PEMETREXED FORMULATIONS
The present invention is directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable after dilution for at least about 48 hours when stored at 2° C. to 8° C. The present invention is also directed to pemetrexed formulations comprising a non-aqueous solvent that remains stable for at least about 24 months when stored at 2° C. to 8° C.
1 . A pharmaceutical composition comprising:
a) pemetrexed:
b) a non-aqueous solvent present at less than 0.30 mL/mL; and
c) at least about 600 μL/mL of water,
wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2° C. to 8° C. for at least 12 hours and the composition is substantially free of an anti-oxidant.
2 . The pharmaceutical composition of claim 1 wherein the composition retains at least 90% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:
a) at least 24 hours, and
b) at least 48 hours.
3 . The pharmaceutical composition of claim 1 wherein the composition retains at least 95% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:
a) at least 12 hours,
b) at least 24 hours, and
c) at least 48 hours.
4 . The pharmaceutical composition of claim 1 wherein the composition retains at least 98% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:
a) at least 12 hours,
b) at least 24 hours, and
c) at least 48 hours.
5 . The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer's Injection, and Lactated Ringer's Injection.
6 . The pharmaceutical composition of claim 1 comprising 10 to 50 mg/mL pemetrexed.
7 . The pharmaceutical composition of claim 6 comprising 25 mg/mL pemetrexed.
8 . The pharmaceutical formulation of claim 1 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
9 . The pharmaceutical formulation of claim 8 wherein the non-aqueous solvent is propylene glycol.
10 . The pharmaceutical formulation of claim 9 wherein propylene glycol is present at 250 μL/mL.
11 . (canceled)
12 . The pharmaceutical composition of claim 1 wherein the pemetrexed is in the form of pemetrexed diacid.
13 . The pharmaceutical composition of claim 1 wherein the pemetrexed is in the form of pemetrexed disodium.
14 . (canceled)
15 . A pharmaceutical composition comprising
a) 25 mg/mL pemetrexed:
b) propylene glycol at 250 μL/mL; and
c) at least about 600 μL/mL water
wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2° C. to 8° C. for at least 24 hours and the composition is substantially free of an anti-oxidant.
16 . The pharmaceutical composition of claim 15 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2° C. to 8° C. for at least 48 hours.
17 . A pharmaceutical composition comprising:
a) pemetrexed at an initial concentration of 10 to 50 mg/mL
b) a non-aqueous solvent present at less than 0.30 mL/mL; and
c) at least about 600 μL/mL water
wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 months and the composition is substantially free of an anti-oxidant.
18 . The pharmaceutical composition of claim 17 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage for a period selected from:
a) at least 18 months, and
b) at least 24 months.
19 . The pharmaceutical composition of claim 17 wherein the composition comprises at least 95% of the initial pemetrexed concentration after storage for a period selected from:
a) at least 12 months,
b) at least 18 months, and
c) at least 24 months.
20 . The pharmaceutical composition of claim 17 wherein the composition comprises at least 98% of the initial pemetrexed concentration after storage for a period selected from:
a) at least 12 months,
b) at least 18 months, and
c) at least 24 months.
21 . The pharmaceutical composition of claim 17 having an initial pemetrexed concentration of 25 mg/mL.
22 . The pharmaceutical formulation of claim 17 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
23 . The pharmaceutical formulation of claim 22 wherein the non-aqueous solvent is propylene glycol.
24 . The pharmaceutical formulation of claim 23 wherein propylene glycol is present at 250 μL/mL.
25 . (canceled)
26 . The pharmaceutical composition of claim 17 wherein the pemetrexed is in the form of pemetrexed diacid.
27 . The pharmaceutical composition of claim 17 wherein the pemetrexed is in the form of pemetrexed disodium.
28 . (canceled)
29 . A pharmaceutical composition comprising
a) an initial pemetrexed concentration of 25 mg/mL,
b) propylene glycol at 250 μL/mL, and
c) at least about 600 μL/mL water;
wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 12 months and the composition is substandtially free of an anti-oxidant.
30 . The pharmaceutical composition of claim 29 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2° C. to 8° C. for at least 24 months.
31 . The pharmaceutical formulation of claim 1 wherein the non-aqueous solvent is present at a concentration of about 0.050 mL/mL to 0.30 mL/mL.
32 . The pharmaceutical formulation of claim 15 wherein the non-aqueous solvent is present at a concentration of about 0.050 mL/mL to 0.30 mL/mL.
33 . The pharmaceutical formulation of claim 17 wherein the non-aqueous solvent is present at a concentration of about 0.050 mL/mL to 0.30 mL/mL.