JP7543365B2 - Pemetrexed formulations - Google Patents

Description

2. Background of the Invention Compounds that exhibit antifolate activity have a well-known role as chemotherapeutic agents. One such compound is pemetrexed, which has the chemical name N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid and the formula (1):


It has the structure:

Pemetrexed is used in the treatment of pleural mesothelioma and non-small cell lung cancer. Eli Lilly's pemetrexed product, ALIMTA, is currently supplied in 100 mg and 500 mg vials of lyophilized pemetrexed disodium for injection. According to the prescribing information, to prepare ALIMTA for injection, the vial is reconstituted in sufficient 0.9% Sodium Chloride Injection (preservative free) to obtain a solution containing 25 mg/mL of ALIMTA. This concentrated solution is then further diluted in a solution of 0.9% Sodium Chloride Injection (preservative free). The prescribing information warns that reconstitution and further dilution are recommended only with 0.9% Sodium Chloride Injection (preservative-free) and that "ALIMTA is physically incompatible with, and therefore should not be used with, calcium-containing diluents, including Lactated Ringer's Injection, USP and Ringer's Injection, USP."

Calcium-containing diluents, such as Lactated Ringer's Injection and Ringer's Injection, are common solutions used in medical practice for reconstitution and/or dilution of drug products prior to intravenous administration. There is a need for a pemetrexed dosage form that is chemically stable after reconstitution and/or dilution with a calcium-containing diluent. 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 form due to improper reconstitution or dilution and the risk that a patient may receive pemetrexed that has been reconstituted or diluted in an incompatible diluent.

In solution, pemetrexed undergoes rapid hydrolysis and decomposition. Due to this rapid degradation, pemetrexed formulations must be either lyophilized or contain stabilizers for long-term stability. 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.

Stable ready-to-use formulations of pemetrexed are known, but they require stabilizers such as antioxidants or amino acids as described in US 6,686,365, CN 101081305 and WO2012015810, or high levels of non-aqueous solvents as described in WO2013144814. It would be advantageous to minimize patient exposure to these additional ingredients.

Therefore, there is a need for a stable, non-lyophilized pemetrexed composition with minimal amounts of additional ingredients. To this end, the present inventors have developed a stable pemetrexed formulation.

U.S. Pat. No. 6,686,365 Chinese Patent No. 101081305 International Publication No. 2012015810 International Publication No. 2013144814

SUMMARY OF THE DISCLOSURE In certain embodiments, the present invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration of less than 0.30 ml/mL, the pharmaceutical composition comprising, upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, 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 a further embodiment, the present invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol, and water, which upon dilution with a pharma- ceutically acceptable diluent to the initial dosage concentration of pemetrexed, contains 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 yet a further embodiment, the present 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 of less than 0.30 ml/mL, the pharmaceutical composition comprising at least 90% of the initial pemetrexed concentration after storage for at least 12 months at a temperature between 2°C and 8°C.

In a further embodiment, the present invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol, and water, the pharmaceutical composition comprising at least 90% of the initial pemetrexed concentration after storage for at least 12 months at a temperature between 2° C. and 8° C.

In certain embodiments, the present invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration of less than 0.30 ml/mL, the pharmaceutical composition containing 8% w/w or less total impurities upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed after storage at a temperature between 2° C. and 8° C. for at least 24 hours.

In a further embodiment, the present invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol, and water, the pharmaceutical composition containing 8% w/w or less total impurities upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed after storage at a temperature between 2° C. and 8° C. for at least 24 hours.

In yet a further embodiment, the present 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 of less than 0.30 ml/mL, the pharmaceutical composition containing 8% w/w or less total impurities after storage for at least 24 hours at a temperature between 2° C. and 8° C.

In a further embodiment, the present invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol, and water, the pharmaceutical composition containing 8% w/w or less total impurities after storage for at least 24 hours at a temperature between 2° C. and 8° C.

