| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 5, 1996 |
| PATENT TITLE |
Phosphate-binding polymers for oral administration |
| PATENT ABSTRACT | Phosphate-binding polymers are provided for removing phosphate from the gastrointestinal tract. The polymers are orally administered, and are useful for the treatment of hyperphosphatemia |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | May 5, 1994 |
| PATENT REFERENCES CITED |
Medline, Abstract 8530168, McGary et al., 1984. McGary, T. J. et al., "Polycation as an Alternative Osmotic Agent and Phosphate Binder in Peritoneal Dialysis," Uremia Investigation, 8(2):79-84 (1984-1985). Physicians' Desk Reference, Consult 1992 Supplements for Revisions "PhosLo, Calcium Acetate Tablets". Physicians' Desk Reference, Consult 1992 Supplements for Revisions "Amphojel, Suspension Tablets". Burt et al., Journal of Pharmaceutical Sciences, 76:379-383, May, 1987. Delmez, M.D. et al., The Official Journal of The National Kidney Foundation, 19:303-17, Apr., 1992. Emmett, M.D. et al., American Journal of Kidney Diseases, 17:544-550, May, 1991. Ghosh et al., Lalanta, 28:957-959, 1981. Mai et al., Kidney International, 36:690-695, 1989. Munson, Annals New York Academy of Sciences, pp. 776-795. Salusky, M.D., et al., The New England Journal of Medicine, 324:527-531, Feb., 1991. Slatopolsky, M.D. et al., The New England Journal of Medicine, 315:157-161, Jul., 1986. Warshawsky, Chemistry, 15:166-225, 1987. Winston et al., Macromolecules, 11:597-603, May-Jun., 1978. Winston et al., Hydroxamic Acid Polymers, 14:2155-2165 (1976). McGary et al., Medline Abstract 85301681, 1984. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method for removing phosphate from a patient by ion exchange comprising orally administering to said patient a therapeutically effective amount of a composition comprising at least one polymer characterized by a repeat unit having the formula ##STR28## or a copolymer thereof, wherein n is an integer and each R, independently, is H or a lower alkyl, alkylamino, or aryl group. 2. The method of claim 1 wherein said polymer is crosslinked with a crosslinking agent wherein said crosslinking agent is present in said composition from about 0.5% to about 75% by weight. 3. The method of claim 2 wherein said crosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride, or pyromellitic dianhydride. 4. The method of claim 3 wherein said crosslinking agent comprises epichlorohydrin. 5. The method of claim 2 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 6. A method for removing phosphate from a patient by ion exchange comprising orally administering to said patient a therapeutically effective amount of a composition comprising at least one polymer characterized by a repeat unit having the formula ##STR29## or a copolymer thereof, wherein each n is an integer, each R, independently, is H or a lower alkyl, alkylamino, or aryl group, and each X.sup.- is an exchangeable negatively charged counterion. 7. The method of claim 6 wherein said polymer is crosslinked with a crosslinking agent wherein said crosslinking agent is present in said composition from about 0.5% to about 75% by weight. 8. The method of claim 7 wherein said crosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride, or pyromellitic dianhydride. 9. The method of claim 7 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 10. The method of claim 6 wherein the polymer is a copolymer comprising a second repeat unit having the formula ##STR30## wherein each n, independently, is an integer and each R, independently, is H or a lower alkyl, alkylamino, or aryl group. 11. The method of claim 10 wherein said polymer is crosslinked with a crosslinking agent wherein said crosslinking agent is present in said composition from about 0.5% to about 75% by weight. 12. The method of claim 11 wherein said crosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride, or pyromellitic dianhydride. 13. The method of claim 11 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. 14. A therapeutic composition for removing phosphate from a patient by ion exchange comprising a therapeutically effective amount of at least one polymer characterized by a repeat unit having the formula ##STR31## or copolymer thereof, wherein n is an integer and each R, independently, is H or a lower alkyl, alkylamino, or aryl group. 15. The composition of claim 14 wherein said polymer is crosslinked with a crosslinking agent wherein said crosslinking agent is present in said composition from about 0.5% to about 75% by weight. 16. The composition of claim 15 wherein said crosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride, or pyromellitic dianhydride. 17. The composition of claim 16 wherein said crosslinking agent comprises epichlorohydrin. 18. The composition of claim 15 wherein said crosslinking agent is present in said composition from about 2% to about 20% by weight. