Compositions and methods for treating nocturnal acid breakthrough and other 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.