Claims for Patent: 5,917,007

Summary for Patent: 5,917,007

Title:	Process for removing bile salts from a patient and alkylated compositions therefor
Abstract:	The invention relates to a method for removing bile salts from a patient in need thereof and compositions useful in the method. The method comprises administering to the patient a therapeutically effective amount of an alkylated and crosslinked polymer. The alkylated and crosslinked polymer comprises the reaction product of polymers, or salts and copolymers thereof having amine containing repeat units, with at least one aliphatic alkylating agent and a crosslinking agent.
Inventor(s):	Mandeville, III; W. Harry (Lynnfield, MA), Holmes-Farley; Stephen Randall (Arlington, MA)
Assignee:	GelTex Pharmaceuticals, Inc. (Waltham, MA)
Application Number:	09/129,286
Patent Claims:	1. An alkylated and crosslinked polymer comprising the reaction product of: (a) one or more polymers, or salts and copolymers thereof having a repeat unit selected from the group consisting of: ##STR3## where n is a positive integer and each R, independently, is H or a C.sub.1 -C.sub.8 alkyl group; (b) at least one aliphatic alkylating agent; and (c) a crosslinking agent, wherein in said reaction product: (i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and (ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units. 2. The polymer of claim 1 wherein the polymer, alkylating agent and crosslinking agent are reacted simultaneously. 3. The polymer of claim 2 wherein said polymer is crosslinked by means of a multifunctional crosslinking agent, said agent being present in an amount from about 0.5-25% by weight, based upon the combined weight of monomer and crosslinking agent. 4. The polymer of claim 2 wherein said crosslinking agent is present in an amount from about 2.5-20% by weight, based upon the combined weight of monomer and crosslinking agent. 5. The polymer of claim 2 wherein the crosslinking agent comprises epichlorohydrin. 6. The polymer of claim 2 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 alkylammonium, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 7. The polymer of claim 6 wherein X is a halide, epoxy, tosylate, or mesylate. 8. The polymer of claim 7 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide. 9. The polymer of claim 8 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide. 10. The polymer of claim 6 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide ammonium salt. 11. The polymer of claim 10 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.20 alkyl halide ammonium salt. 12. The polymer of claim 11 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.12 haloalkyl trimethylammonium salt. 13. The polymer of claim 6 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 dihaloalkane. 14. The polymer of claim 6 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 hydroxyalkyl halide. 15. The polymer of claim 6 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl epoxy ammonium salt. 16. The polymer of claim 6 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 epoxy alkylamide. 17. The polymer of claim 2 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents has 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 has 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. 18. The polymer of claim 17 wherein one of said alkylating agents having the formula RX is an alkyl halide and the other of said alkylating agents having the formula R'X is an alkyl halide ammonium salt. 19. The polymer of claim 18 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide and said alkyl halide ammonium salt is a C.sub.4 -C.sub.8 alkyl halide ammonium salt. 20. The polymer of claim 19 wherein said alkyl halide is a C.sub.10 alkyl halide and said alkyl halide ammonium salt is a C.sub.6 alkyl halide ammonium salt. 21. The polymer of claim 2 wherein said polymer is reacted with at least two of said alkylating agents, one of said alkylating agents has 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 has 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. 22. The polymer of claim 2 wherein said polymer is reacted with at least two of said 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 alkyl halide ammonium salt. 23. An alkylated and crosslinked polymer comprising the reaction product of: (a) one or more polymers, or salts and copolymers thereof having a repeat unit selected from the group consisting of: ##STR4## where n is a positive integer and each R, independently, is H or a C.sub.1 -C.sub.8 alkyl group; (b) at least one aliphatic alkylating agent which provides a hydrophobic region; and (c) a crosslinking agent, wherein in said reaction product: (i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and (ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units. 24. The polymer of claim 23 wherein the polymer, alkylating agent and crosslinking agent are reacted simultaneously. 25. The polymer of claim 24 wherein the crosslinking agent is a multifunctional crosslinking agent, and is present in an amount from about 0.5%-25% by weight, based upon the combined weight of monomer and crosslinking agent. 26. The polymer of claim 24 wherein the crosslinking agent comprises epichlorohydrin. 27. The polymer of claim 24 wherein the alkylating agent has the formula RX where R is a C.sub.4 -C.sub.20 alkyl and X is one or more electrophilic leaving groups. 