LINEAR POLYOL STABILIZED POLYFLUOROACRYLATE COMPOSITIONS

• US 20100111891A1
• Filed: 08/22/2009
• Published: 05/06/2010
• Est. Priority Date: 08/22/2008
• Status: Active Grant

• Current Assignee: Vifor (International) Ltd.
• Original Assignee: Relypsa Incorporated (CSL Limited)
• Inventors: Charmot, Dominique, Liu, Mingjun, Chang, Han-Ting, Chidambaram, Ramakrishnan, Strüver, Werner, Albrecht, Detlef, Mills, Jonathan, Huang, I-Zu, Connor, Eric, Halfon, Sherin, Burdick, Michael
• Granted Patent: US 8,337,824 B2
• Time in Patent Office: Days
• US Class Current: 424/78.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: A61K 31/78 of acrylic acid or derivatives thereof
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: C08K 5/053 Polyhydroxylic alcohols

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.

Claims

1. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt and from about 10 wt. % to about 40 wt. % of a linear polyol based on the total weight of the composition, the crosslinked cation exchange polymer comprising structural units corresponding to Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, wherein

Formula 1, Formula 2, and Formula 3 are represented by the following structures:

wherein

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, or aryl;

A₁ is carboxylic, phosphonic, or phosphoric;

X₁ is arylene; and

X₂ is alkylene, an ether moiety, or an amide moiety.

3. The pharmaceutical composition of claim 1 wherein the structural units represented by Formulae 1, 2, and 3 are represented by the following structures:

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

6. The pharmaceutical composition of claim 1 wherein the polymer comprises structural units corresponding to Formulae 1 and 2.

7. The pharmaceutical composition of claim 1 wherein the polymer comprises structural units corresponding to Formulae 1 and 3.

23. The pharmaceutical composition of claim 1 wherein the cation of the salt is calcium, sodium, or a combination thereof.

25. The pharmaceutical composition of claim 1 wherein the composition comprises from about 15 wt. % to about 35 wt. % linear polyol based on the total weight of the composition.

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

28. The pharmaceutical composition of claim 1 wherein the linear polyol is sorbitol, xylitol, or a combination thereof.

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

31. The pharmaceutical composition of claim 1 wherein the concentration of inorganic fluoride is less than about 1000 ppm after storage at about 40°

C. for about 6 weeks.

32. The pharmaceutical composition of claim 1 wherein the concentration of inorganic fluoride is less than about 500 ppm after storage at about 25°

C. for about 6 weeks.

35. A method for removing potassium from the gastrointestinal tract of an animal subject in need thereof, the method comprising administering a 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.

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

39. A method of removing potassium from the gastrointestinal tract of an animal subject in need thereof, comprising administering once per day to the subject an effective amount of a crosslinked cation exchange polymer or the pharmaceutical composition of claim 1, wherein less than 25% of subjects taking the polymer or the composition once per day experience mild or moderate gastrointestinal adverse events, the polymer comprising structural units corresponding to Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, wherein Formula 1, Formula 2, and Formula 3 are represented by the following structures:

wherein

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, or aryl;

A₁ is carboxylic, phosphonic, or phosphoric;

X₁ is arylene; and

X₂ is alkylene, an ether moiety, or an amide moiety.

2. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt and a linear polyol, the crosslinked cation exchange polymer comprising structural units corresponding to Formulae 1 and 2, Formulae 1 and 3, or Formulae 1, 2, and 3, wherein

Formula 1, Formula 2, and Formula 3 are represented by the following structures:

wherein

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, or aryl;

A₁ is carboxylic, phosphonic, or phosphoric;

X₁ is arylene; and

X₂ is alkylene, an ether moiety, or an amide moiety; and

the linear polyol being present in the composition in an amount sufficient to reduce the release of fluoride ion from the cation exchange polymer upon storage as compared to an otherwise identical composition containing no linear polyol at the same temperature and storage time, and wherein there is no more than 1000 ppm of inorganic fluoride in the composition after storage.

5. (canceled)

8. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt and from about 10 wt. % to about 40 wt. % of a linear polyol based on the total weight of the composition, the crosslinked cation exchange polymer being 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, wherein

Formula 11, Formula 22, and Formula 33 are represented by the following structures:

and wherein

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, or aryl;

A₁₁ is an optionally protected carboxylic, phosphonic, or phosphoric;

X₁ is arylene; and

X₂ is alkylene, an ether moiety, or an amide moiety.

10. The pharmaceutical composition of claim 8 wherein A₁₁ is a protected carboxylic, phosphonic, or phosphoric.

11. The pharmaceutical composition of claim 8 wherein Formulae 11, 22, and 33 are represented by the following structures:

12. The pharmaceutical composition of claim 8 wherein the polymer comprises structural units corresponding to Formulae 11, 22, and 33.

14. The pharmaceutical composition of claim 8 wherein the polymer comprises structural units corresponding to Formulae 11 and 22.

15. The pharmaceutical composition of claim 8 wherein the polymer comprises structural units corresponding to Formulae 11 and 33.

20. The pharmaceutical composition of claim 8 wherein A₁₁ is carboxylic, phosphonic, or phosphoric.

40. A method of removing potassium from the gastrointestinal tract of an animal subject in need thereof, comprising administering once per day to the subject an effective amount of a crosslinked cation exchange polymer or the pharmaceutical composition of claim 8 wherein less than 25% of subjects taking the polymer or composition once per day experience mild or moderate gastrointestinal adverse events, the polymer being 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, wherein Formula 11, Formula 22, and Formula 33 are represented by the following structures:

wherein

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, or aryl;

A₁₁ is an optionally protected carboxylic, phosphonic, or phosphoric;

X₁ is arylene; and

X₂ is alkylene, an ether moiety, or an amide moiety.

9. A pharmaceutical composition comprising a crosslinked cation exchange polymer salt and a linear polyol, the crosslinked cation exchange polymer being 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 linear polyol being present in the composition in an amount sufficient to reduce the release of fluoride ion from the polymer upon storage as compared to an otherwise identical composition containing no linear polyol 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 are represented by the following structures;

wherein

R₁ and R₂ are each independently hydrogen, alkyl, cycloalkyl, or aryl;

A₁₁ is an optionally protected carboxylic, phosphonic, or phosphoric;

X₁ is arylene; and

X₂ is alkylene, an ether moiety, or an amide moiety.

13. (canceled)

16-19. -19. (canceled)

21-22. -22. (canceled)

24. (canceled)

27. (canceled)

30. (canceled)

33-34. -34. (canceled)

37-38. -38. (canceled)

41-55. -55. (canceled)

56. A method for removing potassium from the gastrointestinal tract of an animal subject in need thereof, comprising administering an effective amount of a linear polyol stabilized crosslinked aliphatic carboxylic polymer, which extracts about 5% more potassium as compared to the same dose and same administration frequency of the same polymer without stabilization by a linear polyol.

57-82. -82. (canceled)