CA3014755A1

CA3014755A1 - Stable pemetrexed formulations comprising propylene glycol

Info

Publication number: CA3014755A1
Application number: CA3014755A
Authority: CA
Inventors: Feng-Jing Chen; Steven L. Krill
Original assignee: Eagle Pharmaceuticals Inc
Current assignee: Eagle Pharmaceuticals Inc
Priority date: 2016-02-19
Filing date: 2016-02-19
Publication date: 2017-08-24
Anticipated expiration: 2036-02-19
Also published as: IL261179B; CN109152778A; JP2019505561A; IL290647B2; IL290647A; IL301291A; AU2016393213B2; AU2016393213A1; CA3014755C; AU2023202089A1; IL290647B1; EP3416646A1; MX2018010037A; CN109152778B; MX2022009547A; EP3416646A4; IL261179A; WO2017142556A1; KR20180132643A

Abstract

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.

Description

PEMETREXED FORMULATIONS
BACKGROUND OF THE INVENTION
Compounds exhibiting anti-folate activity have a well known role as chemotherapeutic agents. One such compound is pemetrexed, which has the chemical name N-P1-12-(2-amino-4,7-di hydro-4-oxo-IH-pyrrolo [2,3-d] py ri m idin-5-yl)ethyl]benzoy1]-1,-gl utami c acid and the structure of formula (1):

HN
HN
Pemetrexed is used in the treatment of pleural mesothelioma and non-small cell lung cancer. ALIMTA, Eli Lilly's pemetrexed product is presently supplied in 100 mg and 500 mg vials of lyophilized pemetrexed disodium for injection. According to the prescribing information, in order to prepare ALIMTA for infusion the vials are reconstituted in sufficient 0.9% Sodium Chloride Injection (preservative free) to give a solution containing 25 mg/tnL of ALIMTA. This concentrated solution is then further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free). The prescribing information cautions that reconstitution and further dilution is only recommended with 0.9% Sodium Chloride Injection (preservative free), and that "ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used."
Calcium containing diluents, such as Lactated Ringer's Injection and Ringer's Injection, are common solutions used in medical settings for the reconstitution and/or dilution of drug products prior to intravenous administration. There is a need for pemetrexed dosage forms that are chemically stable after reconstitution and/or dilution with diluents containing calcium. In addition to being useful with a wider range of available diluents, the use of such a dosage form would minimize both the loss of dosage forms due to improper reconstitution or dilution and the risk that a patient would be administered pemetrexed reconstituted or diluted in an incompatible diluent.
In solution, pemetrexed undergoes hydrolysis and degrades rapidly. Due to this rapid degradation, pemetrexed formulations must either be lyophilized for long term stability or comprise stabilizers. However, reconstitution of a lyophilized formulation requires multiple steps, each of which increases the risk of user error. In addition, reconstitution of a lyophilized formulation is clinically inconvenient and can take up to 30 minutes.
While stable, ready to use formulations of pemetrexed are known, they require stabilizers, such as anti-oxidants or amino acids as described in US6,686,365;
CN 101081305;
and WO 2012015810, or high levels of non-aqueous solvents, as described in W02013144814. It would be advantageous to minimize patient exposure to these additional ingredients.
As such, there is a need for a stable, non-lyophilized pemetrexed composition with a minimal amount of additional ingredients. To this end, we have developed a stable pemetrexed formulation.
SUMMARY OF THE INVENTION
In certain embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration less than 0.30m1/mL, 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.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 AlAIL propylene glycol, and 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.
In still further embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed at an initial concentration of 10 to 50 mg/mL and a non-aqueous solvent

2 present at a concentration less than 0.30m1/mL, 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.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 L/mL propylene glycol, and 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.
In certain embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration less than 0.30m1/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 1.1L/mL propylene glycol, and water, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 24 hours.
In still further embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed at an initial concentration of 10 to 50 mg/mL and a non-aqueous solvent present at a concentration less than 0.30m1/mL, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 LtL/mL propylene glycol, and water, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 24 hours.
Additional embodiments of the invention include:

3 1. A pharmaceutical composition comprising:
a) pemetrexed and b) a non-aqueous solvent present at less than 0.30 mL/mL;
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.
2. The pharmaceutical composition of embodiment 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 embodiment 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 embodiment 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 embodiment 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 PCT/US2016/018703 6. The pharmaceutical composition of embodiment 1 comprising 10 to 50 mg/mL

pemetrexed.

