Wet granulation using a water sequestering agent

1. A formulation comprising water, (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt and a sufficient amount of a water sequestering agent to inhibit decomposition of (6-(5-fluoro-2-(3,4,5-trimethoxyphenyl-amino) pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt during granulation, tablet formation and/or storage, wherein said formulation, after drying, has a bulk density sufficient to form tablets having a hardness in the range of about 6 kp to about 30 kp.

2. The formulation of claim 1 , wherein after drying the formulation has a bulk density of between about 0.35 to about 0.65 g/mL.

3. The formulation of claim 1 , wherein the water sequestering agent is selected from the group consisting of starch, magnesium sulfate, calcium chloride, silica gel, and kaolin.

4. The formulation of claim 3 , wherein the water sequestering agent is starch.

5. The formulation of claim 4 , wherein the starch is partially pregelatinized.

6. The formulation of claim 5 , wherein the starch is derived from Maize.

7. The formulation of claim 1 which further comprises at least one of a filler, a lubricant, a suspending/dispersing agent, a binding agent, and a disintegrant.

8. A tablet comprising water, a therapeutically effective amount of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino) pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt and a sufficient amount of a water sequestering agent to inhibit decomposition of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino) pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt, wherein said tablet has a hardness in the range of about 6 kp to about 30 kp.

9. The tablet of claim 8 , wherein said tablet exhibits at least 75% dissolution in less than 45 minutes in an aqueous solution maintained at pH 7.4, a temperature of 37° C.+0.5° C., and a paddle speed of 75 rpm.

10. The tablet of claim 8 which further comprises at least one of a filler, a lubricant, a suspending/dispersing agent, a binding agent, and a disintegrant.

11. The tablet of any of claim 8 , 9 or 10 , wherein the tablet comprises from greater than 25 mg to about 200 mg of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino) pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt.

12. The tablet of claim 11 , wherein the tablet comprises about 50 mg to about 100 mg of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino) pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt.

13. The tablet of claim 12 , wherein the tablet comprises about 100 mg of (6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino) pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate disodium salt.

14. A formulation comprising a therapeutically effective amount of Compound 1, a water sequestering agent, a lubricant, and about 5% to about 11% water, wherein the water sequestering agent is present in an amount sufficient to inhibit decomposition of Compound 1.

15. The formulation of claim 14 , wherein the formulation has a bulk density of between about 0.35 to about 0.65 g/mL.

16. A tablet formed by compressing the wet granulated formulation of claim 14 .