Lyophilized preparation of cytotoxic dipeptides
The present invention is directed to novel lyophilized pharmaceutical preparations comprising a cytotoxic dipeptides such as melphalan flufenamide and one or more excipient(s) selected from the group comprising a polysorbate; a polyethylene glycol; β-cyclodextrin; ocyclodextrin; hydroxypropyl-β-cyclodextrin; sulfobutylether-β-cyclodextrin; lactose; benzyl alcohol; disodium succinate; propylene glycol; Cremophor EL; Dimethyl sulfoxide; D-mannitol; Trehalose; Sucrose and an amino acid. This preparation may be further formulated and is useful in cancer therapy.
1. A method for treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition prepared by directly dissolving a lyophilized pharmaceutical preparation comprising melphalan flufenamide or a pharmaceutically acceptable salt thereof and sucrose in a physiologically acceptable aqueous solution, wherein the cancer is ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer.
2. The method of claim 1 , wherein the amount of sucrose in the lyophilized pharmaceutical preparation is 10-100% by weight of said melphalan flufenamide.
3. The method of claim 1 , wherein the lyophilized pharmaceutical preparation consists essentially of melphalan flufenamide or a pharmaceutically acceptable salt thereof and sucrose.
4. The method of claim 1 , wherein sucrose is the sole excipient in the lyophilized pharmaceutical preparation.
5. The method of claim 1 , wherein the lyophilized pharmaceutical preparation is free from organic solvents.
6. The method of claim 1 , wherein the lyophilized pharmaceutical preparation contains less than 0.1% by weight organic solvents.
7. The method of claim 1 , wherein the lyophilized pharmaceutical preparation is obtained by lyophilizing a solution comprising melphalan flufenamide or a pharmaceutically acceptable salt thereof, sucrose, an organic solvent and water.
8. The method of claim 1 , wherein the physiologically acceptable solution comprises glucose.
9. The method of claim 1 , wherein the pharmaceutical composition is free from organic solvents.
10. The method of claim 1 , wherein the pharmaceutical composition consists essentially of melphalan flufenamide or a pharmaceutically acceptable salt thereof, sucrose, glucose, and water.
11. The method of claim 1 , further comprising preparing the pharmaceutical composition by dissolving the lyophilized pharmaceutical preparation in the physiologically acceptable solution.
12. The method of claim 1 , wherein the lyophilized pharmaceutical preparation contains less than 0.5% by weight organic solvents.
13. The method of claim 1 , wherein the pharmaceutical composition contains less than 0.1% by weight organic solvents.
14. The method of claim 1 , wherein the pharmaceutical composition contains less than 0.5% by weight organic solvents.
15. A method for treating a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition prepared by directly dissolving a lyophilized pharmaceutical preparation comprising melphalan flufenamide hydrochloride (J1) and sucrose in a physiologically acceptable aqueous solution, wherein the cancer is ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer.
16. The method of claim 15 , wherein the amount of sucrose in the lyophilized pharmaceutical preparation is 10-100% by weight of said J1.
17. The method of claim 15 , wherein the lyophilized pharmaceutical preparation consists essentially of J1 and sucrose.
18. The method of claim 15 , wherein sucrose is the sole excipient in the lyophilized pharmaceutical preparation.
19. The method of claim 15 , wherein the lyophilized pharmaceutical preparation is free from organic solvents.
20. The method of claim 15 , wherein the lyophilized pharmaceutical preparation contains less than 0.1% by weight organic solvents.
21. The method of claim 15 , wherein the physiologically acceptable solution comprises glucose.