Viscosity-stable compositions useful for treating gastrointestinal disorders
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, water, and a stabilizing means for reducing viscosity change upon storage of the composition. The suspension exhibits reduced change in viscosity by comparison with an otherwise similar suspension excepting the stabilizing means. Such compositions are useful in the prevention and treatment of gastrointestinal diseases and/or disorders.
1 . An orally deliverable pharmaceutical composition comprising
(a) at least one pharmaceutically acceptable bismuth-containing agent;
(b) at least one pharmaceutically acceptable non-clay-derived suspending agent;
c) at least one stabilizing means for reducing viscosity change during storage of the composition;
(d) and water;
wherein the composition is in the form of a suspension.
2 . The composition of claim 1 wherein the at least one stabilizing means is present at a concentration effective to prevent more than about a 50% viscosity change during a 5 week storage period at 50° C., the storage period being initiated within a reasonably short time after preparation of the composition.
3 . The composition of claim 1 wherein the at least one stabilizing means is present at a concentration effective to prevent more than about a 50% viscosity change during a 4 week storage period at 50° C., the storage period being initiated within a reasonably short time after preparation of the composition.
4 . The composition of claim 1 wherein the at least one pharmaceutically acceptable bismuth-containing agent is present in the composition at more than about 55 mM, wherein the at least one stabilizing means is present at a concentration effective to prevent more than about a 75% viscosity change during a 3 week storage period at 50° C., the storage period being initiated within a reasonably short time after preparation of the composition.
5 . The composition of claim 1 wherein the at least one stabilizing means is present at a concentration to prevent more than about 10% decrease in viscosity during a 3 month storage period at 24° C., the storage period being initiated within a reasonably short time after preparation of the composition.
6 . The composition of claim 1 wherein the at least one stabilizing means is selected from the group consisting of buffering agents, hydronium ions at a concentration effective to achieve a pH of the composition of about 4.0 to about 5.2, electrolytes, and salicylate agents.
7 . The composition of claim 1 wherein the at least one stabilizing means comprises at least one buffering agent.
8 . The composition of claim 7 wherein the at least one buffering agent is selected from the group consisting of acetates, sorbates, lactates, malates, tartrates, citrates, and phosphates.
9 . The composition of claim 7 wherein the at least one buffering agent comprises citrate.
10 . The composition of claim 9 wherein the citrate comprises citric acid and citrate salt wherein the citrate is present in an amount effective to achieve a pH of about 4.5 to about 5.2.
11 . The composition of claim 7 wherein the at least one buffering agent is present in the composition in a total concentration of about 5 to about 100 mM.
12 . The composition of claim 7 wherein the at least one buffering agent is present in the composition in a total concentration of about 20 to about 65 mM.
13 . The composition of claim 1 wherein the at least one stabilizing means comprises at least one electrolyte.
14 . The composition of claim 13 wherein the at least one electrolyte is selected from the group consisting of NaCl, KCl, CaCl 2 , and potassium sorbate.
15 . The composition of claim 13 wherein the at least one electrolyte is present in the composition in a total concentration of about 10 to about 200 mM.
16 . The composition of claim 13 wherein the at least one electrolyte is present in the composition in a total concentration of about 20 to about 100 mM.
17 . The composition of claim 13 wherein the at least one electrolyte is present in the composition in a total concentration of about 30 to about 90 mM.
18 . The composition of claim 1 wherein the at least one stabilizing means comprises hydronium ions at a concentration effective to achieve a pH of the composition of about 4.0 to about 5.2.
19 . The composition of claim 18 wherein the hydronium ions are present at a concentration effective to achieve a pH of the composition of about 4.3 to about 5.2.
20 . The composition of claim 18 wherein the hydronium ions are present at a concentration effective to achieve a pH of the composition of about 4.5 to about 5.2.
21 . The composition of claim 18 wherein the hydronium ions are present at a concentration effective to achieve a pH of the composition of about 4.7 to about 5.1.
22 The composition of claim 1 wherein the at least one stabilizing means consists of at least one salicylate agent.
23 . The composition of claim 22 wherein the at least one salicylate agent is present in an amount of about 0.5 to about 50 mg/ml of the composition.
24 . The composition of claim 1 wherein the at least one stabilizing means comprises
(a) a buffering agent selected from the group consisting of acetates, sorbates, lactates, malates, tartrates, citrates, and phosphates, wherein the buffering agent is present in the composition in a total concentration of about 5 to about 100 mM.
(b) an electrolyte selected from the group consisting of NaCl, KCl, CaCl 2 , and potassium sorbate, wherein the electrolyte is present in the composition in a total concentration of about 10 to about 200 mM.
(c) hydronium ions present at a concentration effective to achieve a pH of the composition of about 4.7 to about 5.1, and
(d) at least one salicylate agent.
25 . The composition of claim 1 wherein the suspending agent comprises substantially no amount of a clay-derived suspending agent.
26 . The composition of claim 25 wherein the suspending agent is a polymer.
27 . The composition of claim 26 wherein the suspending agent is cellulosic.
28 . The composition of claim 26 wherein the suspending agent is selected from the group consisting of guar gum, propylene glycol alginate, locust bean gum, and xanthan gum.
29 . The composition of claim 1 wherein the bismuth-containing agent 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, and bismuth subsalicylate.
30 . The composition of claim 1 wherein the bismuth-containing agent is present in a total agent amount of about 0.1 to about 500 mg/ml of the composition.
31 . The composition of claim 1 wherein the bismuth-containing agent is present in a total agent amount of about 5 to about 50 mg/ml of the composition.
32 . The composition of claim 1 further comprising at least one preservative agent comprising an antimicrobial compound having antimicrobial activity.
33 . The composition of claim 32 wherein the at least one preservative agent substantially retains said antimicrobial activity during a 6 month storage period of the composition at room temperature.