Additional embodiments of the present invention include the following.
1. a) pemetrexed,
b) a non-aqueous solvent present at less than 0.30 mL/mL,
A pharmaceutical composition, which upon dilution with a pharma- ceutical acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains at least 90% of said initial dosage concentration of pemetrexed after storage for at least 12 hours at a temperature between 2°C and 8°C.
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. Dilution and a) at least 12 hours;
The pharmaceutical composition of embodiment 1, wherein the composition retains at least 95% of the initial dosage concentration of pemetrexed upon storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
4. Dilution and a) at least 12 hours;
The pharmaceutical composition of embodiment 1, wherein the composition retains at least 98% of the initial dosage concentration of pemetrexed upon storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
5. The pharmaceutical composition of embodiment 1, wherein said pharma- ceutically 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 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 a combination 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 μL/mL.
11. The pharmaceutical composition of embodiment 1, comprising at least 0.50 mL/mL of water.
12. The pharmaceutical composition of embodiment 1, 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, which is substantially free of antioxidants.
15. a) 25 mg/mL pemetrexed;
b) 250 μL/mL propylene glycol;
c) water,
A pharmaceutical composition, which upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains at least 90% of said initial dosage concentration of pemetrexed after storage for at least 24 hours at a temperature between 2°C and 8°C.
16. The pharmaceutical composition of embodiment 15, wherein upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of said initial dosage concentration of pemetrexed after storage for at least 48 hours at a temperature between 2° C. and 8° C.
17. 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,
A pharmaceutical composition, wherein after storage at a temperature between 2°C and 8°C for at least 12 months, said composition comprises at least 90% of its initial pemetrexed concentration.
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. a) At least 12 months;
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: b) at least 18 months; and c) at least 24 months.
20. a) At least 12 months;
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: 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/mL.
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 a combination 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 μL/mL.
25. The pharmaceutical composition of embodiment 17, comprising at least 0.50 mL/mL of 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, which is substantially free of antioxidants.
29. a) an initial pemetrexed concentration of 25 mg/mL;
b) 250 μL/mL propylene glycol;
c) water,
A pharmaceutical composition, wherein after storage for at least 12 months at a temperature between 2°C and 8°C, said composition comprises at least 90% of said initial pemetrexed concentration.
30. The pharmaceutical composition of embodiment 29, wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature between 2° C. and 8° C. for at least 24 months.
31. a) pemetrexed,
b) a non-aqueous solvent present at less than 0.30 mL/mL,
A pharmaceutical composition, wherein upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains 8% w/w or less of total impurities after storage for at least 12 hours at a temperature between 2°C and 8°C.
32. The pharmaceutical composition of embodiment 1, wherein after dilution and storage for a period selected from a) at least 24 hours, and b) at least 48 hours, the composition contains 8% w/w or less of total impurities.
33. Dilution and a) at least 12 hours;
2. The pharmaceutical composition of embodiment 1, wherein the composition contains 5% w/w or less of total impurities after storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
34. Dilution and a) at least 12 hours;
2. The pharmaceutical composition of embodiment 1, wherein the composition contains 2% w/w or less of total impurities after storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
35. The pharmaceutical composition according to embodiment 31, wherein said pharma- ceutically 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 a combination 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 250 μL/mL.
41. The pharmaceutical composition of embodiment 31, comprising at least 0.50 mL/mL of 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, which is substantially free of antioxidants.
45. a) 25 mg/mL pemetrexed;
b) 250 μL/mL propylene glycol;
and c) water, wherein upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains 8% w/w or less of total impurities after storage for at least 24 hours at a temperature between 2° C. and 8° C.
46. The pharmaceutical composition of embodiment 45, wherein upon dilution with a pharma- ceutically acceptable diluent to the initial dosage concentration of pemetrexed, the composition contains 8% w/w or less of total impurities after storage for at least 48 hours at a temperature between 2° C. and 8° C.
47. 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,
A pharmaceutical composition, wherein after storage for at least 12 months at a temperature between 2°C and 8°C, said composition contains less than 8% w/w of total impurities.
48. The pharmaceutical composition of embodiment 47, wherein the composition contains 8% w/w or less of total impurities after storage for a period selected from: a) at least 18 months, and b) at least 24 months.
49. a) At least 12 months;
The pharmaceutical composition of embodiment 47, wherein the composition contains 5% w/w or less of total impurities after storage for a period selected from: b) at least 18 months; and c) at least 24 months.
50. a) At least 12 months;
The pharmaceutical composition of embodiment 47, wherein said composition contains 2% w/w or less of total impurities after storage for a period selected from: 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 250 μL/mL.
55. The pharmaceutical composition of embodiment 47, comprising at least 0.50 mL/mL of 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, which is substantially free of antioxidants.
59. a) an initial pemetrexed concentration of 25 mg/mL;
b) 250 μL/mL propylene glycol;
c) water,
A pharmaceutical composition, wherein after storage for at least 12 months at a temperature between 2°C and 8°C, said composition contains less than 8% w/w of total impurities.
60. The pharmaceutical composition of embodiment 59, wherein the composition contains 8% w/w or less of total impurities after storage at a temperature between 2° C. and 8° C. for at least 24 months.

