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Claims for Patent: 8,337,824

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Claims for Patent: 8,337,824

Title:Linear polyol stabilized polyfluoroacrylate compositions
Abstract: The present invention is directed to compositions of a linear polyol and a salt of a crosslinked cation exchange polymer comprising a fluoro group and an acid group. These compositions are useful to bind potassium in the gastrointestinal tract.
Inventor(s): Albrecht; Detlef (Saratoga, CA), Burdick; Michael (Los Altos, CA), Chang; Han-Ting (Livermore, CA), Charmot; Dominique (Campbell, CA), Chidambaram; Ramakrishnan (Pleasanton, CA), Connor; Eric (Los Gatos, CA), Halfon; Sherin (Palo Alto, CA), Huang; I-Zu (Mountain View, CA), Liu; Mingjun (Campbell, CA), Mills; Jonathan (San Jose, CA), Struver; Werner (Leverkusen, DE)
Assignee: Relypsa, Inc. (Santa Clara, CA)
Application Number:12/545,810
Patent Claims: 1. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt loaded with a stabilizing amount of a linear sugar alcohol by slurrying in a solution the linear sugar alcohol with the crosslinked cation exchange polymer salt, wherein the stabilizing amount of the linear sugar alcohol is from about 10 wt. % to about 35 wt. % based on the total weight of the composition, and the crosslinked cation exchange polymer salt comprising structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, wherein Formula 1, Formula 2, and Formula 3 have the following structures: ##STR00017## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, cycloalkyl, or aryl; A.sub.1 is carboxylic, phosphonic, or phosphoric; X.sub.1 is arylene; and X.sub.2 is alkylene, an ether moiety, or an amide moiety; and either the structural unit of Formula 1 constituting at least about 80 wt. % based on the total weight of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt, or the mole fraction of the structural unit of Formula 1 in the polymer salt being at least about 0.87 based on the total number of moles of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt.

2. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt and a linear sugar alcohol, wherein the cation exchange polymer salt is loaded with the linear sugar alcohol by slurrying in a solution the linear sugar alcohol with the crosslinked cation exchange polymer salt, the crosslinked cation exchange polymer salt comprising structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, wherein Formula 1, Formula 2, and Formula 3 have the following structures: ##STR00018## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, cycloalkyl, or aryl; A.sub.1 is carboxylic, phosphonic, or phosphoric; X.sub.1 is arylene; and X.sub.2 is alkylene, an ether moiety, or an amide moiety; and either the structural unit of Formula 1 constituting at least about 80 wt. % based on the total weight of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt, or the mole fraction of the structural unit of Formula 1 in the polymer salt being at least about 0.87 based on the total number of moles of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt; and the polymer salt is loaded with the linear sugar alcohol in an amount sufficient to reduce the release of fluoride ion from the cation exchange polymer salt upon storage as compared to an otherwise identical composition containing no linear sugar alcohol at the same temperature and storage time, and wherein there is no more than 1000 ppm of inorganic fluoride in the composition after storage.

3. The pharmaceutical composition of claim 1 wherein the structural units of Formulae 1, 2, and 3 have the following structures: ##STR00019##