7. The pharmaceutical composition of embodiment 6 comprising 25 mg/mL
pemetrexed.

8. The pharmaceutical formulation of embodiment 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 embodiment 8 wherein the non-aqueous solvent is propylene glycol.

10. The pharmaceutical formulation of embodiment 9 wherein propylene glycol is present at 250 pL/mL.

11. The pharmaceutical composition of embodiment 1 comprising at least 0.50mL/mL water.

12. The pharmaceutical composition of embodiment] wherein the pemetrexed is in the form of pemetrexed diacid.

13. The pharmaceutical composition of embodiment 1 wherein the pemetrexed is in the form of pemetrexed disodium.

14. The pharmaceutical composition of embodiment 1 substantially free of an anti-oxidant.

15. A pharmaceutical composition comprising a) 25 mg/mL pemetrexed, and b) propylene glycol at 250 tiL/mL
c) 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.

16. The pharmaceutical composition of embodiment 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 and b) a non-aqueous solvent present at less than 0.30 inL/mL, 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.

18. The pharmaceutical composition of embodiment 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 embodiment 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 embodiment 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 embodiment 17 having an initial pemetrexed concentration of 25 mg/inL.

22. The pharmaceutical formulation of embodiment 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 embodiment 22 wherein the non-aqueous solvent is propylene glycol.

24. The pharmaceutical formulation of embodiment 23 wherein propylene glycol is present at 250 1.tL/mL.

25. The pharmaceutical composition of embodiment 17 comprising at least 0.50mL/mL
water.

26. The pharmaceutical composition of embodiment 17 wherein the pemetrexed is in the form of pemetrexed diacid.

27. The pharmaceutical composition of embodiment 17 wherein the pemetrexed is in the form of pemetrexed disodium.

28. The pharmaceutical composition of embodiment 17 substantially free of an anti-oxidant.

29. A pharmaceutical composition comprising a) an initial pemetrexed concentration of 25 mg/mL, b) propylene glycol at 250 tiLirriL, and c) 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.

30. The pharmaceutical composition of embodiment 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. A pharmaceutical composition comprising:
a) pemetrexed and b) a non-aqueous solvent present at less than 0.30 mL/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 12 hours.

32. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 8% w/w total impurities after dilution and storage for a period selected from:
a) at least 24 hours, and b) at least 48 hours.

33. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 5% w/w total impurities after dilution and storage for a period selected from:
a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.

34. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 2% w/w total impurities after dilution and storage for a period selected from:
a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.

35. The pharmaceutical composition of embodiment 31 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.

36. The pharmaceutical composition of embodiment 31 comprising 10 to 50 mg/mL
pemetrexed.

37. The pharmaceutical composition of embodiment 36 comprising 25 mg/mL
pemetrexed.

38. The pharmaceutical formulation of embodiment 31 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.

39. The pharmaceutical formulation of embodiment 38 wherein the non-aqueous solvent is propylene glycol.

40. The pharmaceutical formulation of embodiment 39 wherein propylene glycol is present at

41. The pharmaceutical composition of embodiment 31 comprising at least 0.50mL/mL
water.

42. The pharmaceutical composition of embodiment 31 wherein the pemetrexed is in the form of pemetrexed diacid.

43. The pharmaceutical composition of embodiment 31 wherein the pemetrexed is in the form of pemetrexed disodium.

44. The pharmaceutical composition of embodiment 31 substantially free of an anti-oxidant.

45. A pharmaceutical composition comprising a) 25 mg/mL pemetrexed, b) propylene glycol at 250 [IL/mL, and c) water;

wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 24 hours.

46. The pharmaceutical composition of embodiment 45 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 48 hours.

47. A pharmaceutical composition comprising:
a) pemetrexed at an initial concentration of 10 to 50 mg/mL and b) a non-aqueous solvent present at less than 0.30 mL/mL, wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 12 months.

48. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 8% w/w total impurities after storage for a period selected from:
a) at least 18 months, and b) at least 24 months.

49. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 5% w/w total impurities after storage for a period selected from:
a) at least 12 months, b) at least 18 months, and c) at least 24 months.

50. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 2% w/w total impurities after storage for a period selected from:
a) at least 12 months, b) at least 18 months, and c) at least 24 months.

