Pharmaceutical compositions comprising crosslinked polyamine polymers
Anion-binding polymers are described. The anion-binding polymers in some cases are low swelling anion-binding polymers. In some cases, the anion-binding polymers have a pore volume distribution such that a fraction of the polymer is not available for non-interacting solutes above a certain percentage of the MW of the target ion for the polymer. In some cases, the anion-binding polymers are characterized by low ion-binding interference, where the interference is measured in, for example, a gastrointestinal simulant, relative to non-interfering buffer. Pharmaceutical composition, methods of use, and kits are also described.
1. A pharmaceutical composition comprising a phosphate binding crosslinked amine polymer as an active ingredient and a pharmaceutically acceptable excipient, the crosslinked amine polymer comprising a polyamine polymer derived from the polymerization of an amine monomer, the polyamine polymer being crosslinked with a crosslinking agent, wherein the crosslinked amine polymer has a gel pore volume and less than about 20% of the gel pore volume is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium which is isotonic and neutral pH.
2. A pharmaceutical composition comprising a phosphate binding crosslinked amine polymer as an active ingredient and a pharmaceutically acceptable excipient, the crosslinked amine polymer comprising a polyamine polymer derived from the polymerization of an amine monomer, the polyamine polymer being crosslinked with a crosslinking agent, wherein the crosslinked amine polymer has an ion-binding interference for phosphate lower than about 60% when measured in a gastrointestinal simulant, relative to a non-interfering buffer.
3. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer is active for removing phosphate ions from the gastrointestinal tract.
4. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer binds phosphate ion in vivo with a binding capacity of greater than 0.5 mmol/g.
5. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer is insoluble in a physiological isotonic buffer.
6. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer is formulated as a free amine, free of counter-ions.
7. The pharmaceutical composition of claim 2 wherein the crosslinked amine polymer has a gel pore volume and less than about 20% of the gel pore volume is accessible to non-interacting solutes of molecular weight greater than about 200 when measured in a gastrointestinal simulant, relative to a non-interfering buffer.
8. The pharmaceutical composition of claim 1 or 7 wherein less than about 20% of the gel pore volume is accessible to non-interacting solutes of molecular weight greater than about 180.
9. The pharmaceutical composition of claim 1 or 7 wherein less than about 20% of the gel pore volume is accessible to non-interacting solutes of molecular weight greater than about 160.
10. The pharmaceutical composition of claim 1 or 7 wherein less than about 20% of the gel pore volume is accessible to non-interacting solutes of molecular weight greater than about 140.
11. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer has an ion-binding interference for phosphate lower than about 40% when measured in a gastrointestinal simulant, relative to a non-interfering buffer.
12. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer has an ion-binding interference for phosphate lower than about 20% when measured in a gastrointestinal simulant, relative to a non-interfering buffer.
13. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer binds bile acids or citrate with a capacity of less than about 2 mmol/g.
14. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer has a swelling ratio in physiological isotonic buffer of less than about 5.
15. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer has a swelling ratio in physiological isotonic buffer of less than about 3.
16. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer comprises a polyamine polymer selected from Formula 1 and Formula 2,
crosslinked with a crosslinking agent.
17. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer comprises a polyamine polymer of the formula
crosslinked with a crosslinking agent, wherein R″′ is H or CH 3 , and R can include H, halogen, R″, CO 2 H, CO 2 R″, COR″, C(═N R″)(N R), CN, CONH 2 , CONR 2 , OR″, SO 3 R, Si(R″) 3 , and P(O)(OR″) 2 , where R″ groups include H, optionally substituted alkyl, acyl, alkylamino, alkenyl, heterocyclyl, and aryl group, and where substituents for R″ groups can be ionic entities with oxygen, nitrogen, phosphorus, or sulfur.
18. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer comprises a polyamine polymer of the formula
crosslinked with a crosslinking agent, wherein each R, independently, is H or a substituted or unsubstituted alkyl, alkylamino or aryl group, or of the formula
crosslinked with a crosslinking agent, wherein each R, independently, is H or a substituted or unsubstituted alkyl, alkylamino or aryl group, and each X − is an exchangeable negatively charged counterion.
19. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer comprises a polyamine polymer of the formula
crosslinked with a crosslinking agent, wherein R is H or a substituted or unsubstituted alkyl, alkylamino, or aryl group, or of the formula
crosslinked with a crosslinking agent, wherein each R 1 and R 2 , independently, is H or a substituted or unsubstituted alkyl, alkylamino, or aryl group, and each X − is an exchangeable negatively charged counterion.
20. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer comprises a polyamine polymer of the formula
crosslinked with a crosslinking agent, wherein each R 1 and R 2 , independently, is H, a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, an alkylamino group, or an aryl group containing 6 to 12 atoms, or of the formula
crosslinked with a crosslinking agent, wherein each R 1 and R 2 and R 3 , independently, is H, a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, an alkylamino group, or an aryl group containing 6 to 12 atoms, and each X − is an exchangeable negatively charged counterion.
21. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer comprises guanidine groups.