4. The pharmaceutical composition of claim 1 wherein the polymer salt comprises structural units of Formulae 1, 2 and 3.

5. The pharmaceutical composition of claim 1 wherein the polymer salt comprises structural units of Formulae 1 and 2.

6. The pharmaceutical composition of claim 1 wherein the polymer salt comprises structural units of Formulae 1 and 3.

7. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt and from about 10 wt. % to about 35 wt. % of a linear sugar alcohol based on the total weight of the composition, wherein a crosslinked cation exchange polymer is a reaction product of a polymerization mixture comprising monomers of either (i) Formulae 11 and 22, (ii) Formulae 11 and 33, or (iii) Formulae 11, 22, and 33, the crosslinked cation exchange polymer is converted to the crosslinked cation exchange polymer salt, and the crosslinked cation exchange polymer salt is slurried in a solution of the linear sugar alcohol, wherein Formula 11, Formula 22, and Formula 33 have the following structures: ##STR00020## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, cycloalkyl, or aryl; A.sub.11 is an optionally protected carboxylic, phosphonic, or phosphoric; X.sub.1 is arylene; and X.sub.2 is alkylene, an ether moiety, or an amide moiety; and either the monomer of Formula 11 constituting at least about 80 wt. % based on the total weight of the monomers of Formulae 11 and 22, Formulae 11 and 33, or Formulae 11, 22, and 33 in the polymerization mixture, or the mole fraction of the monomer of Formula 11 in the polymer salt being at least about 0.87 based on the total number of moles of the monomers of Formulae 11 and 22, Formulae 11 and 33, or Formulae 11, 22, and 33 in the polymerization mixture.

8. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt and a linear sugar alcohol, wherein a crosslinked cation exchange polymer is a reaction product of a polymerization mixture comprising monomers of either (i) Formulae 11 and 22, (ii) Formulae 11 and 33, or (iii) Formulae 11, 22, and 33, the crosslinked cation exchange polymer is converted to the crosslinked cation exchange polymer salt, and the crosslinked cation exchange polymer salt is slurried in a solution of the linear sugar alcohol; the linear sugar alcohol is in an amount sufficient to reduce the release of fluoride ion from the polymer salt upon storage as compared to an otherwise identical composition containing no linear sugar alcohol at the same temperature and storage time, and wherein there is no more than 1000 ppm of inorganic fluoride in the composition after storage, and Formula 11, Formula 22, and Formula 33 have the following structures: ##STR00021## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, cycloalkyl, or aryl; A.sub.11 is an optionally protected carboxylic, phosphonic, or phosphoric; X.sub.1 is arylene; and X.sub.2 is alkylene, an ether moiety, or an amide moiety; and either the monomer of Formula 11 constituting at least about 80 wt. % based on the total weight of the monomers of Formulae 11 and 22, Formulae 11 and 33, or Formulae 11, 22, and 33 in the polymerization mixture, or the mole fraction of the monomer of Formula 11 in the polymer salt being at least about 0.87 based on the total number of moles of the monomers of Formulae 11 and 22, Formulae 11 and 33, or Formulae 11, 22, and 33 in the polymerization mixture.

9. The pharmaceutical composition of claim 7 wherein Formulae 11, 22, and 33 have the following structures: ##STR00022##

10. The pharmaceutical composition of claim 7 wherein the polymer comprises structural units of Formulae 11, 22, and 33.

11. The pharmaceutical composition of claim 7 wherein the polymer comprises structural units of Formulae 11 and 22.

12. The pharmaceutical composition of claim 7 wherein the polymer comprises structural units of Formulae 11 and 33.

13. The pharmaceutical composition of claim 1 wherein the salt comprises calcium, sodium, or a combination thereof.

14. The pharmaceutical composition of claim 1 wherein the linear sugar alcohol is selected from the group consisting of arabitol, erythritol, glycerol, maltitol, mannitol, ribitol, sorbitol, xylitol, threitol, galactitol, isomalt, iditol, lactitol and combinations thereof.

15. The pharmaceutical composition of claim 1 wherein the linear sugar alcohol is sorbitol, xylitol, or a combination thereof.

16. The pharmaceutical composition of claim 1 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer and moisture or water.

17. The pharmaceutical composition of claim 2 wherein the concentration of inorganic fluoride is less than about 1000 ppm after storage at about 40.degree. C. for about 6 weeks.

18. The pharmaceutical composition of claim 2 wherein the concentration of inorganic fluoride is less than about 500 ppm after storage at about 25.degree. C. for about 6 weeks.

19. A method for removing potassium from the gastrointestinal tract of an animal subject in need thereof, the method comprising administering the pharmaceutical composition of claim 1 to the subject, whereby the pharmaceutical composition passes through the gastrointestinal tract of the subject, and removes a therapeutically effective amount of potassium ion from the gastrointestinal tract of the subject.

20. A method for removing potassium from the gastrointestinal tract of an animal subject, the method comprising administering once per day to the subject the pharmaceutical composition of claim 1, wherein a daily amount of the polymer salt has a potassium binding capacity of at least 75% of the same daily amount of the same polymer salt administered three times per day.

