Claims for Patent: 5,624,963

Summary for Patent: 5,624,963

Title:	Process for removing bile salts from a patient and compositions therefor
Abstract:	A method for removing bile salts from a patient by ion exchange by administering to the patient a therapeutically effective amount of one or more highly crosslinked polymers characterized by a repeat unit having the formula ##STR1## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; M is ##STR2## or --Z--R.sup.2 ; Z is O, NR.sup.3, S, or (CH.sub.2).sub.m ; m=0-10; R.sup.3 is H or a C.sub.1 -C.sub.8 alkyl group; and R.sup.2 is ##STR3## where p=0-10, and each R.sup.4, R.sup.5, and R.sup.6, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group, the polymers being non-toxic and stable once ingested.
Inventor(s):	Mandeville, III; W. Harry (Lynnfield, MA), Holmes-Farley; Stephen R. (Arlington, MA)
Assignee:	GelTex Pharmaceuticals, Inc. (Waltham, MA)
Application Number:	08/258,477
Patent Claims:	1. A method for removing bile salts from a patient by ion exchange comprising administering to said patient a therapeutically effective amount of one or more crosslinked polymers comprising (1) a monoreactive hydrophobic co-monomer and (2) a repeat unit having the formula ##STR24## where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; M is ##STR25## or --Z--R.sup.2 ; Z is O, NR.sup.3 S or (CH.sub.2).sub.m ; m=0-10; R.sup.3 is H or a C.sub.1 -C.sub.8 alkyl group; and R.sup.2 is ##STR26## where p=0-10, and each R.sup.4, R.sup.5, and R.sup.6, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group, said polymers being non-toxic and stable once ingested. 2. The method of claim 1 wherein said polymer is crosslinked by means of a multifunctional crosslinking co-monomer, said co-monomer being present in an amount from about 0.5-25% by weight, based upon total monomer weight. 3. The method of claim 2 wherein said crosslinking co-monomer is present in an amount from about 1-10% by weight, based upon total monomer weight. 4. The method of claim 1 wherein said monoreactive hydrophobic co-monomer is selected from the group consisting of styrene and fluorinated derivatives thereof; vinyl naphthalene and fluorinated derivatives thereof; ethyl vinylbenzene and fluorinated derivatives thereof; N-alkyl and N-aryl derivatives of acrylamide and methacrylamide, and fluorinated derivatives thereof; alkyl and aryl acrylates and fluorinated derivatives thereof; alkyl and aryl methacrylates and fluorinated derivatives thereof; 4-vinylbiphenyl and fluorinated derivatives thereof; 4-vinylanisole and fluorinated derivatives thereof; and 4-aminostyrene and fluorinated derivatives thereof. 5. The method of claim 1 wherein said polymer further comprises one or more amine co-monomers. 6. The method of claim 5 wherein said amine co-monomer is vinyl pyridine, dimethylaminmethyl styrene, or vinyl imidazole. 7. The method of claim 1 wherein said repeat unit (2) has the formula ##STR27## or copolymer thereof wherein R.sup.1, n and p are as defined in claim 1. 8. The method of claim 7 wherein said monoreactive hydrophobic co-monomer is n-butylmethacrylamide, hexafluorobutylmethacrylate, heptadecafluorodecylmethacrylate, styrene or a fluorinated derivative thereof, 2-vinyl naphthalene, 4-vinyl imidazole, vinyl pyridine, 4-vinylbiphenyl or a fluorinated derivative thereof, 4-vinylanisole or a fluorinated derivative thereof, or 4-aminostyrene or a fluorinated derivative thereof. 9. The method of claim 11 wherein said polymer further comprises a co-monomer selected from the group consisting of trimethylammoniumethylmethacrylate and trimethylammoniumethylacrylate. 10. The method of claim 11 wherein said repeat unit (2) has the formula ##STR28## or copolymer thereof, wherein R.sup.1, n and p are as defined in claim 1. 11. The method of claim 10 wherein said monoreactive hydrophobic co-monomer is isopropylacrylamide, styrene or a fluorinated derivative thereof or hexafluoroisopropylacrylate. 12. The method of claim 10 wherein said polymer further comprises, as a co-monomer, trimethylammoniumethylmethacrylate. 