Method for determining in vitro bioequivalence of a sucralfate suspension sample to a sucralfate suspension reference listed drug (rld)

Abstract

The invention provides methods for determining in vitro bioequivalence of a sucralfate suspension sample to a sucralfate suspension RLD.

1 .- 5 . (canceled) 
     
     
         6 . A sucralfate suspension sample so obtained by a method for determining in vitro bioequivalence of a sucralfate suspension sample to a sucralfate suspension RLD comprising:
 a) contacting the sucralfate suspension sample with a bile acid, bile salt and/or a conjugated bile acid or a combination thereof, so as to permit sucralfate-bile interaction, quantifying the interaction so as to obtain quantified values of the interaction and comparing said values to reference values for the sucralfate suspension RLD; and   b) contacting the sucralfate suspension sample with a cell culture system in the presence of a Non-Steroidal Anti-Inflammatory Drug (NSAID) or a nonselective inhibitor of cyclooxygenase (COX) 1 and 2 so as to inhibit cell damage induced by the NSAID or nonselective inhibitor of COX 1 and 2 in the cell culture system, quantifying the cell damage so as to obtain quantified value(s) for the sucralfate suspension sample and comparing the said value(s) to reference values for the sucralfate suspension RLD;   wherein the reference values for the sucralfate suspension RLD in (a) are derived from a set of values obtained from quantifying the sucralfate-bile interaction for 2 or more lots of the sucralfate suspension RLD; wherein sucralfate-bile interaction is interaction between sucralfate and bile acid, bile salt and/or conjugated bile acid or a combination thereof; wherein the reference values of the sucralfate suspension RLD in (b) are derived from a set of values obtained from quantifying the reduction in cell damage for 2 or more lots of the sucralfate suspension RLD; and wherein the sucralfate suspension sample is to have said in vitro bioequivalence to a sucralfate suspension RLD when the values determined in (a) and (b) for the sucralfate suspension sample are within the reference values in (a) and (b) for the sucralfate suspension RLD, respectively.   
     
     
         7 . The sucralfate suspension sample of  claim 6 , wherein the conjugated bile acid (a) is selected from the group consisting of glycocholate, glycochenodeoxycholate, taurochenodeoxycholate and taurodeoxycholate or a combination thereof. 
     
     
         8 . The sucralfate suspension sample of  claim 6 , wherein the bile acid is or comprises a taurodeoxycholic acid (2-(((3alpha,5beta,12alpha)-3,12-dihydroxy-24-oxocholan-24-yl)amino)-ethanesulfonic acid; CAS No.: 516-50-7). 
     
     
         9 . The sucralfate suspension sample of  claim 6 , wherein the bile salt is or comprises a sodium taurodeoxycholate (CAS No.: 1180-95-6). 
     
     
         10 . The sucralfate suspension sample of  claim 6 , wherein the conjugated bile acid is or comprises taurodeoxycholate. 
     
     
         11 . The sucralfate suspension sample of  claim 6 , wherein the bile salt comprises of a bile acid and a cation selected from the group consisting of an alkali metal, alkaline earth metal, transition metal, ammonium, amine and a quaternary ammonium. 
     
     
         12 . The sucralfate suspension sample of  claim 11 , wherein the alkali metal is selected from the group consisting of lithium, sodium, potassium, rubidium and cesium. 
     
     
         13 . The sucralfate suspension sample of  claim 11 , wherein the alkaline earth metal is selected from the group consisting of beryllium, magnesium, calcium, strontium and barium. 
     
     
         14 . The sucralfate suspension sample of  claim 11 , wherein the transition metal is selected from the group consisting of chromium, molybdenum, manganese, iron, cobalt, nickel, copper, silver, gold, zinc and cadmium. 
     
     
         15 . The sucralfate suspension sample of  claim 11 , wherein the amine is selected from the group consisting of methylamine, methoxylamine, methylenediamine, bromoethylamine, chloroethylamine, fluoroethylamine, dimethylamine, ethylenediamine, diethylamine, cystamine, aniline, nitro-benzenediamine, phenylenediamine, tris(2-chloroethyl)amine, tromethamine, ethanolamine, diethanolamine and triethanolamine. 
     
     
         16 . The sucralfate suspension sample of  claim 11 , wherein the quaternary ammonium is selected from the group consisting of tetramethylammonium, tetrabutylammonium, tetraethylammonium, triethylmethylammonium and tributylmethylammonium. 
     
