Compositions for treating acid-base disorders

Abstract

Pharmaceutical compositions for and methods of treating an animal, including a human, and methods of preparing such compositions. The pharmaceutical compositions contain nonabsorbable compositions and may be used, for example, to treat diseases or other metabolic conditions in which removal of protons, the conjugate base of a strong acid and/or a strong acid 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 - 237 . (canceled) 
     
     
         238 . A method of treating metabolic acidosis in an adult human patient, said patient having a serum bicarbonate level of less than 18 mEq/L prior to treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein about 3 g of the composition is administered to the patient per day, the composition is administered once per day in order to provide the total specified daily dose, and the composition is a pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising 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, and 
         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. 
       
     
     
         239 . The method according to  claim 238 , wherein the patient's serum bicarbonate level is less than
 (a) 17 mEq/L,   (b) 16 mEq/L, or   (c) 15 mEq/L prior to treatment.   
     
     
         240 . The method according to  claim 238  wherein said patient's serum bicarbonate value is increased by at least 1 mEq/L over 15 days of treatment. 
     
     
         241 . The method according to  claim 238  wherein the treatment increases the individual's serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by:
 (a) at least 1.5 mEq/l, 
 (b) at least 2 mEq/l, 
 (c) at least 2.5 mEq/l, 
 (d) at least 3 mEq/l, 
 (e) at least 3.5 mEq/l, or 
 (f) at least 4 mEq/l. 
 
     
     
         242 . The method according to  claim 238  wherein the adult human patient has chronic kidney disease. 
     
     
         243 . The method according to  claim 238  wherein the nonabsorbable composition is characterized by a chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay of
 (a) at least 2.5 mEq/g, 
 (b) at least 3 mEq/g, 
 (c) at least 3.5 mEq/g, 
 (d) at least 4 mEq/g, 
 (e) at least 4.5 mEq/g, or 
 (f) at least 5 mEq/g. 
 
     
     
         244 . The method according to  claim 238  wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of
 (a) about 1.5 or less, or 
 (b) about 1 or less. 
 
     
     
         245 . The method according to  claim 238  wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of
 (a) at least 0.5:1, respectively, 
 (b) at least 1:1, respectively, or 
 (c) at least 2:1, 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. 
 
     
     
         246 . The method according to  claim 238  wherein the crosslinked amine polymer has
 (a) a proton binding capacity of at least 10 mmol/g and a chloride ion binding capacity of at least 10 mmol/g, or 
 (b) an equilibrium proton binding capacity of at least 12 mmol/g and a chloride ion binding capacity of at least 12 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. 
 
     
     
         247 . The method according to  claim 238  wherein m and z are independently 0-3 and n is 0 or 1. 
     
     
         248 . The method according to  claim 238  wherein (i) m is a positive integer and R 12 , R 22  and R 42 , in combination comprise at least two allyl or vinyl moieties or (ii) n is a positive integer and R 12 , R 32  and R 42 , in combination, comprise at least two allyl or vinyl moieties. 
     
     
         249 . The method according to  claim 238  wherein the crosslinked amine polymer comprises the residue of an amine, or the salt thereof, selected from 1,4-bis(allylamino)butane, 1,2-bis(allylamino)ethane, 2-(allylamino)-1-[2-(allylamino)ethylamino]ethane, 1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol, 2-propen-1-ylamine, 1-(allylamino)-2-aminoethane, 1-[N-allyl(2-aminoethyl)amino]-2-aminoethane and N,N,N-triallylamine. 
     
     
         250 . The method according to  claim 238  wherein the crosslinked amine polymer comprises the residue of an amine, or the salt thereof, selected from 1,3-bis(allylamino)propane and 2-propen-1-ylamine. 
     
     
         251 . The method according to  claim 238  wherein the crosslinked amine polymer is crosslinked with a crosslinking agent selected from bis(3-chloropropyl)amine, 1,3-dichloro-2-propanol, 1,2-dichloroethane, 1,3-dichloropropane, 1-chloro-2,3-epoxypropane, tris[(2-oxiranyl)methyl]amine, 3-chloro-1-(3-chloropropylamino)-2-propanol, and 1,2-bis(3-chloropropylamino)ethane. 
     
     
         252 . The method according to  claim 238  wherein the composition is in a dosage unit form, wherein the dosage unit form is a capsule, tablet or sachet dosage form.