STABLE READY TO DILUTE FORMULATIONS OF CARFILZOMIB
The invention provides room temperature stable ready to dilute injectable formulation comprising carfilzomib or it pharmaceutically acceptable derivatives. The invention further provides methods for treating patients with multiple myeloma by administering room temperature stable ready to dilute injectable formulations comprising carfilzomib or its pharmaceutically acceptable derivatives.
1 .- 34 . (canceled)
35 . A room temperature stable ready to dilute injectable formulation comprising carfilzomib or its pharmaceutically acceptable derivatives thereof and one or more solvents; wherein the formulation contains no more than 6% total impurities when stored for at least three months.
36 . The room temperature stable ready to dilute injectable formulation according to claim 35 , wherein the concentrations of carfilzomib or its pharmaceutically acceptable derivatives thereof are in the range from about 10 mg/mL to about 100 mg/mL.
37 . The room temperature stable ready to dilute injectable formulation according to claim 36 , wherein the concentrations of carfilzomib or its pharmaceutically acceptable derivatives thereof are in the range from about 10 mg/mL to about 60 mg/mL.
38 . The room temperature stable ready to dilute injectable formulation according to claim 35 and optionally one or more pharmaceutically acceptable excipients selected from antioxidant, buffer, preservative, and surfactant.
39 . The room temperature stable ready to dilute injectable formulation according to claim 35 , wherein the formulation contains no more than 6% total impurities when stored for at least six months.
40 . The room temperature stable ready to dilute injectable formulation according to claim 35 , wherein the one or more solvents is selected from ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide (DMSO), diethylene glycol monoethyl ethers, caprylocaproyl polyoxyl-8 glycerides, glycofurol, or mixtures thereof.
41 . The room temperature stable ready to dilute injectable formulation according to claim 40 , wherein the solvent is mixed in suitable ratio (w/w) with carfilzomib or its pharmaceutically acceptable derivatives thereof which is from about 100:1 to 8:1.
42 . The room temperature stable ready to dilute injectable formulation according to claim 38 , wherein the antioxidant is selected from butylated hydroxytoluene, butylated hydroxy anisole, propyl gallate, and C.-tocopherol, DL-tocopherol, C-tocopherol acetate, C.-tocopherol Tocopherol Polyethylene Glycol Succinate (Vitamin E TPGS), L-cysteine ascorbyl palmitate thioglycolic acid, sodium metabisulfite (SMBS), ascorbic acid, sodium formaldehyde sulfoxylate, or hydrophilic antioxidants, including sodium EDTA and thioglycerol.
43 . The room temperature stable ready to dilute injectable formulation according to claim 42 , wherein the antioxidant is present in concentration from about 0.005% to about 5% weight/weight of the total composition.
44 . The room temperature stable ready to dilute injectable formulation according to claim 35 , wherein the formulation is stored at 25° C. and 60% relative humidity or at 40° C. and 75% relative humidity.
45 . The room temperature stable ready to dilute injectable formulation according to claim 35 , wherein the formulation contains no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1.5%, no more than 1% or no more than 0.5% of total impurities upon storage period.
46 . A method for treating patients with relapsed or refractory multiple myeloma which comprises administering a room temperature stable ready to dilute injectable formulation of carfilzomib or its pharmaceutically acceptable derivatives thereof; and one or more solvents; wherein the formulation contains no more than 6% total impurities when stored for at least three months.
47 . The method for treating patients with relapsed or refractory multiple myeloma according to claim 46 , wherein the ready to dilute injectable formulation is stable when stored for at least six month.
48 . A method of administering a reconstituted ready to dilute formulation comprising mixing of a component 1 and a component 2 to form the reconstituted ready to dilute formulation followed by diluting the reconstituted ready to dilute formulation with an infusion media; wherein component 1 comprises a room temperature stable ready to dilute formulation of carfilzomib or its pharmaceutically acceptable derivatives thereof and contains no more than 6% of total impurities when stored for at least three months; and component 2 is an acidifying agent.
49 . The method of administering reconstituted ready to dilute formulation according to claim 48 wherein component 1 and component 2 are in the range from about 10 mg/mL to about 60 mg/m
50 . The method of administering reconstituted ready to dilute formulation according to claim 48 , wherein the acidifying agent is mixed with carfilzomib or its pharmaceutically acceptable derivatives thereof in a suitable ratio (w/w) selected from about 1:50 to about 1:1.
51 . The method of administering reconstituted ready to dilute formulation according to claim 48 , wherein the component 1 is stored for at least three months at 25° C. and 60% relative humidity or at 40° C. and 75% relative humidity.
52 . The method of administering reconstituted ready to dilute formulation according to claim 48 , wherein the component 1 comprises room temperature stable ready to dilute formulation of carfilzomib or its pharmaceutically acceptable derivatives and contains no more than 6% of total impurities when stored for at least six months.
53 . The method of administering reconstituted ready to dilute formulation according to claim 48 , wherein component 1 contains no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1.5%, no more than 1% or no more than 0.5% of total impurities upon storage period.
54 . The method of administering reconstituted ready to dilute formulation according to claim 48 wherein the acidifying agent is selected from citric acid, acetic acid, maleic acid, phosphoric acid, succinic acid, tartaric acid, ascorbic acid, benzene sulfonic acid, oxalic acid, fumaric acid, ortho phosphoric acid, gluconic acid, malic acid, methane sulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic acid, lacturonic acids, lactic acid, lactobionic acid, edetic acid, gentisic acid, meta phosphoric acid, nitric acid, pentetic acid, glycolic acid or mixtures thereof.
55 . A method for treating patients with relapsed or refractory multiple myeloma which method comprises administering a reconstituted ready to dilute formulation comprising mixing of component 1 and component 2 to form reconstituted ready to dilute formulation followed by diluting the reconstituted ready to dilute formulation with an infusion media; wherein component 1 is a room temperature stable ready to dilute parenteral formulation of carfilzomib or its pharmaceutically acceptable derivatives and component 2 is an acidifying agent and wherein the reconstituted ready to dilute composition has total impurity of not more than 2% up to 6 hours after mixing when the mixture is stored at room temperature.
56 . The method for treating patients with relapsed or refractory multiple myeloma according to claim 55 , wherein the reconstituted ready to dilute composition has total impurity not more than 1% up to 6 hours, not more than 2% up to 5 hours, not more than 1% up to 5 hours, not more than 2% up to 4 hours or not more than 1% up to 4 hours after mixing when the mixture is stored at room temperature.