Solid preparation
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. A tablet comprising 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 40 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, 51 mg of D-mannitol particles having an average particle size of 70-200 μm, 5 mg of sodium starch glycolate, 3 mg of hydroxypropylcellulose, and 1 mg of magnesium stearate.
2. The tablet according to claim 1 , further comprising a film-coating, wherein the film-coating comprises hydroxypropylmethylcellulose, titanium oxide, and red ferric oxide.
3. The tablet according to claim 1 , further comprising a film-coating, wherein the film-coating comprises 3.56 mg of hydroxypropylmethylcellulose, 0.40 mg of titanium oxide, and 0.04 mg of red ferric oxide.
4. The tablet of claim 1 , wherein the D-mannitol particles have an average particle size of 75-150 μm.
5. A tablet comprising 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 120 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, 153 mg of D-mannitol particles having an average particle size of 70-200 μm, 15 mg of sodium starch glycolate, 9 mg of hydroxypropylcellulose, and 3 mg of magnesium stearate.
6. The tablet according to claim 5 , further comprising a film-coating, wherein the film-coating comprises hydroxypropylmethylcellulose, titanium oxide, and red ferric oxide.
7. The tablet of claim 5 , wherein the D-mannitol particles have an average particle size of 75-150 μm.
8. A tablet comprising 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, 102 mg of D-mannitol particles having an average particle size of 70-200 μm, 10 mg of sodium starch glycolate, 6 mg of hydroxypropylcellulose, and 2 mg of magnesium stearate.
9. The tablet according to claim 8 , further comprising a film-coating, wherein the film-coating comprises hydroxypropylmethylcellulose, titanium oxide, and red ferric oxide.
10. The tablet according to claim 8 , further comprising a film-coating, wherein the film-coating comprises 7.12 mg of hydroxypropylmethylcellulose, 0.80 mg of titanium oxide, and 0.08 mg of red ferric oxide.
11. The tablet of claim 8 , wherein the D-mannitol particles have an average particle size of 75-150 μm.
12. A method of making a tablet of claim 1 , said method comprising:
1) mixing 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 with D-mannitol particles having an average particle size of 70-200 μm and sodium starch glycolate;
2) spraying into a mixture of step 1) a solution of hydroxypropylcellulose in a solvent or dispersing medium;
3) drying or sieving a mixture of step 2) to afford a granulated powder or a sieved powder;
4) adding magnesium stearate to the granulated powder or sieved powder of step 3) and mixing to afford granules for tableting;
5) tableting the granules of step 4) to afford a core tablet; and, optionally,
6) spraying a film-coating solution onto the core tablet of step 5) to afford a film-coated tablet.
13. A method of making a tablet of claim 5 , said method comprising:
1) mixing 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 with D-mannitol particles having an average particle size of 70-200 μm and sodium starch glycolate;
2) spraying into a mixture of step 1) a solution of hydroxypropylcellulose in a solvent or dispersing medium;
3) drying or sieving a mixture of step 2) to afford a granulated powder or a sieved powder;
4) adding magnesium stearate to the granulated powder or sieved powder of step 3) and mixing to afford granules for tableting;
5) tableting the granules of step 4) to afford a core tablet; and, optionally,
6) spraying a film-coating solution onto the core tablet of step 5) to afford a film-coated tablet.
14. A method of making a tablet of claim 8 , said method comprising:
1) mixing 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 with D-mannitol particles having an average particle size of 70-200 μm and sodium starch glycolate;
2) spraying into a mixture of step 1) a solution of hydroxypropylcellulose in a solvent or dispersing medium;
3) drying or sieving a mixture of step 2) to afford a granulated powder or a sieved powder;
4) adding magnesium stearate to the granulated powder or sieved powder of step 3) and mixing to afford granules for tableting;
5) tableting the granules of step 4) to afford a core tablet; and, optionally,
6) spraying a film-coating solution onto the core tablet of step 5) to afford a film-coated tablet.