Lyophilized preparation of cytotoxic dipeptides

Abstract

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 - 40 . (canceled) 
     
     
         41 . 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) one or more of β-cyclodextrin, α-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutylether-β-cyclodextrin. 
     
     
         42 . The lyophilized pharmaceutical preparation according to  claim 41 , wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1). 
     
     
         43 . The lyophilized pharmaceutical preparation according to  claim 41 , wherein the amount of β-cyclodextrin, α-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutylether-β-cyclodextrin is 10-100% by weight of said melphalan flufenamide. 
     
     
         44 . The lyophilized pharmaceutical preparation according to  claim 41 , which contains less than 0.5% by weight organic solvents. 
     
     
         45 . The lyophilized pharmaceutical preparation according to  claim 42 , which contains less than 0.5% by weight organic solvents. 
     
     
         46 . The lyophilized pharmaceutical preparation according to  claim 43 , which contains less than 0.5% by weight organic solvents. 
     
     
         47 . The lyophilized pharmaceutical preparation according to  claim 41 , which comprises β-cyclodextrin, α-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutylether-β-cyclodextrin as the sole excipient. 
     
     
         48 . The lyophilized pharmaceutical preparation according to  claim 47 , which contains trace amounts of an organic solvent. 
     
     
         49 . The lyophilized pharmaceutical preparation according to  claim 41 , which consists essentially of (i) melphalan flufenamide or a pharmaceutically acceptable salt thereof and (ii) β-cyclodextrin, α-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutylether-β-cyclodextrin. 
     
     
         50 . The lyophilized pharmaceutical preparation according to  claim 49 , which contains trace amounts of an organic solvent. 
     
     
         51 . The lyophilized pharmaceutical preparation according to  claim 47 , which consists essentially of (i) melphalan flufenamide or a pharmaceutically acceptable salt thereof and (ii) β-cyclodextrin, α-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutylether-β-cyclodextrin. 
     
     
         52 . The lyophilized pharmaceutical preparation according to  claim 51 , which contains trace amounts of an organic solvent. 
     
     
         53 . The lyophilized pharmaceutical preparation according to  claim 51 , wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1). 
     
     
         54 . A method for preparing a lyophilized pharmaceutical preparation comprising melphalan flufenamide or a pharmaceutically acceptable salt thereof that is directly soluble in a physiologically acceptable aqueous solution, said method comprising lyophilizing a solution comprising (i) melphalan flufenamide or a pharmaceutically acceptable salt thereof, (ii) one or more of β-cyclodextrin, α-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutylether-β-cyclodextrin, (iii) an organic solvent, and (iv) water. 
     
     
         55 . A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of  claim 41  and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution. 
     
     
         56 . A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of  claim 42  and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution. 
     
     
         57 . A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of  claim 43  and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution. 
     
     
         58 . A pharmaceutical composition consisting of the lyophilized pharmaceutical preparation of  claim 44  and a physiologically acceptable solution, wherein said physiologically acceptable solution is a glucose solution. 
     
     
         59 . A method for treating and/or preventing metastasis of a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the lyophilized pharmaceutical preparation of  claim 41 . 
     
     
         60 . The method of  claim 59 , wherein said cancer is ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer.