LIQUID FORMULATIONS OF BENDAMUSTINE
Stable liquid formulations of bendamustine, and pharmaceutically acceptable salts thereof, and polar aprotic solvents, are described.
1 . A liquid pharmaceutical formulation comprising bendamustine, or a pharmaceutically acceptable salt or prodrug thereof, and a polar aprotic solvent.
2 . The formulation of claim 1 , wherein the polar aprotic solvent is 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, or a mixture thereof.
3 . The formulation of claim 1 , further comprising a non-aqueous polar protic solvent.
4 . The formulation of claim 3 , wherein the non-aqueous polar protic solvent is an alcohol, a polyalkylene glycol, an amide, or a mixture thereof.
5 . The formulation of claim 3 , wherein the non-aqueous polar protic solvent is an alcohol.
6 . The formulation of claim 5 , wherein the alcohol is a glycol.
7 . The formulation of claim 5 , wherein the alcohol is a cyclodextrin.
8 . The formulation of claim 7 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin.
9 . The formulation of claim 3 , wherein the formulation comprises 90% or less, by volume of the formulation, of the non-aqueous polar protic solvent.
10 . The formulation of claim 3 , wherein the polar aprotic solvent is dimethylacetamide and the nonaqueous polar protic solvent is propylene glycol.
11 . The formulation of claim 1 , further comprising a pharmaceutically acceptable antioxidant.
12 . The formulation of claim 1 , comprising about 5 mg/ml to about 200 mg/mL of bendamustine, or the pharmaceutically acceptable salt thereof.
13 . The formulation of claim 1 , comprising about 5 mg/ml to about 120 mg/mL of bendamustine, or the pharmaceutically acceptable salt thereof.
14 . The formulation of claim 1 , comprising at least about 5 mg/mL of bendamustine, or the pharmaceutically acceptable salt thereof.
15 . The formulation of claim 1 , wherein the formulation is stable at about 5° C. for about 30 days to about 365 days.
16 . The formulation of claim 1 , wherein the formulation is stable at about 5° C. for at least about 180 days.
17 . The formulation of claim 1 , wherein analysis of the formulation indicates that the formulation contains no less than about 90% of the amount of bendamustine present prior to exposure to storage conditions.
18 . The formulation of claim 1 , wherein analysis of the formulation indicates that the formulation contains no less than about 95% of the amount of bendamustine present prior to exposure to storage conditions.
19 . The formulation of claim 17 where the storage conditions are about 5° C. for about 30 days to about 365 days.
20 . The formulation of claim 17 where the storage conditions are about 5° C. for at least about 30 days.
21 . The formulation of claim 17 where the storage conditions are about 5° C. for at least about 90 days.
22 . The formulation of claim 17 , where the storage conditions are about 5° C. for at least about 180 days.
23 . The formulation of claim 1 , further comprising at least one pharmaceutically acceptable excipient.
24 . The formulation of claim 3 , further comprising at least one pharmaceutically acceptable excipient.
25 . The formulation of claim 1 , further comprising an antioxidant, a surfactant, a lipid, a filler, an organic acid, a hydrophilic polymer, a complexing agent, a preservative, or a combination thereof.
26 . The formulation of claim 3 , further comprising an antioxidant, a surfactant, a lipid, a filler, an organic acid, a hydrophilic polymer, a complexing agent, a preservative, or a combination thereof.
27 . The formulation of claim 1 , further comprising at least one anti-neoplastic agent.
28 . The formulation of claim 3 , further comprising at least one anti-neoplastic agent.
29 . The formulation of claim 3 , wherein the formulation comprises 10 moles per liter, or less, of the non-aqueous polar protic solvent.
30 . The formulation of claim 3 , wherein the formulation comprises between about 4 to about 9.5 moles per liter of the non-aqueous polar protic solvent.
31 . The formulation of claim 3 , wherein the formulation comprises 90% or less, by volume of the formulation, of the non-aqueous polar protic solvent.
32 . The formulation of claim 1 , comprising about 0.4% or less of HP1.
33 . The formulation of claim 3 , comprising about 0.4% or less of HP1.
34 . The formulation of claim 1 , comprising about 0.1% or less of HP1.
35 . The formulation of claim 3 , comprising about 0.1% or less of HP1.
36 . The formulation of claim 1 , comprising about 1.5% of less of DCE.
37 . The formulation of claim 3 , comprising about 1.5% of less of DCE.
38 . The formulation of claim 1 , comprising about 0.7% or less of BM1 dimer.
39 . The formulation of claim 3 , comprising about 0.7% or less of BM1 dimer.
40 . The formulation of claim 10 , comprising about 1.5% or less of PG-1, PG-2, or a combination thereof.
41 . A method of preparing an injectable formulation of bendamustine, or a pharmaceutically acceptable salt thereof, comprising:
providing a liquid pharmaceutical formulation comprising bendamustine, or a pharmaceutically acceptable salt thereof, and a nonaqueous solvent;
diluting the liquid pharmaceutical formulation with a pharmaceutically acceptable injectable diluent.
42 . The method of claim 41 , wherein the nonaqueous solvent is a polar aprotic solvent.
43 . The method of claim 42 , wherein the polar aprotic solvent is 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, or a mixture thereof.
44 . The method of claim 41 , wherein the liquid pharmaceutical formulation further comprising a non-aqueous polar protic solvent.
45 . The method of claim 44 , wherein the nonaqueous polar protic solvent is an alcohol, a polyalkylene glycol, a primary amide, or a mixture thereof.
46 . The method of claim 41 wherein the pharmaceutically acceptable injectable diluent is Sodium Chloride Injection.
47 . A method of treating cancer comprising
identifying a patient in need of treatment of cancer;
providing a liquid pharmaceutical formulation comprising a therapeutically effective amount of bendamustine, or a pharmaceutically acceptable salt thereof, and nonaqueous solvent;
diluting the liquid pharmaceutical formulation with a pharmaceutically acceptable injectable diluent to form a pharmaceutical preparation;
administering the pharmaceutical preparation to the patient in need of treatment.
48 . The method of claim 47 , wherein the nonaqueous solvent is a polar aprotic solvent.
49 . The method of claim 48 , wherein the polar aprotic solvent is 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, or a mixture thereof.
50 . The method of claim 47 , wherein the liquid pharmaceutical formulation further comprising a non-aqueous polar protic solvent.
51 . The method of claim 50 , wherein the nonaqueous polar protic solvent is an alcohol, a polyalkylene glycol, a primary amide, or a mixture thereof.
52 . The method of claim 47 , wherein the pharmaceutically acceptable injectable diluent is Sodium Chloride Injection.