1A-1D depict the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations. 1A-1D depict the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations. 1A-1D depict the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations. 1A-1D depict the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations.

DETAILED DESCRIPTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are a plurality of definitions for terms used herein, those in this section prevail unless otherwise stated.

As used herein, "single largest impurity" refers to the impurity with the largest HPLC peak in percentage.

As used herein, "initial dosing concentration of pemetrexed" refers to the concentration of pemetrexed upon 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 pharma- ceutically acceptable salt thereof is present in the compositions of the invention at a concentration of between about 10 mg/mL and about 50 mg/mL, calculated as anhydrous pemetrexed diacid. In certain embodiments of the invention, pemetrexed is present at about 10 mg/mL to about 40 mg/mL, about 10 mg/mL to about 30 mg/mL, about 10 mg/mL to about 20 mg/mL, about 20 mg/mL to about 50 mg/mL, about 20 mg/mL to about 40 mg/mL, about 20 mg/mL to about 30 mg/mL, about 30 mg/mL to about 50 mg/mL, about 30 mg/mL to about 40 mg/mL, or 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 about 50 mg/mL.

Pemetrexed is present in the composition as a diacid, a monoacid, a pharma- ceutically acceptable salt, or a combination thereof. In certain embodiments of the invention, pemetrexed is present as pemetrexed disodium, and 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 yet 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 ethyl alcohol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, polyhydroxy alcohols such as 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 yet 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 certain embodiments of the invention, the non-aqueous solvent is a 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 a concentration of 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 certain embodiments, the non-aqueous solvent is present at a concentration of 30 weight percent (wt.%) or less 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 certain 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. %.

In certain embodiments, the non-aqueous solvent is present at a concentration of 300 μL/mL or less prior to dilution. In further embodiments, the non-aqueous solvent is present at a concentration of at least 50 μL/mL prior to dilution. In certain embodiments of the invention, the non-aqueous solvent is present at a concentration of about 50 μL/mL to 300 μL/mL. In further embodiments of the invention, the non-aqueous solvent is present at about 50 μL/mL to 100 μL/mL, 50 μL/mL to 200 μL/mL, 50 μL/mL to 250 μL/mL, 50 μL/mL to 275 μL/mL, 50 μL/mL to 300 μL/mL, 100 μL/mL to 200 μL/mL, 100 μL/mL to 250 μL/mL, 100 μL/mL to 275 μL/mL, 100 μL/mL to 300 μL/mL, 200 μL/mL to 250 μL/mL, 200 μL/mL to 300 μL/mL, or 250 μL/mL to 300 μL/mL prior to dilution.

