Bendamustine HCL Stable Lyophilized Formulations
The present invention provides a lyophilized bendamustine hydrochloride (HCL) pharmaceutical composition. The present invention further provides methods of producing the lyophilized bendamustine HCL composition from a composition including bendamustine HCL, mannitol, formic acid, and water. The pharmaceutical formulation can be used for any disease that is sensitive to treatment with bendamustine, such as neoplastic diseases.
1 . A pharmaceutical composition comprising bendamustine or bendamustine hydrochloride, mannitol, formic acid, and water.
2 . The pharmaceutical composition according to claim 1 , wherein said formic acid is present at a concentration of about 5% (v/v) to about 70% (v/v).
3 . The pharmaceutical composition according to claim 2 , wherein said formic acid is present at a concentration of about 10% (v/v) to about 60% (v/v).
4 . The pharmaceutical composition according to claim 1 , wherein said bendamustine or bendamustine hydrochloride is present at a concentration of about 5 mg/mL to about 20 mg/mL, and said mannitol is present at a concentration of about 10 mg/mL to about 30 mg/mL.
5 . The pharmaceutical composition according to claim 4 , wherein said bendamustine hydrochloride is present at a concentration of about 14.7 mg/mL, and said mannitol is present at a concentration of about 25 mg/mL.
6 . The pharmaceutical composition according to claim 5 , wherein said formic acid is present at a concentration of about 10% (v/v) to about 30% (v/v).
7 . The pharmaceutical composition according to claim 6 , wherein said pharmaceutical composition, after being held at a temperature from about 2° C. to about 5° C. for about 4.5 hours, contains not more than 0.5% of monohydroxy bendamustine hydrochloride.
8 . The pharmaceutical composition according to claim 7 , wherein said lyophilized pharmaceutical composition contains not more than 0.25% of monohydroxy bendamustine hydrochloride.
9 . A lyophilized pharmaceutical composition made from the pharmaceutical composition according to claim 1 .
10 . A lyophilized pharmaceutical composition made from the pharmaceutical composition according to claim 4 .
11 . A lyophilized pharmaceutical composition made from the pharmaceutical composition according to claim 5 .
12 . A lyophilized pharmaceutical composition made from the pharmaceutical composition according to claim 6 .
13 . The lyophilized pharmaceutical composition according to claim 9 , containing not more than 0.5% of monohydroxy bendamustine hydrochloride as measured upon reconstitution of said lyophilized pharmaceutical composition with water, at time zero.
14 . The lyophilized pharmaceutical composition according to claim 9 containing not more than 0.25% of monohydroxy bendamustine hydrochloride as measured upon reconstitution of said lyophilized pharmaceutical composition with water, at time zero.
15 . A process for preparing a lyophilized pharmaceutical composition comprising: preparing the composition of claim 1 , and lyophilizing the composition of claim 1 to obtain the lyophilized pharmaceutical composition.
16 . The process for preparing a lyophilized pharmaceutical composition comprising:
freezing the composition of claim 1 to a temperature of from about −50° C. to about −45° C. to produce a frozen mixture;
holding the frozen mixture at a temperature of from about −45° C. to about −40° C. for no less than 200 minutes;
subjecting the frozen mixture to a primary drying stage, which comprises applying a vacuum to reduce the pressure by an amount effective to remove water and formic acid from the frozen mixture, and while applying the vacuum, raising the temperature to a primary drying temperature, wherein the primary drying temperature is from about −40° C. to about −25° C. to produce a partially dried mass; and
subjecting the partially dried mass to a secondary drying stage, which comprises applying a vacuum to reduce the pressure by an amount effective to further remove water and formic acid from the partially dried mass, and while applying the vacuum, raising the temperature to a secondary drying temperature, wherein the secondary drying temperature is from about −10° C. to about 30° C., to produce the lyophilized pharmaceutical composition.
17 . A method of treating a neoplastic disease in mammals, comprising: reconstituting the lyophilized pharmaceutical composition of claim 9 into an aqueous bendamustine solution; and administering an effective amount of said aqueous bendamustine solution to a mammal in need thereof.
18 . The method of treating neoplastic diseases in mammals according to claim 17 , wherein the neoplastic disease is leukemia or Hodgkin's disease.