1, 4-butanediol diglycidyl ether, 1, 2-ethylene glycol diglycidyl ether, glycerol diglycidyl ether (glycidyl ether), 1, 3-diglycidyl ether glycerol (1, 3-diglycidyl ether), N-diglycidyl aniline (N, N-diglycidyl aniline), neopentyl glycol diglycidyl ether (neopentylglycol diglycidyl ether), diethylene glycol diglycidyl ether (diethylene glycol diglycidyl ether), 1, 4-bis (glycidyloxy) benzene, resorcinol diglycidyl ether, 1, 6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1, 4-cyclohexanedimethanol diglycidyl ether (1, 4-cyclohexanedimethylene diglycidyl ether), 1, 3-bis- (2, 3-epoxypropyloxy) -2- (2, 3-dihydroxypropyloxy) propane, 1, 2-cyclohexanedicarboxylic acid diglycidyl ester (1, 2-cyclohexanedicarboxylic acid diglycidyl ester), 2' -bis (glycidyloxy) diphenylmethane, bisphenol F diglycidyl ether (bisphenol F diglycidyl ether), 1, 4-bis (2',3' epoxypropyl) n-butane, 2, 6-bis (oxido-2-ylmethyl) -1,2,3,5,6, 7-hexahydropyrrolo [3,4-f ] isoindol-1, 3,5, 7-tetraone, bisphenol A diglycidyl ether (bisphenol A diglycidyl ether), ethyl 5-hydroxy-6, 8-bis (oxiranyl-2-ylmethyl) -4-oxo-4-h-chromene-2-carboxylate, bis [4- (2, 3-oxiranylthio) phenyl ] -sulfide, 1, 3-bis (3-glycidoxypropyl) tetramethyldisiloxane (1, 3-bis (3-glycidoxypropyl) tetramethyldisiloxane), 9-bis [4- (glycidyloxy) phenyl ] fluoride, trisepoxyisocyanurate (trisaccharide), glycerol triglycidyl ether (glycidyl triglycidyl ether), N, N-diglycidyl-4-glycidyloxyaniline, (S, S, S) -triglycidyl isocyanurate, (R, R, R) -triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycidyloxy triglycidyl ether, triphenylmethyl methane triglycidyl ether, triphenylpropyloxy triglycidyl ether, triphenylmethyl methane triglycidyl ether, 3,7, 14-tris [ [3- (glycidoxy) propyl ] dimethylsilyloxy ] -1,3,5,7,9,11, 14-heptacyclopentyltricyclo [7,3, 15,11] heptasiloxane, 4' methylenebis (N, N-diglycidylaniline), bis (halomethyl) benzene, bis (halomethyl) biphenyl and bis (halomethyl) naphthalene, Toluene diisocyanate, acryloyl chloride, methyl acrylate, ethylene bisacrylamide (ethylene bisacrylamide), pyromellitic dianhydride (pyrometric dianhydrides), succinyl chloride, dimethyl succinate, 3-chloro-1- (3-chloropropylamino-2-propanol, 1, 2-bis (3-chloropropylamino) ethane, bis (3-chloropropyl) amine, 1, 3-dichloro-2-propanol, 1, 3-dichloropropane, 1-chloro-2, 3-epoxypropane, tris [ (2-oxiranyl) methyl ] amine.

For free radical polymerization, the amine monomer is typically a monofunctional vinyl, allyl, or acrylamide (e.g., allylamine), and the crosslinker has two or more vinyl, allyl, or acrylamide functional groups (e.g., diallylamine). The simultaneous polymerization and crosslinking occurs by free radical initiated polymerization of a mixture of monofunctional and multifunctional allylamines. The resulting polymer network is thus crosslinked by the carbon skeleton. Each crosslinking reaction forms a carbon-carbon bond (unlike the substitution reaction, a carbon-heteroatom bond is formed during crosslinking in the substitution reaction). During the simultaneous polymerization and crosslinking, the amine functionality of the monomer does not undergo a crosslinking reaction and is protected in the final polymer (i.e., the primary amine remains "primary", the secondary amine remains "secondary", and the tertiary amine remains "tertiary").

In those embodiments in which the preparation of the polymer comprises free radical polymerization, a variety of initiators may be used, including cationic and free radical initiators. Some examples of suitable initiators that may be used include: radical peroxy and azo-type compounds, for example azobisisobutyronitrile, azobisisovaleronitrile, dimethyl azobisisobutyrate, 2' -azobis (isobutyronitrile), 2' -azobis (N, N ' -dimethyl-1-ylisobutyramidine) dihydrochloride, 2' -azobis (2-amidinopropane) dihydrochloride, 2' -azobis (N, N ' -dimethyleneisobutyramidine), 1 ' -azobis (l-cyclohexanecarbonitrile), 4' -azobis (4-cyanovaleric acid), 2' -azobis (isobutyramide) dihydrate, 2' -azobis (2-methylpropane), 2' -azobis (2-methylbutyronitrile), VAZO 67, cyanovaleric acid, peroxypivalate (peroxoxival), Dodecylbenzene peroxide (dodekelbenzene peroxide), benzoyl peroxide, di-tert-butyl hydroperoxide (di-t-butyl hydroperoxide), tert-butyl peracetate, acetyl peroxide, dicumyl peroxide (dicumyl peroxide), cumyl hydroperoxide (cumyl hydroperoxide), dimethyl bis (butylperoxy) hexane (butyl peroxide) hexane).

