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 lyophilized pharmaceutical preparation which is directly soluble in a physiologically acceptable aqueous solution, comprising (i) melphalan flufenamide or a pharmaceutically acceptable salt thereof and (ii) hydroxypropyl-β-cyclodextrin and/or sulfobutylether-β-cyclodextrin.
2. The lyophilized pharmaceutical preparation according to claim 1 , wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1).
3. The lyophilized pharmaceutical preparation according to claim 1 , wherein the amount of hydroxypropyl-8-cyclodextrin and/or sulfobutylether-β-cyclodextrin is 10-100% by weight of said melphalan flufenamide.
4. The lyophilized pharmaceutical preparation according to claim 1 , which contains less than 0.5% by weight organic solvents.
5. The lyophilized pharmaceutical preparation according to claim 2 , which contains less than 0.5% by weight organic solvents.
6. The lyophilized pharmaceutical preparation according to claim 3 , which contains less than 0.5% by weight organic solvents.
7. The lyophilized pharmaceutical preparation according to claim 1 , which comprises hydroxypropyl-β-cyclodextrine or sulfobutylether-β-cyclodextrin as the sole excipient.
8. The lyophilized pharmaceutical preparation according to claim 7 , which contains trace amounts of an organic solvent.
9. The lyophilized pharmaceutical preparation according to claim 1 , which consists essentially of (i) melphalan flufenamide or a pharmaceutically acceptable salt thereof and (ii) hydroxypropylβ-cyclodextrin or sulfobutylether-β-cyclodextrin.
10. The lyophilized pharmaceutical preparation according to claim 9 , which contains trace amounts of an organic solvent.
11. The lyophilized pharmaceutical preparation according to claim 7 , which consists essentially of (i) melphalan flufenamide or a pharmaceutically acceptable salt thereof and (ii) hydroxypropylβ-cyclodextrin sulfobutylether-β-cyclodextrin.
12. The lyophilized pharmaceutical preparation according to claim 11 , which contains trace amounts of an organic solvent.
13. The lyophilized pharmaceutical preparation according to claim 11 , wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1).
14. A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of claim 1 and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution.
15. A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of claim 2 and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution.
16. A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of claim 3 and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution.
17. A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of claim 4 and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution.
18. The lyophilized pharmaceutical preparation according to claim 1 , which comprises hydroxypropyl-β-cyclodextrin.
19. The lyophilized pharmaceutical preparation according to claim 1 , which comprises sulfobutylether-β-cyclodextrin.
20. The lyophilized pharmaceutical preparation according to claim 1 , in which hydroxypropyl-β-cyclodextrin is the sole excipient.
21. The lyophilized pharmaceutical preparation according to claim 1 , in which sulfobutylether-β-cyclodextrin is the sole excipient.