Lyophilized formulations of tegavivint
Lyophilized formulations of tegavivint, methods of making such formulations, and methods of treatment of cancer by administering the formulations.
1. A lyophilized formulation comprising particles of Form I polymorph of tegavivint or a pharmaceutically acceptable salt thereof; wherein the particles have a median particle diameter D50 of less than or equal to 500 nm and wherein 90% of particles have a diameter D90 of less than or equal to 1.0 micron when measured using laser diffraction, wherein the lyophilized formulation comprises a poloxamer and one or more stabilizers selected from the group consisting of sucrose, trehalose, and sorbitol; and wherein the formulation is stable for at least eighteen months during a storage at a temperature of between 5-25° C.
2. The lyophilized formulation of claim 1 , wherein the formulation is anhydrous.
3. A lyophilized formulation comprising particles of Form I polymorph of tegavivint; wherein the particles have a median particle diameter D50 of less than or equal to 500 nm and wherein 90% of particles have a diameter D90 of less than or equal to 1.0 micron when measured using laser diffraction, wherein the formulation is stable for at least eighteen months during a storage at a temperature of between 5-25° C., and wherein the formulation is prepared by a lyophilization process comprising: a) freezing a pre-lyophilized formulation comprising tegavivint, a poloxamer, and one or more stabilizers selected from the group consisting of sucrose, trehalose and sorbitol; b) a primary drying step; and c) a secondary drying step.
4. The lyophilized formulation of claim 3 , wherein tegavivint concentration prior to lyophilization was 25 mg/mL.
5. The lyophilized formulation of claim 3 , wherein tegavivint concentration prior to lyophilization was 50 mg/ml.
6. The lyophilized formulation of claim 3 , wherein the poloxamer is poloxamer 188.
7. The lyophilized formulation of claim 3 , wherein the poloxamer concentration prior to lyophilization was 6 mg/ml.
8. The lyophilized formulation of claim 3 , wherein the poloxamer concentration prior to lyophilization was 12.5 mg/ml.
9. The lyophilized formulation of claim 3 , wherein the sucrose concentration prior to lyophilization was 100 mg/ml.
10. The lyophilized formulation of claim 3 , wherein the trehalose concentration prior to lyophilization was 100 mg/ml.
11. The lyophilized formulation of claim 3 , wherein the sorbitol concentration prior to lyophilization was 50 mg/ml.
12. The lyophilized formulation of claim 3 , wherein the formulation is autoclaved prior to lyophilization.
13. The lyophilized formulation of claim 3 , wherein the freezing step is at about −40° C., the primary drying step is at about −30° C. and the secondary drying step is at about −10° C.
14. The lyophilized formulation of claim 3 , wherein the pre-lyophilized formulation was prepared by ball milling at a temperature of between about 40° C. and about 60° C.
15. The lyophilized formulation of claim 3 , wherein the pre-lyophilized formulation was prepared by ball milling at a temperature of about 60° C.
16. The lyophilized formulation of claim 3 , wherein the pre-lyophilized formulation was prepared by high energy agitator milling at a temperature of between about 40° C. and 60° C.
17. The lyophilized formulation of claim 3 , wherein the pre-lyophilized formulation was prepared by high energy agitator milling at a temperature of about 60° C.
18. The lyophilized formulation of claim 3 , wherein a starting material to produce the lyophilized formulation is Form I polymorph of tegavivint.
19. The lyophilized formulation of claim 3 , wherein the starting material to produce the lyophilized formulation is Form IV polymorph of tegavivint.
20. A method for treating a cancer or tumor metastasis in a mammal in need thereof comprising administering to said mammal an effective amount of the lyophilized formulation according to claim 1 .
21. The method of claim 20 , wherein the cancer is acute myeloid leukemia.