In some embodiments, the crosslinked amine polymer comprises amine residues of formula 1:

wherein R is₁、R₂And R₃Independently hydrogen, hydrocarbyl, substituted hydrocarbyl, provided that R₁、R₂And R₃At least one of which is not hydrogen. Described in a different way, R₁、R₂And R₃At least one of which is a hydrocarbyl or substituted hydrocarbyl group, and the remainder of R₁、R₂And R₃Independently hydrogen, hydrocarbyl or substituted hydrocarbyl. At one endIn one embodiment, for example, R₁、R₂And R₃Independently hydrogen, aryl, aliphatic, heteroaryl or heteroaliphatic, provided that R₁、R₂And R₃Each is not hydrogen. As another example, in one such embodiment, R₁、R₂And R₃Independently hydrogen, a saturated hydrocarbon, an unsaturated aliphatic group, an unsaturated heteroaliphatic group, a heteroalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, provided that R₁、R₂And R₃Each is not hydrogen. As another example, in one such embodiment, R₁、R₂And R₃Independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic, provided that R₁、R₂And R₃Each is not hydrogen. As another example, in one such embodiment, R₁、R₂And R₃Independently hydrogen, alkyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, heteroaryl or heterocyclic, provided that R₁、R₂And R₃Each is not hydrogen. As another example, in one such embodiment, R₁And R₂Together (in combination with the nitrogen atom to which they are attached) form part of a ring structure such that the monomer described by formula 1 is a nitrogen-containing heterocycle (e.g., piperidine), and R is₃Is hydrogen or a heteroaliphatic group. As another example, in one embodiment, R₁、R₂And R₃Independently hydrogen, an aliphatic group or a heteroaliphatic group, provided that R₁、R₂And R₃At least one of which is not hydrogen. As another example, in one embodiment, R₁、R₂And R₃Independently hydrogen, allyl or aminoalkyl.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 1, wherein R₁、R₂And R₃Independently hydrogen, heteroaryl, aryl, aliphatic or heteroaliphatic, provided that R₁、R₂And R₃At least one of which is aryl or heteroaryl. For example, in this embodiment, R₁And R₂Taken together with the nitrogen atom to which they are attached may form a saturated or unsaturated nitrogen-containing heterocyclic ring. As another example, R₁And R₂Taken together with the nitrogen to which they are attached may form part of a pyrrolidino, pyrrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, pyridine, piperazine, diazine or triazine ring structure. As another example, R₁And R₂Together with the nitrogen to which they are attached may form part of a piperidine ring structure.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 1, wherein R₁、R₂And R₃Independently hydrogen, an aliphatic group or a heteroaliphatic group, provided that R₁、R₂And R₃At least one of which is not hydrogen. For example, in this embodiment, R₁、R₂And R₃May independently be hydrogen, alkyl, alkenyl, allyl, vinyl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether or heterocyclic group, provided that R₁、R₂And R₃At least one of which is not hydrogen. As another example, in one such embodiment, R₁And R₂Taken together with the nitrogen to which they are attached may form a saturated or unsaturated nitrogen-containing heterocyclic ring. As another example, in one such embodiment, R₁And R₂Together with the nitrogen atom to which they are attached may form part of a pyrrolidino, pyrrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, piperazine, or diazine ring structure. As another example, in one such embodiment, R₁And R₂Together with the nitrogen atom to which they are attached may form part of a piperidine ring structure. As another example, in one such embodiment, the amine of formula 1 is acyclic and R₁、R₂And R₃At least one of which is an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment,R₁、R₂and R₃Independently hydrogen, alkyl, allyl, vinyl, cycloaliphatic, aminoalkyl, alkanol or heterocyclic group, with the proviso that R is₁、R₂And R₃At least one of which is not hydrogen.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 1, and the crosslinked amine polymer is prepared by substituted polymerization of an amine of formula 1 with a multifunctional crosslinker (optionally also comprising an amine moiety), wherein R₁、R₂And R₃Independently hydrogen, alkyl, aminoalkyl or alkanol, with the proviso that R₁、R₂And R₃At least one of which is not hydrogen.

In some embodiments, the crosslinked amine polymer comprises amine residues of formula 1a, and the crosslinked amine polymer is prepared by free radical polymerization of an amine of formula 1 a:

wherein R is₄And R₅Independently hydrogen, hydrocarbyl or substituted hydrocarbyl. In one embodiment, for example, R₄And R₅Independently hydrogen, a saturated hydrocarbon, an unsaturated aliphatic group, an aryl group, a heteroaryl group, an unsaturated heteroaliphatic group, a heterocyclic group, or a heteroalkyl group. As another example, in one such embodiment, R₄And R₅Independently hydrogen, an aliphatic group, a heteroaliphatic group, an aryl group, or a heteroaryl group. As another example, in one such embodiment, R₄And R₅Independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic. As another example, in one such embodiment, R₄And R₅Independently hydrogen, alkyl, allyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether or heterocyclic. As another example, in one such embodiment, R₄And R₅(with the nitrogen to which they are attachedA combination of atoms) together form part of a ring structure such that the monomer described by formula 1a is a nitrogen-containing heterocycle (e.g., piperidine). As another example, in one embodiment, R₄And R₅Independently hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one embodiment, R₄And R₅Independently hydrogen, allyl or aminoalkyl.

In some embodiments, the crosslinked amine polymer comprises amine residues of formula 1b, and the crosslinked amine polymer is prepared by substitution polymerization of an amine of formula 1b with a multifunctional crosslinker (optionally also comprising an amine moiety):

wherein R is₄And R₅Independently is hydrogen, hydrocarbyl or substituted hydrocarbyl, R₆Is an aliphatic radical, and R₆₁And R₆₂Independently hydrogen, an aliphatic group or a heteroaliphatic group. In one embodiment, for example, R₄And R₅Independently hydrogen, a saturated hydrocarbon, an unsaturated aliphatic group, an aryl group, a heteroaryl group, a heteroalkyl group, or an unsaturated heteroaliphatic group. As another example, in one such embodiment, R₄And R₅Independently hydrogen, an aliphatic group, a heteroaliphatic group, an aryl group, or a heteroaryl group. As another example, in one such embodiment, R₄And R₅Independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic. As another example, in one such embodiment, R₄And R₅Independently hydrogen, alkyl, alkenyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ether, heteroaryl, or heterocyclic. As another example, in one such embodiment, R₄And R₅Together (in combination with the nitrogen atom to which they are attached) form part of a ring structure such that the monomer described by formula 1a is a nitrogen-containing heterocycle (e.g., piperidine). As another example, inIn one embodiment, R₄And R₅Independently hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one embodiment, R₄And R₅Independently hydrogen, allyl or aminoalkyl. As another example, in each of the embodiments in this paragraph, R₆May be methylene, ethylene or propylene, and R₆₁And R₆₂And may independently be hydrogen, allyl, or aminoalkyl.

