Proton-binding polymers for oral administration

Abstract

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.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen, the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less, and the crosslinked amine polymer binds a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, in an interfering ion buffer at 37° C. wherein (i) the interfering ions are phosphate ions and the interfering ion buffer is a buffered solution at pH 5.5 of 36 mM chloride and 20 mM phosphate or (ii) the interfering ions are phosphate, citrate and taurocholate ions (combined amount) and the interfering ion buffer is a buffered solution at pH 6.2 including 36 mM chloride, 7 mM phosphate, 1.5 mM citrate, and 5 mM taurocholate. 
       
     
     
         2 . The pharmaceutical composition of  claim 1  where the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol/g and a chloride ion binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C., and (ii) an equilibrium swelling ratio in deionized water of about 2 or less. 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer binds more chloride than any one of the interfering anions in the interfering ion buffer, the interfering ions are phosphate, citrate and taurocholate ions and the interfering ion buffer is a buffered solution at pH 6.2 including 36 mM chloride, 7 mM phosphate, 1.5 mM citrate, and 5 mM taurocholate 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein R 1 , R 2  and R 3  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. 
     
     
         6 . The pharmaceutical composition of  claim 1  wherein R 1 , R 2  and R 3  are independently hydrogen, aliphatic or heteroaliphatic provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. 
     
     
         7 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer is prepared by substitution polymerization of the amine with a polyfunctional crosslinker, optionally also comprising amine moieties. 
     
     
         8 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1a and the crosslinked amine polymer is prepared by radical polymerization of an amine corresponding to Formula 1a: 
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. 
       
     
     
         9 . The pharmaceutical composition of  claim 8  wherein R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. 
     
     
         10 . The pharmaceutical composition of  claim 8  wherein R 4  and R 5  are independently hydrogen, aliphatic or heteroaliphatic. 
     
     
         11 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1b and the crosslinked amine polymer is prepared by substitution polymerization of the amine corresponding to Formula 1b with a polyfunctional crosslinker: 
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, R 6  is aliphatic and R 61  and R 62  are independently hydrogen, aliphatic, or heteroaliphatic. 
       
     
     
         12 . The pharmaceutical composition of  claim 11  wherein R 4  and R 5  are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic. 
     
     
         13 . The pharmaceutical composition of  claim 11  wherein R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. 
     
     
         14 . The pharmaceutical composition of  claim 11  wherein R 4  and R 5  are independently hydrogen, allyl, or aminoalkyl. 
     
     
         15 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1c: 
       
         
           
           
               
               
           
         
         wherein R 7  is hydrogen, aliphatic or heteroaliphatic and R 8  is aliphatic or heteroaliphatic. 
       
     
     
         16 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2: 
       
         
           
           
               
               
           
         
         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, hydroxy, or amino; and 
         z is a non-negative number. 
       
     
     
         17 . The pharmaceutical composition of  claim 16  wherein R 11  is independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or heteroaryl, R 21  and R 31  are independently hydrogen or heteroaliphatic and R 41  is hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. 
     
     
         18 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2a: 
       
         
           
           
               
               
           
         
         wherein 
         m and n are independently non-negative integers; 
         each R 11  is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl; 
         R 21  and R 31 , are independently hydrogen or heteroaliphatic; 
         R 41  is hydrogen, substituted hydrocarbyl, or hydrocarbyl; 
         X 1  is 
       
       
         
           
           
               
               
           
         
         X 2  is alkyl or substituted hydrocarbyl; 
         each X 12  is independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halo; and 
         z is a non-negative number. 
       
     
     
         19 . The pharmaceutical composition of  claim 18  wherein each R 11  is hydrogen, aliphatic, aminoalkyl, or haloalkyl, R 21  and R 31  are hydrogen or aminoalkyl, and R 41  is hydrogen, aliphatic, or heteroaliphatic. 
     
     
         20 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2b: 
       
         
           
           
               
               
           
         
         wherein 
         m and n are independently non-negative integers; 
         each R 12  is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl; 
         R 22  and R 32  are independently hydrogen substituted hydrocarbyl, or hydrocarbyl; 
         R 42  is hydrogen, hydrocarbyl or substituted hydrocarbyl; 
         X 1  is 
       
       
         
           
           
               
               
           
         
         X 2  is alkyl, aminoalkyl, or alkanol; 
         each X 13  is independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl; 
         z is a non-negative number; and 
         the amine corresponding to Formula 2b comprises at least one allyl group. 
       
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the crosslinked amine polymer comprises the residue of an amine appearing in Table 1. 
     
     
         22 . The pharmaceutical composition of  claim 20  wherein the crosslinked amine polymer is crosslinked with a crosslinking agent appearing in Table 2. 
     
     
         23 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer comprises a repeat unit corresponding to Formula 3: 
       
         
           
           
               
               
           
         
         wherein 
         R 15 , R 16  and R 17  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid or halo; 
         X 15  is 
       
       
         
           
           
               
               
           
         
         X 5  is hydrocarbyl, substituted hydrocarbyl, oxo (—O—), or amino; and 
         z is a non-negative number. 
       
     
     
         24 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer is prepared by (i) 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. 
     
     
         25 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 1:1, respectively, in an aqueous simulated small intestine inorganic buffer (“SIB”) containing 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5 and at 37° C. 
     
     
         26 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer has a chloride binding capacity of at least 3 mmol/g in an aqueous simulated small intestine organic and inorganic buffer (“SOB”) 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, buffered to pH 6.2 and at 37° C. 
     
     
         27 . The pharmaceutical composition of  claim 1  wherein the percentage of quaternized amines is less than 40%. 
     
     
         28 . The pharmaceutical composition of  claim 1  wherein the percentage of quaternized amines is less than 10%. 
     
     
         29 . The pharmaceutical composition of  claim 1  wherein the crosslinked amine polymer is a gel or a bead having a mean particle size of 40 to 180 micrometers. 
     
     
         30 . The pharmaceutical composition of  claim 1  in a dosage unit form.