Pharmaceutical Formulations Useful for Inhibiting Acid Secretion and Methods for Making and Using Them

Abstract

The present invention relates to pharmaceutical formulations comprising at least one acid-labile proton pump inhibiting agent and at least one antacid, which have improved bioavailability, chemical stability, physical stability, dissolution profiles, disintegration times, safety, as well as other improved pharmacokinetic, pharmacodynamic, chemical and/or physical properties. The present invention is directed to methods, kits, combinations, and compositions for treating, preventing or reducing the risk of developing a gastrointestinal disorder or disease, or the symptoms associated with, or related to, a gastrointestinal disorder or disease in a subject in need thereof.

What is claimed is: 
     
         1 . A pharmaceutical formulation in a capsule or caplet oral dosage form comprising:
 (a) about 5 mgs to about 200 mgs of at least one acid-labile proton pump inhibitor;   (b) at least one antacid in an amount sufficient to increase gastric fluid pH to a pH that prevents acid degradation of at least some of the proton pump inhibitor in the gastric fluid; wherein the antacid comprises at least about 400 mgs of NaHCO 3 ; and   (c) greater than about 2 wt-% of disintegrant;   
       wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered; and T max  of the proton pump inhibitor is obtained within about 60 minutes after administration. 
     
     
         2 . A pharmaceutical formulation according to  claim 1 , wherein the proton pump inhibitor is omeprazole, or a free base, free acid, salt, hydrate, or prodrug thereof. 
     
     
         3 . A pharmaceutical formulation according to  claim 1 , wherein the proton pump inhibitor is esomeprazole, or a free base, free acid, salt, hydrate, or prodrug thereof. 
     
     
         4 . A pharmaceutical formulation according to  claim 1 , wherein the proton pump inhibitor is lansoprazole, or a free base, free acid, salt, hydrate, or prodrug thereof. 
     
     
         5 . A pharmaceutical formulation according to  claim 1  comprising about 20 mgs of the proton pump inhibitor. 
     
     
         6 . A pharmaceutical formulation according to  claim 1  comprising about 40 mgs of the proton pump inhibitor. 
     
     
         7 . A pharmaceutical formulation according to  claim 1 , wherein the antacid is selected from sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof. 
     
     
         8 . A pharmaceutical formulation according to  claim 1 , wherein the sodium bicarbonate is present in an amount of at least about 800 mgs. 
     
     
         9 . A pharmaceutical formulation according to  claim 1 , wherein the antacid is sodium bicarbonate. 
     
     
         10 . A pharmaceutical formulation according to  claim 1 , wherein the antacid is present in an amount of about 400 mgs to about 1600 mgs. 
     
     
         11 . A pharmaceutical formulation according to  claim 1 , wherein the antacid is present in an amount of about 5 mEq to about 20 mEq. 
     
     
         12 . A pharmaceutical formulation according to  claim 1 , wherein the antacid is present in an amount of about 8 mEq to about 12 mEq. 
     
     
         13 . A pharmaceutical formulation according to  claim 1 , wherein the solid oral dosage form is a capsule. 
     
     
         14 . A pharmaceutical formulation according to  claim 13 , wherein the pharmaceutical formulation is administered as a single capsule. 
     
     
         15 . A pharmaceutical formulation according to  claim 1 , wherein the disintegrant is Ac-Di-Sol. 
     
     
         16 . A pharmaceutical formulation according to  claim 1 , wherein the disintegrant is present in an amount of about 2 wt-% to about 8 wt-%. 
     
     
         17 . A pharmaceutical formulation according to  claim 1 , wherein the formulation does not comprise a binder. 
     
     
         18 . A pharmaceutical formulation according to  claim 1 , further comprising a binder, wherein the disintegrant is present in at least the same wt-% as the binder. 
     
     
         19 . A pharmaceutical formulation according to  claim 18 , wherein the binder is present in an amount of less than about 10 wt-%. 
     
     
         20 . A pharmaceutical formulation according to  claim 1 , wherein the formulation does not comprise a flavoring agent. 
     
     
         21 . A pharmaceutical formulation according to  claim 1 , wherein an initial serum concentration of the proton pump inhibitor is greater than about 0.1 μg/ml at any time within about 30 minutes after administration of the pharmaceutical formulation. 
     
     
         22 . A pharmaceutical formulation in a capsule dosage form comprising:
 (a) at least one acid-labile proton pump inhibitor;   (b) between about 5 to about 20 mEq of sodium bicarbonate; and   (c) between about 2 wt-% to about 5 wt-% of a disintegrant;   
       wherein upon oral administration to a patient: a therapeutically effective amount of the proton pump inhibitor is delivered; and T max  of the proton pump inhibitor is obtained within about 45 minutes. 
     
     
         23 . A pharmaceutical formulation according to  claim 22 , wherein the proton pump inhibitor is omeprazole, or a free base, free acid, salt, hydrate, or prodrug thereof. 
     
     
         24 . A pharmaceutical formulation according to  claim 23 , wherein the omeprazole is present in an amount of about 20 mgs. 
     
     
         25 . A pharmaceutical formulation according to  claim 23 , wherein the omeprazole is present in an amount of about 20 mgs. 
     
     
         26 . A pharmaceutical formulation according to  claim 22 , wherein the sodium bicarbonate is present in an amount of about 800 mgs to about 1300 mgs. 
     
     
         27 . The pharmaceutical formulation of  claim 22 , wherein the sodium bicarbonate is present in an amount of about 1100 mgs. 
     
     
         28 . A pharmaceutical formulation according to  claim 22 , wherein the pharmaceutical formulation is administered as a single capsule. 
     
     
         29 . The pharmaceutical formulation of  claim 22 , wherein the disintegrant is Ac-Di-Sol. 
     
     
         30 . A pharmaceutical formulation according to  claim 22 , wherein the formulation does not comprise a binder. 
     
     
         31 . A pharmaceutical formulation according to  claim 22 , wherein the formulation does not comprise a binder. 
     
     
         32 . A pharmaceutical formulation according to  claim 22 , wherein an initial serum concentration of the proton pump inhibitor is greater than about 0.1 μg/ml at any time within about 30 minutes after administration of the pharmaceutical formulation. 
     
     
         33 . A method of administering a compound according to  claim 1 , for the treatment of a gastric acid related disorder. 
     
     
         34 . The method according to  claim 33 , wherein the gastric acid related disorder is duodenal ulcer disease, gastric ulcer disease, gastroesophageal reflux disease, erosive esophagitis, poorly responsive symptomatic gastroesophageal reflux disease, pathological gastrointestinal hypersecretory disease, Zollinger Ellison syndrome, heartburn, esophageal disorder, upper GI bleeding, or acid dyspepsia.