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, 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.