Pharmaceutical compositions containing pemetrexed having extended storage stability
Long term storage stable pemetrexed-containing liquid pharmaceutical compositions are disclosed. The compositions can include pemetrexed or pharmaceutically acceptable salts thereof; an antioxidant selected from lipoic acid, dihydrolipoic acid, methionine and mixtures thereof; a chelating agent selected from lactobionic acid, sodium citrate, tribasic and mixtures thereof; and a pharmaceutically acceptable fluid. The pH of the compositions is in a range of about 8 to about 9.5. The pemetrexed-containing compositions have less than about 5% total impurities, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 227 nm, after at least about 18 months of storage at a temperature of from about 5° C. to about 25° C. Methods of preparing the formulation as well as methods of treatment of pemetrexed-susceptible diseases using the same are also disclosed.
1. A long term storage stable pemetrexed-containing aqueous liquid pharmaceutical composition, comprising:
a) pemetrexed or a pharmaceutically acceptable salt thereof;
b) 1 mg/ml to about 20 mg/ml L-methionine; and
c) 0.005M to about 0.5M sodium citrate, tribasic; and
d) an aqueous pharmaceutically acceptable fluid; and optionally
e) propylene glycol;
wherein the composition has a pH of from about 8.0 to about 9.5; and
said pemetrexed-containing composition has less than about 5% total impurities, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 227 nm, after at least about 18 months of storage at a temperature of from about 5° C. to about 25° C.
2. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein the pemetrexed is the disodium salt thereof.
3. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein the concentration of the pemetrexed is from about 1 mg/ml to about 50 mg/ml.
4. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein the concentration of the pemetrexed is from about 20 mg/ml to about 30 mg/ml.
5. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein the concentration of the pemetrexed is about 25 mg/ml.
6. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein the composition contains up to about 50% propylene glycol, relative to the total amount of the composition.
7. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 6 , wherein the composition contains about 10% propylene glycol, relative to the total amount of the composition.
8. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 6 , wherein the composition contains about 25% propylene glycol, relative to the total amount of the composition.
9. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 6 , wherein the composition contains about 30% propylene glycol, relative to the total amount of the composition.
10. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein the concentration of the L-methionine is from about 2.5 mg/ml to about 10 mg/ml.
11. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 10 , wherein the concentration of the L-methionine is about 5 mg/ml.
12. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein the concentration of the sodium citrate, tribasic is about 0.05M.
13. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , wherein said long term storage is at least about 2 years.
14. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 , said pemetrexed-containing composition having less than about 1% total impurities, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 227 nm, after at least about 18 months of storage at a temperature of from about 5° C. to about 25° C.
15. A long term storage stable pemetrexed-containing aqueous liquid pharmaceutical composition, comprising:
a) pemetrexed or a pharmaceutically acceptable salt thereof;
b) 1 mg/ml to about 20 mg/ml of an antioxidant selected from the group consisting of lipoic acid, dihydrolipoic acid, methionine and mixtures thereof;
c) 0.005M to about 0.5M of a chelating agent selected from the group consisting of lactobionic acid, sodium citrate, tribasic and mixtures thereof; and
d) an aqueous pharmaceutically acceptable fluid; and
e) up to 50% propylene glycol, relative to the total amount of the composition;
wherein the pH is in a range of about 8 to about 9.5, and
said pemetrexed-containing composition has less than about 1% total impurities, on a normalized peak area response (“PAR”) basis as determined by high performance liquid chromatography (“HPLC”) at a wavelength of 227 nm, after at least about 2 months of storage at a temperature of about 40° C.
16. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 15 , wherein the propylene glycol is present in an amount of about 10%, relative to the total amount of the composition.
17. The long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 15 , wherein the propylene glycol is present in an amount of about 25%, relative to the total amount of the composition.
18. A method of treating of a pemetrexed sensitive disease in mammals, comprising administering an effective amount of a long term storage stable pemetrexed-containing aqueous pharmaceutical composition of claim 1 to a mammal in need thereof.