BENDAMUSTINE COMPOSITIONS AND METHODS THEREFORE
Aqueous Bendamustine formulations with improved stability are disclosed. Especially preferred formulations are low-dose ready-to-use liquid formulations in which Bendamustine is in a non-aqueous vehicle in combination with an aqueous phase that contains significant quantities of chloride.
1 . A ready-to-use liquid Bendamustine formulation for injection, comprising:
a mixture of a non-aqueous solvent system and an aqueous chloride-containing water phase;
wherein Bendamustine is present in the mixture in a therapeutically effective amount;
wherein the chloride is present in the mixture at a precipitating amount with respect to Bendamustine in the water phase, and wherein the non-aqueous solvent system is present in the mixture in an amount effective to prevent Bendamustine precipitation from the water phase; and
wherein the precipitating amount of chloride is effective to stabilize Bendamustine as compared to a mixture without chloride.
2 . The formulation of claim 1 wherein the non-aqueous solvent system comprises at least one of propylene glycol or polyethylene glycol.
3 . The formulation of claim 1 wherein the non-aqueous solvent system essentially consists of propylene glycol or polyethylene glycol.
4 . The formulation of claim 1 wherein the Bendamustine is present at a concentration of at least 5 mg/ml.
5 . The formulation of claim 1 wherein the Bendamustine is present at a concentration of equal or less than 5 mg/ml.
6 . The formulation of claim 1 wherein the chloride is present at a concentration of at least 5 mg/ml.
7 . The formulation of claim 1 wherein the chloride is present at a concentration of at least 14 mg/ml.
8 . The formulation of claim 1 wherein the aqueous chloride-containing water phase is present in an amount of at least 10 vol %.
9 . The formulation of claim 1 wherein the Bendamustine is present at a concentration of equal or less than 5 mg/ml, wherein the aqueous chloride-containing water phase is present in an amount of at least 10 vol %, wherein the non-aqueous solvent system comprises propylene glycol, and wherein the chloride is present in the mixture at a concentration of at least 5 mg/ml.
10 . A reconstitution solution for lyophilized Bendamustine to thereby produce a ready-to-use liquid formulation for injection, comprising:
a mixture of a non-aqueous solvent system and an aqueous chloride-containing water phase;
wherein the chloride is present in the mixture at a precipitating amount with respect to Bendamustine in the water phase, and wherein the non-aqueous solvent system is present in the mixture in an amount effective to prevent Bendamustine precipitation from the water phase; and
wherein the precipitating amount of chloride is effective to stabilize Bendamustine in the mixture when the mixture is combined with the lyophilized Bendamustine.
11 . The reconstitution solution of claim 10 , wherein the precipitating amount of chloride is at least 5 mg/ml.
12 . The reconstitution solution of claim 11 , wherein the non-aqueous solvent system comprises at least one of propylene glycol or polyethylene glycol and wherein the aqueous chloride-containing water phase is present in an amount of at least 10 vol %.
13 . The reconstitution solution of claim 12 , wherein the Bendamustine is stabilized in the mixture to limit total degradation product formation after at least three days under refrigeration at between 2-8° C. to equal or less than 1.0% of total Bendamustine combined with the mixture.
14 . The reconstitution solution of claim 12 , wherein the Bendamustine is stabilized in the mixture to limit total degradation product formation after at least three days under refrigeration at between 2-8° C. to equal or less than 0.5% of total Bendamustine combined with the mixture.
15 . The reconstitution solution of claim 12 , wherein the Bendamustine is stabilized in the mixture to limit total degradation product formation after at least three days under refrigeration at between 2-8° C. to equal or less than 0.2% of total Bendamustine combined with the mixture.
16 . A pharmaceutical kit for administration of Bendamustine, comprising a quantity of lyophilized Bendamustine and the reconstitution solution of claim 10 .
17 . The pharmaceutical kit of claim 16 , wherein the quantity of lyophilized Bendamustine is sufficient for at least two independent administrations.
18 . A method of stabilizing Bendamustine in a ready-to-use aqueous liquid formulation for multiple independent injections, comprising:
providing a mixture of a non-aqueous solvent system and an aqueous chloride-containing water phase;
wherein the chloride is present in the mixture at a precipitating amount with respect to Bendamustine in the water phase, and wherein the non-aqueous solvent system is present in the mixture in an amount effective to prevent Bendamustine precipitation from the water phase;
wherein the precipitating amount of chloride is effective to stabilize Bendamustine in the mixture when the mixture is combined with the lyophilized Bendamustine; and
dissolving the Bendamustine in a volume of the mixture to thereby form the ready-to-use liquid formulation for injection, wherein the volume is sufficient to form the ready-to-use liquid formulation for multiple independent injections.
19 . The method of claim 1 , wherein the Bendamustine is present at a concentration of at least 5 mg/ml, wherein the aqueous chloride-containing water phase is present in an amount of at least 10 vol %, wherein the non-aqueous solvent system comprises propylene glycol, and wherein the chloride is present in the mixture at a concentration of at least 5 mg/ml.
20 . The method of claim 17 , wherein the Bendamustine is stabilized in the mixture to limit total degradation product formation after at least three days under refrigeration at between 2-8° C. to equal or less than 1.0% of total Bendamustine combined with the mixture.