51. The pharmaceutical composition of embodiment 47 comprising 25 mg/mL
pemetrexed.

52. The pharmaceutical formulation of embodiment 47 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.

53. The pharmaceutical formulation of embodiment 52 wherein the non-aqueous solvent is propylene glycol.

54. The pharmaceutical formulation of embodiment 53 wherein propylene glycol is present at 2501.1L/mL.

55. The pharmaceutical composition of embodiment 47 comprising at least 0.50mL/mL
water.

56. The pharmaceutical composition of embodiment 47 wherein the pemetrexed is in the form of pemetrexed diacid.

57. The pharmaceutical composition of embodiment 47 wherein the pemetrexed is in the form of pemetrexed disodium.

58. The pharmaceutical composition of embodiment 47 substantially free of an anti-oxidant.

59. A pharmaceutical composition comprising a) an initial pemetrexed concentration of 25 mg/mL, b) propylene glycol at 250 p.L/mL, and c) water;
wherein the composition comprises no more than 8% wlw total impurities after storage at a temperature of 2 C to 8 C for at least 12 months.

60. The pharmaceutical composition of embodiment 59 wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2 C to 8 C for at least 24 months.

BRIEF DESCRIPTION OF THE FIGURES
FIGS 1A-1D: Depicts the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations.
DETAILED DESCRIPTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there is a plurality of definitions for a term used herein, those definitions in this section prevail unless stated otherwise.
As used herein "single largest impurity" refers to the impurity with the largest HPLC
peak by percentage.
As used herein "initial dosage concentration of pemetrexed" refers the concentration of pemetrexed at the time of dilution, prior to storage.
As used herein "initial pemetrexed concentration" refers to the concentration of pemetrexed at the time of formulation, prior to dilution and/or storage.
As used herein "room temperature" is about 20 C to about 25 C.
Pemetrexed or a pharmaceutically acceptable salt thereof is present in the compositions of the present invention at concentrations of between about 10 mg/mL to about 50 mg/mL when calculated as anhydrous pemetrexed diacid. In certain embodiments of the invention, pemetrexed is present at about 10 mg/mL to about 40 mg/mL, at about 10 mg/mL
to about 30 mg/mL, at about 10 mg/mL to about 20 mg/mL, at about 20 mg/mL to about 50 mg/mL, at about 20 mg/mL to about 40 mg/mL, at about 20 mg/mL to about 30 mg/mL, at about 30 mg/mL to about 50 mg/mL, at about 30 mg/mL to about 40 mg/mL, or at about 40 mg/mL to about 50 mg/mL. In further embodiments of the invention, pemetrexed is available at about 10 mg/mL, about 15 mg/mL, 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, or at about 50 mg/mL.
Pemetrexed is present in the composition as the diacid, monoacid, a pharmaceutically acceptable salt, or as combinations thereof. In certain embodiments of the invention, pemetrexed is present as pemetrexed disodium, in further embodiments of the invention, pemetrexed is present as pemetrexed dipotassium. In yet further embodiments of the invention, pemetrexed is present as pemetrexed meglumine. In still further embodiments of the invention, pemetrexed is present as pemetrexed tromethamine.
Non-Aqueous Solvents Suitable non-aqueous solvents include, but are not limited to alcohols, ketones, esters, ethers, aromatic hydrocarbons, nitriles, aprotic polar solvents, acidic solvents, and mixtures of any two or more thereof. Useful alcohols include, for example, methanol, ethanol, denatured spirits, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, polyhydroxy alcohols example glycerin, propylene glycol, polyethylene glycol, diethylene glycol, diglycerin, triethylene glycol, tetraethylene glycol, trimethylolpropane and the like. Useful ketones include propanone, 2-butanone, and the like. Useful esters include, for example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, and the like. Useful ethers include, for example, dimethyl ether, diethyl ether, methyl t-butyl ether, ethyl methyl ether, diisopropyl ether, and the like. Useful aromatic hydrocarbons include, for example, and the like.
Useful nitriles include acetonitrile, propionitrile, and the like. Useful aprotic polar solvents include N,N-dimethylformide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like.
In certain embodiments of the invention, the non-aqueous solvent is an alcohol. In further embodiments of the invention, the non-aqueous solvent is a polyhydroxy alcohol. In still further embodiments of the invention, the non-aqueous solvent is propylene glycol. In yet further embodiments of the invention, the non-aqueous solvent is polyethylene glycol.
In particular embodiments of the invention, the non-aqueous solvent is low molecular weight polyethylene glycol. In other embodiments of the invention, the non-aqueous solvent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, or combinations thereof. In certain embodiments of the invention, more than one non-aqueous solvent is present, such as, but not limited to polyethylene glycol and propylene glycol.

