Preparation containing tetracyclic compound at high dose

Abstract

An improved solubility of a pharmaceutical composition or formulation containing a large amount of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or a salt thereof can be achieved by forming granules of the compound or salt thereof and allowing the granules to be present together with a disintegrating agent.

1 . A pharmaceutical composition comprising (i) a granule containing a compound represented by formula (I) or a salt thereof and (ii) a disintegrating agent. 
       
         
           
           
               
               
           
         
       
     
     
         2 . The composition according to  claim 1 , wherein the disintegrating agent (ii) is contained in an amount of 5 wt % or more based on the total amount of the composition. 
     
     
         3 . The composition according to  claim 1 , wherein the disintegrating agent (ii) is contained in an amount of 7.5 wt % or more based on the total amount of the composition. 
     
     
         4 . The composition according to  claim 1 , wherein the disintegrating agent (ii) is selected from sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose calcium, sodium hydrogen carbonate, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carmellose. 
     
     
         5 . The composition according to  claim 1 , wherein the disintegrating agent (ii) is selected from low-substituted hydroxypropylcellulose, carmellose calcium, sodium hydrogen carbonate and pregelatinized starch. 
     
     
         6 . The composition according to  claim 1 , wherein the granule contains a disintegrating agent therein. 
     
     
         7 . The composition according to  claim 6 , wherein the disintegrating agent contained in the granule is selected from sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose calcium, sodium hydrogen carbonate, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carmellose. 
     
     
         8 . The composition according to  claim 7 , wherein the disintegrating agent contained in the granule is selected from carmellose calcium, low-substituted hydroxypropylcellulose and sodium starch glycolate. 
     
     
         9 . The composition according to  claim 1 , wherein the granule contains a solubilizing agent therein. 
     
     
         10 . The composition according to  claim 9 , wherein the solubilizing agent is sodium lauryl sulfate. 
     
     
         11 . The composition according to  claim 10 , wherein sodium lauryl sulfate is obtained by crystallization. 
     
     
         12 . The composition according to  claim 9 , wherein the weight ratio of the compound represented by formula (I) to the solubilizing agent is 100:2 to 100:60. 
     
     
         13 . The composition according to  claim 1 , wherein the granule contains a binder therein. 
     
     
         14 . The composition according to  claim 13 , wherein the binder is hydroxypropylcellulose. 
     
     
         15 . The composition according to  claim 1 , wherein the granule has a mean particle diameter of 150 μm or more. 
     
     
         16 . The composition according to  claim 1 , wherein the granule has a mean particle diameter of 200 μm or more. 
     
     
         17 . The composition according to  claim 1 , wherein a compound represented by formula (I) or a salt thereof is contained in an amount of 20 to 70 wt % in terms of the free form based on the total amount of the composition. 
     
     
         18 . The composition according to  claim 1 , wherein the compound represented by formula (I) or a salt thereof is contained in an amount of 35 to 60 wt % based on the total amount of the composition. 
     
     
         19 . A pharmaceutical formulation comprising the composition according to  claim 1 . 
     
     
         20 . The formulation according to  claim 19 , wherein the compound represented by formula (I) or a salt thereof is contained in an amount of 60 mg to 240 mg in terms of the free form per unit formulation. 
     
     
         21 . The formulation according to  claim 19 , wherein the compound represented by formula (I) or a salt thereof is contained in an amount of 140 mg to 190 mg per unit formulation. 
     
     
         22 . A method for producing a formulation improved in solubility of a compound represented by formula (I) or a salt thereof, comprising (i) granulating a granule containing a compound represented by formula (I) or a salt thereof and (ii) blending a disintegrating agent and optionally other additives as external additives 
       
         
           
           
               
               
           
         
       
     
     
         23 . The method according to  claim 22 , wherein the disintegrating agent (ii) is selected from sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose calcium, sodium hydrogen carbonate, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carmellose. 
     
     
         24 . The method according to  claim 22 , wherein the disintegrating agent (ii) is contained in an amount of 7.5 wt % or more and 30 wt % or less based on the total amount of the formulation. 
     
     
         25 . The method according to  claim 22 , wherein the granule has a mean particle diameter of 150 μm or more and 1 mm or less. 
     
     
         26 . The method according to  claim 22 , wherein the granule has a mean particle diameter of 180 μm or more and 1 mm or less. 
     
     
         27 . The method according to  claim 22 , wherein the granule (i) has a disintegrating agent therein. 
     
     
         28 . The method according to  claim 27 , wherein the disintegrating agent contained in the granule is selected from sodium starch glycolate, low-substituted hydroxypropylcellulose, carmellose calcium, sodium hydrogen carbonate, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carmellose. 
     
     
         29 . The method according to  claim 22 , wherein the granule contains a solubilizing agent therein. 
     
     
         30 . The method according to  claim 29 , wherein the solubilizing agent is sodium lauryl sulfate obtained by crystallization. 
     
     
         31 . The method according to  claim 29 , wherein the dissolution aid is NIKKOL SLS. 
     
     
         32 . The method according to  claim 29 , wherein a weight ratio of the compound represented by formula (I) to the solubilizing agent is 100:2 to 100:60 
     
     
         33 . The method according to  claim 22 , wherein the granule contains a binder therein. 
     
     
         34 . The method according to  claim 33 , wherein the binder is hydroxypropylcellulose. 
     
     
         35 . The method according to  claim 22 , wherein the compound represented by formula (I) or a salt thereof is contained in an amount of 60 mg to 240 mg in terms of the free form per unit formulation. 
     
     
         36 . A pharmaceutical formulation comprising a compound less soluble or insoluble in water and sodium lauryl sulfate, wherein the sodium lauryl sulfate is obtained by crystallization. 
     
     
         37 . A method for producing a pharmaceutical formulation improved in solubility of a compound less soluble or insoluble in water, comprising blending sodium lauryl sulfate crystallized and optionally other additives with the compound. 
     
     
         38 . A method for improving solubility of a compound less soluble or insoluble in water contained in a pharmaceutical formulation, comprising blending sodium lauryl sulfate obtained by crystallization and optionally other additives with the compound.