Formulations of a PI3K/mTor-inhibitor for intravenous administration

1. A lyophilized formulation obtained by freeze drying a pharmaceutical aqueous solution formulation comprising: 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a lactate salt thereof, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 6 mg/ml and sufficient lactic acid is present to provide a clear solution; or 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt thereof, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.

2. A lyophilised formulation as claimed in claim 1 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a lactate salt thereof, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 6 mg/ml and sufficient lactic acid is present to provide a clear solution.

3. A lyophilised formulation as claimed in claim 2 wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of from 2.5 to 5.5 mg/ml.

4. A lyophilised formulation as claimed in claim 3 wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of from 5.0 to 5.5 mg/ml and at least 2.5 mole equivalents of lactic acid are present.

5. A lyophilised formulation as claimed in claim 4 wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of about 5 mg/ml.

6. A lyophilised formulation as claimed in claim 5 wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of about 5 mg/ml and at least 2.5 mole equivalents of lactic acid are present.

7. A lyophilised formulation as claimed in claim 2 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea lactate, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5 mg/ml, and at least 1.5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed.

8. A lyophilised formulation as claimed in claim 2 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of from 2.5 to 5.5 mg/ml, and from above 2.5 to 8.0 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed.

9. A lyophilised formulation as claimed in claim 1 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 6 mg/ml and sufficient lactic acid is present to provide a clear solution.

10. A lyophilised formulation as claimed in claim 9 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5 mg/ml, and at least 2.5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed.

11. A lyophilised formulation as claimed in claim 10 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5 mg/ml, and about 4.1 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed with a pH of no greater than 3.7.

12. A lyophilised formulation as claimed in any one of claims 1 to 8 wherein DL-lactic acid, L-lactic acid or D-lactic acid is used in the pharmaceutical aqueous solution formulation.

13. A lyophilised formulation as claimed in claim 12 wherein DL-lactic acid is used in the pharmaceutical aqueous solution formulation.

14. A lyophilised formulation as claimed in claim 1 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt thereof, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.

15. A lyophilised formulation as claimed in claim 14 , the pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.

16. A lyophilised formulation as claimed in claim 15 wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of from 3.0 to 3.5 mg/ml.

17. A lyophilised formulation as claimed in claim 15 wherein at least 5 mole equivalents of orthophosphoric acid are used in the pharmaceutical aqueous solution formulation.

18. A lyophilised formulation as claimed in claim 17 wherein from 5 to 7 mole equivalents of orthophosphoric acid are used in the pharmaceutical aqueous solution formulation.

19. A lyophilised formulation as claimed in any one of claims 1 - 8 and 13 - 18 additionally containing a bulking agent.

20. A lyophilised formulation as claimed in claim 19 wherein the bulking agent is mannitol.

21. A pharmaceutical aqueous solution formulation obtained as a clear solution by reconstitution or constitution of a lyophilized formulation as claimed in any one of claims 1 - 8 and 13 - 18 using water or an aqueous solution comprising a tonicity modifier.

22. A pharmaceutical aqueous solution formulation as claimed in claim 21 wherein the tonicity modifier is dextrose, sucrose or mannitol, or is a mixture of any 2 or more thereof.

23. A pharmaceutical aqueous solution formulation as claimed in claim 21 , that is adjusted, as necessary, to have a pH suitable for intravenous or parenteral administration.

24. A pharmaceutical aqueous solution formulation as claimed in claim 23 wherein the pH is from 3 to 4.5.

25. A pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt thereof, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.

26. A pharmaceutical aqueous solution formulation as claimed in claim 25 comprising 1-(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.

27. A pharmaceutical aqueous solution formulation as claimed in claim 26 wherein 1-(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of from 3.0 to 3.5mg/ml.

28. A pharmaceutical aqueous solution formulation as claimed in claim 26 or 27 wherein at least 5 mole equivalents of orthophosphoric acid are used.

29. A pharmaceutical aqueous solution formulation as claimed in claim 28 wherein from 5 to 7 mole equivalents of orthophosphoric acid are used.