Pharmaceutical solid preparation comprising benzazepines and production method thereof

Abstract

The subject invention provides a novel pharmaceutical solid preparation that has superior disintegration properties and excellent solubility, leading to sufficient absorbability of active ingredients through the gastrointestinal tract. The pharmaceutical solid preparation of the present invention comprises: (a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or salt thereof; (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and (c) at least one member selected from the group consisting of carmellose, sodium carboxy methyl starch, crospovidone, and low substituted hydroxypropylcellulose with an average particle diameter of 30 to 70 μm, and a 90% cumulative particle diameter of 100 to 200 μm.

1 . A pharmaceutical solid preparation comprising:
 (a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or salt thereof;   (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and   (c) at least one member selected from the group consisting of carmellose, sodium carboxy methyl starch, crospovidone, and low substituted hydroxypropylcellulose with an average particle diameter of 30 to 70 μm, and a 90% cumulative particle diameter of 100 to 200 μm.   
     
     
         2 . A pharmaceutical solid preparation comprising:
 (a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or salt thereof;   (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and   (c-1) low substituted hydroxypropylcellulose, an average particle diameter of 30 to 70 μm, and a 90% cumulative particle diameter of 100 to 200 μm.   
     
     
         3 . The pharmaceutical solid preparation according to  claim 2 , wherein the low substituted hydroxypropylcellulose has an average particle diameter of 45 to 65 μm, and a 90% cumulative particle diameter of 100 to 200 μm. 
     
     
         4 . The pharmaceutical solid preparation according to  claim 2 , wherein the pharmaceutical solid preparation is a form of tablet. 
     
     
         5 . The pharmaceutical solid preparation according to  claim 2 , obtained by a method, comprising:
 Step 1 of producing an amorphous composite from 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or salt thereof, and hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater;   Step 2 of mixing the amorphous composite obtained in Step 1 with low substituted hydroxypropylcellulose, an average particle diameter of 30 to 70 μm, and a 90% cumulative particle diameter of 100 to 200 μm; and   Step 3 of processing the mixture obtained in Step 2 into a solid preparation.   
     
     
         6 . The pharmaceutical solid preparation according to  claim 5 , produced by a method further comprising, between Step 1 and Step 2, the step of processing the amorphous composite obtained in Step 1 into granules using a granulation method. 
     
     
         7 . The pharmaceutical solid preparation according to  claim 5 , produced by a method further comprising, between Step 2 and Step 3, the step of processing the mixture obtained in Step 2 into granules using a granulation method. 
     
     
         8 . A method for producing the pharmaceutical solid preparation according to  claim 2 , the method comprising:
 Step 1 of producing an amorphous composite from 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or a salt thereof, and hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater;   Step 2 of mixing the amorphous composite obtained in Step 1 with low substituted hydroxypropylcellulose, an average particle diameter of 30 to 70 μm, and a 90% cumulative particle diameter of 100 to 200 μm; and   Step 3 of processing the mixture obtained in Step 2 into a solid preparation.   
     
     
         9 . The method according to  claim 8 , wherein Step 3 is carried out by processing the mixture obtained Step 2 into tablets. 
     
     
         10 . The method according to  claim 8 , further comprising, between Step 1 and Step 2, the step of processing the amorphous composite obtained in Step 1 into granules using a granulation method. 
     
     
         11 . The method according to  claim 8 , further comprising, between Step 2 and Step 3, the step of processing the mixture obtained in Step 2 into granules using a granulation method. 
     
     
         12 . A pharmaceutical solid preparation comprising:
 (a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or a salt thereof;   (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and   (c-2) carmellose.   
     
     
         13 . The pharmaceutical solid preparation according to  claim 12 , wherein the content of the carmellose is 7 to 15 wt. %, based on the total quantity of the pharmaceutical solid preparation. 
     
     
         14 . A pharmaceutical solid preparation comprising:
 (a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or salt thereof;   (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and   (c-3) sodium carboxy methyl starch.   
     
     
         15 . The pharmaceutical solid preparation according to  claim 14 , wherein the content of the sodium carboxy methyl starch is 0.5 to 15 wt. %, based on the total quantity of the pharmaceutical solid preparation. 
     
     
         16 . A pharmaceutical solid preparation comprising:
 (a) 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine and/or a salt thereof;   (b) hydroxypropylcellulose containing a hydroxypropoxyl group in an amount of 50% or greater; and   (c-4) crospovidone.   
     
     
         17 . The pharmaceutical solid preparation according to  claim 16 , wherein the content of the crospovidone is 2 to 15 wt. %, based on the total quantity of the pharmaceutical solid preparation. 
     
     
         18 . The method according to  claim 9 , further comprising, between Step 1 and Step 2, the step of processing the amorphous composite obtained in Step 1 into granules using a granulation method. 
     
     
         19 . The method according to  claim 9 , further comprising, between Step 2 and Step 3, the step of processing the mixture obtained in Step 2 into granules using a granulation method.