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION This invention relates to phosphate-binding polymers for oral administration. People with inadequate renal function, hypoparathyroidism, or certain other medical conditions often have hyperphosphatemia, meaning serum phosphate levels of over 6 mg/dL. Hyperphosphatemia, especially if present over extended periods of time, leads to severe abnormalities in calcium and phosphorus metabolism, often manifested by aberrant calcification in joints, lungs, and eyes. Therapeutic efforts to reduce serum phosphate include dialysis, reduction in dietary phosphate, and oral administration of insoluble phosphate binders to reduce gastrointestinal absorption. Dialysis and reduced dietary phosphate are usually insufficient to adequately reverse hyperphosphatemia, so the use of phosphate binders is routinely required to treat these patients. Phosphate binders include calcium or aluminum salts, or organic polymers such as ion exchange resins. Calcium salts have been widely used to bind intestinal phosphate and prevent absorption. The ingested calcium combines with phosphate to form insoluble calcium phosphate salts such as Ca.sub.3 (PO.sub.4).sub.2, CaHPO.sub.4, or Ca(H.sub.2 PO.sub.4).sub.2. Different types of calcium salts, including calcium carbonate, acetate (such as the pharmaceutical "PhosLo.RTM."), citrate, alginate, and ketoacid salts have been utilized for phosphate binding. The major problem with all of these therapeutics is the hypercalcemia which often results from absorption of the high amounts of ingested calcium. Hypercalcemia causes serious side effects such as cardiac arrhythmias, renal failure, and skin and visceral calcification. Frequent monitoring of serum calcium levels is required during therapy with calcium-based phosphate binders. Aluminum-based phosphate binders, such as the aluminum hydroxide gel "Amphojel.RTM.", have also been used for treating hyperphosphatemia. These compounds complex with intestinal phosphate to form highly insoluble aluminum phosphate; the bound phosphate is unavailable for absorption by the patient. Prolonged use of aluminum gels leads to accumulations of aluminum, and often to aluminum toxicity, accompanied by such symptoms as encephalopathy, osteomalacia, and myopathy. Organic polymers that have been used to bind phosphate have typically been ion exchange resins. Those tested include "Dowex.RTM." anion-exchange resins in the chloride form, such as XF 43311, XY 40013, XF 43254, XY 40011, and XY 40012. These resins have several drawbacks for treatment of hyperphosphatemia, including poor binding efficiency, necessitating use of high dosages for significant reduction of absorbed phosphate. In addition, the ion exchange resins also bind bile salts. SUMMARY OF THE INVENTION In general, the invention features a method of removing phosphate from a patient by ion exchange, which involves oral administration of a therapeutically effective amount of a composition containing at least one phosphate-binding polymer that is non-toxic and stable once ingested. The polymers of the invention may be crosslinked with a crosslinking agent. Examples of preferred crosslinking agents include epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride, and pyromellitic dianhydride. The crosslinking agent is present in an amount ranging from about 0.5% to about 75% by weight, more preferably from about 2% to about 20% by weight. By "non-toxic" it is meant that when ingested in therapeutically effective amounts neither the polymers nor any ions released into the body upon ion exchange are harmful. By "stable" it is meant that when ingested in therapeutically effective amounts the polymers do not dissolve or otherwise decompose to form potentially harmful by-products, and remain substantially intact so that they can transport bound phosphate out of the body. By "therapeutically effective amount" is meant an amount of the composition which, when administered to a patient, causes decreased serum phosphate. In one aspect, the polymer is characterized by a repeating unit having the formula ##STR1## or a copolymer thereof, wherein n is an integer and each R, independently, is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl (e.g., phenyl) group. In a second aspect, the polymer is characterized by a repeating unit having the formula ##STR2## or a copolymer thereof, wherein n is an integer, each R, independently, is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl (e.g., phenyl) group, and each X.sup.- is an exchangeable negatively charged counterion. One example of a copolymer according to the second aspect of the invention is characterized by a first repeating unit having the formula ##STR3## wherein n is an integer, each R, independently, is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl), and each X.sup.