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 method of treating metabolic acidosis in a patient, the method comprising orally administering to the patient a pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1:
wherein R 1 , R 2 and R 3 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R 1 , R 2 and R 3 is other than hydrogen, the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of less than 2, and the crosslinked amine polymer has an equilibrium proton binding capacity and a chloride binding capacity of at least 5 mmol/g in Simulated Gastric Fluid (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH1.2 and 37° C.
2. The method of claim 1 , wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1a and the crosslinked amine polymer is prepared by radical polymerization of an amine corresponding to Formula 1a:
wherein R 4 and R 5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
3. The method of claim 2 , wherein R 4 and R 5 are independently hydrogen, aliphatic or heteroaliphatic.
4. The method of claim 1 , wherein the patient is a human patient.
5. The method according to claim 1 , wherein the serum bicarbonate is controlled or normalized.
6. The method according to claim 1 , wherein the pharmaceutical composition is administered to the patient as a daily dose.
7. The method according to claim 6 , wherein the daily dose administered is less than 20 g.
8. The method according to claim 6 , wherein the daily dose administered is less than 15 g.
9. The method according to claim 6 , wherein the daily dose administered is less than 10 g.
10. The method according to claim 6 , wherein the daily dose administered is less than 5 g.
11. The method according to claim 6 , wherein the daily dose is administered once a day.
12. The method according to claim 6 , wherein the daily dose results in a sustained serum bicarbonate increase of ≥3 mEq/L.
13. The method according to claim 6 , wherein a daily dose of 10 g or less per day results in an increase in serum bicarbonate of ≥3 mEq/L.
14. The method according to claim 2 , wherein the pharmaceutical composition is administered to the patient as a daily dose.
15. The method according to claim 14 , wherein the daily dose administered is less than 20 g.
16. The method according to claim 14 , wherein the daily dose administered is less than 15 g.
17. The method according to claim 14 , wherein the daily dose administered is less than 10 g.
18. The method according to claim 14 , wherein the daily dose administered is less than 5 g.
19. The method according to claim 14 , wherein the daily dose is administered once a day.
20. The method according to claim 14 , wherein the daily dose results in a sustained serum bicarbonate increase of ≥3 mEq/L.
21. The method according to claim 14 , wherein a daily dose of 10 g or less per day results in an increase in serum bicarbonate of ≥3 mEq/L.