In certain embodiments of the invention, the non-aqueous solvent is present at a concentration of about 50 mg/mL to 300 mg/mL prior to dilution. In further embodiments of the invention, the non-aqueous solvent is present at about 50 mg/mL to 100 mg/mL, 50 mg/mL to 200 mg/mL, 50 mg/mL to 250 mg/mL, 50 mg/mL to 300 mg/mL, 100 mg/mL to 200 mg/mL, 100 mg/mL to 250 mg/mL, 100 mg/mL to 300 mg/mL, 200 mg/mL to 250 mg/mL, 200 mg/mL
to 300 mg/mL, or 250 mg/mL to 300 mg/mL prior to dilution.
In particular embodiments, the non-aqueous solvent is present at a concentration of no more than 30 weight percent (wt.%) of the formulation prior to dilution. In further embodiments, the non-aqueous solvent is present at a concentration of at least 5 weight percent (wt.%) of the formulation prior to dilution. In certain embodiments of the invention the non-aqueous solvent is present at 5-30 weight percent (wt.%) of the formulation prior to dilution. In particular embodiments of the invention the non-aqueous solvent is present at about 10-30 wt.%, 15-30 wt.%, 20-30 wt.%, 25-30 wt.%, 5-28%, 10-28 wt.%, 15-28 wt.%, 20-28 wt.%, 25-28 wt.%, 5-25%, 10-25 wt.%, 15-25 wt.%, 20-25 wt.%, 25-28 wt.%, 5-20%, 10-20 wt.%, 15-20 wt.%, 5-15%, 10-15 wt.%, or 5-10 wt% prior to dilution.
In particular embodiments, the non-aqueous solvent is present at a concentration of no more than 300 pL/mL prior to dilution. In further embodiments, the non-aqueous solvent is present at a concentration of at least 50 pL/nriL prior to dilution. In certain embodiments of the invention, the non-aqueous solvent is present at a concentration of about 50 ItL/mL to 300 pL/mL. In further embodiments of the invention, the non-aqueous solvent is present at about 50 pi../ML to 100 pL/mL, 50 pt/mL to 200 pL/mL, 50 pL/mL to 250 pL/mL, 50 pL/mL
to 275 tiL/mL, 50 pl_lrnL to 300 p.L/mL, 100 pL/mL to 200 pL/mL, 100 pL/mL to 250 pL/mL, 100 pL/mL to 275 pL/mL, 100 pL/mL to 300 pL/mL, 200 pL/mL to 250 pL/mL, 200 pL/mL
to 300 pL/mL, or 250 pL/mL to 300 pL/mL prior to dilution.
In certain embodiments, water is present at a concentration of at least about 500 pL/mL
prior to dilution. In other embodiments of the invention, water is present at a concentration of at least about 600 pL/mL, 750 pL/mL, or 950 pL/mL prior to dilution. In further embodiments of the invention, water is present at a concentration of about 500 pt/mL to 950 pL/mL prior to dilution. In still further embodiments of the invention, water is present at about 500 TAIL to 800 1.11,/mL, 500 pL/mL to 700 pL/mL, 500 1.11.,/mL to 600 [1.1_,/mL, 600 pL/mL to 750 pL/mL, 600 pL/mL to 800 111_,/mL, 600 to 950 LtL/mL, 700 pL/mL to 800 pL/mL, 700 1,111mL to 950 pL/mL, or 750 pL/mL to 9504/mL prior to dilution.
In particular embodiments, water is present at a concentration of at least about 50 wt.% of the formulation prior to dilution. In further embodiments, water is present at a concentration of at least about 60 wt.%, 75 w wo, or 95 wt% prior to dilution. In certain embodiments of the invention water is present at a concentration of at least about 50-95 wt.%
prior to dilution. of the invention water is present at a concentration of at least about 50-60 wt.%, 50-70 wt.%, 50-80 wt.%, 60-70 wt.%, 60-80 wt.%, 60-95 wt.%, 70-80 wt.%, or 70-95 wt.% prior to dilution In certain embodiments of the invention the formulation is substantially free of anti-oxidants and/or amino acids. In particular embodiments of the invention, the formulation is substantially free of anti-oxidants. In further embodiments of the invention, the formulation is substantially free of chelating agents. As used herein, substantially free of anti-oxidants, amino acids, and/or chelating agents means the formulation does not comprise one or more anti-oxidants, amino acids, and/or chelating agents, at a concentration sufficient to have a stabilizing effect.
In particular embodiments, the formulation is substantially free of additives selected from the group consisting of ascorbic acid and derivatives, tocopherols and derivatives, propyl gallate, thioglycerol, lactobionic acid, methionine, tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium formaldehyde sulfoxylate, sodium hydrogen sulfite, Eethylenediaminetetraacetic acid (EDTA) and derivatives, monoethanolamine gentisate, glutathione, propionic acid, acetone sodium bisulfite, sodium dithionite, citric acid and derivatives, tribasic (tri sodium citrate dihydrate), or suitable mixtures thereof. As used herein, substantially free means the formulation does not comprise one or more additives listed above at a concentration sufficient to have a stabilizing effect.
In particular embodiments of the invention, the formulation comprises tromethamine. In certain embodiments of the invention, the formulation comprises about 12 to 24 mg/mL
tromethamine. In further embodiments of the invention, the formulation comprises about 12 to 14 mg/mL tromethamine, about 12 to 16 mg/mL tromethamine, about 14 to 16 mg/mL

