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 - 30 . (canceled)
31 . 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 the composition is substantially free of an anti-oxidant and comprises no more than about 5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
32 . The pharmaceutical composition of claim 1 comprising 10 to 50 mg/mL pemetrexed.
33 . The pharmaceutical composition of claim 6 comprising 25 mg/mL pemetrexed.
34 . 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.
35 . The pharmaceutical formulation of claim 8 wherein the non-aqueous solvent is propylene glycol.
36 . The pharmaceutical formulation of claim 9 wherein propylene glycol is present at 250 μL/mL.
37 . The pharmaceutical composition of claim 1 wherein the pemetrexed is in the form of pemetrexed diacid.
38 . The pharmaceutical composition of claim 1 wherein the pemetrexed is in the form of pemetrexed disodium.
39 . 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 the composition is substantially free of an anti-oxidant and comprises no more than about 5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
40 . The pharmaceutical formulation of claim 31 wherein the composition comprises no more than about 4% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
41 . The pharmaceutical formulation of claim 31 wherein the composition comprises no more than about 3.5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
42 . The pharmaceutical formulation of claim 31 wherein the composition comprises no more than about 3% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
43 . The pharmaceutical formulation of claim 39 wherein the composition comprises no more than about 4% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
44 . The pharmaceutical formulation of claim 39 wherein the composition comprises no more than about 3.5% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
45 . The pharmaceutical formulation of claim 39 wherein the composition comprises no more than about 3% w/w impurities after storage at 2-8° C. for about 12 months at about 20% head space oxygen.
46 . 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 is substantially free of an anti-oxidant and 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 at about 20% head space oxygen.
47 . The pharmaceutical composition of claim 46 having an initial pemetrexed concentration of 25 mg/mL.
48 . The pharmaceutical formulation of claim 46 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol; polyethylene glycol, or combinations thereof.
49 . The pharmaceutical formulation of claim 48 wherein the non-aqueous solvent is propylene glycol.
50 . The pharmaceutical formulation of claim 49 wherein propylene glycol is present at 250 μL/mL.
51 . The pharmaceutical composition of claim 46 wherein the pemetrexed is in the form of pemetrexed di acid.
52 . The pharmaceutical composition of claim 46 wherein the pemetrexed is in the form of pemetrexed disodium.
53 . 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 is substantially free of an anti-oxidant and 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 at about 20% head space oxygen.