Solid preparation

Abstract

Provided is a solid preparation showing improved stability of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea and a salt thereof in the solid preparation, and a method of stabilizing the compound in a solid preparation. A tablet containing not less than 25 mass % of the compound; a solid preparation containing (1) the compound, and (2) a fat and oil-like substance having a low melting point, which is selected from polyethylene glycol, glycerol monostearate and triethyl citrate; a method of stabilizing the compound in a tablet, including adding not less than 25 mass % of the compound; and a method of stabilizing the compound, including adding a fat and oil-like substance having a low melting point, which is selected from polyethylene glycol, glycerol monostearate and triethyl citrate to a solid preparation containing the compound.

1 - 6 . (canceled) 
     
     
         7 . A tablet comprising
 (1) N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a salt thereof and   (2) a fat and oil-like substance having a low melting point, which is selected from polyethylene glycol and glycerol monostearate, wherein the tablet comprises 0.1-10 mass % of the fat and oil-like substance having a low melting point.   
     
     
         8 - 12 . (canceled) 
     
     
         13 . The tablet according to  claim 7 , wherein the tablet comprises 0.2-1.7 mass % of the fat and oil-like substance having a low melting point, and wherein the fat and oil-like substance having a low melting point is polyethylene glycol. 
     
     
         14 . The tablet according to  claim 13 , wherein the tablet comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a salt thereof in an amount of 80 mg measured based on free form N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, 157.2 mg of D-mannitol, 20 mg of crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 4.8 mg of polyethylene glycol 6000, 12.7 mg of croscarmellose sodium, and 2.5 mg of magnesium stearate. 
     
     
         15 . The tablet according to  claim 13 , wherein the tablet comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a salt thereof in an amount of 80 mg measured based on free form N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, 157.2 mg of D-mannitol, 20 mg of crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 4.8 mg polyethylene glycol with an average molecular weight of 100000, 12.7 mg of croscarmellose sodium, and 2.5 mg of magnesium stearate. 
     
     
         16 . The tablet according to  claim 7 , wherein the tablet comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a salt thereof in an amount of 80 mg measured based on free form N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, 147.2 mg of D-mannitol, 20 mg of crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 10 mg of glycerol monostearate, 12.7 mg of croscarmellose sodium, and 2.5 mg of magnesium stearate. 
     
     
         17 . The tablet according to  claim 16 , further comprising a film-coating, wherein the film-coating comprises hypromellose, titanium oxide, red ferric oxide, and yellow ferric oxide. 
     
     
         18 . The tablet according to  claim 16 , further comprising a film-coating, wherein the film-coating comprises 9.06 mg of hypromellose, 1.02 mg of titanium oxide, 0.026 mg of red ferric oxide, and 0.077 mg yellow ferric oxide. 
     
     
         19 . The tablet according to  claim 13 , wherein the tablet comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a salt thereof in an amount of 80 mg measured based on free form N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, 156 mg of D-mannitol, 20 mg of crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 1.2 mg of polyethylene glycol 6000, 12.7 mg of croscarmellose sodium, and 2.5 mg of magnesium stearate. 
     
     
         20 . The tablet according to  claim 19 , further comprising a film-coating, wherein the film-coating comprises hypromellose, titanium oxide, red ferric oxide, and yellow ferric oxide. 
     
     
         21 . The tablet according to  claim 19 , further comprising a film-coating, wherein the film-coating comprises 9.06 mg of hypromellose, 1.02 mg of titanium oxide, 0.026 mg of red ferric oxide, and 0.077 mg yellow ferric oxide. 
     
     
         22 . The tablet according to  claim 13 , wherein the tablet comprises N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea or a salt thereof in an amount of 80 mg measured based on free form N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea, 152.4 mg of D-mannitol, 20 mg of crystalline cellulose, 7.6 mg of hydroxypropylcellulose, 4.8 mg of polyethylene glycol 400, 12.7 mg of croscarmellose sodium, and 2.5 mg of magnesium stearate. 
     
     
         23 . The tablet according to  claim 22 , further comprising a film-coating, wherein the film-coating comprises hypromellose, titanium oxide, red ferric oxide, and yellow ferric oxide. 
     
     
         24 . The tablet according to  claim 22 , further comprising a film-coating, wherein the film-coating comprises 9.06 mg of hypromellose, 1.02 mg of titanium oxide, 0.026 mg of red ferric oxide, and 0.077 mg yellow ferric oxide.