13. The method of claim 1 wherein said repeat unit (2) has the formula ##STR29## or copolymer thereof, wherein Z is NR.sup.3 or (CH.sub.2).sub.m, R.sup.2 is ##STR30## R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, n, m and p are as defined in claim 1. 14. The method of claim 13 wherein said monoreactive hydrophobic co-monomer is selected from the group consisting of styrene and fluorinated derivatives thereof; vinyl naphthalene and fluorinated derivatives thereof; ethyl vinylbenzene and fluorinated derivatives thereof; N-alkyl and N-aryl derivatives of acrylamide and methacrylamide, and fluorinated derivatives thereof; alkyl and aryl acrylates and fluorinated derivatives thereof; alkyl and aryl methacrylates and fluorinated derivatives thereof; 4-vinylbiphenyl and fluorinated derivatives thereof; 4-vinylanisole and fluorinated derivatives thereof; and 4-aminostyrene and fluorinated derivatives thereof. 15. The method of claim 1 wherein said polymer further comprises one or more exchangeable counterions. 16. The method of claim 15 wherein at least one of said counterions is Cl.sup.-, Br.sup.-, CH.sub.3 OSO.sub.3.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid. 17. A method for removing bile salts from a patient by ion exchange comprising administering to said patient a therapeutically effective amount of one or more crosslinked polymers comprising a repeat unit having the formula ##STR31## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; L is --NH--or ##STR32## and each R.sup.2, R.sup.3, and R.sup.4, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group, said polymers being non-toxic and stale once ingested. 18. The method of claim 17 wherein said polymer is crosslinked by means of a multifunctional crosslinking co-monomer, said co-monomer being present in an amount from about 0.5-25% by weight, based upon total monomer weight. 19. The method of claim 18 wherein said crosslinking co-monomer is present in an amount from about 1-10% by weight, based upon total monomer weight. 20. The method of claim 17 wherein said polymer further comprises one or more monoreactive hydrophobic co-monomers. 21. The method of claim 20 wherein said monoreactive hydrophobic co-monomer is selected from the group consisting of styrene and fluorinated derivatives thereof; vinyl naphthalene and fluorinated derivatives thereof; ethyl vinylbenzene and fluorinated derivatives thereof; N-alkyl and N-aryl derivatives of acrylamide and methacrylamide, and fluorinated derivatives thereof; alkyl and aryl acrylates and fluorinated derivatives thereof; alkyl and aryl methacrylates and fluorinated derivatives thereof; 4-vinylbiphenyl and fluorinated derivatives thereof; 4-vinylanisole and fluorinated derivatives thereof; and 4-aminostyrene and fluorinated derivatives thereof. 22. The method of claim 17 wherein said polymer comprising a repeat unit having the formula ##STR33## or copolymer thereof. 23. The method of claim 17 wherein said polymer comprising a repeat unit having the formula ##STR34## or copolymer thereof. 24. The therapeutic composition effective for removing bile salts by ion exchange comprising a therapeutic amount of a crosslinked polymer comprising a repeat unit having the formula ##STR35## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; M is ##STR36## or --Z--R.sup.2 ; Z is O NR.sup.3, S, or (CH.sub.2).sub.m ; m=0-10; R.sup.3 is H or a C.sub.1 -C.sub.8 alkyl group; and R.sup.2 is ##STR37## where p=0-10, and each R.sup.4, R.sup.5, and R.sup.6, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group, said polymer being non-toxic and stable once ingested. 25. A therapeutic composition effective for removing bile salts by ion exchange comprising a therapeutic amount of a crosslinked polymer comprising a repeat unit having the formula ##STR38## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub..sub.8 alkyl group; L is --NH--or ##STR39## and each R.sup.2, R.sup.3, and R.sup.4, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group, said polymer being non-toxic and stable once ingested. 