In some embodiments, the crosslinked amine polymer comprises amine residues of formula 1 c:

wherein R is₇Is hydrogen, an aliphatic or heteroaliphatic radical, and R₈Is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, for example, R₇Is hydrogen, and R₈Is an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, R₇And R₈Independently an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, R₇And R₈At least one of which comprises an allyl moiety. As another example, in one such embodiment, R₇And R₈At least one of which comprises an aminoalkyl moiety. As another example, in one such embodiment, R₇And R₈Each containing an allyl moiety. As another example, in one such embodiment, R₇And R₈Each comprising an aminoalkyl moiety. As another example, in one such embodiment, R₇Contains an allyl moiety, and R₈Comprising an aminoalkyl moiety.

In some embodiments, the crosslinked amine polymer comprises amine residues of formula 2:

wherein

m and n are independently non-negative integers;

R₁₀、R₂₀、R₃₀and R₄₀Independently hydrogen, hydrocarbyl or substituted hydrocarbyl;

X₁is that

X₂Is a hydrocarbyl or substituted hydrocarbyl group;

X₁₁each independently is hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, amino, boronic acid or halo; and is

z is a non-negative number.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2, which is prepared by: (i) substitution polymerization of an amine of formula 2 with a multifunctional crosslinker (optionally also comprising an amine moiety), or (2) free radical polymerization of an amine of formula 2, and m and n are independently 0,1, 2, or 3, and n is 0 or 1.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2, which is prepared by: (i) a substitution polymerization of an amine of formula 2 with a multifunctional crosslinker, optionally also comprising an amine moiety, or (2) a free radical polymerization of an amine of formula 2, and R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, an aliphatic group, an aryl group, a heteroaliphatic group, or a heteroaryl group. As another example, in one such embodiment, R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, alkyl, allyl, vinyl or aminoalkyl. As another example, in one such embodiment, R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, alkyl, allyl, vinyl, - (CH)₂)_dNH₂、-(CH₂)_dN[(CH₂)_eNH₂)]₂Wherein d and e are independently 2-4. In each of the above exemplary embodiments of this paragraph, m and z can independently be 0,1, 2, or 3, and n is 0 or 1.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2, which is prepared by: (i) a substitution polymerization of an amine of formula 2 with a multifunctional crosslinker (optionally also comprising an amine moiety), or (2) a free radical polymerization of an amine of formula 2, and X₂Is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, X₂Is an aliphatic or heteroaliphatic radical, and R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, aliphatic groups, heteroaliphatic groups. As another example, in one such embodiment, X₂Is alkyl or aminoalkyl, and R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, X₂Is alkyl or aminoalkyl, and R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, alkyl, allyl, vinyl or aminoalkyl. In each of the above exemplary embodiments of this paragraph, m and z can independently be 0,1, 2, or 3, and n is 0 or 1.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2, which is prepared by: (i) substitution polymerization of the amine of formula 2 with a multifunctional crosslinker (optionally also comprising an amine moiety), or (2) free radical polymerization of the amine of formula 2, and m is a positive integer. For example, in one such embodiment, m is a positive integer, z is 0, and R is₂₀Is hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, m is a positive integer (e.g., 1-3), z is a positive integer (e.g., 1-2), X₁₁Is hydrogen, an aliphatic or heteroaliphatic radical, and R₂₀Is hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such classIn embodiments, m is a positive integer, z is 0,1 or 2, X₁₁Is hydrogen, alkyl, alkenyl or aminoalkyl, and R₂₀Is hydrogen, alkyl, alkenyl or aminoalkyl.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2, which is prepared by: (i) substitution polymerization of an amine of formula 2 with a multifunctional crosslinker (optionally also comprising an amine moiety), or (2) free radical polymerization of an amine of formula 2, and n is a positive integer, and R₃₀Is hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, n is 0 or 1, and R₃₀Is hydrogen, alkyl, alkenyl or aminoalkyl.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2, which is prepared by: (i) a substitution polymerization of an amine of formula 2 with a multifunctional crosslinker (optionally also comprising an amine moiety), or (2) a free radical polymerization of an amine of formula 2, and m and n are independently non-negative integers, and X₂Is an aliphatic group or a heteroaliphatic group. For example, in one such embodiment, m is 0-2, n is 0 or 1, X2 is an aliphatic or heteroaliphatic group, and R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, m is 0-2, n is 0 or 1, X₂Is alkyl or aminoalkyl, and R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, m is 0-2, n is 0 or 1, X₂Is alkyl or aminoalkyl, and R₁₀、R₂₀、R₃₀And R₄₀Independently hydrogen, alkyl, alkenyl or aminoalkyl.

