US2014128462A1PendingUtilityA1

Lyophilized preparation of cytotoxic dipeptides

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Assignee: ONCOPEPTIDES ABPriority: Apr 28, 2011Filed: Apr 25, 2012Published: May 8, 2014
Est. expiryApr 28, 2031(~4.8 yrs left)· nominal 20-yr term from priority
Inventors:Jack SpiraFredrik Lehmann
A61P 35/02A61P 35/00A61K 47/26A61K 9/19A61K 38/00A61K 31/198A61K 31/195A61K 38/05F26B 5/06A61K 47/40A61K 47/10A61K 31/222A61K 47/02A61K 47/12A61K 38/105
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Claims

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.

Claims

exact text as granted — not AI-modified
1 . A lyophilized pharmaceutical preparation, comprising:
 (i) melphalan flufenamide, or a pharmaceutically acceptable salt thereof; and   (ii) at least one excipient selected from the group consisting of a polysorbate; a polyethylene glycol; β-cyclodextrin; α-cyclodextrin; 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.   
     
     
         2 . The lyophilized pharmaceutical preparation according to  claim 1 , wherein the at least one excipient is selected from the group consisting of Polysorbate 80; PEG 400; lactose; benzyl alcohol; disodium succinate; propylene glycol; PEG 300; Cremophor EL; Dimethyl sulfoxide; D-mannitol; Trehalose; Sucrose; and histidine. 
     
     
         3 . The lyophilized pharmaceutical preparation according to  claim 1 , wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1). 
     
     
         4 . The lyophilized pharmaceutical preparation according to  claim 1 , wherein said at least one excipient has surfactant properties. 
     
     
         5 . The lyophilized pharmaceutical preparation according to  claim 1 , wherein said at least one excipient is a polysorbate or polyethylene glycol. 
     
     
         6 . The lyophilized pharmaceutical preparation according to  claim 5 , wherein said at least one excipient is Polysorbate 80. 
     
     
         7 . The lyophilized pharmaceutical preparation according to  claim 5 , wherein said at least one excipient is PEG400. 
     
     
         8 . The lyophilized pharmaceutical preparation according to  claim 1 , comprising melphalan flufenamide hydrochloride (J1) and the excipient Polysorbate 80. 
     
     
         9 . The lyophilized pharmaceutical preparation according to  claim 1 , comprising:
 (i) melphalan flufenamide, or a pharmaceutically acceptable salt thereof; and   (ii) a combination of two or more excipients selected from the group consisting of a polysorbate; a polyethylene glycol; β-cyclodextiin; α-cyclodextrin; 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.   
     
     
         10 . The lyophilized pharmaceutical preparation according to  claim 9 , wherein the combination of excipients is a mixture of Polysorbate 80 and PEG400. 
     
     
         11 . The lyophilized pharmaceutical preparation according to  claim 9 , wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1). 
     
     
         12 . The lyophilized pharmaceutical preparation according to  claim 1 , wherein the amount of said at least one excipient is about 10-100% by weight of said melphalan flufenamide. 
     
     
         13 . The lyophilized pharmaceutical preparation according to  claim 12 , wherein the amount of the at least one excipient is 10-50% by weight of said melphalan flufenamide. 
     
     
         14 . The lyophilized pharmaceutical preparation according to  claim 1 , further comprising a physiologically acceptable solution. 
     
     
         15 . The lyophilized pharmaceutical preparation according to  claim 14 , wherein said physiologically acceptable solution is a glucose solution. 
     
     
         16 . The lyophilized pharmaceutical preparation according to  claim 15 , wherein the amount of glucose is 4.5-5.5% by weight of the lyophilized preparation. 
     
     
         17 . The lyophilized pharmaceutical preparation according to  claim 1 , comprising 25 mg melphalan flufenamide hydrochloride (J1) and 12.5 mg Polysorbate 80. 
     
     
         18 . The lyophilized pharmaceutical preparation according to  claim 1 , which is free, or substantially free from organic solvents. 
     
     
         19 . The lyophilized pharmaceutical preparation according to  claim 9 , wherein said excipient has surfactant properties. 
     
     
         20 . A kit of parts combination, comprising:
 (i) a lyophilized pharmaceutical preparation according to  claim 1 ; and   (ii) a physiologically acceptable solution.   
     
     
         21 . The kit of parts combination according to  claim 20 , wherein the physiologically acceptable solution is a glucose solution. 
     
     
         22 . The kit of parts combination according to  claim 21 , wherein the amount of glucose is 4.5-5.5% by weight. 
     
     
         23 . The lyophilized pharmaceutical preparation according to  claim 1 , which is suitable for use as a medicament. 
     
     
         24 . The lyophilized pharmaceutical preparation according to  claim 1 , which is suitable for use in the treatment and/or prevention of cancer. 
     