22. The pharmaceutical composition of claim 1 or 2 wherein the polyamine polymer is a copolymer.
23. The pharmaceutical composition of claim 1 or 2 wherein the polyamine polymer is a random copolymer.
24. The pharmaceutical composition of claim 1 or 2 wherein the polyamine polymer is a copolymer comprising the amine monomer copolymerized with one or more monomers selected from the group consisting of styrene, substituted styrene, alkyl acrylate, substituted alkyl acrylate, alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide, N,N-dialkylacrylamide, N,N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinyl amide, maleic acid derivatives, vinyl ether, allyl, methallyl monomers, combinations thereof, and functionalized versions thereof.
25. The pharmaceutical composition of claim 1 or 2 wherein the polyamine polymer is a polymer or copolymer polymerized with a monomer selected from the group consisting of methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, α-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, triethyleneglycol methacrylate, itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl acrylate, N,N-diethylaminoethyl acrylate, triethyleneglycol acrylate, methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-tert-butylmethacrylamide, N-n-butylmethacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylamide, N-n-butylacrylamide, N-methylolacrylamide, N-ethylolacrylamide, 4-acryloylmorpholine, vinyl benzoic acid (all isomers), diethylaminostyrene (all isomers), α-methylvinyl benzoic acid (all isomers), diethylamino a-methylstyrene (all isomers), p-vinylbenzene sulfonic acid, p-vinylbenzene sulfonic sodium salt, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoxysilylpropyl methacrylate, dimethoxymethylsilyipropyl methacrylate, diethoxymethylsilylpropyl methacrylate, dibutoxymethylsilylpropyl methacrylate, diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl acrylate, diisopropoxymethylsilylpropylacrylate, dimethoxysilyipropyl acrylate, diethoxysilyipropyl acrylate, dibutoxysilyipropyl acrylate, diisopropoxysilylpropyl acrylate, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, N-vinylformamide, N-vinyl acetamide, allylamine, methallylamine, allylalcohol, methyl-vinylether, ethylvinylether, butylvinylether, butadiene, isoprene, chioroprene, ethylene, vinyl acetate and combinations thereof.
26. The pharmaceutical composition of claim 1 or 2 wherein the crosslinking agent is a compound having at least two functional groups, each functional group being selected from halogen, carbonyl, epoxy, ester, acid anhydride, acid halide, isocyanate, vinyl, and chloroformate.
27. The pharmaceutical composition of claim 1 or 2 wherein the crosslinking agent is 1,3-dichloropropane or epichlorohydrin.
28. The pharmaceutical composition of claim 1 or 2 wherein the crosslinked amine polymer is in the form of spherical beads.
29. The pharmaceutical composition comprising a phosphate binding particulate crosslinked amine polymer as an active ingredient and a pharmaceutically acceptable excipient, the polymer particles having a size in the range of 5 to 500 microns, the crosslinked amine polymer comprising a polyamine polymer derived from the polymerization of an amine monomer, the polyamine polymer being crosslinked with a crosslinking agent, wherein the crosslinked amine polymer has a gel pore volume and less than about 20% of the gel pore volume is accessible to non-interacting solutes of molecular weight greater than about 200 as measured in a physiological medium which is isotonic and neutral pH.
30. The pharmaceutical composition of claim 29 wherein the crosslinked amine polymer comprises a polyamine selected from Formula 1 and Formula 2,
crosslinked with a crosslinking agent.
31. The pharmaceutical composition of claim 29 wherein the crosslinked amine polymer comprises a polyamine of the formula
crosslinked with a crosslinking agent, wherein R″′ is H or CH 3 , and R can include H, halogen, R″, CO 2 H, CO 2 R″, COR″, C(═N R″)(N R), CN, CONH 2 , CONR 2 , OR″, SO 3 R, Si(R″) 3 , and P(O)(OR″) 2 , where R″ groups include H, optionally substituted alkyl, acyl, alkylamino, alkenyl, heterocyclyl, and aryl group, and where substituents for R″ groups can be ionic entities with oxygen, nitrogen, phosphorus, or sulfur.
32. The pharmaceutical composition of claim 29 wherein the crosslinked amine polymer comprises a polyamine of the formula
crosslinked with a crosslinking agent, wherein each R, independently, is H or a substituted or unsubstituted alkyl, alkylamino or aryl group, or of the formula
crosslinked with a crosslinking agent, wherein each R, independently, is H or a substituted or unsubstituted alkyl, alkylamino or aryl group, and each X − is an exchangeable negatively charged counterion.
33. The pharmaceutical composition of claim 29 wherein the crosslinked amine polymer comprises a polyamine of the formula
crosslinked with a crosslinking agent, wherein R is H or a substituted or unsubstituted alkyl, alkylamino, or aryl group, or of the formula
crosslinked with a crosslinking agent, wherein each R 1 and R 2 , independently, is H or a substituted or unsubstituted alkyl, alkylamino, or aryl group, and each X − is an exchangeable negatively charged counterion.
34. The pharmaceutical composition of claim 29 wherein the crosslinked amine polymer comprises a polyamine of the formula
crosslinked with a crosslinking agent, wherein each R 1 and R 2 , independently, is H, a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, an alkylamino group, or an aryl group containing 6 to 12 atoms, or of the formula
crosslinked with a crosslinking agent, wherein each R 1 and R 2 and R 3 , independently, is H, a substituted or unsubstituted alkyl group containing 1 to 20 carbon atoms, an alkylamino group, or an aryl group containing 6 to 12 atoms, and each X − is an exchangeable negatively charged counterion.