tromethamine, about 14 to 18 mg/mL tromethamine, about 16 to 18 mg/mL
tromethamine, about 16 to 20 mg/mL tromethamine, about 17 to 19 mg/mL tromethamine, about 17 to 21 mg/mL
tromethamine, about 18 to 20 mg/mL tromethamine, about 18 to 22 mg/mL
tromethamine, about 20 to 22 mg/mL tromethamine, about 20 to 24 mg/mL tromethamine, or about 22 to 24 mg/mL tromethamine. In yet further embodiments of the invention, the formulation comprises about 18 mg/mL tromethamine.
In certain embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 6 months. In particular embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 1 year. In further embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 18 months. In still further embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 2 years.
In further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8 C for at least about 6 months. In certain embodiments of the invention, the formulation is not substantially degraded after storage at 2-8 C for at least about 1 year. In further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8 C for at least about 18 months. In still further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8 C for at least about 2 years.
In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w nnpurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.

In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after storage at 2-8 C for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%
w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In yet further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%
w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after storage at 2-8 C for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In particular embodiments of the invention, the formulation retains at least about 85% of its initial pemetrexed concentration, at least about 90% of its initial pemetrexed concentration, the formulation retains at least about 92% of its initial pemetrexed concentration, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5%
of its initial pemetrexed concentration, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In further embodiments of the invention, the formulation retains at least about 85% of its initial pemetrexed concentration, at least about 90% of its initial pemetrexed concentration, the formulation retains at least about 92% of its initial pemetrexed concentration, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5%
of its initial pemetrexed concentration, after storage at 2-8 C for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In certain embodiments of the invention, the formulation is further diluted in a pharmaceutically acceptable diluent. Suitable diluents include, but are not limited to saline, dextrose, water, Ringer's Injection, and Lactated Ringer's Injection. In certain embodiments of the invention, the formulation can be diluted in a calcium containing diluent, such as Ringer's Injection or Lactated Ringer's Injection.
In particular embodiments of the invention, the formulation is diluted in a pharmaceutically acceptable diluent to a suitable initial dosage concentration of pemetrexed. In certain embodiments of the invention the initial dosage concentration of pemetrexed is based on various factors, such as, but not limited to the patient's weight, age, and condition as well as the volume of diluent and can be determined by a practitioner or one of skill in the art. In further embodiments, pemetrexed is diluted to an initial dosage concentration and can be further diluted prior to administration.
In other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2 C to about 8 C for at least about 12 hours.
In still other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2 C to about 8 C for at least about24 hours.
In yet other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2 C to about 8 C for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after dilution and storage at about 2 C to about 8 C for at least about 12 hours.
In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after dilution and storage at about 2 C to about 8 C for at least about 24 hours.
In yet other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after dilution and storage at about 2 C to about 8 C for at least about 48 hours.
In still other embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%

w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2 C to about 8 C for at least about 12 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%
w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2 C to about 8 C for at least about 24 hours.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%
w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2 C to about 8 C for at least about 48 hours.
In other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its dosage concentration of pemetrexed, at least about 97% of its dosage concentration of pemetrexed, at least about 98% of its dosage concentration of pemetrexed, at least about 99% of its dosage concentration of pemetrexed, at least about 99.5% of its dosage concentration of pemetrexed, after dilution and storage at room temperature for at least about 12 hours.
In still other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its dosage concentration of pemetrexed, at least about 97% of its dosage concentration of pemetrexed, at least about 98% of its dosage concentration of pemetrexed, at least about 99% of its dosage concentration of pemetrexed, at least about 99.5%
of its dosage concentration of pemetrexed, after dilution and storage at room temperature for at least about 24 hours.
In yet other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98%
of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration, after dilution and storage at about room temperature for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after dilution and storage at room temperature for at least about 12 hours.