21. A method of removing potassium from the gastrointestinal tract of an animal subject in need thereof, the method comprising administering once per day to the subject an effective amount of the pharmaceutical composition of claim 1.

22. A method of removing potassium from the gastrointestinal tract of an animal subject in need thereof, the method comprising administering the pharmaceutical composition of claim 7 to the subject, whereby the pharmaceutical composition passes through the gastrointestinal tract of the subject, and removes a therapeutically effective amount of potassium ion from the gastrointestinal tract of the subject.

23. A method for removing potassium from the gastrointestinal tract of an animal subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition of claim 1, which extracts about 5% more potassium as compared to the same dose and same administration frequency of the same polymer salt without stabilization by a linear sugar alcohol.

24. The pharmaceutical composition of claim 1 wherein the salt comprises calcium.

25. The pharmaceutical composition of claim 1 wherein the linear sugar alcohol comprises sorbitol.

26. The pharmaceutical composition of claim 1 wherein the linear sugar alcohol comprises sorbitol and the salt comprises calcium.

27. The pharmaceutical composition of claim 26 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

28. The pharmaceutical composition of claim 27 wherein the polymer salt comprises structural units of Formulae 1, 2 and 3 of the following structures: ##STR00023##

29. The pharmaceutical composition of claim 28 wherein the polymer salt comprises structural units of Formulae 1A, 2A, and 3A and either: (i) the structural units of Formula 1A constitute at least about 85 wt. % based on the total weight of structural units of Formulae 1A, 2A, and 3A in the polymer salt calculated from the amounts of monomers used in the polymerization reaction, and the weight ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 4:1 to about 1:4, or (ii) the mole fraction of the structural unit of Formula 1A in the polymer salt is at least about 0.87 based on the total number of moles of the structural units of Formulae 1A, 2A, and 3A calculated from the amounts of monomers used in the polymerization reaction, and the mole ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 0.2:1 to about 7:1.

30. The pharmaceutical composition of claim 2 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

31. The pharmaceutical composition of claim 2 wherein the salt comprises calcium, the linear sugar alcohol comprises sorbitol, and the structural units of Formulae 1, 2, and 3 have the following structures: ##STR00024##

32. The pharmaceutical composition of claim 31 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

33. The pharmaceutical composition of claim 32 wherein the polymer salt comprises structural units of Formulae 1A, 2A and 3A and either: (i) the structural units of Formula 1A constitute at least about 85 wt. % based on the total weight of structural units of Formulae 1A, 2A, and 3A in the polymer salt calculated from the amounts of monomers used in the polymerization reaction, and the weight ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 4:1 to about 1:4, or (ii) the mole fraction of the structural unit of Formula 1A in the polymer salt is at least about 0.87 based on the total number of moles of the structural units of Formulae 1A, 2A, and 3A calculated from the amounts of monomers used in the polymerization reaction, and the mole ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 0.2:1 to about 7:1.

34. The pharmaceutical composition of claim 7 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

35. The pharmaceutical composition of claim 7 wherein the salt comprises calcium.

36. The pharmaceutical composition of claim 7 wherein the linear sugar alcohol comprises sorbitol.

37. The pharmaceutical composition of claim 7 wherein the linear sugar alcohol comprises sorbitol and the salt comprises calcium.

38. The pharmaceutical composition of claim 37 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

39. The pharmaceutical composition of claim 38 wherein the polymer salt comprises the monomers of Formulae 11, 22, and 33 of the following structures: ##STR00025##

40. The pharmaceutical composition of claim 39 wherein the polymer salt comprises the monomers of Formulae 11A, 22A, and 33A and either: (i) the monomers of Formula 11A constitute at least about 85 wt. % based on the total weight of monomers of Formulae 11A, 22A, and 33A in the polymerization mixture and the weight ratio of monomers of Formula 22A to monomers of Formula 33A is from about 4:1 to about 1:4, or (ii) the mole fraction of the monomer of Formula 11A in the polymerization mixture is at least about 0.87 based on the total number of moles of the monomers of Formulae 11A, 22A, and 33A and the mole ratio of the monomer of Formula 22A to the monomer of Formula 33A in the polymerization mixture is from about 0.2:1 to about 7:1.

