Novel substituted benzimidazole dosage forms and method of using same

Abstract

A method of treating gastric acid disorders by administering to a patient a pharmaceutical composition comprising a proton pump inhibitor (PPI) in a pharmaceutically acceptable carrier. The present invention provides an oral solution/suspension comprising a proton pump inhibitor and at least one buffering agent. The PPI can be any substituted benzimidazole compound having H + ,K + -ATPase inhibiting activity and being unstable to acid. Omeprazole and lansoprazole are the preferred PPIs for use in oral suspensions in concentrations of at least greater than 1.2 mg/ml and 0.3 mg, respectively. The liquid oral compositions can be further comprised of parietal cell activators, anti-foaming agents and/or flavoring agents. The inventive compositions can alternatively be formulated as a powder, tablet, suspension tablet, chewable tablet, capsule, effervescent powder, effervescent tablet, pellets and granules. Such dosage forms are advantageously devoid of any enteric coating or delayed or sustained-release delivery mechanisms, and comprise a PPI and at least one buffering agent to protect the PPI against acid degradation. Similar to the liquid dosage form, the dry forms can further include anti-foaming agents, parietal cell activators and flavoring agents. Kits utilizing the inventive dry dosage forms are also disclosed herein to provide for the easy preparation of a liquid composition from the dry forms. In accordance with the present invention, there is further provided a method of treating gastric acid disorders by administering to a patient a pharmaceutical composition comprising a proton pump inhibitor in a pharmaceutically acceptable carrier and at least one buffering agent wherein the administering step comprises providing a patient with a single dose of the composition without requiring further administering of the buffering agent. Additionally, the present invention relates to a method for enhancing the pharmacological activity of an intravenously administered proton pump inhibitor in which at least one parietal cell activator is orally administered to the patient before, during or after the intravenous administration of the proton pump inhibitor.

1 - 22 . (Cancelled).  
     
     
         23 . A pharmaceutical composition in the form of a suspension, wherein: 
 (a) the suspension is produced by constituting a storage stable powder with a liquid medium;    (b) the powder comprises a therapeutically effective amount of at least one acid labile substituted benzimidazole H + ,K + -ATPase proton pump inhibitor and at least one buffering agent;    (c) the at least one buffering agent is present in the powder in a total amount of about 0.1 mEq to about 2.5 mEq per mg of proton pump inhibitor; and    (d) after constitution, the suspension is substantially stable upon storage in a closed container maintained at 4° C. for a period of at least about 1 day.    
     
     
         24 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 4° C. for a period of at least about 2 days.  
     
     
         25 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 4° C. for a period of at least about 7 days.  
     
     
         26 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 4° C. for a period of at least about 14 days.  
     
     
         27 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 4° C. for a period of at least about 12 months.  
     
     
         28 . The composition of  claim 23 , wherein after constitution and storage of the suspension in a closed container maintained at 4° C. for a period of at least about 12 months, at least about 90%, by weight, of said proton pump inhibitor is still present in the suspension.  
     
     
         29 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 25° C. for a period of at least about 1 day.  
     
     
         30 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 25° C. for a period of at least about 2 days.  
     
     
         31 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 25° C. for a period of at least about 7 days.  
     
     
         32 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 25° C. for a period of at least about 14 days.  
     
     
         33 . The composition of  claim 23 , wherein after constitution, the suspension is substantially stable upon storage in a closed container maintained at 25° C. for a period of at least about 12 months.  
     
     
         34 . The composition of  claim 23 , wherein after constitution and storage of the suspension in a closed container maintained at 25° C. for a period of at least about 12 months, at least about 90%, by weight, of said proton pump inhibitor is still present in the suspension.  
     
     
         35 . The composition of  claim 23 , wherein the at least one proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, rabeprazole, esomeprazole (s-omeprazole), pantoprazole, pariprazole, leminoprazole, or an enantiomer, an alkaline salt of an enantiomer, an isomer, a prodrug, a derivative or a salt thereof.  
     
     
         36 . The composition of  claim 23 , wherein the at least one proton pump inhibitor is omeprazole, or an enantiomer, an alkaline salt of an enantiomer, an isomer, a prodrug, a derivative or a salt thereof.  
     
     
         37 . The composition of  claim 23 , wherein the at least one proton pump inhibitor is lansoprazole, or an enantiomer, an alkaline salt of an enantiomer, an isomer, a prodrug, a derivative or a salt thereof.  
     
     
         38 . The composition of  claim 23 , wherein the at least one proton pump inhibitor is esomeprozole, or an enantiomer, an alkaline salt of an enantiomer, an isomer, a prodrug, a derivative or a salt thereof.  
     
     
         39 . The composition of  claim 23 , wherein the at least one buffering agent is selected from the group consisting of a calcium buffering agent, a magnesium buffering agent, an aluminum buffering agent, a sodium buffering agent, a bicarbonate salt of a Group IA metal, an alkaline earth metal buffering agent, an amino acid, an alkali salt of an amino acid, or mixtures thereof.  
     
     
         40 . The composition of  claim 23 , wherein the at least one buffering agent is selected from the group consisting of, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, magnesium oxide, magnesium aluminate, magnesium carbonate, magnesium silicate, magnesium citrate, aluminum hydroxide, aluminum hydroxide/magnesium carbonate, aluminum hydroxide/sodium bicarbonate coprecipitate, aluminum glycinate, sodium citrate, calcium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, potassium carbonate, potassium metaphosphate, calcium acetate, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium carbonate, calcium gluconate, calcium bicarbonate, potassium phosphate, potassium citrate, and mixtures thereof.  
     
     
         41 . The composition of  claim 23 , wherein the at least one buffering agent and the at least one proton pump inhibitor are present in a mEq:mg ratio of about 1:1 to about 1:3.5.  
     
     
         42 . The composition of  claim 23 , further comprising a pharmaceutically acceptable excipient selected from the group consisting of a binder, a flavoring agent, a sweetening agent, a disintegrant, a flow aid, a lubricant, an adjuvant, an antioxidant, a chelating agent, an isotonic agent, a thickening agent, a carrier, a colorant, a diluent, a moistening agent, a preservative, a parietal cell activator, and an anti-foaming agent, or combinations thereof.  
     
     
         43 . The composition of  claim 23 , wherein after constitution, the suspension comprises substantially no solid enteric-coating material.  
     
     
         44 . A method for treating a gastric acid related disorder in a subject in need thereof, the method comprising administering the suspension of  claim 23  to the subject.  
     
     
         45 . The method of  claim 44 , wherein the proton pump inhibitor is omeprazole.  
     
     
         46 . The method of  claim 44 , wherein the proton pump inhibitor is lansoprazole.  
     
     
         47 . The method of  claim 44 , wherein the proton pump inhibitor is esomeprazole (s-omeprazole).  
     
     
         48 . The method of  claim 44 , wherein the gastric acid related disorder is selected from the group consisting of a duodenal ulcer disease, a gastric ulcer disease, a gastroesophageal reflux disease, a erosive esophagitis, a poorly responsive symptomatic gastroesophageal reflux disease, a pathological gastrointestinal hypersecretory disease, and Zollinger Ellison Syndrome.