28. The polymer of claim 27 wherein X is halide, epoxy, tosylate, or mesylate. 29. The polymer of claim 28 wherein said alkylating agent comprises a C.sub.4 -C.sub.20 alkyl halide. 30. The polymer of claim 23 further comprising reaction with a second alkylating agent having the formula R'X where R' is a C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 alkylammonium, C.sub.1 -C.sub.20 hydroxyalkyl, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 31. The polymer of claim 30 wherein said aliphatic alkylating agent which provides a hydrophobic region is a C.sub.4 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups and the second alkylating agent has the formula R'X where R' is a C.sub.1 -C.sub.20 alkylammonium group and X is one or more electrophilic leaving groups. 32. The polymer of claim 31 wherein said aliphatic alkylating agent which provides a hydrophobic region is an alkyl halide and the second alkylating agent is an alkylhalide ammonium salt. 33. The polymer of claim 32 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide and said alkyl halide ammonium salt is a C.sub.4 -C.sub.18 alkylhalide ammonium salt. 34. The polymer of claim 33 wherein said alkyl halide is a C.sub.10 alkyl halide and said alkyl halide ammonium salt is a C.sub.6 alkylhalide ammonium salt. 35. The polymer of claim 30 wherein said aliphatic alkylating agent which provides a hydrophobic region is a C.sub.4 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups and the second alkylating agent has 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. 36. The polymer of claim 30 wherein said aliphatic alkylating agent which provides a hydrophobic region is a C.sub.1 -C.sub.20 dihaloalkane and the other of said alkylating agents is a C.sub.1 -C.sub.20 alkylhalide ammonium salt. 37. An alkylated and crosslinked polymer comprising the reaction product of: (a) one or more polymers, or salts and copolymers thereof having a repeat unit selected from the group consisting of: ##STR5## where n is a positive integer and each R, independently, is H or a C.sub.1 -C.sub.8 alkyl group; (b) at least one aliphatic alkylating agent; and (c) a crosslinking agent, wherein in said reaction product: (i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; (ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units; and (iii) said polymer is crosslinked by means of a multifunctional crosslinking agent, said agent being present in an amount form 1-10% by weight based upon the combined weight of monomer and crosslinking agent. 38. The polymer of claim 37 wherein the polymer, alkylating agent, and crosslinking agent are reacted simultaneously. 39. The polymer of claim 38 wherein the crosslinking agent comprises epichlorohydrin. 40. The polymer of claim 38 wherein the 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 alkylammonium, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 41. The polymer of claim 40 wherein X is a halide, epoxy, tosylate, or mesylate group. 42. The polymer of claim 41 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide. 43. The polymer of claim 42 wherein said alkyl halide is a C.sub.4 -C.sub.18 alkyl halide. 44. The polymer of claim 41 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 dihaloalkane. 45. The polymer of claim 44 wherein said dihaloalkane is a 1,10-dihalodecane. 46. The polymer of claim 41 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 hydroxyalkyl halide. 47. The polymer of claim 46 wherein said hydroxyalkyl halide is an 11-halo-1-undecanol. 48. The polymer of claim 41 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide ammonium salt. 49. The polymer of claim 48 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.20 alkyl halide ammonium salt. 50. The polymer of claim 49 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.12 haloalkyl trimethylammonium salt 51. The polymer of claim 41 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl epoxy ammonium salt. 52. The polymer of claim 51 wherein said alkyl epoxy ammonium salt is a (glycidylpropyl)trimethyl ammonium salt. 53. The polymer of claim 41 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 epoxy alkylamide. 54. The polymer of claim 53 wherein said epoxy alkylamide is selected from the group consisting of N-(2,3-epoxypropane)butyramide, N-(2,3-epoxypropane)hexanamide, and combinations thereof. 55. The polymer of claim 38 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 alkyl ammonium group and X is one or more electrophilic leaving groups. 56. The polymer of claim 55 wherein one of said alkylating agents having the formula RX is an alkyl halide and the other of said alkylating agents having the formula R'X is an alkyl halide ammonium salt. 57. The polymer of claim 56 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide and said alkyl halide ammonium salt is a C.sub.4 -C.sub.18 alkyl halide ammonium salt. 58. The polymer of claim 57 wherein said alkyl halide is a C.sub.10 alkyl halide and said alkyl halide ammonium salt is a C.sub.6 alkyl halide ammonium salt. 59. The polymer of claim 38 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. 60. The polymer of claim 59 wherein one of said alkylating agents having the formula RX is an alkyl halide and the other of said alkylating agents having the formula R'X is a hydroxy alkyl halide. 