- is an exchangeable negatively charged counterion; and further characterized by a second repeating unit having the formula ##STR4## wherein each n, independently, is an integer and each R, independently, is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl). In a fourth aspect, the polymer is characterized by a repeating unit having the formula ##STR5## or a copolymer thereof, wherein n is an integer, and R is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl). One example of a copolymer according to the second aspect of the invention is characterized by a first repeating unit having the formula ##STR6## wherein n is an integer, and R is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl); and further characterized by a second repeating unit having the formula ##STR7## wherein each n, independently, is an integer and R is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl). In a fifth aspect, the polymer is characterized by a repeating group having the formula ##STR8## or a copolymer thereof, wherein n is an integer, and each R.sub.1 and R.sub.2, independently, is H or a lower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive), and alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl), and each X.sup.- is an exchangeable negatively charged counterion. In one preferred polymer according to the fifth aspect of the invention, at least one of the R groups is a hydrogen group. In a sixth aspect, the polymer is characterized by a repeat unit having the formula ##STR9## or a copolymer thereof, where n is an integer, each R.sub.1 and R.sub.2, independently, is H, an alkyl group containing 1 to 20 carbon atoms, an alkylamino group (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino), or an aryl group containing 1 to 12 atoms (e.g., phenyl). In a seventh aspect, the polymer is characterized by a repeat unit having the formula ##STR10## or a copolymer thereof, wherein n is an integer, each R.sub.1, R.sub.2 and R.sub.3, independently, is H, an alkyl group containing 1 to 20 carbon atoms, an alkylamino group (e.g., having between 1 and 5 carbons atoms, inclusive, such as ethylamino), or an aryl group containing 1 to 12 atoms (e.g., phenyl), and each X.sup.- is an exchangeable negatively charged counterion. In all aspects, the negatively charged counterions may be organic ions, inorganic ions, or combination thereof. The inorganic ions suitable for use in this invention include the halides (especially chloride), phosphate, phosphite, carbonate, bicarbonate, sulfate, bisulfate, hydroxide, nitrate, persulfate, sulfite, and sulfide. Suitable organic ions include acetate, ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate, tartrate, taurocholate, glycocholate, and cholate. The invention provides an effective treatment for decreasing the serum level of phosphate by binding phosphate in the gastrointestinal tract, without comcomittantly increasing the absorption of any clinically undesirable materials, particularly calcium or aluminum. Other features and advantages will be apparent from the following description of the preferred embodiments and from the claims. DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred polymers have the structures set forth in the Summary of the Invention, above. The polymers are preferably crosslinked, in some cases by adding a crosslinking agent to the reaction mixture during polymerization. Examples of suitable crosslinking agents are diacrylates and dimethacrylates (e.g., ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, propylene glycol dimethacrylate, butylene glycol dimethacrylate, polyethyleneglycol dimethacrylate, polyethyleneglycol diacrylate), methylene bisacrylamide, methylene bismethacrylamide, ethylene bisacrylamide, epichlorohydrin, toluene diisocyanate, ethylenebismethacrylamide, ethylidene bisacrylamide, divinyl benzene, bisphenol A dimethacrylate, bisphenol A diacrylate, 1,4 butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, acryloyl chloride, or pyromellitic dianhydride. The amount of crosslinking agent is typically between about 0.5 and about 75 weight %, and preferably between about 1 and about 25% by weight, based upon combined weight of crosslinking agent and monomer. In another embodiment, the crosslinking agent is present between about 2 and about 20% by weight. In some cases the polymers are crosslinked after polymerization. One method of obtaining such crosslinking involves reaction of the polymer with difunctional crosslinkers, such as epichlorohydrin, succinyl dichloride, the diglycidyl ether of bisphenol A, pyromellitic dianhydride, toluene diisocyanate, and ethylenediamine. A typical example is the reaction of poly(ethyleneimine) with epichlorohydrin. In this example the epichlorohydrin (1 to 100 parts) is added to a solution containing polyethyleneimine (100 parts) and heated to promote reaction. Other methods of inducing crosslinking on already polymerized materials include, but are not limited to, exposure to ionizing radiation, ultraviolet radiation, electron beams, radicals, and pyrolysis. |
| PATENT EXAMPLES | Available on request |
| PATENT PHOTOCOPY | Available on request |
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