In some embodiments, the crosslinked amine polymer comprises amine residues of formula 2a, and the crosslinked amine polymer is prepared by substitution polymerization of an amine of formula 2a with a multifunctional crosslinker (optionally also comprising an amine moiety):

wherein

m and n are independently non-negative integers;

R₁₁each independently is hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl;

R₂₁and R₃₁Independently hydrogen or a heteroaliphatic group;

R₄₁is hydrogen, a substituted hydrocarbyl group or a hydrocarbyl group;

X₁is that

X₂Is an alkyl or substituted hydrocarbyl group;

X₁₂each independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halogen; and is

z is a non-negative number.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2a, which crosslinked amine polymer is prepared by substitution polymerization of an amine of formula 1 with a multifunctional crosslinker (optionally also comprising an amine moiety). For example, in one such embodiment, m and z are independently 0,1, 2, or 3, and n is 0 or 1.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2a, the crosslinked amine polymer is prepared by substituted polymerization of an amine of formula 2a with a multifunctional crosslinker (optionally also comprising an amine moiety), and R₁₁Each independently hydrogen, aliphatic, aminoalkyl, haloalkyl or heteroaryl, R₂₁And R₃₁Independently is hydrogen or a heteroaliphatic group, and R₄₁Is hydrogen, aliphatic, aryl, heteroaliphatic or heteroaryl. For example, in one such embodiment, R₁₁Each is hydrogen, an aliphatic group, aminoalkyl or haloalkyl, R₂₁And R₃₁Independently is hydrogen or a heteroaliphatic group, and R₄₁Is hydrogen, alkylamino, aminoalkyl, aliphatic or heteroaliphatic. As another example, in oneIn such embodiments, R₁₁Each is hydrogen, an aliphatic group, aminoalkyl or haloalkyl, R₂₁And R₃₁Is hydrogen or aminoalkyl, and R₄₁Is hydrogen, an aliphatic group or a heteroaliphatic group. As another example, in one such embodiment, R₁₁And R₄₁Each independently is hydrogen, alkyl or aminoalkyl, and R₂₁And R₃₁Independently hydrogen or a heteroaliphatic group. As another example, in one such embodiment, R₁₁And R₄₁Each independently is hydrogen, alkyl, - (CH)₂)_dNH₂、-(CH₂)_dN[(CH₂)_eNH₂)]₂Wherein d and e are independently 2-4, and R₂₁And R₃₁Independently hydrogen or a heteroaliphatic group. In each of the above exemplary embodiments of this paragraph, m and z can independently be 0,1, 2, or 3, and n is 0 or 1.

Exemplary amines useful in the synthesis of polymers comprising repeat units of formula 2a include, but are not limited to, the amines given in table 1.

Exemplary crosslinking agents for use in synthesizing polymers comprising amine residues of formula 2a include, but are not limited to, the crosslinking agents set forth in table 2.

TABLE 2

In some embodiments, the crosslinked amine polymer comprises amine residues of formula 2b, the crosslinked amine polymer is prepared by free radical polymerization of an amine of formula 2 b:

wherein

m and n are independently non-negative integers;

R₁₂each independently is hydrogen, a substituted hydrocarbyl group, or a hydrocarbyl group;

R₂₂and R₃₂Independently hydrogen, substituted hydrocarbyl or hydrocarbyl;

R₄₂is hydrogen, hydrocarbyl or substituted hydrocarbyl;

X₁is that

X₂Is alkyl, aminoalkyl or alkanol;

X₁₃each independently is hydrogen, hydroxy, cycloaliphatic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid, or aryl;

z is a non-negative number; and is

The amine of formula 2b comprises at least one allyl group.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2b, the crosslinked amine polymer is prepared by free radical polymerization of an amine of formula 1, and (i) R₁₂Or R₄₂Independently contain at least one allyl or vinyl moiety, (ii) m is a positive integer, and R₂₂(ii) contains at least one allyl or vinyl moiety, and/or (iii) n is a positive integer, and R₃₂Comprising at least one allyl moiety. For example, in one such embodiment, m and z are independently 0,1, 2, or 3, and n is 0 or 1. For example, in one such embodiment, R₁₂Or R₄₂The combination comprises at least two allyl or vinyl moieties. As another example, in one such embodiment, m is a positive integer, and R is₁₂、R₂₂And R₄₂The combination comprises at least two allyl or vinyl moieties. As another example, in one such embodiment, n is a positive integer, and R is₁₂、R₃₂And R₄₂The combination comprises at least two allyl or vinyl moieties. As another example, in one such embodiment, m is a positive integer, n is a positive integer, and R is a positive integer₁₂、R₂₂、R₃₂And R₄₂The combination comprises at least two allyl or vinyl moieties.

In one embodiment, the crosslinked amine polymer comprises amine residues of formula 2b, the crosslinked amine polymer is prepared by free radical polymerization of an amine of formula 2b, and R is₁₂Each independently hydrogen, aminoalkyl, allyl or vinyl, R₂₂And R₃₂Independently is hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, alkanol, heteroaryl, alicyclic, heterocyclic or aryl, and R is₄₂Is hydrogen or a substituted hydrocarbon group. For example, in one such embodiment, R₁₂Each being aminoalkyl, allyl or vinyl, R₂₂And R₃₂Independently is hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl or alkanol, and R₄₂Is hydrogen or a substituted hydrocarbon group. As another example, in one such embodiment, R₁₂And R₄₂Each independently hydrogen, alkyl, allyl, vinyl, - (CH)₂)_dNH₂Or- (CH)₂)_dN[(CH₂)_eNH₂]₂Wherein d and e are independently 2-4, and R₂₂And R₃₂Independently hydrogen or a heteroaliphatic group.

Exemplary amines and crosslinking agents (or salts thereof, such as hydrochloride, phosphate, sulfate, or hydrobromide salts thereof) for use in synthesizing polymers comprising formula 2b include, but are not limited to, those in table 3.

TABLE 3

In some embodiments, the crosslinked amine polymer is obtained from the reaction of a resulting polymer using a monomer described by any one of formulas 1, 1a, 1b, 1c, 2a, and 2b or a linear polymer composed of a repeating unit described by formula 3 with an external crosslinking agent or a pre-existing polymer functional group that can serve as a crosslinking site. Formula 3 can be a repeat unit of a copolymer or terpolymer, wherein X₁₅Is a random copolymer, an alternating copolymer or a block copolymer. The repeating units in formula 3 may also represent repeating units of a branched or hyperbranched (hyperbranched) polymer, wherein the main branching points may come from any atom on the backbone of the polymer:

wherein

R₁₅、R₁₆And R₁₇Independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, amino, boronic acid or halo;

X₁₅is that

X₅Is a hydrocarbon group, a substituted hydrocarbon group, an oxo (-O-) or an amino group, and

z is a non-negative number.

