Compositions and methods for treating nocturnal acid breakthrough and other acid related disorders

Abstract

The present invention relates to, inter alia, pharmaceutical compositions comprising an acid labile proton pump inhibitor and a buffering agent; to methods for manufacture of such compositions, and to use of such compositions in treating and preventing diseases and/or disorders.

1 . A method for treating and/or preventing nocturnal acid breakthrough in a subject in need thereof, the method comprising: administering to the subject a solid pharmaceutical composition comprising an acid labile proton pump inhibitor and a buffering agent, wherein: 
 (a) the proton pump inhibitor is not enteric coated;    (b) the proton pump inhibitor is present in the composition in an amount of about 5 mg to about 60 mg;    (c) the buffering agent is present in the composition in an amount of about 200 mg to about 3500 mg; and    (d) the administration step is performed between about 8:00 pm and about 12:00 am, inclusive.    
     
     
         2 . The method of  claim 1 , wherein the administration step is performed between about 9:00 pm and about 12:00 am, inclusive.  
     
     
         3 . The method of  claim 1 , wherein the administration step is performed between about 9:30 pm and about 11:30 pm, inclusive.  
     
     
         4 . The method of  claim 1  wherein the proton pump inhibitor is of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;  
 R 2  is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;  
 R 3  and R 5  are the same or different and each is hydrogen, alkyl, alkoxy, amino, or alkoxyalkoxy;  
 R 4  is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy;  
 Q is nitrogen, CH, or CR 1 ;  
 W is nitrogen, CH, or CR 1 ;  
 y is an integer of 0 through 4; and  
 Z is nitrogen, CH, or CR 1 ;  
 or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.  
 
     
     
         5 . The method of  claim 1  wherein the proton pump inhibitor is omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.  
     
     
         6 . The method of  claim 1  wherein the proton pump inhibitor is omeprazole or lansoprazole.  
     
     
         7 . The method of  claim 1  wherein the proton pump inhibitor is omeprazole.  
     
     
         8 . The method of  claim 1  wherein the proton pump inhibitor is present in an amount of about 10 mg to about 40 mg on a dry weight basis.  
     
     
         9 . The method of  claim 1  wherein the buffering agent is present in an amount of about 400 mg to about 3000 mg on a dry weight basis.  
     
     
         10 . The method of  claim 1  wherein the buffering agent is present in an amount of about 500 mg to about 2500 mg on a dry weight basis.  
     
     
         11 . The method of  claim 1  wherein the composition further comprises at least one pharmaceutically acceptable excipient.  
     
     
         12 . The method of  claim 1  wherein the composition is a dosage form is selected from a tablet, a suspension tablet, a bite suspension tablet, a rapid dispersion tablet, a chewable tablet, an effervescent tablet, a bilayer tablet, a caplet, a capsule, a powder, a lozenge, a sachet, a cachet, a troche, a pellet, a granule and a microgranule.  
     
     
         13 . A method for treating and/or preventing nocturnal acid breakthrough in a subject in need thereof, the method comprising: administering to the subject a solid pharmaceutical composition comprising an acid labile proton pump inhibitor and a buffering agent, wherein: 
 (a) the proton pump inhibitor is not enteric coated,    (b) the proton pump inhibitor is present in the composition in an amount of about 5 mg to about 60 mg;    (c) the buffering agent is present in the composition in an amount of about 200 mg to about 3500 mg; and    (d) the administration step is performed prior to 12:00 am and at such a time so as to result in a blood serum concentration of the proton pump inhibitor of at least about 0.1 micromolar at any time point from about 12:00 am to about 6:00 am following administration.    
     
     
         14 . The method of  claim 13  wherein the administration step is performed at such a time so as to result in a blood serum concentration of the proton pump inhibitor of at least about 0.9 micromolar at any time point from about 1:00 am to about 5:00 am following administration.  
     
     
         15 . The method of  claim 13  wherein the proton pump inhibitor is of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, alkoxy which is optionally fluorinated, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl;  
 R 2  is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl;  
 R 3  and R 5  are the same or different and each is hydrogen, alkyl, alkoxy, amino, or alkoxyalkoxy;  
 R 4  is hydrogen, alkyl, alkoxy which may optionally be fluorinated, or alkoxyalkoxy;  
 Q is nitrogen, CH, or CR 1 ;  
 W is nitrogen, CH, or CR 1 ;  
 y is an integer of 0 through 4; and  
 Z is nitrogen, CH, or CR 1 ;  
 or a free base, salt, ester, hydrate, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof.  
 
     
     
         16 . The method of  claim 13  wherein the proton pump inhibitor is omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole and nepaprazole or a free base, a free acid, or a salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, prodrug, or derivative of such compounds.  
     
     
         17 . The method of  claim 13  wherein the proton pump inhibitor is omeprazole or lansoprazole.  
     
     
         18 . The method of  claim 13  wherein the proton pump inhibitor is omeprazole.  
     
     
         19 . The method of  claim 13  wherein the proton pump inhibitor is present in an amount of about 10 mg to about 40 mg on a dry weight basis.  
     
     
         20 . The method of  claim 13  wherein the buffering agent is present in an amount of about 400 mg to about 3000 mg on a dry weight basis.  
     
     
         21 . The method of  claim 13  wherein the buffering agent is present in an amount of about 500 mg to about 2500 mg on a dry weight basis.  
     
     
         22 . The method of  claim 13  wherein the composition further comprises at least one pharmaceutically acceptable excipient.  
     
     
         23 . The method of  claim 13  wherein the composition is a solid dosage form is selected from a tablet, a suspension tablet, a bite suspension tablet, a rapid dispersion tablet, a chewable tablet, an effervescent tablet, a bilayer tablet, a caplet, a capsule, a powder, a lozenge, a sachet, a cachet, a troche, a pellet, a granule and a microgranule.  
     
     
         24 . A method for treating and/or preventing nocturnal acid breakthrough in a subject in need thereof, the method comprising: administering to the subject a solid pharmaceutical composition comprising an acid labile proton pump inhibitor and a buffering agent, wherein: 
 (a) the proton pump inhibitor is not enteric coated;    (b) the proton pump inhibitor is present in the composition in an amount of about 5 mg to about 60 mg;    (c) the buffering agent is present in the composition in an amount of about 200 mg to about 3500 mg; and    (d) the administration step is performed prior to 2:00 am and at such a time so as to result in a blood serum concentration of the proton pump inhibitor of at least about 1 micromolar at any time point from about 2:00 am to about 4:00 am following administration.    
     
     
         25 . A method for treating and/or preventing nocturnal acid breakthrough in a subject in need thereof, the method comprising the steps of: 
 (a) determining the subject's typical period of nocturnal acid breakthrough; and    (b) providing the subject with a pharmaceutical composition comprising an acid labile, substituted benzimidazole H + , K + -ATPase proton pump inhibitor and a buffering agent at a time such that the subject exhibits a blood serum concentration of the proton pump inhibitor of at least about 0.1 micromolar at any time point during the subject's determined typical period of nocturnal acid breakthrough.    
     
     
         26 . A method for treating and/or preventing nocturnal acid breakthrough in a subject in need thereof, the method comprising the steps of: 
 (a) determining the subject's typical period of nocturnal acid breakthrough; and    (b) providing the subject with a pharmaceutical composition comprising an acid labile, substituted benzimidazole H + , K + -ATPase proton pump inhibitor and a buffering agent at a time such that the subject exhibits a blood serum concentration of the proton pump inhibitor of at least about 1 micromolar at any time point during the subject's determined typical period of nocturnal acid breakthrough.