61. The polymer of claim 37 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 alkyl halide ammonium salt. 62. A method for removing bile salts from a patient comprising administering to said patient a therapeutically effective amount of an alkylated and crosslinked polymer comprising the reaction product of: (a) one or more polymers, or salts and copolymers thereof having a repeat unit selected from the group consisting of: ##STR6## where n is a positive integer and each R, independently, is H or a C.sub.1 -C.sub.8 alkylgroup; (b) at least one aliphatic alkylating agent; and (c) a crosslinking agent, wherein in said reaction product: (i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and (ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units. 63. The method of claim 62 wherein the polymer, alkylating agent and crosslinking agent are reacted simultaneously. 64. The method of claim 63 wherein said polymer is crosslinked by means of a multifunctional crosslinking agent, said agent being present in an amount from about 0.5-25% by weight, based upon the combined weight of monomer and crosslinking agent. 65. The method of claim 63 wherein said crosslinking agent is present in an amount from about 2.5-20% by weight, based upon the combined weight of monomer and crosslinking agent. 66. The method of claim 63 wherein the crosslinking agent comprises epichlorohydrin. 67. The method of claim 63 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 alkylammonium, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 68. The method of claim 67 wherein X is a halide, epoxy, tosylate, or mesylate. 69. The method of claim 68 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide. 70. The method of claim 69 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide. 71. The method of claim 67 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide ammonium salt. 72. The method of claim 71 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.20 alkyl halide ammonium salt. 73. The method of claim 72 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.12 haloalkyl trimethylammonium salt. 74. The method of claim 67 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 dihaloalkane. 75. The method of claim 67 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 hydroxyalkyl halide. 76. The method of claim 67 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl epoxy ammonium salt. 77. The method of claim 67 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 epoxy alkylamide. 78. The method of claim 63 wherein said polymer is reacted with at least two of said alkylating agent, one of said alkylating agents has 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 has 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. 79. The method of claim 78 wherein one of said alkylating agents having the formula RX is an alkyl halide and the other of said alkylating agents having the formula R'X is an alkyl halide ammonium salt. 80. The method of claim 79 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide and said alkyl halide ammonium salt is a C.sub.4 -C.sub.18 alkyl halide ammonium salt. 81. The method of claim 80 wherein said alkyl halide is a C.sub.10 alkyl halide and said alkyl halide ammonium salt is a C.sub.6 alkyl halide ammonium salt. 82. The method of claim 63 wherein said polymer is reacted with at least two of said alkylating agents, one of said alkylating agents has 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 has 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. 83. The method of claim 63 wherein said polymer is reacted with at least two of said 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 alkylhalide ammonium salt. 84. A method for removing bile salts from a patient comprising administering to said patient a therapeutically effective amount of an alkylated and crosslinked polymer comprising the reaction product of: (a) one or more polymers, or salts and copolymers thereof having a repeat unit selected from the group consisting of: ##STR7## where n is a positive integer and each R, independently, is H or a C.sub.1 -C.sub.8 alkyl group; (b) at least one aliphatic alkylating agent which provides a hydrophobic region; and (c) a crosslinking agent, wherein in said reaction product: (i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; and (ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units. 85. The method of claim 84 wherein the polymer, alkylating agent and crosslinking agent are reacted simultaneously. 86. The method of claim 85 wherein the crosslinking agent is a multifunctional crosslinking agent, and is present in an amount from about 0.5%-25% by weight, based upon the combined weight of monomer and crosslinking agent. 87. The method of claim 85 wherein the crosslinking agent comprises epichlorohydrin. 88. The method of claim 85 wherein the alkylating agent has the formula RX where R is a C.sub.4 -C.sub.20 alkyl and X is one or more electrophilic leaving groups. 89. The method of claim 88 wherein X is halide, epoxy, tosylate, or mesylate. 90. The method of claim 89 wherein said alkylating agent comprises a C.sub.4 -C.sub.20 alkyl halide. 