In certain embodiments, water is present at a concentration of at least about 500 μL/mL prior to dilution. In other embodiments of the invention, water is present at a concentration of at least about 600 μL/mL, 750 μL/mL, or 950 μL/mL prior to dilution. In further embodiments of the invention, water is present at a concentration of about 500 μL/mL to 950 μL/mL prior to dilution. In yet further embodiments of the invention, the water is present at about 500 μL/mL to 800 μL/mL, 500 μL/mL to 700 μL/mL, 500 μL/mL to 600 μL/mL, 600 μL/mL to 750 μL/mL, 600 μL/mL to 800 μL/mL, 600 μL/mL to 950 μL/mL, 700 μL/mL to 800 μL/mL, 700 μL/mL to 950 μL/mL, or 750 μL/mL to 950 μL/mL prior to dilution.

In certain 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 wt. %, 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. In certain embodiments 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 antioxidants and/or amino acids. In certain embodiments of the invention, the formulation is substantially free of antioxidants. In further embodiments of the invention, the formulation is substantially free of chelating agents. As used herein, substantially free of antioxidants, amino acids and/or chelating agents means that the formulation does not contain one or more antioxidants, amino acids and/or chelating agents in a concentration sufficient to have a stabilizing effect.

In certain embodiments, the formulation may include ascorbic acid and derivatives, tocopherol and derivatives, propyl gallate, thioglycerol, lactobionic acid, methionine, tertiary butyl hydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium formaldehyde sulfoxylate, sodium bisulfite, ethylenediaminetetraacetic acid (EDTA),
and derivatives, gentisic acid monoethanolamine, glutathione, propionic acid, acetone sodium bisulfite, sodium dithionite, citric acid and derivatives, tribasic (trisodium citrate dihydrate), or suitable mixtures thereof. As used herein, substantially free means that the formulation does not contain one or more of the additives listed above in a concentration sufficient to have a stabilizing effect.

In certain 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 a further embodiment 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 certain 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 yet 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 yet 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less 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 yet further embodiments of the invention, the formulation contains about 10% w/w or less of a single maximum impurity, about 8% w/w or less of a single maximum impurity, about 6% w/w or less of a single maximum impurity, about 5% w/w or less of a single maximum impurity, about 4% w/w or less of a single maximum impurity, about 3.5% w/w or less of a single maximum impurity, about 3% w/w or less of a single maximum impurity, about 2.5% w/w or less of a single maximum impurity, about 2% w/w or less of a single maximum impurity, about 1.5% w/w or less of a single maximum impurity, about 1% w/w or less of a single maximum impurity, about 0.5% w/w or less of a single maximum impurity, about 0.2% w/w or less of a single maximum impurity, about 0.1% w/w or less of a single maximum 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 contains about 10% w/w or less of a single maximum impurity, about 8% w/w or less of a single maximum impurity, about 6% w/w or less of a single maximum impurity, about 5% w/w or less of a single maximum impurity, about 4% w/w or less of a single maximum impurity, about 3.5% w/w or less of a single maximum impurity, about 3% w/w or less of a single maximum impurity, about 2.5% w/w or less of a single maximum impurity, about 2% w/w or less of a single maximum impurity, about 1.5% w/w or less of a single maximum impurity, about 1% w/w or less of a single maximum impurity, about 0.5% w/w or less of a single maximum impurity, about 0.2% w/w or less of a single maximum impurity, about 0.1% w/w or less of a single maximum impurity 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 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 pharma- ceutically 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 certain embodiments of the invention, the formulation is diluted in a pharma- ceutically acceptable diluent to a suitable initial dosage concentration of pemetrexed. In certain embodiments of the invention, the initial dosage concentration of pemetrexed can be determined by a physician or a person skilled in the art based on various factors, such as, but not limited to, the patient's weight, age, and condition, and the volume of diluent. 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, or 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 yet another embodiment 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, or 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 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 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, or 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less 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 yet another embodiment of the invention, the formulation, after dilution and storage at about 2°C to about 8°C for at least about 12 hours, contains about 10% w/w or less of a single maximum impurity, about 8% w/w or less of a single maximum impurity, about 6% w/w or less of a single maximum impurity, about 5% w/w or less of a single maximum impurity, about 4% w/w or less of a single maximum impurity, about 3.5% w/w or less of a single maximum impurity, about 3% w/w or less of a single maximum impurity, about 2.5% w/w or less of a single maximum impurity, about 2% w/w or less of a single maximum impurity, about 1.5% w/w or less of a single maximum impurity, about 1% w/w or less of a single maximum impurity, about 0.5% w/w or less of a single maximum impurity, about 0.2% w/w or less of a single maximum impurity, about 0.1% w/w or less of a single maximum impurity.