In one embodiment, R₁₅、R₁₆And R₁₇Independently is hydrogen, aryl or heteroaryl, X₅Is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and m and z are non-negative integers. In another embodiment, R₁₅、R₁₆And R₁₇Independently is an aliphatic or heteroaliphatic radical, X₅Is a hydrocarbyl, substituted hydrocarbyl, oxo (-O-) or amino group, and m and z are non-negative integers. In another embodiment, R₁₅、R₁₆And R₁₇Independently is an unsaturated aliphatic radicalOr an unsaturated heteroaliphatic radical, X₅Is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer. In another embodiment, R₁₅、R₁₆And R₁₇Independently is alkyl or heteroalkyl, X₅Is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer. In one embodiment, R₁₅、R₁₆And R₁₇Independently is alkylamino, aminoalkyl, hydroxyl, amino, boronic acid, halo, haloalkyl, alkanol or ether group, X₅Is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer. In another embodiment, R₁₅、R₁₆And R₁₇Independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, amino, boronic acid or halogen, X₅Is oxo, amino, alkylamino, ether, alkanol or haloalkyl, and z is a non-negative integer.

Exemplary crosslinking agents that can be used in the free radical polymerization reaction include, but are not limited to, one or more multifunctional crosslinking agents, such as: 1, 4-bis (allylamino) butane, 1, 2-bis (allylamino) ethane, 2- (allylamino) -1- [2- (allylamino) ethylamino ] ethane, 1, 3-bis (allylamino) propane, 1, 3-bis (allylamino) -2-propanol, triallylamine, diallylamine, divinylbenzene, 1, 7-octadiene, 1, 6-heptadiene, 1, 8-nonadiene, 1, 9-decadiene, 1, 4-divinyloxybutane, 1, 6-hexamethylenebisacrylamide (1, 6-hexamethylenebisacrylamide), ethylenebisacrylamide (ethylene bisacrylamide), N' -bis (vinylsulfonylacetyl) ethylenediamine, 1, 3-bis (vinylsulfonyl) 2-propanol, triallylamine, and the like, Vinyl sulfone, N' -methylenebisacrylamide polyvinyl ether (polyvinylather), polyallyl ether (polyallylether), divinylbenzene, 1, 4-divinyloxybutane, and combinations thereof.

The crosslinked polymers derived from the monomers and polymers of formulas 1-3 can be synthesized in solution or bulk (bulk) or in a dispersion medium. Examples of solvents suitable for synthesizing the polymers of the present application include, but are not limited to, water, low boiling alcohols (methanol, ethanol, propanol, butanol), dimethylformamide, dimethyl sulfoxide, heptane, chlorobenzene, toluene.

Alternative polymerization methods may include single (l0ne) polymerization reactions, step-wise addition of each starting material monomer through a series of reactions, step-wise addition of monomer blocks, combinations, or any other polymerization method such as living polymerization, direct polymerization, indirect polymerization, condensation, free radical, emulsion, precipitation methods, spray-drying polymerization, or the use of some bulk cross-linking reaction methods and size reduction methods such as milling, pressing, extrusion. The process can be carried out in batch, semi-continuous and continuous processes. For the process in a dispersion medium, the continuous phase may be a non-polar solvent, such as toluene, benzene, hydrocarbons, halogenated solvents, supercritical carbon dioxide. For direct suspension reactions, water may be used, and the properties of the suspension may be adjusted with salts.

The starter molecules described in formulas 1-3 may be copolymerized with one or more other monomers, oligomers, or other polymerizable groups of the present invention. Such copolymer structures may include, but are not limited to, block or block-like polymers, graft copolymers, and random copolymers. The monomers described by formulas 1-3 can be incorporated at 1% to 99%. In some embodiments, the comonomer incorporation is from 20% to 80%.

Non-limiting examples of comonomers that may be used alone or in combination include: styrene, allylamine hydrochloride, substituted styrene, alkyl acrylate, substituted alkyl acrylate, alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide, N-dialkylacrylamide, N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinylamide, maleic acid derivatives, vinyl ethers, allyl compounds (allyle), methallyl monomers, and combinations thereof. Functionalized forms of these monomers may also be used. Additional specific monomers or comonomers that may be used in the present invention include, but are not limited to, 2-propen-1-ylamine, 1- (allylamino) -2-aminoethane, 1- [ N-allyl (2-aminoethyl) amino ] -2-aminoethane, methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, alpha-methylstyrene (ammonylstyrene), methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, Isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N-dimethylaminoethyl methacrylate, N-diethylaminoethyl methacrylate, triethylene glycol methacrylate (triethyleneglycomethacrylate), itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N-dimethylaminoethyl acrylate, N-diethylaminoethyl acrylate, triethylene glycol acrylate (triethyleneglycoacrylate, methacrylamide), styrene, glycidyl methacrylate, styrene, N-dimethylaminoethyl methacrylate, N-diethylaminoethyl acrylate, N-diethylaminoethyl acrylate, styrene, N-dimethylaminoethyl acrylate, N-diethylaminoethyl acrylate, styrene, N-dimethylaminoethyl acrylate, N-diethylaminoethyl acrylate, styrene, N-methyl, N-methylacrylamide, N-dimethylacrylamide, N-tert-butylmethacrylamide, N-N-butylmethacrylamide, N-hydroxymethylmethacrylamide, N-hydroxyethylmethacrylamide, N-tert-butylacrylamide, N-hydroxymethylacrylamide, N-hydroxyethylacrylamide, 4-acryloylmorpholine, vinylbenzoic acid (all isomers), diethylaminostyrene (all isomers), a-methylvinylbenzoic acid (all isomers), diethylaminoa-methylstyrene (all isomers), p-vinylbenzenesulfonic acid sodium salt, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, N-butylmethacrylamide, N-hydroxyethylmethacrylamide, N-methylmethacrylamide, N-tert-butylacrylamide, N-hydroxyethylacrylamide, N-vinylbenzenesulfonic acid (, Tributoxysilylpropyl methacrylate, dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl methacrylate, dibutoxymethylsilylpropyl methacrylate, diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl methacrylate, diisopropoxysilylsilylpropyl methacrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl acrylate, diisopropoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, tributoxymethylsilylpropyl acrylate, diisopropoxymethylsilylpropyl acrylate, diisobutoxysilylpropyl acrylate, dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylsilylpropyl acrylate, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, N-vinylformamide, N-vinylacetamide, allylamine, methallylamine, allyl alcohol, methyl-vinyl ether, ethyl vinyl ether, butyl vinyl ether, butadiene, isoprene, chloroprene, ethylene, vinyl acetate, and combinations thereof.

