Claims for Patent: 6,509,013

Summary for Patent: 6,509,013

Title:	Method of making phosphate-binding polymers for oral administration
Abstract:	Phosphate-binding polymers are provided for removing phosphate from the gastrointestinal tract. The polymers are orally administered, and are useful for the treatment of hyperphosphatemia.
Inventor(s):	Holmes-Farley; Stephen Randall (Arlington, MA), Mandeville, III; W. Harry (Lynnfield, MA), Whitesides; George M. (Newton, MA)
Assignee:	GelTex Pharmaceuticals, Inc. (Waltham, MA)
Application Number:	09/542,329
Patent Claims:	1. A pharmaceutical composition consisting essentially of a carrier and at least one water insoluble, crosslinked polymer characterized by a repeat unit having the formula ##STR28## or a copolymer thereof, wherein each n is an integer, each R, independently, is H or an alkyl, alkylamino, or aryl group optionally substituted with a quaternary ammonium, primary alkyl amine, secondary alkyl amine, primary aryl amine, secondary aryl amine, hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanidine, urea, or carboxylic acid ester group, or a combination thereof. 2. The pharmaceutical composition of claim 1 wherein said polymer is crosslinked with a crosslinking agent, wherein said agent is present in said composition from about 0.5% to about 75% by weight. 3. The pharmaceutical composition of claim 2 wherein said crosslinking agent is selected from the group consisting of epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence diisocyanate, acryloyl chloride, and pyromellitic dianhydride. 4. The pharmaceutical composition of claim 2 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 5. The pharmaceutical composition of claim 1 wherein the polymer is a copolymer comprising a second repeat unit having the formula ##STR29## wherein each n, independently, is an integer and each R, independently, is H or a substituted or unsubstituted alkyl, alkylamino, or aryl group and each X.sup.- is an exchangeable negatively charged counterion. 6. The pharmaceutical composition of claim 5 wherein said polymer is crosslinked with a crosslinking agent wherein said crosslinking agent is present in said composition from about 0.5% to about 75% by weight. 7. The pharmaceutical composition of claim 6 wherein said crosslinking agent is selected from the group consisting of epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence diisocyanate, acryloyl chloride, and pyromellitic dianhydride. 8. The pharmaceutical composition of claim 6 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 9. A pharmaceutical composition comprising a carrier and at least one water insoluble, crosslinked polymer characterized by a repeat unit having the formula ##STR30## or a copolymer thereof, wherein n is an integer, each R, independently, is H or an alkyl, alkylamino, or aryl group optionally substituted with a quaternary ammonium, primary alkyl amine, secondary alkyl amine, primary aryl amine, secondary aryl amine, hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl; aryl, hydrazine, guanidine, urea, or carboxylic acid ester group, or a combination thereof. 10. The pharmaceutical composition of claim 9 wherein said polymer is crosslinked with a crosslinking agent, wherein said agent is present in said composition from about 0.5% to about 75% by weight. 11. The pharmaceutical composition of claim 10 wherein said crosslinking agent is selected from the group consisting of epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence diisocyanate, acryloyl chloride, and pyromellitic dianhydride. 12. The pharmaceutical composition of claim 10 wherein said polymer is crosslinked with a crosslinking agent, wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 13. The pharmaceutical composition of claim 9 wherein the polymer is a copolymer comprising a second repeat unit having the formula ##STR31## wherein each n, independently, is an integer and R is a substituted or unsubstituted alkyl, alkylamino, or aryl group and each X.sup.- is an exchangeable negatively charged counterion. 14. The pharmaceutical composition of claim 13 wherein said polymer is crosslinked with a crosslinking agent wherein said crosslinking agent is present in said composition from about 1% to about 75% by weight. 15. The pharmaceutical composition of claim 14 wherein said crosslinking agent is selected from the group consisting of epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence diisocyanate, acryloyl chloride, and pyromellitic dianhydride. 16. The pharmaceutical composition of claim 14 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 17. A pharmaceutical composition comprising a carrier and at least one water insoluble, crosslinked polymer characterized by a repeat unit having the formula ##STR32## or a copolymer thereof, wherein n is an integer, and each R.sub.1 and R.sub.2, independently, is H or an alkyl, alkylamino, or aryl group optionally substituted with a quaternary ammonium, primary alkyl amine, secondary alkyl amine, primary aryl amine, secondary aryl amine, hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanidine, urea, or carboxylic acid ester group, or a combination thereof, and each X.sup.- is an exchangeable negatively charged counterion. 