In a further embodiment of the invention, the formulation, after dilution and storage at about 2°C to about 8°C for at least about 24 hours, contains about 10% w/w or less of a single maximum impurity, about 8% w/w or less of a single maximum impurity, about 6% w/w or less of a single maximum impurity, about 5% w/w or less of a single maximum impurity, about 4% w/w or less of a single maximum impurity, about 3.5% w/w or less of a single maximum impurity, about 3% w/w or less of a single maximum impurity, about 2.5% w/w or less of a single maximum impurity, about 2% w/w or less of a single maximum impurity, about 1.5% w/w or less of a single maximum impurity, about 1% w/w or less of a single maximum impurity, about 0.5% w/w or less of a single maximum impurity, about 0.2% w/w or less of a single maximum impurity, about 0.1% w/w or less of a single maximum impurity.

In yet further embodiments of the invention, the formulation, after dilution and storage at about 2°C to about 8°C for at least about 48 hours, contains about 10% w/w or less of a single maximum impurity, about 8% w/w or less of a single maximum impurity, about 6% w/w or less of a single maximum impurity, about 5% w/w or less of a single maximum impurity, about 4% w/w or less of a single maximum impurity, about 3.5% w/w or less of a single maximum impurity, about 3% w/w or less of a single maximum impurity, about 2.5% w/w or less of a single maximum impurity, about 2% w/w or less of a single maximum impurity, about 1.5% w/w or less of a single maximum impurity, about 1% w/w or less of a single maximum impurity, about 0.5% w/w or less of a single maximum impurity, about 0.2% w/w or less of a single maximum impurity, about 0.1% w/w or less of a single maximum impurity.

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, or 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 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 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, or 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less 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 contains less than about 10% w/w impurities, less than about 8% w/w impurities, less than about 6% w/w impurities, less than about 5% w/w impurities, less than about 4% w/w impurities, less than about 3.5% w/w impurities, less than about 3% w/w impurities, less than about 2.5% w/w impurities, less than about 2% w/w impurities, less than about 1.5% w/w impurities, less than about 1% w/w impurities, less than about 0.5% w/w impurities, less than about 0.2% w/w impurities, less than about 0.1% w/w impurities after dilution and storage at room temperature for at least about 48 hours.

In a further embodiment of the invention, the formulation, after dilution and storage at room temperature for at least about 12 hours, contains no more than about 10% w/w single maximum impurities, no more than about 8% w/w single maximum impurities, no more than about 6% w/w single maximum impurities, no more than about 5% w/w single maximum impurities, no more than about 4% w/w single maximum impurities, no more than about 3.5% w/w single maximum impurities, no more than about 3% w/w single maximum impurities, no more than about 2.5% w/w single maximum impurities, no more than about 2% w/w single maximum impurities, no more than about 1.5% w/w single maximum impurities, no more than about 1% w/w single maximum impurities, no more than about 0.5% w/w single maximum impurities, no more than about 0.2% w/w single maximum impurities, no more than about 0.1% w/w single maximum impurities.