Additional modifications to the preformed crosslinked polymer may be accomplished by the addition of modifiers (modiffers) including, but not limited to, amine monomers, additional crosslinking agents, and polymers. Modification may be accomplished by covalent or non-covalent means. These modifications may be uniformly or non-uniformly dispersed throughout the preformed polymeric material, including modifications that are biased to the surface of the preformed crosslinked polymer. In addition, modifications may be made to alter the physical properties of the preformed crosslinked polymer, including, but not limited to, reactions with residual reactive groups in the preformed polymer, such as haloalkyl and allyl groups. Reactions with and modifications to preformed crosslinked polymers may include, but are not limited to, acid-base reactions, nucleophilic substitution reactions, michael addition reactions, non-covalent electrostatic interactions, hydrophobic interactions, physical interactions (crosslinking), and free radical reactions.

As described in more detail in the examples, it was found that polymers in which crosslinking and/or entanglement was increased had lower swelling than those with lower crosslinking and/or entanglement, but also had as much or greater binding capacity for target ions (e.g., chloride ions) than the lower crosslinking and/or entanglement polymers, while binding of interfering ions, such as phosphate, was significantly reduced. The selective action is introduced in two different ways: 1) the total capacity is sacrificed for chloride ion specificity. Crosslinking agents that do not include chloride ion binding sites (e.g., epichlorohydrin) allow for increased crosslinking while the overall capacity decreases in proportion to the amount of crosslinking agent incorporated into the polymer. 2) Total capacity for chloride ion specificity retention: a crosslinking agent (e.g. diallylamine) comprising chloride binding sites allows for increased crosslinking while the total capacity remains the same or only decreases by a small amount.

The polymers described herein exhibit ion binding properties, typically proton binding, to form a positive charge followed by anion binding. In a preferred embodiment, the polymer exhibits chloride ion binding properties. Ion (e.g., chloride) binding capacity is a measure of the amount of a particular ion that an ionic binder can bind in a given solution. For example, the binding capacity of the ion-binding polymer can be determined in vitro, e.g., in water or in saline solution or in a solution/matrix containing the representative cations and anions of gastrointestinal lumen conditions, or in vivo, e.g., by urinary excretion of ions (e.g., bicarbonate or citrate), or ex vivo, e.g., using aspiration of a liquid, e.g., a chime/gastrointestinal lumen content obtained from a laboratory animal, patient, or volunteer. The assay may be performed in a solution containing only the target ion, or at least no other competitive solutes that compete with the target ion for binding to the polymer. In these cases, a non-interfering buffer (e.g., hydrochloric acid solution with or without additional sodium chloride) may be used. Alternatively, the assay may be performed in an interference buffer containing other competing solutes that compete with the target ion for binding to the resin, such as other ions or metabolites.

In some embodiments, the polymer binds hydrochloric acid. For in vivo use, for example in the treatment of metabolic acidosis, it is desirable that the polymer has a high proton and chloride ion binding capacity. In vitro determination of binding capacity does not necessarily account for in vivo binding capacity. Therefore, it is useful to define the binding capacity in both in vivo and in vitro capacities.

The polymers of the invention may have an in vitro chloride binding capacity in HCl of greater than about 5,6,7, 8, 9,10, 11, 12, 13, 14, or 15 mmol/g. In some embodiments, the polymers of the present invention have an in vitro chloride binding capacity to a target ion of greater than about 5.0mmol/g, preferably greater than about 7.0mmol/g, even more preferably greater than about 9.0mmol/g, and even more preferably greater than about 10.0 mmol/g. In some embodiments, the chloride ion binding capacity can be from about 5.0mmol/g to about 25mmol/g, preferably from about 7.5mmol/g to about 20mmol/g, even more preferably from about 10mmol/g to about 15 mmol/g. Various techniques for determining chloride binding capacity are known in the art.

The maximum binding capacity in vivo (i.e., the maximum amount of [ protons and ] chloride ions bound under conditions likely to be encountered in the human gastrointestinal tract) can be assessed in simulated gastric fluid assays ("SGF") with 12-16h chloride ion binding and is a structural measure of how well the monomer and crosslinker are incorporated. Experiments in which the SGF value represents the theoretical maximum binding capacity of the polymer confirm that it falls within the same range as the capacity calculated on the basis of the stoichiometry of the starting material.

To counter proton binding, chloride is the anion of choice that is bound because its removal has no negative effect on serum bicarbonate. Non-chloride anions that are bound to neutralize the positive proton charge include phosphate, short chain fatty acids, long chain fatty acids, bile acids, or other organic or inorganic anions. The binding of these non-chloride anions affects the overall bicarbonate stores in the intracellular and extracellular compartments.

The selectivity of polymer binding to chloride can be assessed in vitro using conditions that mimic different conditions, anions encountered in the gastrointestinal lumen, and anion concentrations. Chloride binding can be compared to phosphate alone (e.g., SIB [ simulated intestinal buffer ], or to a range of anions present in the gastrointestinal tract (e.g., SOB).