41. The pharmaceutical composition of claim 8 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

42. The pharmaceutical composition of claim 8 wherein the salt comprises calcium, the linear sugar alcohol comprises sorbitol, and the polymer comprises the monomers of Formulae 11, 22, and 33 of the following structures: ##STR00026##

43. The pharmaceutical composition of claim 42 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

44. The pharmaceutical composition of claim 43 wherein the polymer salt comprises the monomers of Formulae 11A, 22A and 33A and either: (i) the monomers of Formula 11A constitute at least about 85 wt. % based on the total weight of monomers of Formulae 11A, 22A, and 33A in the polymerization mixture and the weight ratio of monomers of Formula 22A to monomers of Formula 33A is from about 4:1 to about 1:4, or (ii) the mole fraction of the monomer of Formula 11A in the polymerization mixture is at least about 0.87 based on the total number of moles of the monomers of Formulae 11A, 22A, and 33A and the mole ratio of the monomer of Formula 22A to the monomer of Formula 33A in the polymerization mixture is from about 0.2:1 to about 7:1.

45. The pharmaceutical composition of claim 2 wherein the salt comprises calcium, sodium, or a combination thereof.

46. The pharmaceutical composition of claim 2 wherein the salt comprises calcium.

47. The pharmaceutical composition of claim 2 wherein the linear sugar alcohol is selected from the group consisting of arabitol, erythritol, glycerol, maltitol, mannitol, ribitol, sorbitol, xylitol, threitol, galactitol, isomalt, iditol, lactitol and combinations thereof.

48. The pharmaceutical composition of claim 47 wherein the linear sugar alcohol is sorbitol, xylitol, or a combination thereof.

49. The pharmaceutical composition of claim 2 wherein the linear sugar alcohol comprises sorbitol.

50. The pharmaceutical composition of claim 2 wherein the linear sugar alcohol comprises sorbitol and the salt comprises calcium.

51. The pharmaceutical composition of claim 2 wherein the structural units of Formulae 1, 2, and 3 have the following structures: ##STR00027##

52. The pharmaceutical composition of claim 7 wherein the crosslinked cation exchange polymer salt is in bead form.

53. The pharmaceutical composition of claim 7 wherein the salt comprises calcium, sodium, or a combination thereof.

54. The pharmaceutical composition of claim 8 wherein the salt comprises calcium.

55. The pharmaceutical composition of claim 7 wherein the linear sugar alcohol is selected from the group consisting of arabitol, erythritol, glycerol, maltitol, mannitol, ribitol, sorbitol, xylitol, threitol, galactitol, isomalt, iditol, lactitol and combinations thereof.

56. The pharmaceutical composition of claim 55 wherein the linear sugar alcohol is sorbitol, xylitol, or a combination thereof.

57. The pharmaceutical composition of claim 8 wherein the linear sugar alcohol comprises sorbitol.

58. The pharmaceutical composition of claim 8 wherein the linear sugar alcohol comprises sorbitol and the salt comprises calcium.

59. The pharmaceutical composition of claim 8 comprising the monomers of Formulae 11A, 22A, and 33A having the following structures: ##STR00028##

60. The pharmaceutical composition of claim 8 wherein the crosslinked cation exchange polymer salt is in bead form.

61. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt in bead form having a stabilizing amount of a linear sugar alcohol loaded onto the polymer salt by slurrying in a solution the linear sugar alcohol with the crosslinked cation exchange polymer salt, wherein the stabilizing amount of the linear sugar alcohol is from about 10 wt. % to about 35 wt. % based on the total weight of the composition, the crosslinked cation exchange polymer salt comprising structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, wherein Formula 1, Formula 2, and Formula 3 have the following structures: ##STR00029## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, cycloalkyl, or aryl; A.sub.1 is carboxylic, phosphonic, or phosphoric; X.sub.1 is arylene; and X.sub.2 is alkylene, an ether moiety, or an amide moiety; and either the structural unit of Formula 1 constituting at least about 80 wt. % based on the total weight of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt, or the mole fraction of the structural unit of Formula 1 in the polymer salt being at least about 0.87 based on the total number of moles of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt.

