CROSSLINKED POLY(ALLYLAMINE) POLYMER PHARMACEUTICAL COMPOSITIONS
Pharmaceutical compositions for and methods of treating an animal, including a human, and methods of preparing such compositions. The pharmaceutical compositions contain crosslinked amine polymers and may be used, for example, to treat diseases or other metabolic conditions in which removal of a target species from the gastrointestinal tract would provide physiological benefits.
1 . A crosslinked poly(allylamine) polymer in bead form comprising the residues of a monoallylamine or a salt thereof and a multiallylamine or a salt thereof wherein (i) the crosslinked poly(allylamine) polymer has a swelling ratio of less than 2 and (ii) sp 2 allyl carbons comprised by the crosslinked poly(allylamine) polymer constitute less than 1.0% of the total number of carbon atoms comprised by the crosslinked poly(allylamine) polymer.
2 . The crosslinked poly(allylamine) polymer of claim 1 wherein the residues of the multiallylamine or salt thereof are residues of a multiallylamine corresponding to Formula 3 or a salt thereof:
wherein each R 20 is hydrogen, hydrocarbyl or substituted hydrocarbyl, each X 1 is independently hydrocarbyl or substituted hydrocarbyl, X 2 is hydrocarbyl or substituted hydrocarbyl, m is a non-negative integer and n is at least 1.
3 . The crosslinked poly(allylamine) polymer of claim 1 wherein the residue of the monoallylamine or salt thereof are residues of a monoallylamine corresponding to Formula 1 or a salt thereof:
wherein R 4 and R 5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
4 . The crosslinked poly(allylamine) polymer of claim 2 wherein each R 20 is independently hydrogen, aliphatic, or heteroaliphatic.
5 . The crosslinked poly(allylamine) polymer of claim 1 wherein the crosslinked poly(allylamine) polymer comprises the residue of a dihaloalkane.
6 . The crosslinked poly(allylamine) polymer of claim 1 wherein the crosslinked poly(allylamine) polymer comprises the residue of 1,2-dibromoethane, 1,2-dichloroethane, 1-bromo-2-chloroethane, 1,3-dichloropropane, 1,3-dibromopropane, and 1-bromo-3-chloropropane.
7 . The crosslinked poly(allylamine) polymer of claim 1 wherein sp 2 allyl carbons comprised by the crosslinked poly(allylamine) polymer constitute less than 1% of the total number of carbon atoms comprised by the crosslinked poly(allylamine) polymer.
8 . The crosslinked poly(allylamine) polymer of claim 1 wherein sp 2 allyl carbons comprised by the crosslinked poly(allylamine) polymer constitute less than 0.1% of the total number of carbon atoms comprised by the crosslinked poly(allylamine) polymer.
9 . The crosslinked poly(allylamine) polymer of claim 1 wherein the crosslinked poly(allylamine) polymer contains less than 20 ppm allylamine.
10 . The crosslinked poly(allylamine) polymer of claim 1 wherein the crosslinked poly(allylamine) polymer contains less than 1 ppm allylamine.
11 . The crosslinked poly(allylamine) polymer of claim 1 wherein the crosslinked poly(allylamine) polymer has a structure corresponding to Formula 4:
wherein each R is independently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer
and a, b, c, and m are integers.
12 . The crosslinked poly(allylamine) polymer of claim 11 wherein the crosslinked poly(allylamine) polymer has a structure corresponding to Formula 4 and the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 9:1.
13 . The crosslinked poly(allylamine) polymer of claim 11 wherein the crosslinked poly(allylamine) polymer has a structure corresponding to Formula 4 and the sum of a and b to c (i.e., a+b:c) is in the range of about 2:1 to 2.5:1.
14 . The crosslinked poly(allylamine) polymer of claim 11 wherein the crosslinked poly(allylamine) polymer has a structure corresponding to Formula 4 and the sum of a and b is 57 and c is 24.
15 . The crosslinked poly(allylamine) polymer of claim 1 wherein the crosslinked poly(allylamine) polymer comprises 15-30 mol % of the residue of a crosslinker selected from the group consisting of 1,2-dibromoethane, 1,2-dichloroethane, 1-bromo-2-chloroethane, 1,3-dichloropropane, 1,3-dibromopropane, 1-bromo-3-chloropropane and combinations thereof.
16 . The crosslinked poly(allylamine) polymer of claim 1 wherein the crosslinked poly(allylamine) polymer comprises the residue of N,N′-diallyl-1,3-diaminopropane or a salt thereof, the residue of 2-Propen-1-ylamine or a salt thereof, and the residue of 1,2-dichloroethane.
17 . The crosslinked poly(allylamine) polymer of claim 16 wherein sp 2 allyl carbons comprised by the crosslinked poly(allylamine) polymer constitute less than 0.1% of the total number of carbon atoms comprised by the crosslinked poly(allylamine) polymer.
18 . The crosslinked poly(allylamine) polymer of claim 16 wherein the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay.
19 . The crosslinked poly(allylamine) polymer of claim 16 wherein the crosslinked poly(allylamine) polymer is characterized by a chloride ion to phosphate ion binding ratio in a SIB assay of at least 1:1, respectively.
20 . The crosslinked poly(allylamine) polymer of claim 1 wherein (a) the multiallylamine or salt thereof is N,N′-diallyl-1,3-diaminopropane or a salt thereof, (b) the monoallylamine or salt thereof is 2-Propen-1-ylamine or a salt thereof, and (c) the crosslinked poly(allylamine) polymer comprises (i) 10-35 mol % residue of N,N′-diallyl-1,3-diaminopropane or a salt thereof, (ii) 30-80 mol % residue of 2-Propen-1-ylamine or a salt thereof, and (iii) 10-35 mol % residue of 1,2-dichloroethane.
21 . The crosslinked poly(allylamine) polymer of claim 20 wherein the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least of at least 1.5 mEq/g in a SIB assay.
22 . The crosslinked poly(allylamine) polymer of claim 20 wherein the crosslinked poly(allylamine) polymer is characterized by a chloride ion to phosphate ion binding ratio in a SIB assay of at least 1:1, respectively.
23 . The crosslinked poly(allylamine) polymer of claim 20 wherein sp 2 allyl carbons comprised by the crosslinked poly(allylamine) polymer constitute less than 0.1% of the total number of carbon atoms comprised by the crosslinked poly(allylamine) polymer
24 . The crosslinked poly(allylamine) polymer of claim 1 wherein (a) the multiallylamine or salt thereof is N,N′-diallyl-1,3-diaminopropane or a salt thereof, (b) the monoallylamine or salt thereof is 2-Propen-1-ylamine or a salt thereof, and (c) the crosslinked poly(allylamine) polymer comprises (i) 20-25 mol % residue of N,N′-diallyl-1,3-diaminopropane or a salt thereof, (ii) 50-60 mol % residue of 2-Propen-1-ylamine or a salt thereof, and (iii) 20-25 mol % residue of 1,2-dichloroethane.
25 . The crosslinked poly(allylamine) polymer of claim 24 wherein the crosslinked poly(allylamine) polymer is characterized by a chloride ion binding capacity of at least of at least 1.5 mEq/g in a SIB assay.
26 . The crosslinked poly(allylamine) polymer of claim 24 wherein the crosslinked poly(allylamine) polymer is characterized by a chloride ion to phosphate ion binding ratio in a SIB assay of at least 1:1, respectively.
27 . The crosslinked poly(allylamine) polymer of claim 24 wherein the crosslinked poly(allylamine) polymer is characterized by a proton-binding capacity and a chloride binding capacity in Simulated Gastric Fluid of at least 5 mEq/g in a SGF assay.
28 . The crosslinked poly(allylamine) polymer of claim 24 wherein the crosslinked poly(allylamine) polymer has a swelling ratio of less than 1.5.
29 . The crosslinked poly(allylamine) polymer of claim 24 wherein sp 2 allyl carbons comprised by the crosslinked poly(allylamine) polymer constitute less than 0.8% of the total number of carbon atoms comprised by the crosslinked poly(allylamine) polymer.
30 . The crosslinked poly(allylamine) polymer of claim 25 wherein sp 2 allyl carbons comprised by the crosslinked poly(allylamine) polymer constitute less than 0.1% of the total number of carbon atoms comprised by the crosslinked poly(allylamine) polymer.