Proton-binding polymers for oral administration
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 protons and/or chloride ions from the gastrointestinal tract would provide physiological benefits such as normalizing serum bicarbonate concentrations and the blood pH in an animal, including a human.
1. A pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 2 or a salt thereof:
wherein
m and n are independently non-negative integers;
R 10 , R 20 , R 30 , and R 40 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl;
X 1 is
X 2 is hydrocarbyl or substituted hydrocarbyl;
each X 11 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo;
z is a non-negative number;
the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 5 or less, and the crosslinked amine polymer binds at least 3 mmol of chloride per gram and a molar ratio of chloride ions to phosphate ions of at least 1:1, respectively, when added at a concentration of 2.5 mg/ml to an interfering ion buffer and incubated for one hour at 37° C. wherein the interfering ion buffer is a solution of 36 mM NaCI, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5.
2. The pharmaceutical composition of claim 1 where the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
3. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer has an equilibrium proton binding capacity of at least 10 mmol/g and an equilibrium chloride binding capacity of at least 10 mmol/g when added at a concentration of 2.5 mg/ml to an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 at 37° C.
4. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1a or a salt thereof and the crosslinked amine polymer is prepared by radical polymerization of the amine corresponding to Formula 1a or the salt thereof:
wherein R 4 and R 5 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl.
5. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer is prepared by (1) substitution polymerization of polyfunctional reagents at least one of which comprises amine moieties, (2) radical polymerization of a monomer comprising at least one amine moiety or nitrogen containing moiety, or (3) crosslinking of an amine-containing intermediate with a crosslinking agent, optionally containing amine moieties.
6. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 1.5:1, respectively, when added at a concentration of 2.5 mg/ml to an interfering ion buffer and incubated for one hour at 37° C. where the interfering ion buffer is a solution of 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5.
7. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer is in the form of a bead having a mean particle diameter of 40 to 180 micrometers.
8. The pharmaceutical composition of claim 1 in a dosage unit form.
9. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer comprises a residue of a monoallylamine and a residue of a multiallylamine crosslinker.
10. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer is prepared by radical polymerization to form an intermediate containing amine moieties and crosslinking the intermediate with a polyfunctional crosslinker.
11. The pharmaceutical composition of claim 10 wherein the polyfunctional crosslinker is a dihaloalkane.
12. The pharmaceutical composition of claim 10 wherein the polyfunctional crosslinker is 1,3-dichloropropane.
13. The pharmaceutical composition of claim 10 wherein the crosslinked amine polymer comprises a residue of a monoallylamine and a residue of a multiallylamine crosslinker.
14. The pharmaceutical composition of claim 10 wherein the crosslinked amine polymer comprises a residue of allylamine or a salt thereof, and a residue of 1,3-bis(allylamino)propane or a salt thereof.
15. The pharmaceutical composition of claim 14 wherein the polyfunctional crosslinker is 1,3-dichloropropane.
16. The pharmaceutical composition of claim 1 wherein m is 0 to 2, n is 0 or 1, X 2 is alkyl or aminoalkyl, and R 10 , R 20 , R 30 , and R 40 are independently hydrogen, alkyl, alkenyl, or aminoalkyl.
17. The pharmaceutical composition of claim 1 wherein the crosslinked amine polymer is prepared by crosslinking a preformed linear or branched polymer with a polyfunctional crosslinking agent.
18. A pharmaceutical composition comprising a proton-binding, crosslinked amine polymer wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2 or a salt thereof:
wherein
m and n are independently non-negative integers;
R 10 , R 20 , R 30 , and R 40 are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl;
X 1 is
X 2 is hydrocarbyl or substituted hydrocarbyl;
each X 11 is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo;
z is a non-negative number;
the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less,
the crosslinked amine polymer has an equilibrium proton binding capacity of at least 10 mmol/g and an equilibrium chloride binding capacity of at least 10 mmol/g when added at a concentration of 2.5 mg/ml to an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 at 37° C.,
the crosslinked amine polymer binds at least 3 mmol of chloride per gram when added at a concentration of 2.5 mg/ml to an interfering ion buffer and incubated for one hour at 37° C. wherein the interfering ion buffer is a solution of 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-N-morpholino ethanesulfonic acid (MES) buffered to pH 5.5, and
the crosslinked amine polymer retains in a two-step chloride retention assay more than 50% of the HCl bound in the first step of the two-step chloride retention assay, wherein in the first step, the crosslinked amine polymer is added at a concentration of 2.5 mg/ml to an interfering ion solution at pH 6.2 containing 50 mM 2-(N-morpholino)ethanesulfonic acid (MES), 50 mM sodium acetate, 36 mM sodium chloride, 7 mM sodium phosphate, 1.5 mM sodium citrate, 30 mM oleic acid and 5 mM sodium taurocholate, and incubated for two hours at 37° C., then in the second step the buffer is replaced with a chloride retention assay solution at pH 6.2 containing 50 mM 2-(N-morpholino)ethanesulfonic acid (MES), 100 mM sodium acetate, 5 mM sodium phosphate, and 15 mM sulphate and the polymer is incubated for forty eight hours at 37° C.
19. The pharmaceutical composition of claim 18 where the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of 1.5 or less.
20. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer binds at least 1 mmol of chloride per gram and less than 0.3 mmol phosphate per gram when added at a concentration of 2.5 mg/ml to an interfering ion buffer and incubated for two hours at 37° C. wherein the interfering ions are phosphate, citrate and taurocholate ions (combined amount) and the interfering ion buffer is 50 mM 2-(N-morpholino)ethanesulfonic acid (MES), 50 mM sodium acetate, 36 mM sodium chloride, 7 mM sodium phosphate, 1.5 mM sodium citrate, 30 mM oleic acid and 5 mM sodium taurocholate at pH 6.2.
21. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer is prepared by (1) substitution polymerization of polyfunctional reagents at least one of which comprises amine moieties, (2) radical polymerization of a monomer comprising at least one amine moiety or nitrogen containing moiety, or (3) crosslinking of an amine-containing intermediate with a crosslinking agent, optionally containing amine moieties.
22. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer is in the form of a bead having a mean particle diameter of 40 to 180 micrometers.
23. The pharmaceutical composition of claim 18 in a dosage unit form.
24. The pharmaceutical composition of claim 18 wherein the crosslinked amine comprises the residue of a mono-functional vinyl, allyl, or acrylamide amine monomer and the residue of a crosslinker having two or more vinyl, allyl or acrylamide functionalities.
25. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer further comprises the residue, or corresponding salts, of diallylbutyldiamine, diallylethyldiamine, diallyldiethylenetriamine, diallylpropyldiamine, diallylamineisopropanol, allylamine, aminoethylallylamine, bis(2-aminoethyl)allylamine, or triallylamine.
26. The pharmaceutical composition of claim 18 wherein the crosslinked amine polymer is prepared by radical polymerization to form an intermediate containing amine moieties and crosslinking the intermediate with a polyfunctional crosslinker.
27. The pharmaceutical composition of claim 26 wherein the polyfunctional crosslinker is a dihaloalkane selected from the group consisting of 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,3-dibromopropane.
28. The pharmaceutical composition of claim 26 wherein the intermediate comprises the residue of a monoallylamine and the residue of a multiallylamine crosslinker.
29. The pharmaceutical composition of claim 26 wherein the crosslinked amine polymer comprises the residue of allylamine or a salt thereof, and the residue of 1,3-bis(allylamino)propane or a salt thereof.
30. The pharmaceutical composition of claim 29 wherein the polyfunctional crosslinker is 1,3-dichloropropane.