Pharmaceutical compositions comprising cross-linked small molecule amine polymers
Anion-binding polymers are described. The anion-binding polymers in some cases are low swelling anion-binding polymers. In some cases, the anion-binding polymers have a pore volume distribution such that a fraction of the polymer is not available for non-interacting solutes above a certain percentage of the MW of the target ion for the polymer. In some cases, the anion-binding polymers are characterized by low ion-binding interference, where the interference is measured in, for example, a gastrointestinal simulant, relative to non-interfering buffer. Pharmaceutical composition, methods of use, and kits are also described.
1. A pharmaceutical composition comprising a particulate crosslinked amine polymer as an active ingredient and a pharmaceutically acceptable excipient, the particulate crosslinked amine polymer particles having a chloride content of less than about 20 mol % of the amine group content and a size in the range of 5 to 500 microns, the crosslinked amine polymer comprising repeat units derived from polymerization of a non- polymeric amine and a crosslinking agent such that the polymer has a swelling ratio of less than about 5 as measured in a physiological medium, the non-polymeric amine being selected from the group consisting of
(i) a non-polymeric amine of formula (I)
wherein each n, independently, is equal to or greater than 3; m is equal to or greater than 1; and each R 1, independently, is H or optionally substituted alkyl or aryl or is linked to a neighboring R 1 to form an optionally substituted alicyclic, aromatic, or heterocyclic group; provided the non-polymeric amine of formula I is not 1,3-diaminopropane, and
(ii) a non-polymeric amine of formula (IV)
wherein each n, independently, is equal to or greater than 3; each r, independently, is 0, 1, or 2; and each R 1 , independently, is H or optionally substituted alkyl or aryl or is linked to a neighboring R 1 to form an optionally substituted alicyclic, aromatic, or heterocyclic group.
2. The pharmaceutical composition of claim 1 wherein the non-polymeric amine is a non-polymeric amine of formula IV.
3. The pharmaceutical composition of claim 2 wherein the non- polymeric amine is
and n is 3, 4 or 5.
4. The pharmaceutical composition of claim 3 wherein n is 3.
5. The pharmaceutical composition of claim 3 wherein n is 5.
6. The pharmaceutical composition of claim 3 wherein the polymer particles have a size in the range of 25 to 250 microns.
7. The pharmaceutical composition of 3 wherein the polymer particles are spherical beads having a diameter of 25 to 250 microns.
8. The pharmaceutical composition of claim 1 wherein the polymer particles have a size in the range of 25 to 250 microns.
9. The pharmaceutical composition of 1 wherein the polymer particles are spherical beads having a diameter of 25 to 250 microns.
10. The pharmaceutical composition of claim 1 wherein the crosslinking agent is 1,3-dichloropropane or epichlorohydrin.
11. The pharmaceutical composition of claim 1 wherein the crosslinking agent is epichlorohydrin.
12. The pharmaceutical composition of claim 2 wherein the polymer particles have a size in the range of 25 to 250 microns.
13. The pharmaceutical composition of 2 wherein the particles are spherical beads having a diameter of 25 to 250 microns.
14. The pharmaceutical composition of claim 2 wherein the crosslinking agent is 1,3-dichloropropane or epichlorohydrin.
15. The pharmaceutical composition of claim 2 wherein the crosslinking agent is epichlorohydrin.
16. The pharmaceutical composition of claim 1 wherein the polymer has a gel pore volume distribution where less than about 20% of the pore volume of the gel is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium.
17. The pharmaceutical composition of claim 3 wherein the polymer has a gel pore volume distribution where less than about 20% of the pore volume of the gel is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium.
18. The pharmaceutical composition of claim 1 wherein the polymer binds phosphate ion in vivo with a binding capacity of greater than 0.5 mmol/g.
19. The pharmaceutical composition of claim 3 wherein the polymer binds phosphate ion in vivo with a binding capacity of greater than 0.5 mmol/g.
20. The pharmaceutical composition of claim 1 wherein the polymer has a gel pore volume distribution where less than about 20% of the pore volume of the gel is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium, and the polymer binds phosphate ion in vivo with a binding capacity of greater than 0.5 mmol/g.