     
         25 . The lyophilized pharmaceutical preparation according to  claim 24 , wherein said cancer is any one of ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer. 
     
     
         26 . The kit of parts combination according to  claim 20 , which is suitable for use in the treatment of cancer. 
     
     
         27 . The kit of parts combination according to  claim 26 , wherein said cancer is any one of ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer. 
     
     
         28 . A method for the treatment and/or prevention of cancer, comprising:
 administering a lyophilized pharmaceutical preparation according to  claim 1  to a subject in need thereof.   
     
     
         29 . The method according to  claim 28 , wherein said cancer is any one of ovarian cancer, lung cancer, bladder cancer, mesothelioma, multiple myeloma, breast cancer or hematological cancer. 
     
     
         30 . A method for preparing a lyophilized pharmaceutical preparation according to  claim 1 , comprising:
 a. dissolving melphalan flufenamide, or a pharmaceutically acceptable salt thereof, in an organic solvent to obtain a melphalan flufenamide solution;   b. adding water to the melphalan flufenamide solution in order to obtain an aqueous melphalan flufenamide solution, in a concentration of about 0.2-3.0 mg/ml;   c. adding at least one excipient selected from the group consisting of a polysorbate; a polyethylene glycol; β-cyclodextrin; α-cyclodextrin; 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 to the melphalan flufenamide solution; and   d. lyophilizing the aqueous melphalan flufenamide solution containing excipient(s).   
     
     
         31 . The method according to  claim 30 , comprising:
 a. dissolving melphalan flufenamide, or a pharmaceutically acceptable salt thereof, in an organic solvent;   b. adding water to the solution obtained in step a) in order to obtain a solution of said melphalan flufenamide or a pharmaceutically acceptable salt thereof, in a concentration of about 0.2-3.0 mg/ml;   c. adding at least one excipient selected from the group consisting of a polysorbate; a polyethylene glycol; β-cyclodextrin; α-cyclodextrin; 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 to the solution obtained in step b); and   d. lyophilizing the solution obtained in step c).   
     
     
         32 . The method according to  claim 30 , wherein the organic solvent is selected from the group consisting of ethanol, ethanol containing acid, glycerin, propylene glycol, benzyl alcohol, dimethylacetamide (DMA), N-methyl-2-pyrrolidone, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, propylene glycol, dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, acetone, dimethylformamide, acetonitrile, dioxane, acetic acid, lactic acid, propionic acid, n-butanol, isopropanol, n-propanol, tert-butanol, sec-butanol, methanol, and a mixture of ethanol and water. 
     
     
         33 . The method according to  claim 30 , wherein the at least one excipient is selected from the group consisting of Polysorbate 80; PEG 400; β-cyclodextrin; α-cyclodextrin; hydroxypropyl-β-cyclodextrin; sulfobutylether-β-cyclodextrin; lactose; benzyl alcohol; disodium succinate; propylene glycol; PEG 300; Cremophor EL; Dimethyl sulfoxide; D-mannitol; Trehalose; Sucrose; and histidine. 
     
     
         34 . The method according to  claim 30 , wherein said melphalan flufenamide is melphalan flufenamide hydrochloride (J1). 
     
     
         35 . The method according to  claim 30 , wherein the organic solvent is ethanol. 
     
     
         36 . The method according to  claim 30 , wherein the at least one excipient is selected the group consisting of from Polysorbate 80 and PEG 400. 
     
     
         37 . A method for decreasing the reconstitution time of a lyophilized preparation of melphalan flufenamide or a pharmaceutically acceptable salt thereof, when reconstituted in an aqueous solvent comprising:
 adding at least one excipient selected from the group consisting of Polysorbate 80; PEG 400; β-cyclodextrin; α-cyclodextrin; hydroxypropyl-β-cyclodextrin; sulfobutylether-β-cyclodextrin; lactose; benzyl alcohol; disodium succinate; propylene glycol; PEG 300; Cremophor EL; Dimethyl sulfoxide; D-mannitol; Trehalose; Sucrose; and histidine, to said lyophilized preparation of melphalan flufenamide, or a pharmaceutically acceptable salt thereof, when reconstituted in an aqueous solvent.   
     
     
         38 . The method according to  claim 37 , wherein said melphalan flufenamide, or a pharmaceutically acceptable salt thereof, is melphalan flufenamide hydrochloride (J1). 
     
     
         39 . The method according to  claim 37 , wherein said at least one excipient is selected from the group consisting of Polysorbate 80 and PEG 400. 
     
     
         40 . The method according to  claim 37 , wherein said melphalan flufenamide, or a pharmaceutically acceptable salt thereof, is dissolved in ethanol prior to adding said at least one excipient.

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