62. The pharmaceutical composition of claim 61 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

63. The pharmaceutical composition of claim 61 wherein the salt comprises calcium.

64. The pharmaceutical composition of claim 61 wherein the linear sugar alcohol comprises sorbitol.

65. The pharmaceutical composition of claim 61 wherein the linear sugar alcohol comprises sorbitol and the salt comprises calcium.

66. The pharmaceutical composition of claim 65 wherein the structural units of Formulae 1, 2, and 3 have the following structures: ##STR00030##

67. The pharmaceutical composition of claim 66 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

68. The pharmaceutical composition of claim 67 wherein the polymer salt comprises structural units of Formulae 1A, 2A and 3A and either: (i) the structural units of Formula 1A constitute at least about 85 wt. % based on the total weight of structural units of Formulae 1A, 2A, and 3A in the polymer salt calculated from the amounts of monomers used in the polymerization reaction, and the weight ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 4:1 to about 1:4, or (ii) the mole fraction of the structural unit of Formula 1A in the polymer salt is at least about 0.87 based on the total number of moles of the structural units of Formulae 1A, 2A, and 3A calculated from the amounts of monomers used in the polymerization reaction, and the mole ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 0.2:1 to about 7:1.

69. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt in bead form having a linear sugar alcohol loaded onto the polymer salt by slurrying in a solution the linear sugar alcohol with the crosslinked cation exchange polymer salt, the crosslinked cation exchange polymer comprising structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, wherein Formula 1, Formula 2, and Formula 3 have the following structures: ##STR00031## wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, cycloalkyl, or aryl; A.sub.1 is carboxylic, phosphonic, or phosphoric; X.sub.1 is arylene; and X.sub.2 is alkylene, an ether moiety, or an amide moiety; and either the structural unit of Formula 1 constituting at least about 80 wt. % based on the total weight of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt, or the mole fraction of the structural unit of Formula 1 in the polymer salt being at least about 0.87 based on the total number of moles of the structural units of Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3 in the polymer salt; and the polymer salt is loaded with the linear sugar alcohol in an amount sufficient to reduce the release of fluoride ion from the cation exchange polymer salt upon storage as compared to an otherwise identical composition containing no linear sugar alcohol at the same temperature and storage time, and wherein there is no more than 1000 ppm of inorganic fluoride in the composition after storage.

70. The pharmaceutical composition of claim 69 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

71. The pharmaceutical composition of claim 69 wherein the salt comprises calcium.

72. The pharmaceutical composition of claim 69 wherein the linear sugar alcohol comprises sorbitol.

73. The pharmaceutical composition of claim 69 wherein the linear sugar alcohol comprises sorbitol and the salt comprises calcium.

74. The pharmaceutical composition of claim 73 wherein the structural units of Formulae 1, 2, and 3 have the following structures: ##STR00032##

75. The pharmaceutical composition of claim 74 further comprising from 10 wt. % to 25 wt. % moisture or water based on the total weight of the linear sugar alcohol, polymer salt and moisture or water.

76. The pharmaceutical composition of claim 75 wherein the polymer salt comprises structural units of Formulae 1A, 2A and 3A and either: (i) the structural units of Formula 1A constitute at least about 85 wt. % based on the total weight of structural units of Formulae 1A, 2A, and 3A in the polymer salt calculated from the amounts of monomers used in the polymerization reaction, and the weight ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 4:1 to about 1:4, or (ii) the mole fraction of the structural unit of Formula 1A in the polymer salt is at least about 0.87 based on the total number of moles of the structural units of Formulae 1A, 2A, and 3A calculated from the amounts of monomers used in the polymerization reaction, and the mole ratio of the structural unit of Formula 2A to the structural unit of Formula 3A is from about 0.2:1 to about 7:1.

77. The method of claim 19 wherein the pharmaceutical composition is administered once per day.

78. The method of claim 19 wherein the pharmaceutical composition is administered twice per day.
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