Stable pharmaceutical compositions containing an ACE inhibitor

Abstract

A stable pharmaceutical composition comprising about 1 wt. % to about 80 wt. % of an ACE inhibitor or a pharmaceutical acceptable salt thereof, about 1 wt. % to about 70 wt. % of an alkali or alkaline earth metal carbonate, and about 1 wt. % to about 80 wt. % of hydroxypropyl cellulose, wherein the ACE inhibitor is selected from the group consisting of quinapril, enalapril, spirapril, ramipril, perindopril, indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril, delapril, cilazapril and combinations thereof; wherein the formation of an internal cyclization product, and/or ester hydrolysis product, and/or oxidation product, has been reduced or eliminated, and the weight percents are based on the total weight of the pharmaceutical composition. The stabilized pharmaceutical compositions of the invention exhibit a number of advantages as follows: (i) the ACE inhibitor or a pharmaceutical acceptable salt thereof present in the compositions is preserved from degradation; (ii) the compositions exhibit extended shelf-life under normal storage conditions; (iii) the effect of moisture on the compositions is minimized; (iv) the compositions exhibit minimal, if any, discoloration over a significant period of time; and (v) the compositions exhibit minimal, if any, instability when employed in the presence of colorants.

1 - 21 . (canceled)  
     
     
         22 . A stable pharmaceutical composition comprising about 1 wt. % to about 80 wt. % of an ACE inhibitor or a pharmaceutical acceptable salt thereof, about 1 wt. % to about 70 wt. % of an alkali or alkaline earth metal carbonate, and about 1 wt. % to about 80 wt. % a low-substituted hydroxypropyl cellulose, wherein the ACE inhibitor is selected from the group consisting of enalapril, spirapril, ramipril, perindopril, indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril, delapril, cilazapril and combinations thereof; wherein the weight percents are based on the total weight of the pharmaceutical composition.  
     
     
         23 . The composition according to  claim 22 , wherein the ACE inhibitor is selected from the group consisting of ramipril, enalapril and spirapril.  
     
     
         24 . The composition according to  claim 23 , wherein the ramipril is ramiprilat.  
     
     
         25 . The composition according to  claim 22 , wherein the amount of the ACE inhibitor-or a pharmaceutical acceptable salt thereof is from about 5 wt. % to about 50 wt. %, based on the total weight of the pharmaceutical composition.  
     
     
         26 . The composition according to  claim 25 , wherein the amount of the ACE inhibitor-or a pharmaceutical acceptable salt thereof is from about 10 wt. % to about 15 wt. %, based on the total weight of the pharmaceutical composition.  
     
     
         27 . The composition according to  claim 22 , wherein the alkali metal is selected from the group consisting of lithium, sodium, potassium, rubidium, cesium and francium.  
     
     
         28 . The composition according to  claim 22 , wherein the alkaline earth metal is selected from the group consisting of magnesium, calcium, barium, strontium and radium.  
     
     
         29 . The composition according to  claim 28 , wherein the alkaline earth metal is magnesium.  
     
     
         30 . The composition according to  claim 22 , wherein the amount of the alkali or alkaline earth metal carbonate is from about 10 wt. % to about 60 wt. %, based on the total weight of the pharmaceutical composition.  
     
     
         31 . The composition according to  claim 30 , wherein the amount of the alkali or alkaline earth metal carbonate is from about 45 wt. % to about 55 wt. %, based on the total weight of the pharmaceutical composition.  
     
     
         32 . The composition according to  claim 22 , wherein the low-substituted hydroxypropyl cellulose when dried at 105° C. for 1 hour contains 5-16% of hydroxypropoxy groups.  
     
     
         33 . The composition according to  claim 32 , wherein the low-substituted hydroxypropyl cellulose when dried at 105° C. for 1 hour contains 10-13% of hydroxypropoxy groups.  
     
     
         34 . The composition according to  claim 33 , wherein the low-substituted hydroxypropyl cellulose is selected from the group consisting of: LH-11 having a hydroxypropoxy content of 11% and an average particle size of 50 microns; LH-21 having a hydroxypropoxy content of 11% and an average particle size of 40 microns; LH-31 having a hydroxypropoxy content of 11%, and an average particle size of 25 microns; LH-22 having a hydroxypropoxy content of 8%, and an average particle size of 40 microns; LH-32 having a hydroxypropoxy content of 8%, and an average particle size of 25 microns; LH-20 having a hydroxypropoxy content of 13%, and an average particle size of 40 microns; and LH-30 having a hydroxypropoxy content of 13%, and an average particle size of 25 microns.  
     
     
         35 . The composition according to  claim 34 , wherein the low-substituted hydroxypropyl cellulose is LH-21 or LH-11.  
     
     
         36 . The composition according to  claim 22 , wherein the low-substituted hydroxypropyl cellulose is present in an amount of from about 10 wt. % to about 50 wt. %.  
     
     
         37 . The composition according to  claim 36 , wherein the hydroxypropyl cellulose is present in an amount of from about 30 wt. % to about 40 wt. %.  
     
     
         38 . The composition according to  claim 22 , which is in the form selected from the group consisting of a tablet, granules, bar, block, disc, capsule, caplet and powder.  
     
     
         39 . A method of preparing a stable pharmaceutical composition comprising about 1 wt. % to about 80 wt. % of an ACE inhibitor or a pharmaceutical acceptable salt thereof, about 1 wt. % to about 70 wt. % of an alkali or alkaline earth metal carbonate, and about 1 wt. % to about 80 wt. % a low-substituted hydroxypropyl cellulose, wherein the ACE inhibitor is selected from the group consisting of enalapril, spirapril, ramipril, perindopril, indolapril, lisinopril, alacepril, trandolapril, benazapril, libenzapril, delapril, cilazapril and combinations thereof; wherein the weight percents are based on the total weight of the pharmaceutical composition, said method comprising: 
 (a) mixing the ACE inhibitor or a pharmaceutical acceptable salt thereof, an alkali or alkaline earth metal carbonate, a low-substituted hydroxypropyl cellulose, and optionally one or more excipients, to form a premix;    (b) adding a solvent, and optionally one or more excipients, to the premix formed in Step (a) to form a wet granulation;    (c) drying the wet granulation to form granules, and optionally milling the granules; and    (d) optionally mixing one or more excipients with the granules to form a pharmaceutical composition.