91. The method of claim 84 further comprising reaction with a second alkylating agent having the formula R'X where R' is a C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 alkylammonium, C.sub.1 -C.sub.20 hydroxyalkyl, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 92. The method of claim 91 wherein said aliphatic alkylating agent which provides a hydrophobic region is a C.sub.4 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups and the second alkylating agent has the formula R'X where R' is a C.sub.1 -C.sub.20 alkylammonium group and X is one or more electrophilic leaving groups. 93. The method of claim 92 wherein said aliphatic alkylating agent which provides a hydrophobic region is an alkyl halide and the second alkylating agent is an alkylhalide ammonium salt. 94. The method of claim 93 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide and said alkyl halide ammonium salt is a C.sub.4 -C.sub.18 alkylhalide ammonium salt. 95. The method of claim 94 wherein said alkyl halide is a C.sub.10 alkyl halide and said alkyl halide ammonium salt is a C.sub.6 alkylhalide ammonium salt. 96. The method of claim 91 wherein said aliphatic alkylating agent which provides a hydrophobic region is a C.sub.4 -C.sub.20 alkyl group and X is one or more electrophilic leaving groups and the second alkylating agent has 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. 97. The method of claim 91 wherein said aliphatic alkylating agent which provides a hydrophobic region is a C.sub.1 -C.sub.20 dihaloalkane and the other of said alkylating agents is a C.sub.1 -C.sub.20 alkylhalide ammonium salt. 98. A method for removing bile salts from a patient comprising administering to said patient a therapeutically effective amount of an alkylated and crosslinked polymer comprising the reaction product of: (a) one or more polymers, or salts and copolymers thereof having a repeat unit selected from the group consisting of: ##STR8## where n is a positive integer and each R, independently, is H or a C.sub.1 -C.sub.8 alkyl group; (b) at least one aliphatic alkylating agent; and (c) a crosslinking agent, wherein in said reaction product: (i) at least some of the nitrogen atoms in said repeat units are unreacted with said alkylating agent; (ii) less than 10 mol % of the nitrogen atoms in said repeat units that react with said alkylating agent form quaternary ammonium units; and (iii) said polymer is crosslinked by means of a multifunctional crosslinking agent, said agent being present in an amount form 1-10% by weight based upon the combined weight of monomer and crosslinking agent. 99. The method of claim 98 wherein the polymer, alkylating agent, and crosslinking agent are reacted simultaneously. 100. The method of claim 99 wherein the crosslinking agent comprises epichlorohydrin. 101. The method of claim 99 wherein the 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 alkylammonium, or C.sub.1 -C.sub.20 alkylamido group and X is one or more electrophilic leaving groups. 102. The method of claim 101 wherein X is a halide, epoxy, tosylate, or mesylate group. 103. The method of claim 102 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide. 104. The method of claim 103 wherein said alkyl halide is a C.sub.4 -C.sub.18 alkyl halide. 105. The method of claim 102 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 dihaloalkane. 106. The method of claim 105 wherein said dihaloalkane is a 1,10-dihalodecane. 107. The method of claim 102 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 hydroxyalkyl halide. 108. The method of claim 107 wherein said hydroxyalkyl halide is an 11-halo-1-undecanol. 109. The method of claim 102 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl halide ammonium salt. 110. The method of claim 109 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.20 alkyl halide ammonium salt. 111. The method of claim 110 wherein said alkyl halide ammonium salt is a C.sub.4 -C.sub.12 haloalkyl trimethylammonium salt. 112. The method of claim 102 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 alkyl epoxy ammonium salt. 113. The method of claim 112 wherein said alkyl epoxy ammonium salt is a (glycidylpropyl)trimethyl ammonium salt. 114. The method of claim 102 wherein said alkylating agent comprises a C.sub.1 -C.sub.20 epoxy alkylamide. 115. The method of claim 114 wherein said epoxy alkylamide is selected from the group consisting N-(2,3-epoxypropane)butyramide, N-(2,3-epoxypropane)hexanamide, and combinations thereof. 116. The method of claim 99 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 alkyl ammonium group and X is one or more electrophilic leaving groups. 117. The method of claim 116 wherein one of said alkylating agents having the formula RX is an alkyl halide and the other of said alkylating agents having the formula R'X is an alkyl halide ammonium salt. 118. The method of claim 117 wherein said alkyl halide is a C.sub.4 -C.sub.20 alkyl halide and said alkyl halide ammonium salt is a C.sub.4 -C.sub.18 alkyl halide ammonium salt. 119. The method of claim 118 wherein said alkyl halide is a C.sub.10 alkyl halide and said alkyl halide ammonium salt is a C.sub.6 alkyl halide ammonium salt. 120. The method of claim 99 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. 121. The method of claim 120 wherein one of said alkylating agents having the formula RX is an alkyl halide and the other of said alkylating agents having the formula R'X is a hydroxy alkyl halide. 122. The method of claim 98 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 alkyl halide ammonium salt.