Stable combinations of amlodipine besylate and benazepril hydrochloride

Abstract

The present invention provides a pharmaceutical composition comprising benazepril and amlodipine wherein the benazepril and the amlodipine are not physically separated from one another, and methods for making the same.

1 . A pharmaceutical composition comprising:
 a) Benazepril or its solvates, or a pharmaceutically acceptable salt thereof, and   b) Amlodipine or its solvates, or a pharmaceutically acceptable salt thereof, such that the benazepril and the amlodipine are not physically separated from one another, and wherein after about 3 months at about 40° C. at about 75% relative humidity, the pharmaceutical composition contains:   i) no more than 2.5% of (s,$)-diacid by weight relative to the benazepril; and/or   ii) no more than 0.3% of impurity D by weight relative to the amlodipine.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is encapsulated. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the benazepril is benazepril hydrochloride. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the amlodipine is amlodipine besylate. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the benazepril is prepared by wet granulation, and the amlodipine is prepared by dry processing. 
     
     
         6 . A method comprising:
 a) preparing a benazepril composition by wet granulation;   b) preparing an amlodipine composition by dry processing; and   c) contacting the benazepril composition and the amlodipine composition, and optionally adding excipients, to obtain a combination pharmaceutical composition.   
     
     
         7 . The method of  claim 6 , wherein the benazepril composition comprises benazepril hydrochloride and one or more pharmaceutical excipients. 
     
     
         8 . The method of  claim 7 , wherein benazepril composition comprises one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, microcrystalline cellulose, polysorbate  80 , and povidone. 
     
     
         9 . The method of  claim 8 , wherein the benazepril composition comprises:
 a) about 5% to about 20% benazepril hydrochloride;   b) about 15% to about 20% pregelatinized starch;   c) about 25% to about 35% lactose monohydrate;   d) about 10% to about 15% starch;   e) about 5% crospovidone;   f) about 15% to about 25% microcrystalline cellulose;   g) about 0.1% to about 2% polysorbate  80 ; and   h) about 5% povidone,   by weight percent relative to the total benazepril composition.   
     
     
         10 . The method of  claim 6 , wherein preparing the benazepril composition by wet granulation comprises:
 a) combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose;   b) adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water and optionally, polysorbate  80 , povidone, or both;   c) drying the wet granulate to obtain a dry granulate; and   d) milling the dry granulate.   
     
     
         11 . The method of  claim 6 , wherein the amlodipine composition comprises amlodipine besylate and one or more pharmaceutical excipients. 
     
     
         12 . The method of  claim 6 , wherein the amlodipine composition comprises one or more pharmaceutical excipients selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide. 
     
     
         13 . The method of  claim 12 , wherein the amlodipine composition comprises:
 a) about 2% to about 10% amlodipine besylate;   b) about 25% to about 30% calcium phosphate dibasic;   c) about 1% to about 2% sodium starch glycolate;   d) about 50% to about 60% microcrystalline cellulose;   e) about 1% colloidal silicon dioxide,   by weight percent relative to the total amlodipine composition.   
     
     
         14 . The method of  claim 6 , wherein the optionally added excipients comprise crospovidone and magnesium stearate. 
     
     
         15 . The method of  claim 6 , wherein the optionally added excipients comprise about 1% to about 5% crospovidone and about 0.2% to about 2% magnesium stearate by weight percent relative to the total amlodipine composition. 
     
     
         16 . The method of  claim 6 , wherein preparing the amlodipine composition by dry processing comprises:
 a) sieving a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide; and   b) blending the mixture.   
     
     
         17 . The method of  claim 6 , further comprising:
 a) sieving one or more additional pharmaceutical excipients selected from the group consisting of crospovidone and magnesium stearate; and   b) blending the additional pharmaceutical excipient with the mixture.   
     
     
         18 . The method of  claim 6 , further comprising encapsulating the combined pharmaceutical composition. 
     
     
         19 . The method of  claim 6 , comprising:
 a) combining benazepril hydrochloride with one or more pharmaceutical excipients selected from the group consisting of pregelatinized starch, lactose monohydrate, starch, crospovidone, and microcrystalline cellulose;   b) adding a granulation solution to obtain a wet granulate, wherein the granulation solution comprises water, polysorbate  80 , and povidone;   c) drying the wet granulate to obtain a dry granulate;   d) milling the dry granulate;   e) sieving a mixture of amlodipine besylate and one or more pharmaceutical excipients selected from the group consisting of calcium phosphate dibasic, sodium starch glycolate, microcrystalline cellulose, and colloidal silicon dioxide, through a 30 mesh sieve;   f) blending the mixture with the dry granulate to form a combined pharmaceutical composition;   g) sieving crospovidone through a 30 mesh sieve;   h) blending the crospovidone with the combined pharmaceutical composition;   i) sieving magnesium stearate through a 50 mesh sieve;   j) blending the magnesium stearate with the combined pharmaceutical composition; and   k) encapsulating the combined pharmaceutical composition.   
     
     
         20 . A benazepril composition comprising:
 a) about 5% to about 20% benazepril hydrochloride;   b) about 15% to about 20% pregelatinized starch;   c) about 25% to about 35% lactose monohydrate;   d) about 10% to about 15% starch;   e) about 5% crospovidone;   f) about 15% to about 25% microcrystalline cellulose;   g) about 0.1% to about 2% polysorbate  80 ; and   h) about 5% povidone,   by weight percent relative to the total benazepril composition.   
     
     
         21 . An amlodipine composition comprising:
 a) about 2% to about 10% amlodipine besylate;   b) about 25% to about 30% calcium phosphate dibasic;   c) about 1% to about 2% sodium starch glycolate;   d) about 50% to about 60% microcrystalline cellulose;   e) about 1% colloidal silicon dioxide;   f) about 5% crospovidone; and   g) about 0.2% to about 2% magnesium stearate,   
       by weight percent relative to the total amlodipine composition