26. A crosslinked polymer composition comprising: (1) a monoreactive hydrophobic co-monomer and (2) a repeat unit having the formula ##STR40## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; M is ##STR41## or --Z--R.sup.2 ; Z is O, NR.sup.3, S, or (CH.sub.2).sub.m ; m=0-10; R.sup.3 is H or a C.sub.1 -C.sub.8 alkyl group; and R.sup.2 is ##STR42## where p=0-10 and each R.sup.4, R.sup.5, and R.sup.6 independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group. 27. The polymer composition of claim 26 wherein said polymer is crosslinked by means of a multifunctional crosslinking co-monomer, said co-monomer being present in an amount from about 0.5-25% by weight, based upon total monomer weight. 28. The polymer composition of claim 27 wherein said crosslinking co-monomer is present in an amount from about 1-10% by weight, based upon total monomer weight. 29. The polymer composition of claim 26 wherein said monoreactive hydrophobic co-monomer is selected from the group consisting of styrene and fluorinated derivatives thereof; vinyl naphthalene and fluorinated derivatives thereof; ethyl vinylbenzene and fluorinated derivatives thereof; N-alkyl and N-aryl derivatives of acrylamide and methacrylamide, and fluorinated derivatives thereof; alkyl and aryl acrylates and fluorinated derivatives thereof; alkyl and aryl methacrylates and fluorinated derivatives thereof; 4-vinylbiphenyl and fluorinated derivatives thereof; 4-vinylanisole and fluorinated derivatives thereof; and 4-aminostyrene and fluorinated derivatives thereof. 30. The polymer composition of claim 26 wherein said polymer further comprises one or more amine co-monomers. 31. The polymer composition of claim 30 wherein said amine co-monomer is vinyl pyridine, dimethylaminomethyl styrene, or vinyl imidazole. 32. The polymer composition of claim 26 wherein said repeat unit (2) has the formula ##STR43## or copolymer thereof wherein R.sup.1, n and p are as defined in claim 26. 33. The polymer composition of claim 32 wherein said monoreactive hydrophobic co-monomer is n-butylmethacrylamide, monoreactive hexafluorobutylmethacrylate, heptadecafluorodecylmethacrylate, styrene or a fluorinated derivative thereof, 2-vinyl naphthalene, 4-vinyl imidazole, vinyl pyridine, 4-vinylbiphenyl or a fluorinated derivative thereof, 4-vinylanisole or a fluorinated derivative thereof, or 4-aminostyrene or a fluorinated derivative thereof. 34. The polymer composition of claim 32 wherein said polymer further comprises a co-monomer selected from the group consisting of trimethylammoniumethylmethacrylate and trimethylammoniumethylacrylate. 35. The polymer composition of claim 26 wherein said repeat unit (2) has the formula ##STR44## or copolymer thereof, wherein R.sup.1, n and p are as defined in claim 26. 36. The polymer composition of claim 35 wherein said monoreactive hydrophobic co-monomer is isopropylacrylamide, styrene or a fluorinated derivative thereof or hexafluoroisopropylacrylate. 37. The polymer composition of claim 35 wherein said polymer further comprises, as a co-monomer, trimethylammoniumethylmethacrylate. 38. The polymer composition of claim 26 wherein said repeat unit (2) has the formula ##STR45## or copolymer thereof, wherein Z is NR.sup.3 or (CH.sub.2).sub.m, R.sup.2 is ##STR46## R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, n, m and p are as defined in claim 26. 39. The polymer composition of claim 38 wherein said monoreactive hydrophobic co-monomer is selected from the group consisting of styrene and fluorinated derivatives thereof; vinyl naphthalene and fluorinated derivatives thereof; ethyl vinylbenzene and fluorinated derivatives thereof; N-alkyl and N-aryl derivatives of acrylamide and methacrylamide, and fluorinated derivatives thereof; alkyl and aryl acrylates and fluorinated derivatives thereof; alkyl and aryl methacrylates and fluorinated derivatives thereof; 4-vinylbiphenyl and fluorinated derivatives thereof; 4-vinylanisole and fluorinated derivatives thereof; and 4-aminostyrene and fluorinated derivatives thereof. 40. The polymer composition of claim 26 wherein said polymer further comprises one or more exchangeable counterions. 41. The polymer composition of claim 40 wherein at least one of said counterions is Cl.sup.-, Br.sup.-, CH.sub.3 OSO.sub.3.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2- HCO.sub.3.sup.