Stable pharmaceutical composition useful for treating gastrointestinal disorders

Abstract

The present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable bismuth-containing compound, at least one pharmaceutically acceptable non-clay-derived suspending agent, and water. The suspension exhibits reduced upward pH drift by comparison with an otherwise similar suspension which comprises a clay-derived suspending agent. Such compositions are useful in the prevention and treatment of gastrointestinal diseases and/or disorders.

1 - 68 . (canceled)  
     
     
         69 . An orally deliverable liquid pharmaceutical suspension comprising: 
 (a) at least one pharmaceutically acceptable bismuth-containing compound present in a total amount of about 0. 1% to about 10% by weight,    (b) an effective suspending amount of at least one pharmaceutically acceptable non-clay-derived suspending agent,    (c) at least one pharmaceutically acceptable anti-microbial preservative, selected from the group consisting of butylparaben, editic acid, ethylparaben, glycerol, methylparaben, potassium sorbate, propionic acid, propylene glycol, propylparaben, salicylic acid, sorbic acid, sodium propionate, sodium salicylate, and mixtures thereof, and,    (d) water,    wherein during storage in a closed container maintained under ambient conditions for a period of at least about 5 months, the suspension exhibits reduced upward pH drift by comparison with an otherwise similar comparative suspension that comprises at least 0.1% magnesium aluminum silicate.    
     
     
         70 . The suspension of  claim 69  wherein the suspension comprises zero to not more than 0.08% by weight of a clay-derived suspending agent.  
     
     
         71 . The suspension of  claim 70  substantially free from a clay-derived suspending agent.  
     
     
         72 . The suspension of  claim 69  wherein the at least one pharmaceutically acceptable bismuth-containing compound is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth nitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof.  
     
     
         73 . The suspension of  claim 72  wherein the at least one pharmaceutically acceptable bismuth-containing compound is bismuth subsalicylate.  
     
     
         74 . The suspension of  claim 69  wherein the at least one pharmaceutically acceptable bismuth-containing compound is present in a total amount of about 0.5% to about 5%, by weight.  
     
     
         75 . The suspension of  claim 69  wherein the at least one pharmaceutically acceptable non-clay-derived suspending agent is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, xanthan gum, silicon dioxide, and mixtures thereof.  
     
     
         76 . The suspension of  claim 69  wherein the at least one pharmaceutically acceptable non-clay-derived suspending agent is present in a total amount of about 0.01% to about 15%, by weight.  
     
     
         77 . The suspension of  claim 69  wherein the at least one pharmaceutically acceptable anti-microbial preservative is selected from the group consisting of sorbic acid, methylparaben, sodium salicylate, salicylic acid, and mixtures thereof.  
     
     
         78 . The suspension of  claim 69  wherein the at least one pharmaceutically acceptable anti-microbial preservative is present in a total amount of about 0.01% to about 10%, by weight.  
     
     
         79 . The suspension of  claim 69  having a pH, measured immediately after preparation, of about 2 to about 8.  
     
     
         80 . The suspension of  claim 69  wherein the water is present in a total amount of about 50% to about 99%, by weight.  
     
     
         81 . A method of treating a gastrointestinal disease and/or disorder in a subject in need of such treatment, comprising oral administration to the subject of a therapeutically effective amount of a suspension of  claim 69 .  
     
     
         82 . An orally deliverable liquid pharmaceutical suspension comprising: 
 (a) at least one pharmaceutically acceptable bismuth-containing compound present in a total amount of about 0.1% to about 10% by weight,    (b) an effective suspending amount of at least one pharmaceutically acceptable non-clay-derived suspending agent,    (c) at least one pharmaceutically acceptable anti-microbial preservative, selected from the group consisting of benzoic acid, butylparaben, editic acid, ethylparaben, glycerol, methylparaben, potassium sorbate, propionic acid, propylene glycol, propylparaben, salicylic acid, sorbic acid, sodium benzoate, sodium propionate, sodium salicylate, and mixtures thereof, wherein benzoic acid and sodium benzoate are present in amounts of at least 0.1% by weight, and,    (d) water,    wherein during storage in a closed container maintained under ambient conditions for a period of at least about 5 months, the suspension exhibits reduced upward pH drift by comparison with an otherwise similar comparative suspension that comprises at least 0.1% magnesium aluminum silicate. comprises at least 0.1% magnesium aluminum silicate.    
     
     
         83 . The suspension of  claim 82  wherein the suspension comprises zero to not more than 0.08% by weight of a clay-derived suspending agent.  
     
     
         84 . The suspension of  claim 83  substantially free from a clay-derived suspending agent.  
     
     
         85 . The suspension of  claim 82  wherein the at least one pharmaceutically acceptable bismuth-containing compound is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth nitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof.  
     
     
         86 . The suspension of  claim 85  wherein the at least one pharmaceutically acceptable bismuth-containing compound is bismuth subsalicylate.  
     
     
         87 . The suspension of  claim 82  wherein the at least one pharmaceutically acceptable bismuth-containing compound is present in a total amount of about 0.5% to about 5%, by weight.  
     
     
         88 . The suspension of  claim 82  wherein the at least one pharmaceutically acceptable non-clay-derived suspending agent is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, microcrystalline cellulose, xanthan gum, silicon dioxide, and mixtures thereof.  
     
     
         89 . The suspension of  claim 82  wherein the at least one pharmaceutically acceptable non-clay-derived suspending agent is present in a total amount of about 0.01% to about 15%, by weight.  
     
     
         90 . The suspension of  claim 82  wherein the at least one pharmaceutically acceptable anti-microbial preservative is selected from the group consisting of sorbic acid, methylparaben, sodium salicylate, salicylic acid, and mixtures thereof.  
     
     
         91 . The suspension of  claim 90  wherein the at least one pharmaceutically acceptable anti-microbial preservative is present in a total amount of about 0.01% to about 10%, by weight.  
     
     
         92 . The suspension of  claim 82  having a pH, measured immediately after preparation, of about 2 to about 8.  
     
     
         93 . The suspension of  claim 82  wherein the water is present in a total amount of about 50% to about 99%, by weight.  
     
     
         94 . A method of treating a gastrointestinal disease and/or disorder in a subject in need of such treatment, comprising oral administration to the subject of a therapeutically effective amount of a suspension of  claim 82.