In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after dilution and storage at room temperature for at least about 24 hours.
In yet other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5%
w/w impurities, no more than about 1% w/w impurities, no more than about 0.5%
w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1%
w/w impurities, after dilution and storage at room temperature for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%
w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at room temperature for at least about 12 hours.
In yet further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%
w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at room temperature for at least about 24 hours.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5%
w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1`!/0 w/w of the single largest impurity, after dilution and storage at a room temperature for at least about 48 hours.
In particular embodiments of the invention the formulation is in a vial with a headspace oxygen concentration of less than about 20 v/v%, 18 v/v%, 16 v/v%, 14 v/v%, 12 v/0/0, 10 v/v%, 8 v/v%, 6 v/v%, 5 v/v%, 4 v/v%, 3 v/v%, 2 v/v%, or 1 v/v% oxygen.
In certain embodiments of the invention, the formulation is in a single-dose vial. In further embodiments of the invention, the formulation is in a multi-dose vial.
In yet further embodiments of the invention, the formulation is in a multi-dose vial intended for use by the same patient In still further embodiments of the invention, the formulation is in a multi-dose vial intended for use by different patients.

In another embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation as described herein. In a further embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation comprising pemetrexed and a non-aqueous solvent present at less than 30 wt%. In a further embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation comprising pemetrexed and propylene glycol wherein the propylene glycol is present at 5-30 wt%.
EXAMPLES
Example 1: Effect of Non-Aqueous Solvents on Pemetrexed Stability Formulations as described in Table 1 were prepared as follows:
Water for Injection, a suitable base solution (0.1 - 1 N NaOH or KOH), and citric acid, if present, were combined and mixed to yield a visually uniform mixture.
Pemetrexed diacid was incrementally added to the mixture under continuous agitation, and the resulting homogenous suspension was agitated until all solids were completely dissolved. The pH of the solution was adjusted to about 7.4-7.6. Propylene glycol, if present, was then added to the pemetrexed solution, and the mixture was agitated until a visually uniform mixture was obtained. The pH of the solution was adjusted to 7.4-7.6.
portetaarinininini 25 25 25 25 tthama(fogtmL)E
cifivkadwiniong 13.2 13 . 2 H20.0cogb*Mommg goimotif:Em::00: 250 250 qs to qs to qs to qs to , pH 7.5 pH 7.5 pH 7.5 pH 7.5 ltAtiiiditioric Acid qs to qs to qs to qs to pH 7.5 pH 7.5 pH 7.5 pH 7.5 WEI qs qs qs qs The stability of Formulations B, C, F, and I was tested under accelerated conditions at 60 C and 40 C/75% RH over the course of several days. Samples were taken at various time points and diluted with HPLC diluents (60:40 (v/v, Water:ACN)) prior to testing. Impurities were measured by HPLC.
The results are shown in Tables 2A-2D and Figures 1A-1D.
Table 2A: Single Largest Impurity (% w/w) after storage at 60 C