-, CO.sub.3.sup.2-, acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid. 42. A method for removing bile salts from a patient comprising administering to said patient a therapeutically effective amount of the reaction product of: (a) one or more crosslinked polymers comprising a repeat unit having the formula: ##STR47## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; M is ##STR48## or --Z--R.sup.2 ; Z is O, NR.sup.3, S, or (CH.sub.2).sub.m ; m=0-10; R.sup.3 is H or a C.sub.1 -C.sub.8 alkyl group; and R.sup.2 is ##STR49## where p=0-10, and each R.sup.4, R.sup.5, and R.sup.6, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group; and (b) at least one alkylating agent, said reaction product being non-toxic and stable once ingested. 43. The method of claim 42 wherein said polymer is crosslinked by means of a multifunctional crosslinking co-monomer, said co-monomer being present in an amount from about 0.5-25% by weight, based upon total monomer weight. 44. The method of claim 43 wherein said crosslinking co-monomer is present in an amount from about 1-10% by weight, based upon total monomer weight. 45. The method of claim 42 wherein said repeat unit has the formula ##STR50## or copolymer thereof wherein R.sup.1, n and p are as defined in claim 42. 46. The method of claim 42 wherein said repeat unit has the formula ##STR51## or copolymer thereof, wherein R.sup.1, n and p are as defined in claim 42. 47. The method of claim 42 wherein said repeat unit has the formula ##STR52## or copolymer thereof, wherein Z is NR.sup.3 or (CH.sub.2).sub.m, R.sup.2 is ##STR53## R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, n, m and p are as defined in claim 42. 48. The method of claim 42 wherein said polymer further comprises one or more exchangeable counterions. 49. The method of claim 48 wherein at least one of said counterions is Cl.sup.-, Br.sup.-, CH.sub.3 OSO.sub.3.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid. 50. The method of claim 42 wherein said alkylating agent has the formula RX where R is a C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 hydroxyalkyl, C.sub.1 -C.sub.20 aralkyl, C.sub.1 -C.sub.2 o alkylammonium, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 51. The method of claim 50 wherein X is a halide, epoxy, tosylate, or mesylate group. 52. The method of claim 51 wherein said alkylating agent is a C.sub.1 -C.sub.20 alkyl halide. 53. The method of claim 51 wherein said alkylating agent is a C.sub.1 -C.sub.20 alkyl halide ammonium salt. 54. The method of claim 51 wherein said alkylating agent is a C.sub.1 -C.sub.20 dihaloalkane, C.sub.1 -C.sub.20 hydroxyalkyl halide, C.sub.1 -C.sub.20 aralkyl halide, C.sub.1 -C.sub.20 alkyl epoxy ammonium salt, a C.sub.1 -C.sub.20 epoxy alkylamide. 55. The method of claim 42 wherein said polymer is reacted with at least two alkylating agents, one of said alkylating agents having the formula RX where R is a C.sub.4 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents having the formula R'X where R' is a C.sub.1 -C.sub.20 alkyl ammonium group and X is one or more electrophilic leaving groups. 56. The method of claim 42 wherein said polymer is reacted with at least two alkylating agents, one of said alkylating agents having the formula RX where R is a C.sub.1 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents having the formula R'X where R' is a C.sub.1 -C.sub.20 hydroxyalkyl group and X is one or more electrophilic leaving groups. 57. The method of claim 42 wherein said polymer is reacted with at least two alkylating agents, one of said alkylating agents is a C.sub.1 -C.sub.20 dihaloalkane and the other of said alkylating agents is a C.sub.1 -C.sub.20 alkylammonium salt. 58. A therapeutic composition effective for removing bile salts by ion exchange comprising a therapeutic amount of the reaction product of: (a) one or more crosslinked polymers comprising a repeat unit having the formula: ##STR54## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.s alkyl group; M is ##STR55## or --Z--R.sup.2 ; Z is O, NR.sup.3, S, or (CH.sub.2).sub.m ; m=0-10; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; and R.sup.2 is ##STR56## where p=0-10, and each R.sup.4, R.sup.5, and R.sup.6, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group; and (b) at least one alkylating agent in a pharmaceutically acceptable carrier, said reaction product being non-toxic and stable once ingested. 