In some embodiments, the polymer has chloride ion binding in the SIB assay after exposure to the test buffer for 1 hour at 37 ℃ of greater than about 2.0mmol/g polymer, preferably greater than about 2.5mmol/g polymer, more preferably greater than about 3.0mmol/g polymer, even more preferably greater than about 3.5mmol/g polymer, and most preferably greater than about 4.0mmol/g polymer.

In some embodiments, the polymer has a chloride ion binding in the SOB assay of greater than about 1.0mmol/g polymer, preferably greater than about 2.0mmol/g polymer, more preferably greater than about 3.0mmol/g polymer, even more preferably greater than about 3.5mmol/g polymer, and most preferably greater than about 4.0mmol/g polymer after exposure to the test buffer for 2 hours at 37 ℃.

In some embodiments, the polymer has a chloride ion binding in the SOB assay of greater than about 0.5mmol/g polymer, preferably greater than about 1mmol/g polymer, more preferably greater than about 2.0mmol/g polymer, even more preferably greater than about 3.0mmol/g polymer, and most preferably greater than about 4.0mmol/g polymer after exposure to the test buffer for 48 hours at 37 ℃. Chloride ion binding in the SOB after 48 hours of exposure at 37 ℃ is a measure of the ability of the polymer to retain chloride ions as they pass through the gastrointestinal tract.

Another way to measure (proton and) chloride retention is to first expose the polymer to SOB to isolate the polymer, and then expose the polymer to conditions typical of the colon lumen, for example using a "chloride retention assay" (CRA) buffer. In some embodiments, the amount of chloride ions that remain bound to the polymer after exposure to SOB for 2 hours at 37 ℃ and then to CRA for 48 hours at 37 ℃ is greater than about 0.2mmol/g polymer, preferably greater than about 0.5mmol/g polymer, more preferably greater than about 1.0mmol/g polymer, even more preferably greater than about 2.0mmol/g polymer, and most preferably greater than about 3.0mmol/g polymer.

In some embodiments, the in vivo binding properties of the polymers of the present application can be evaluated by measuring changes in uric acid (urice acid) levels following administration to animals, including humans, having normal renal function. Removal of additional HCl (or HCl equivalent) from the body by the action of the administered polymer if there is sufficient time to reach metabolic equilibrium is reflected in a change in urinary bicarbonate, titratable acid, citrate, or other indicator of uric acid excretion.

For binding protons, the amine component of the polymer may be a primary, secondary or tertiary amine, but not a quaternary amine. Quaternary amines remain substantially charged under all physiological conditions and therefore do not bind protons until they bind anions. The percentage of quaternary amine can be determined in a number of ways, including titration and back titration methods. Another simple but accurate method is to compare the binding of anions (e.g. chloride) at low and high pH. Although chloride binding at low pH (e.g., SGF buffer conditions; pH 1.2) does not distinguish quaternary amines from other amines, chloride binding assays at high pH (e.g., QAA buffer conditions; pH 11.5) can distinguish them. At such high pH, primary, secondary and tertiary amines are not substantially protonated and do not contribute to chloride ion binding. Thus, any binding observed under these conditions can be attributed to the presence of the permanently charged quaternary amine. Chloride binding at lower pH (e.g., SGF conditions) and higher pH (e.g., QAA conditions) is a measure of the degree of quaternization and, by extension, the amount of protons bound with the chloride. The polymers of the present application contain no more than 40%, 30%, 20%, 10%, most preferably 5% quaternary amines.

The swelling ratio of the polymers of the present application, which represents the degree of crosslinking, demonstrates, and by extension represents the relative pore size of the polymer and the accessibility of anions that are larger than (or have a larger hydration ratio than) chloride ions. In some embodiments, swelling is measured in deionized water and is expressed as g water/g dry polymer. The polymers herein have a swell ratio in deionized water of 5g/g or less, 4g/g or less, 3g/g or less, 2g/g or 1g/g or less.

The ability of a polymer to retain chloride (and not release it, thereby allowing exchange with other anions) as it passes through the different conditions experienced in the gastrointestinal lumen is an important property that may be predictive of relative in vivo efficacy. A chloride ion retention assay (CRA) may be used to evaluate chloride ion retention. The SOB (simulated intestinal organic/inorganic buffer) screen was first performed to allow chloride and other anions to bind to the polymer, isolate the polymer and expose it to conditions (e.g., retention of assay matrix) that simulate the lumen of the colon for 40 hours. The polymer was again isolated and the anions remaining bound to the polymer were eluted in sodium hydroxide and assayed. The polymers of the present application retain more than 50%, 60%, 70%, 80%, or most preferably 90% of the chloride ions bound after performing the chloride ion retention assay.

Using a heterogeneous (heterogenous) polymerization process, polymer particles in the form of spherical beads are obtained, the diameter of which is controlled in the range of 5-1000 microns, preferably 10-500 microns, most preferably 40-180 microns.

Typically, the pharmaceutical compositions of the present application comprise proton-binding crosslinked amine polymers as described herein. Preferably, the pharmaceutical composition comprising the crosslinked amine polymer is formulated for oral administration. The pharmaceutical forms in which the polymers are administered include powders, tablets, pills, lozenges (lozenes), sachets, cachets, elixirs, suspensions, syrups, soft or hard capsules and the like. In one embodiment, the pharmaceutical composition comprises only the crosslinked amine polymer. Alternatively, the pharmaceutical composition may comprise a carrier, diluent or excipient in addition to the cross-linked amine polymer. Examples of carriers, excipients, and diluents that may be used in these and other formulations include foods, beverages, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, and talc. Pharmaceutical excipients that may be used in the pharmaceutical composition also include: binders such as microcrystalline cellulose, colloidal silicon dioxide and combinations thereof (Prosolv 90), carbopol, povidone (providone), and xanthan gum; flavoring agents, such as sucrose, mannitol, xylitol, maltodextrin, fructose or sorbitol; lubricants, such as magnesium stearate, stearic acid, sodium stearyl fumarate, and vegetable-based fatty acids; optionally, disintegrating agents are also included, such as croscarmellose sodium, gellan gum (gellan gum), low-substituted hydroxypropyl ethers of cellulose, sodium starch glycolate. Other additives may include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well known in the art; see, e.g., Gennaro A R (eds.), Remington's Pharmaceutical Sciences, 20 th edition.

