FORMULATIONS OF BENDAMUSTINE
Long term storage stable bendamustine-containing compositions are disclosed. The compositions can include bendamustine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable fluid contains a mixture of PEG and PG; an organic or inorganic compound in an amount sufficient to obtain a pH of from about 6.0 to about 11 for the polyethylene glycol, as measured using USP monograph for polyethylene glycol; and optionally an antioxidant. The bendamustine-containing compositions have less than about 5% total esters, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5° C. to about 25° C.
1 . A long term storage stable bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable fluid comprising
i) a mixture of polyethylene glycol, and propylene glycol;
ii) an organic compound or an inorganic compound in an amount sufficient to obtain a pH of from about 6.0 to about 11 for the polyethylene glycol, as measured using USP monograph for polyethylene glycol; and
iii) a stabilizing amount of an antioxidant;
said bendamustine-containing composition having less than about 5% total polyethylene glycol esters and propylene glycol esters, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5° C. to about 25° C.
2 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the amount of the organic compound or an inorganic compound is provided in an amount sufficient to obtain a pH of from about 6.5 to about 8 for the polyethylene glycol, as measured using USP monograph for polyethylene glycol.
3 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the pharmaceutically acceptable fluid comprises an inorganic compound selected from the group consisting of salts of hydroxides and salts of phosphates.
4 . The long term storage stable bendamustine-containing composition of claim 3 , wherein the inorganic compound is sodium hydroxide.
5 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the pharmaceutically acceptable fluid comprises an organic compound selected from the group consisting of carboxylic compounds, nitrogenous compounds, carbonates, and salts thereof.
6 . The long term storage stable bendamustine-containing composition of claim 5 , wherein the organic compound is sodium acetate or is diethanolamine.
7 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the bendamustine concentration is from about 20 mg/mL to about 60 mg/mL.
8 . The long term storage stable bendamustine-containing composition of claim 7 , wherein the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL.
9 . The long term storage stable bendamustine-containing composition of claim 8 , wherein the bendamustine concentration is about 25 mg/mL.
10 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the pharmaceutically acceptable fluid comprises about 90% polyethylene glycol and about 10% propylene glycol.
11 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the pharmaceutically acceptable fluid comprises about 85% polyethylene glycol and about 15% propylene glycol.
12 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the antioxidant is selected from the group consisting of thioglycerol, monothioglycerol, lipoic acid, propyl gallate, methionine, cysteine, metabisulfites, sodium formaldehyde sulfoxylate, phenol-containing aromatic and aliphatic compounds and dihydrolipoic acid.
13 . The long term storage stable bendamustine-containing composition of claim 12 , wherein the antioxidant is thioglycerol or monothioglycerol.
14 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the stabilizing amount of the antioxidant is from about 2.5 mg/mL to about 35 mg/mL.
15 . The long term storage stable bendamustine-containing composition of claim 14 , wherein the stabilizing amount of the antioxidant is from about 5 mg/mL to about 20 mg/mL.
16 . The long term storage stable bendamustine-containing composition of claim 15 , wherein the stabilizing amount of the antioxidant is about 5 mg/mL.
17 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the concentration of the inorganic compound is from about 0.0005 molarity to about 0.04 molarity.
18 . The long term storage stable bendamustine-containing composition of claim 17 , wherein the concentration of the inorganic compound is about 0.01 molarity.
19 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the concentration of the organic compound is from about 0.005M to about 0.1M.
20 . The long term storage stable bendamustine-containing composition of claim 19 , wherein the concentration of the organic compound is about 0.01M.
21 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the pH of the polyethylene glycol, as measured using the USP monograph for polyethylene glycol, is about 6.5 or about 8.
22 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the pH of the long term storage stable bendamustine-containing composition, as measured using the USP monograph for polyethylene glycol, is from about 3.3 to about 4.
23 . The long term storage stable bendamustine-containing composition of claim 22 , wherein the pH of the long term storage stable bendamustine-containing composition, as measured using the USP monograph for polyethylene glycol, is about 3.5.
24 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the amount of total polyethylene glycol esters and propylene glycol esters is less than about 3%.
25 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the amount of total polyethylene glycol esters and propylene glycol esters is less than about 2.4%.
26 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the amount of individual polyethylene glycol esters less than about 0.2% and individual propylene glycol esters is less than about 1.5%.
27 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the amount of total polyethylene glycol esters is less than about 2%.
28 . The long term storage stable bendamustine-containing composition of claim 1 , wherein the amount of total propylene glycol esters is less than about 3%.
29 . The long term storage stable bendamustine-containing composition of claim 1 , wherein said long term storage is at least about 2 years.
30 . A long term storage stable bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable fluid comprising
i) 90% polyethylene glycol and 10% propylene glycol;
ii) sodium hydroxide in an amount sufficient to obtain a pH of from about 6.5 for the polyethylene glycol, as measured using the USP monograph for polyethylene glycol; and
iii) thioglycerol at a concentration of about 5 mg/mL;
said bendamustine-containing composition having less than about 5% total polyethylene glycol esters and propylene glycol esters, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5° C. to about 25° C.
31 . A long term storage stable bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof at a concentration of about 25 mg/mL; and
b) a pharmaceutically acceptable fluid comprising
i) 90% polyethylene glycol and 10% propylene glycol;
ii) sodium acetate in an amount sufficient to obtain a pH of about 6.5 for the polyethylene glycol, as measured using the USP monograph for polyethylene glycol; and
iii) thioglycerol at a concentration of about 5 mg/mL;
said bendamustine-containing composition having less than about 5% total polyethylene glycol esters and propylene glycol esters, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5° C. to about 25° C.
32 . A long term storage stable bendamustine-containing composition, comprising:
a) bendamustine or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable fluid comprising
i) a mixture of polyethylene glycol, and propylene glycol;
ii) an organic compound or an inorganic compound in an amount sufficient to obtain a pH of from about 3.3 to about 4.2 for the long term storage stable bendamustine-containing composition, as measured using the USP monograph for polyethylene glycol; and
iii) a stabilizing amount of an antioxidant;
said bendamustine-containing composition having less than about 5% total polyethylene glycol esters and propylene glycol esters, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 223 nm, after at least about 15 months of storage at a temperature of from about 5° C. to about 25° C.
33 . A method of treating cancer in mammals, comprising administering an effective amount of a long term storage stable bendamustine-containing composition of claim 1 to a mammal in need thereof.