Proton-binding polymers for oral administration
Pharmaceutical compositions for and methods of treating an animal, including a human, and methods of preparing such compositions. The pharmaceutical compositions contain crosslinked amine polymers and may be used, for example, to treat diseases or other metabolic conditions in which removal of protons and/or chloride ions from the gastrointestinal tract would provide physiological benefits such as normalizing serum bicarbonate concentrations and the blood pH in an animal, including a human.
1. A pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine having the formula H 2 C═CH—CH 2 NH 2 or a salt thereof wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less, the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 10 mmol/g and a chloride ion binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. and (ii) a chloride ion to phosphate ion binding molar ratio of at least 0.5:1, respectively, when added at a concentration of 2.5 mg/ml to a simulated intestinal buffer and mixed for one hour at 37° C. wherein the simulated intestinal buffer is a solution of 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5.
2. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 2 or less.
3. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer binds more chloride than any one of the interfering anions in a simulated small intestine organic and inorganic buffer when added at a concentration of 2.5 mg/ml to the simulated small intestine organic and inorganic buffer and incubated at 37° C. for 2 hours with agitation wherein the interfering ions are phosphate, citrate and taurocholate ions and the simulated small intestine organic and inorganic contains 50 mM 2-(N-morpholino)ethanesulfonic acid (MES), 50 mM sodium acetate, 36 mM sodium chloride, 7 mM sodium phosphate, 1.5 mM sodium citrate, 30 mM oleic acid and 5 mM sodium taurocholate, buffered to pH 6.2.
4. The pharmaceutical composition of claim 1 wherein the percentage of quaternized amines is less than 40%.
5. The pharmaceutical composition of claim 1 wherein the percentage of quaternized amines is less than 10%.
6. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer is a gel or a bead having a mean particle size of 40 to 180 micrometers.
7. The pharmaceutical composition of claim 1 in a dosage unit form.
8. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
9. The pharmaceutical composition of claim 8 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
10. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer further comprises the residue of a multiallylamine crosslinker having two or more allyl functionalities.
11. The pharmaceutical composition of claim 10 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
12. The pharmaceutical composition of claim 10 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
13. The pharmaceutical composition of claim 10 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
14. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer further comprises the residue of a polyfunctional crosslinker selected from the group consisting of 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
15. The pharmaceutical composition of claim 14 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
16. The pharmaceutical composition of claim 14 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
17. The pharmaceutical composition of claim 14 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
18. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer further comprises the residue of a multiallylamine crosslinker selected from the group consisting of 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, and N,N,N-triallylamine.
19. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
20. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
21. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
22. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer further comprises a multiallylamine crosslinker selected from the group consisting of 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, and N,N,N-triallylamine and the residue of a polyfunctional crosslinker selected from the group consisting of 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
23. The pharmaceutical composition of claim 22 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
24. The pharmaceutical composition of claim 22 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
25. The pharmaceutical composition of claim 22 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
26. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer comprises the residue of 1,3-Bis(allylamino)propane and the residue of a polyfunctional crosslinker selected from the group consisting of 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
27. The pharmaceutical composition of claim 26 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
28. The pharmaceutical composition of claim 26 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
29. The pharmaceutical composition of claim 26 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
30. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 1:1 respectively, when added at a concentration of 2.5 mg/ml to a simulated intestinal buffer and mixed for one hour at 37° C. wherein the simulated intestinal buffer is a solution of 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5.
31. The pharmaceutical composition of claim 30 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
32. The pharmaceutical composition of claim 30 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
33. The pharmaceutical composition of claim 30 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
34. The pharmaceutical composition of claim 30 wherein the crosslinked amine polymer further comprises the residue of a multiallylamine crosslinker having two or more allyl functionalities.
35. The pharmaceutical composition of claim 34 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
36. The pharmaceutical composition of claim 34 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
37. The pharmaceutical composition of claim 34 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
38. The pharmaceutical composition of claim 30 wherein the crosslinked amine polymer further comprises the residue of a polyfunctional crosslinker selected from the group consisting of 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
39. The pharmaceutical composition of claim 38 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
40. The pharmaceutical composition of claim 38 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
41. The pharmaceutical composition of claim 38 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
42. The pharmaceutical composition of claim 30 wherein the crosslinked amine polymer further comprises the residue of a multiallylamine crosslinker selected from the group consisting of 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, and N,N,N-triallylamine.
43. The pharmaceutical composition of claim 42 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
44. The pharmaceutical composition of claim 42 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
45. The pharmaceutical composition of claim 42 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
46. The pharmaceutical composition of claim 42 wherein the crosslinked amine polymer further comprises a multiallylamine crosslinker selected from the group consisting of 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, and N,N,N-triallylamine and the residue of a polyfunctional crosslinker selected from the group consisting of 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
47. The pharmaceutical composition of claim 46 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
48. The pharmaceutical composition of claim 46 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
49. The pharmaceutical composition of claim 46 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.
50. The pharmaceutical composition of claim 30 wherein the crosslinked amine polymer comprises the residue of 1,3-Bis(allylamino)propane and the residue of a polyfunctional crosslinker selected from the group consisting of 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
51. The pharmaceutical composition of claim 50 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 2 or less.
52. The pharmaceutical composition of claim 50 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
53. The pharmaceutical composition of claim 50 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1 or less.