     
         17 . The sucralfate suspension sample of  claim 6 , wherein the bile salt is sodium or potassium salt of a bile acid. 
     
     
         18 . The sucralfate suspension sample of  claim 6 , wherein the sucralfate-bile interaction is binding of bile acid, bile salt or conjugated bile acid or a combination thereof by sucralfate. 
     
     
         19 . The sucralfate suspension sample of  claim 18 , wherein the binding is in vitro equilibrium binding. 
     
     
         20 . The sucralfate suspension sample of  claim 18 , wherein binding is in vitro kinetic binding. 
     
     
         21 . The sucralfate suspension sample of  claim 18 , wherein the binding is adsorption of bile acid, bile salt or conjugated bile acid or a combination thereof to sucralfate. 
     
     
         22 . The sucralfate suspension sample of  claim 18 , wherein the interaction or association delays the migration of bile acid, bile salt or conjugated bile acid or a combination thereof in the presence of sucralfate. 
     
     
         23 .- 112 . (canceled) 
     
     
         113 . The sucralfate suspension sample of  claim 6 , wherein the bile acid is selected from the group consisting of allocholic acid (3alpha,7alpha,12alpha-trihydroxy-5alpha-cholanoic acid; CAS: 2464-18-8), 5alpha-deoxycholic acid (3alpha,12alpha-dihydroxy-5alpha-cholan-24-oic acid), bitocholic acid, chenodeoxycholic acid (3alpha,7alpha-dihydroxy-5beta-cholan-24-oic acid; CAS: 474-25-9), cholic acid (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid; CAS: 81-25-4), deoxycholic acid (3alpha,12alpha-dihydroxy-5beta-cholanic acid; CAS: 83-44-3), glycochenodeoxycholic acid (2-[[(4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]acetic acid; CAS No.: 640-79-9), glycocholic acid (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oylglycine; CAS: 475-31-0), hyocholic acid (3alpha,6alpha,7alpha-trihydroxy-5beta-cholan-24-oic acid; CAS: 547-75-1), hyodeoxycholic acid (3α,6α-Dihydroxy-5β-cholan-24-oic acid; CAS: 83-49-8), isochenodeoxycholic acid (3beta,7alpha-dihydroxy-5beta-cholanic acid; CAS: 566-24-5), 3beta,12alpha-Dihydroxy-5beta-cholanoic acid (CAS: 570-63-8), isolithocholic acid (3beta-Hydroxy-5beta-cholan-24-oic acid; CAS: 1534-35-6), isoursodeoxycholic acid (3beta,7beta-dihydroxy-5beta-cholan-24-oic acid; CAS: 78919-26-3), 12-epideoxycholic acid, lithocholic acid (3alpha-hydroxy-5beta-cholanic acid; CAS: 434-13-9), alpha-muricholic acid (3alpha,6beta,7alpha-trihydroxy-5beta-cholan-24-oic acid; CAS: 2393-58-0), beta-muricholic acid (3alpha,6beta,7beta-trihydroxy-5beta-cholan-24-oic acid; CAS: 2393-59-1), omega-muricholic acid, murideoxycholic acid (3alpha,6beta-dihydroxy-5beta-cholanic acid), beta-phocaecholic acid (CAS: 105369-89-9), taurochenodeoxycholic acid (2-[[(4R)-4-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonic acid; CAS No.: 516-35-8), taurocholic acid (2-[[(4R)-4-[(3R,5S,7R,8R,9S,10S,12S,13R,14S,17R)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]ethanesulfonic acid; CAS No.: 81-24-3), taurodeoxycholic acid (2-(((3alpha,5beta,12alpha)-3,12-dihydroxy-24-oxocholan-24-yl)amino)-ethanesulfonic acid; CAS No.: 516-50-7), ursocholic acid (3alpha,7beta,12alpha-trihydroxy-5beta-cholan-24-oic acid; CAS: 2955-27-3), ursodeoxycholic acid (3alpha,7beta-dihydroxy-5beta-cholan-24-oic acid; CAS: 128-13-2), and vulpecholic acid (1alpha,3alpha,7alpha-trihydroxy-5beta-cholan-24-oic acid; CAS: 107368-95-6) or a combination thereof. 
     
     
         114 . The sucralfate suspension sample of  claim 6 , wherein the bile salt is salt of a bile acid. 
     
     
         115 . The sucralfate suspension sample of  claim 6 , wherein the conjugated bile acid (a) is the taurine or glycine conjugate of a bile acid.