In one embodiment, a pharmaceutical composition comprising a crosslinked amine polymer of the present application contains a lower amount of sodium. For example, in one such embodiment, the pharmaceutical composition comprises less than 1g sodium per dose. As another example, in one such embodiment, the pharmaceutical composition comprises less than 0.5g sodium per dose. As another example, in one such embodiment, the pharmaceutical composition comprises less than 0.1g sodium per dose. As another example, in one such embodiment, the pharmaceutical composition is sodium-free.

In one embodiment, the daily dose of the novel chronic metabolic acidosis treatment is compliance-enhancing (about 5g or less per day) and achieves a clinically significant and sustained increase in serum bicarbonate of about 3mEq/L at these daily doses. The non-absorbable nature of the polymer and the absence of sodium loading and/or the introduction of other ions detrimental to such oral drugs for the first time enable safe, long-term treatment of metabolic acidosis without worsening blood pressure/hypertension and/or without causing increased fluid retention and fluid overload. Another benefit is further slowing of the progression of kidney disease and the time to initiate life-long renal replacement therapy (end-stage renal disease "ESRD" includes 3 dialysis per week) or the need for kidney transplantation. Both are associated with significant mortality, low quality of life, and significant health care system burden worldwide. In the united states alone, about 20% of 400,000 ESRD patients die and 100,000 new patients begin dialysis each year.

In one embodiment, the pharmaceutical composition comprises a sodium-free nonabsorbent cross-linked amine polymer that increases serum carbon in a mammal by binding HCl for the treatment of metabolic acidosisHydrogen acidote radical and normalize blood pH. One preferred embodiment includes a polymer that binds H in a sufficient amount in the stomach/upper gastrointestinal tract⁺Then combined with Cl^-Resulting in a clinically significant increase in serum bicarbonate of at least 1.6mEq/L, more preferably at least 2mEq/L, most preferably equal to or greater than 3 mEq/L. The amount of HCl binding was determined by the capacity of the polymer (target range of HCl binding capacity of 5-20mEq HCl/1g polymer) and selectivity. In the stomach, free amines are bound by H⁺Becomes protonated. The positive charge formed in situ on the polymer can then be exploited for binding Cl^-(ii) a Anions other than chloride are bound to a lesser extent (if any) by controlling the access of the binding sites via cross-linking (size exclusion, mesh) and chemical moieties (by tailoring the hydrophilicity/hydrophobicity to exclude larger organic ions (e.g., acetate, propionate, and butyrate or other short chain fatty acids typically present in the colon), phosphate, bile acids, and fatty acids). By tailoring the bead cross-linking and amine binding site chemistry, chloride ions can be tightly bound to ensure that it is not released in the lower gastrointestinal tract. HCl is removed from the body by regular bowel movements/feces resulting in net HCl binding. In another embodiment, a polymer with some quaternized/protonated amine groups is preformed and chloride binding is achieved by ion exchange with citrate or carbonate, where up to 90% of the cation binding sites on the polymer are preloaded with citrate and/or carbonate as counterions.

In one embodiment, a key feature of the sodium-free nonabsorbent amine polymer for treating metabolic acidosis that increases serum bicarbonate and normalizes pH in a mammal is that it does not raise blood pressure or exacerbate hypertension, which is of particular concern in diabetic nephropathy patients. Another benefit of not introducing sodium is that there is no associated increase in fluid retention leading to fluid overload, which is of particular concern in heart failure patients. The ability of the polymers to safely, effectively treat metabolic acidosis, and not introduce harmful counterions, allows for slowing the progression of renal disease, which is of particular concern in chronic kidney disease patients who have not yet undergone dialysis. The start of dialysis may be delayed by at least 3, 6, 9 or 12 months.

In another embodiment of the sodium-free non-absorbable amine polymer for use in the treatment of metabolic acidosis, the polymer is crosslinked beads having a preferred particle size range that is (i) large enough to avoid passive or active absorption through the gastrointestinal tract, and (ii) small enough not to cause grittiness or an unpleasant mouthfeel when ingested in the form of a powder, sachet and/or chewable tablet/dosage form having an average particle size of 40-180 microns. Preferably, the desired particle size morphology is achieved by heterogeneous polymerization reactions such as suspension polymerization or emulsion polymerization. To minimize gastrointestinal side effects in patients normally associated with large volume polymer gels that travel through the gastrointestinal tract, low swelling ratio polymers (0.5-5 times their own weight in water) are preferred. In another embodiment, the polymer carries a moiety permanently/covalently and/or transiently attached to the polymer or itself blocks Cl in the colon and intestine^-/HCO3^-Molecular entities of exchangers (antiporters). The net effect of blocking the antiporter is to reduce Cl uptake from the intestinal lumen^-And associated exchange of bicarbonate from the serum, thereby effectively increasing serum bicarbonate.

In one embodiment, the crosslinked amine polymer may be co-administered with an additional pharmaceutically active agent, depending on the condition to be treated. The co-administration may include simultaneous administration of two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, to treat metabolic acidosis, the crosslinked amine polymers may be co-administered with conventional therapies required to treat potential co-morbidities including, but not limited to, hypertension, diabetes, obesity, heart failure, and complications of chronic kidney disease. These drugs and the cross-linked amine polymer may be formulated together in the same dosage form and administered simultaneously, so long as they do not exhibit any clinically significant drug-drug interaction. Alternatively, these treatments and the crosslinked polymer may be administered separately and sequentially, with one administered followed by the other.

In additional embodiments, numbered 1-104 below, the invention comprises:

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Proton-binding polymers for oral administration

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