18. The pharmaceutical composition of claim 17 wherein at least one of said R groups is a hydrogen group. 19. The pharmaceutical composition of claim 17 wherein said polymer is crosslinked with a crosslinking agent, wherein said agent is present in said composition from about 0.5% to about 75% weight. 20. The pharmaceutical composition of claim 19 wherein said crosslinking agent is selected from the group consisting of epichlorohydrin 1,4-butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence diisocyanate, acryloyl chloride, and pyromellitic dianhydride. 21. The pharmaceutical composition of claim 19 wherein said polymer is crosslinked with a crosslinking agent, wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 22. A pharmaceutical composition comprising a carrier and at least one water insoluble, crosslinked polymer characterized by a repeat unit having the formula ##STR33## or a copolymer thereof, wherein n is an integer, each R.sub.1 and R.sub.2, independently, is H or an alkyl group containing 1 to 20 carbon atoms optionally substituted with a quaternary ammonium, primary alkyl amine, secondary alkyl amine, primary aryl amine, secondary aryl amine, hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanidine, urea, or carboxylic acid ester group, or a combination thereof. 23. The pharmaceutical composition of claim 22 wherein said polymer is crosslinked with a crosslinking agent, wherein said agent is present in said composition from about 0.5% to about 75% by weight. 24. The pharmaceutical composition of claim 23 wherein said crosslinking agent is selected from the group consisting of epichlorohydrin 1,4-butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence diisocyanate, acryloyl chloride, and pyromellitic dianhydride. 25. The pharmaceutical composition of claim 23 wherein said polymer is crosslinked with a crosslinking agent, wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 26. A pharmaceutical composition comprising a carrier and at least one water insoluble, crosslinked polymer characterized by a repeat unit having the formula ##STR34## or a copolymer thereof, wherein n is an integer, each R.sub.1, R.sub.2 and R.sub.3, independently, is H, an alkyl group containing 1 to 20 carbon atoms, an aminoalkyl group, or an aryl group containing 1 to 12 atoms, each of which are optionally substituted with a quaternary ammonium, primary alkyl amine, secondary alkyl amine, primary aryl amine, secondary aryl amine, hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanidine, urea, or carboxylic acid ester group, or a combination thereof, and each X.sup.- is an exchangeable negatively charged counterion. 27. The pharmaceutical composition of claim 16 wherein said polymer is crosslinked with a crosslinking agent, wherein said agent is present in said composition from about 0.5% to about 75% by weight. 28. The pharmaceutical composition of claim 19 wherein said crosslinking agent is selected from the group consisting of epichlorohydrin 1,4-butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence duisocyanate, acryloyl chloride, and pyromellitic dianhydride. 29. The pharmaceutical composition of claim 27 wherein said polymer is crosslinked with a crosslinking agent, wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 30. A pharmaceutical composition comprising at least one hydrophilic, water insoluble, cross-linked aliphatic amine polymer and a pharmaceutically acceptable carrier or diluent. 31. A pharmaceutical composition consisting essentially of a carrier and at least one crosslinked, water insoluble polymer characterized by a repeat unit having the formula ##STR35## or a copolymer thereof, wherein each n is an integer, each R, independently, is H or a alkyl, alkylamino, or aryl group optionally substituted with a quaternary ammonium, primary alkyl amine, secondary alkyl amine, primary aryl amine, secondary aryl amine, hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl, hydrazine, guanidine, urea, or carboxylic acid ester group, or a combination thereof, and each X.sup.- is an exchangeable negatively charged counterion. 32. The pharmaceutical composition of claim 31 wherein said polymer is crosslinked with a crosslinking agent, wherein said agent is present in said composition from about 0.5% to about 75% by weight. 33. The pharmaceutical composition of claim 32 wherein said crosslinking agent is selected from the group consisting of epichlofohydrin, 1,4 butanedioldiglycidyl ether, 1,2-ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluence diisocyanate, acryloyl chloride, and pyromellitic dianhydride. 34. The pharmaceutical composition of claim 32 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 35. A pharmaceutical composition consisting essentially of a carrier and a crosslinked, water insoluble, polyallylamine polymer. 36. The pharmaceutical composition of claim 35 wherein the polyallylamine polymer is a homopolymer. 37. The pharmaceutical composition of claim 35 wherein the polyallylamine polymer is crosslinked with epichlorohydrin. 38. A pharmaceutical composition comprising a crosslinked, water insoluble polyallylamine homopolymer, wherein the polyallylamine homopolymer comprises repeat units represented by the structural formula: ##STR36## wherein n is an integer.