Initial 0.09 0.15 0.10 0.07 1 da 0.61 1.26 1.00 0.56 ----------------- 2 da --- 1.16 2.56 1.97 1.04 3 da ....................... 1.68 4.01 2.91 1.50 Table 2B: Total Impurities (% w/w) after storage at 60 C
Tot al ................. Impurity ----------------- Initial -- 0.69 0.92 0.74 0.70 ----------------- 1 day --- 1.50 2.35 2.02 1.39 2dav 2.20 3.93 3.31 2.04 3 da) 2.86 5.63 1 65 Table 2C: Single Largest Impurity (% w/w) after storage at 40 C/75% RH
RRT 0.87 B C
Initial 0.09 0.15 0.10 0.07 ----------------- - 2 days 1.70 6.36 3.36 1.33 4 days 3.29 13.44 9.24 2.35 Table 2D: Total Impurities after (% w/w) storage at 40 C/75% RH
Total lrnpurity Initial 0.69 0.92 0.74 0.70 2 days 3.63 11.75 7.28 2.75 4 days 6.05 20.94 16.71 4.31 The long term stability, real-time, and projected, of formulations B, I, and K
(See Table 4, prepared as described above) were also measured. Results are shown in Table Table 3: Long Term Stability of Pemetrexed Formulations B, I, and K
Storage Single Projected Projected Total Head at 2-8C Largest =TI in SLI in 24 Assay (Month Impurity 24 M M ( ,/o (%LC) Impurities pH
space s) w/ri.) (% (14 w/w) wily) oxygen Formulation B 15 0.57 4.70 7.52 0.91 93.6 7.59 18.1 Formulation 1 15 0.31 1.70 2.72 0.50 97.8 7.50 20.9 Formulation K 14 0.42 2.96 5.07 0.72 95.2 7.47 19.6 Table 4: Pemetrexed Formulation K
Ingredient h'iit:DMMMMTnR
Pemetrexed diacid 25.0 mg Propylene Glycol 250 'IL
Tromethamine qs to pH 7.4-7.6 Hydrochloric Acid qs to pH 7.4-7.6 Water for Injection qs to 1 tnL
Example 2: Stability of Pemetrexed Formulation K after dilution.
The stability of pemetrexed for up to 48 hours after dilution of Formulation K
was evaluated. . Normal saline, water for injection and 5% dextrose in water, Ringer's Injection, and Lactated Ringer's Injection were purchased directly and used as is. The pH of each diluent was tested and recorded in Table 6.
Table 6: pH of diluents ...............
...............................................................................
........................... .....................
Normal Saline (NS) 6.8 Water for Injection (WFI) 7.01 Ringer's Injection (LR) 6.6 Lactated Ringer's Injection (LRS) 6.5 5% Dextrose in Water (D5W) 7.5 Formulation K (25 mg/inL) was diluted to 0.15, 1.5, and 15 mg/niL in the diluents listed above. The mixtures were stored at 2-8 C and tested at 12, 24, and 48 hours for appearance, assay, impurities, and pH. A sample was taken immediately after dilution for the time zero sample. The 0.15 mg/ml, samples were analyzed as is without further dilution, while the 1.5 mg/mL and 15 mg/mL samples were diluted with HPIX diluents (60:40 (v/v, Water:ACN)) prior to testing. Results are in Tables 6 & 7 (each Table represents separate studies).
Table 6: Stability of Formulation K after dilution in Normal Saline or Water for Injection Theoretical *Percentage of Total Assay Diluents 'Time (hrs) Pemetrexed cone 'Theoretical Impurity mg/g) Pennetrexed "A) (%
wiw) Bulk 25.0 24.80 99.2 7.501 0.16 Solution ...............................................................................
...............................................................................
................................................
ID
, NS 0 14.55 98.84 7.471 0.08 24 15 14.61 99.25 7.54 0.19 48 14.71 99.93 7.58 : 0.17 7777777737:77:37,73333:37:7:7:37,37,37:7:7:7:71 .. . .:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.: .. . ... .
..0 7 42 0ft7 ......

wFI 0 14.60 99.18 7.521 0.14 24 14,40 97,82 7.58 0.16 48 14,70 99,86 7.59 0.11 Table 7: Stability of Formulation K after dilution in Ringer's Injection, Lactated Ringer's Injection, or 5% Dextrose Theoretical *Percentage of Time Assay ( T % otal Diluents Periletrexed cone Theoretical pH
(hrs) LC) Inipurity (mglml,) Pemetrexed Bulk 25.0 97.6 NA 7.37 0.35 solution 12 95 9 2 762gggg049:,:m iiiiiiiii4kiii222212222222222222222222222222212N4O 95K 982 745 E22221i2222221ipp',Tigi22222222222111g22222222iFtmi22222, Rs 962 986 73 034 0 97.8 100.2 7.47 0.35 12 98.3 100.7 7.55 0.35 24 15 97.4 99.7 7.39 0.36 48 95.6 98.0 7.53 0.33 98 I 01 9 754 j 47 1013 wig24 1 98 1009 24 048 Aiiin iii]]]]]]---..iiiiiii4aiiiiiiiiiii]]]]i=iii]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]
]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]iii 0 97.8 100.2 7.41 0.33 12 98.3 100.7 7.58 0.32 24 98.2 100.6 7.36 0.34 48 98.7 101.1 7.46 0.33 24 97 loul 734 D5NV 12 96 6 99 0 762 t 24 97 99 9 u 4u iii]]]]]]iiiiii0Ziii]]]]iii]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]
]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]iii972 996 753 039 0 97.7 100.1 7.47 0.31 12 5 98.0 100.3 7.61 0,34 24 97.9 100.3 7.40 0.32 , 48 98.0 100.4 7.59 0.34 The foregoing detailed description has been given for clearness of understanding only and no unnecessary limitations should be understood there from as modifications will be obvious to those skilled in the art.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.
The disclosures, including the claims, figures and/or drawings, of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entireties.