59. A polymer composition effective for removing bile salts by ion exchange comprising a therapeutic amount of the reaction product of: (a) one or more crosslinked polymers comprising a repeat unit having the formula: ##STR57## or copolymer thereof, where n is an integer; R.sup.1 is H or a C.sub.1 -C.sub.8 alkyl group; M is --C--Z--R.sup.2 or --Z--R.sup.2 ; Z is O, NR.sup.3, S, or (CH.sub.2).sub.m ; m=0-10; R.sup.3 is H or a C.sub.1 -C.sub.8 alkyl group; and R.sup.2 is ##STR58## where p - 0-10, and each R.sup.4, R.sup.5, and R.sup.6, independently, is H, a C.sub.1 -C.sub.8 alkyl group, or an aryl group; and (b) at least one alkylating agent, said reaction product being non-toxic and stable once ingested. 60. The polymer composition of claim 59 wherein said polymer is crosslinked by means of a multifunctional crosslinking co-monomer, said co-monomer being present in an amount from about 0.5-25% by weight, based upon total monomer weight. 61. The polymer composition of claim 60 wherein said crosslinking co-monomer is present in an amount from about 1-10% by weight, based upon total monomer weight. 62. The polymer composition of claim 59 wherein said repeat unit has the formula ##STR59## or copolymer thereof wherein R.sup.1, n and p are as defined in claim 59. 63. The polymer composition of claim 59 wherein said repeat unit has the formula ##STR60## or copolymer thereof, wherein R.sup.1, n and p are as defined in claim 59. 64. The polymer composition of claim 59 wherein said repeat unit has the formula ##STR61## or copolymer thereof, wherein Z is NR.sup.3 or (CH.sub.2).sub.m, R.sup.2 is ##STR62## R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, n, m and p are as defined in claim 59. 65. The polymer composition of claim 59 wherein said polymer further comprises one or more exchangeable counterions. 66. The polymer composition of claim 65 wherein at least one of said counterions is Cl.sup.-, Br.sup.-, CH.sub.3 OSO.sub.3.sup.-, HSO.sub.4.sup.-, SO .sub.4 .sub.2-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid. 67. The polymer composition of claim 59 wherein said alkylating agent has the formula Rx where R is a C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 hydroxyalkyl, C.sub.1 -C.sub.20 aralkyl, C.sub.1 -C.sub.20 alkylammonium, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 68. The polymer composition of claim 67 wherein X is a halide, epoxy, tosylate, or mesylate group. 69. The polymer composition of claim 68 wherein said alkylating agent is a C.sub.4 -C.sub.20 alkyl halide. 70. The polymer composition of claim 68 wherein said alkylating agent is a C.sub.1 -C.sub.20 alkyl halide ammonium salt. 71. The polymer composition of claim 68 wherein said alkylating agent is a C.sub.1 -C.sub.20 dihaloalkane, C.sub.1 -C.sub.20 hydroxyalkyl halide, C.sub.1 -C.sub.20 aralkyl halide, C.sub.1 -C.sub.20 alkyl epoxy ammonium salt, a C.sub.1 -C.sub.20 epoxy alkylamide. 72. The polymer composition of claim 59 wherein said polymer is reacted with at least two alkylating agents, one of said alkylating agents having the formula RX where R is a C.sub.4 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents having the formula R'X where R' is a C.sub.1 -C.sub.20 alkyl ammonium group and X is one or more electrophilic leaving groups. 73. The polymer composition of claim 59 wherein said polymer is reacted with at least two alkylating agents, one of said alkylating agents having the formula RX where R is a C.sub.1 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups, and the other of said alkylating agents having the formula R'X where R' is a C.sub.1 -C.sub.20 hydroxyalkyl group and X is one or more electrophilic leaving groups. 74. The polymer composition of claim 59 wherein said polymer is reacted with at least two alkylating agents, one of said alkylating agents is a C.sub.1 -C.sub.20 dihaloalkane and the other of said alkylating agents is a C.sub.1 -C.sub.20 alkylammonium salt.