21. The pharmaceutical composition of claim 3 wherein the polymer has a gel pore volume distribution where less than about 20% of the pore volume of the gel is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium, and the polymer binds phosphate ion in vivo with a binding capacity of greater than 0.5 mmol/g.
22. The pharmaceutical composition of claim 1 wherein the polymer particles have a chloride content of less than about 5 mol % of the amine group content.
23. The pharmaceutical composition of claim 1 wherein the polymer particles are substantially chloride-free.
24. The pharmaceutical composition of claim 1 wherein the composition is in the form of a powder.
25. The pharmaceutical composition of claim 3 wherein the composition is in the form of a powder.
26. The pharmaceutical composition of claim 1 wherein the composition is contained within a sachet.
27. The pharmaceutical composition of claim 3 wherein the composition is contained within a sachet.
28. The pharmaceutical composition of claim 1 wherein the composition is in the form of a sterile packaged powder.
29. The pharmaceutical composition of claim 3 wherein the composition is in the form of a sterile packaged powder.
30. The pharmaceutical composition of claim 1 wherein the composition is in the form of a soft or hard gelatin capsule.
31. The pharmaceutical composition of claim 3 wherein the composition is in the form of a soft or hard gelatin capsule.
32. A pharmaceutical composition comprising a particulate crosslinked amine polymer as an active ingredient and a pharmaceutically acceptable excipient, the particulate crosslinked amine polymer particles being spherical beads having a size in the range of 5 to 500 microns, the crosslinked amine polymer comprising repeat units derived from polymerization of a non-polymeric amine and a crosslinking agent such that the polymer has a swelling ratio of less than about 5 as measured in a physiological medium, the non-polymeric amine being selected from the group consisting of
(i) a non-polymeric amine of formula (I)
wherein each n, independently, is equal to or greater than 3; m is equal to or greater than 1; and each R 1 , independently, is H or optionally substituted alkyl or aryl or is linked to a neighboring R 1 to form an optionally substituted alicyclic, aromatic, or heterocyclic group; provided the non-polymeric amine of formula I is not 1,3-diaminopropane, and
(ii) a non-polymeric amine of formula (IV)
wherein each n, independently, is equal to or greater than 3; each r, independently, is 0, 1, or 2; and each R 1, independently, is H or optionally substituted alkyl or aryl or is linked to a neighboring R 1 to form an optionally substituted alicyclic, aromatic, or heterocyclic group.
33. The pharmaceutical composition of claim 32 wherein the non- polymeric amine is a non-polymeric amine of formula IV.
34. The pharmaceutical composition of claim 33 wherein the non- polymeric amine is
and n is 3, 4 or 5.
35. The pharmaceutical composition of claim 34 wherein n is 3.
36. The pharmaceutical composition of claim 34 wherein n is 5.
37. The pharmaceutical composition of claim 34 wherein the polymer particles have a size in the range of 25 to 250 microns.
38. The pharmaceutical composition of claim 33 wherein the crosslinking agent is 1,3-dichloropropane or epichlorohydrin.
39. The pharmaceutical composition of claim 33 wherein the crosslinking agent is epichlorohydrin.
40. The pharmaceutical composition of claim 32 wherein the polymer has a gel pore volume distribution where less than about 20% of the pore volume of the gel is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium.
41. The pharmaceutical composition of claim 34 wherein the polymer has a gel pore volume distribution where less than about 20% of the pore volume of the gel is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium.
42. The pharmaceutical composition of claim 32 wherein the composition is in the form of a powder.
43. The pharmaceutical composition of claim 34 wherein the composition is in the form of a powder.
44. The pharmaceutical composition of claim 34 wherein the composition is contained within a sachet.
45. The pharmaceutical composition of claim 34 wherein the composition is contained within a sachet.
46. The pharmaceutical composition of claim 32 wherein the composition is in the form of a sterile packaged powder.
47. The pharmaceutical composition of claim 34 wherein the composition is in the form of a sterile packaged powder.
48. The pharmaceutical composition of claim 32 wherein the composition is in the form of a soft or hard gelatin capsule.
49. The pharmaceutical composition of claim 34 wherein the composition is in the form of a soft or hard gelatin capsule.