Claims

What is claimed is:

1. A pharmaceutical composition comprising:
a) pemetrexed and b) a non-aqueous solvent present at less than 0.30 mL/mL;
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

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. The pharmaceutical composition of claim 1 comprising at least 0.50mL/mL
water.

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. The pharmaceutical composition of claim 1 substantially free of an anti-oxidant.

15. A pharmaceutical composition comprising a) 25 mg/mL pemetrexed, and b) propylene glycol at 250µL/mL
c) 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.

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 and b) a non-aqueous solvent present at less than 0.30 mL/mL, 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.

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. The pharmaceutical composition of claim 17 comprising at least 0.50mL/mL water.

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. The pharmaceutical composition of claim 17 substantially free of an anti-oxidant.

29. A pharmaceutical composition comprising a) an initial pemetrexed concentration of 25 mg/mL, b) propylene glycol at 250 µL/mL, and c) 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.

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. A pharmaceutical composition comprising:
a) pemetrexed and b) a non-aqueous solvent present at less than 0.30 mL/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 hours.

32. The pharmaceutical composition of claim 1 wherein the composition comprises no more than 8% w/w total impurities after dilution and storage for a period selected from:
a) at least 24 hours, and b) at least 48 hours.

33. The pharmaceutical composition of claim 1 wherein the composition comprises no more than 5% w/w total impurities after dilution and storage for a period selected from:
a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.

34. The pharmaceutical composition of claim 1 wherein the composition comprises no more than 2% w/w total impurities after dilution and storage for a period selected from:
a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.

35. The pharmaceutical composition of claim 31 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.

36. The pharmaceutical composition of claim 31 comprising 10 to 50 mg/mL
pemetrexed.

37. The pharmaceutical composition of claim 36 comprising 25 mg/mL
pemetrexed.

38. The pharmaceutical formulation of claim 31 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.

39. The pharmaceutical formulation of claim 38 wherein the non-aqueous solvent is propylene glycol.

40. The pharmaceutical formulation of claim 39 wherein propylene glycol is present at 250 µL/mL.

41. The pharmaceutical composition of claim 31 comprising at least 0.50mL/mL water.

42. The pharmaceutical composition of claim 31 wherein the pemetrexed is in the form of pemetrexed diacid.

43. The pharmaceutical composition of claim 31 wherein the pemetrexed is in the form of pemetrexed disodium.

44. The pharmaceutical composition of claim 31 substantially free of an anti-oxidant.

45. A pharmaceutical composition comprising a) 25 mg/mL pemetrexed, b) propylene glycol at 250 µL/mL, and c) water;
wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.

46. The pharmaceutical composition of claim 45 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 48 hours.

47. A pharmaceutical composition comprising:
a) pemetrexed at an initial concentration of 10 to 50 mg/mL and b) a non-aqueous solvent present at less than 0.30 mL/mL, wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.

48. The pharmaceutical composition of claim 47 wherein the composition comprises no more than 8% w/w total impurities after storage for a period selected from:
a) at least 18 months, and b) at least 24 months.

49. The pharmaceutical composition of claim 47 wherein the composition comprises no more than 5% w/w total impurities after storage for a period selected from:
a) at least 12 months, b) at least 18 months, and c) at least 24 months.

50. The pharmaceutical composition of claim 47 wherein the composition comprises no more than 2% w/w total impurities after storage for a period selected from:
a) at least 12 months, b) at least 18 months, and c) at least 24 months.

51. The pharmaceutical composition of claim 47 comprising 25 mg/mL
pemetrexed.

52. The pharmaceutical formulation of claim 47 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.

53. The pharmaceutical formulation of claim 52 wherein the non-aqueous solvent is propylene glycol.

54. The pharmaceutical formulation of claim 53 wherein propylene glycol is present at 250 µL/mL.

55. The pharmaceutical composition of claim 47 comprising at least 0.50mL/mL water.

56. The pharmaceutical composition of claim 47 wherein the pemetrexed is in the form of pemetrexed diacid.

57. The pharmaceutical composition of claim 47 wherein the pemetrexed is in the form of pemetrexed disodium.

58. The pharmaceutical composition of claim 47 substantially free of an anti-oxidant.

59. A pharmaceutical composition comprising a) an initial pemetrexed concentration of 25 mg/mL, b) propylene glycol at 250 gL/mL, and c) water;
wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.

60. The pharmaceutical composition of claim 59 wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 months.