Claims for Patent: 10,350,170

Summary for Patent: 10,350,170

Title:	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-pyr- idazinyl)-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.
Inventor(s):	Yamane; Ikuro (Osaka, JP), Nomura; Yukihiro (Osaka, JP), Nishimoto; Yutaka (Osaka, JP), Hoshina; Wataru (Osaka, JP)
Assignee:	Takeda Pharmaceutical Company Limited (Osaka, JP)
Application Number:	15/553,852
Patent Claims:	1. A tablet comprising N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr- idazinyl)-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-met- hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y- l)phenyl)-N'-methoxyurea, 51 mg of D-mannitol particles having an average particle size of 70-200 .mu.m, 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 .mu.m. 5. A tablet comprising N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr- idazinyl)-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-met- hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y- l)phenyl)-N'-methoxyurea, 153 mg of D-mannitol particles having an average particle size of 70-200 .mu.m, 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 .mu.m. 8. A tablet comprising N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyr- idazinyl)-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-met- hoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-y- l)phenyl)-N'-methoxyurea, 102 mg of D-mannitol particles having an average particle size of 70-200 .mu.m, 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 .mu.m. 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-methox- y-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)p- henyl)-N'-methoxyurea or a salt thereof with D-mannitol particles having an average particle size of 70-200 .mu.m 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-methox- y-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)p- henyl)-N'-methoxyurea or a salt thereof with D-mannitol particles having an average particle size of 70-200 .mu.m 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-methox- y-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)p- henyl)-N'-methoxyurea or a salt thereof with D-mannitol particles having an average particle size of 70-200 .mu.m 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.