In yet further embodiments of the invention, the formulation, after dilution and storage at room temperature for at least about 24 hours, contains no more than about 10% w/w single maximum impurities, no more than about 8% w/w single maximum impurities, no more than about 6% w/w single maximum impurities, no more than about 5% w/w single maximum impurities, no more than about 4% w/w single maximum impurities, no more than about 3.5% w/w single maximum impurities, no more than about 3% w/w single maximum impurities, no more than about 2.5% w/w single maximum impurities, no more than about 2% w/w single maximum impurities, no more than about 1.5% w/w single maximum impurities, no more than about 1% w/w single maximum impurities, no more than about 0.5% w/w single maximum impurities, no more than about 0.2% w/w single maximum impurities, no more than about 0.1% w/w single maximum impurities.

In yet further embodiments of the invention, the formulation, after dilution and storage at room temperature for at least about 48 hours, contains about 10% w/w or less of a single maximum impurity, about 8% w/w or less of a single maximum impurity, about 6% w/w or less of a single maximum impurity, about 5% w/w or less of a single maximum impurity, about 4% w/w or less of a single maximum impurity, about 3.5% w/w or less of a single maximum impurity, about 3% w/w or less of a single maximum impurity, about 2.5% w/w or less of a single maximum impurity, about 2% w/w or less of a single maximum impurity, about 1.5% w/w or less of a single maximum impurity, about 1% w/w or less of a single maximum impurity, about 0.5% w/w or less of a single maximum impurity, about 0.2% w/w or less of a single maximum impurity, about 0.1% w/w or less of a single maximum impurity.

In certain 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/v%, 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 yet further embodiments of the invention, the formulation is in a multi-dose vial intended for use by different patients.

In another embodiment, the present 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 present 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 present 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 propylene glycol is present at 5-30 wt %.

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 (0.1-1N NaOH or KOH) and citric acid, if present, were combined and mixed to obtain a visually homogenous mixture. Pemetrexed diacid was slowly added to the mixture with 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 homogenous mixture was obtained. The pH of the solution was adjusted to about 7.4-7.6.

The stability of formulations B, C, F and I was tested under accelerated conditions at 60°C and 40°C/75% RH over several days. Samples were taken at various time points and diluted with HPLC diluent (60:40 (v/v, water:ACN)) before testing. Impurities were measured by HPLC.

The results are shown in Tables 2A-2D and Figures 1A-1D.

The long-term stability of formulations B, I and K (see Table 4, prepared as described above) was also measured in real time and predictively, and the results are shown in Table 3.

Example 2
Stability of pemetrexed formulation K after dilution.
The stability of pemetrexed was evaluated for up to 48 hours after dilution of Formulation K. Normal Saline, Water for Injection and 5% Dextrose in Water, Ringer's Injection and Lactated Ringer's Injection were purchased directly and used as received. The pH of each diluent was tested and recorded in Table 6.

Formulation K (25 mg/mL) was diluted to 0.15, 1.5 and 15 mg/mL in the diluents listed above. The mixtures were stored at 2-8° C. and tested for appearance, assay, impurities and pH at 12, 24 and 48 hours. Samples were taken immediately after dilution to represent the time zero sample. The 0.15 mg/mL sample was analyzed as is without further dilution, while the 1.5 mg/mL and 15 mg/mL samples were diluted with HPLC diluent (60:40 (v/v, water:ACN)) prior to testing. The results are shown in Tables 6 and 7 (each table represents a separate study).

The foregoing detailed description has been given for clarity of understanding only, and no unnecessary limitations should be understood therefrom, since modifications will be apparent to those skilled in the art.

While the invention has been described with respect to specific embodiments thereof, it will be understood that further modifications are possible, and that this application is intended to cover any variations, uses, or adaptations of the invention which generally conform to the principles of the invention, 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 described above and in the appended claims as follows.

The disclosures, including claims, figures and/or drawings, of any and all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.
The present invention provides, for example, the following items.
(Item 1)
a) pemetrexed,
b) a non-aqueous solvent present at less than 0.30 mL/mL,
A pharmaceutical composition, which upon dilution with a pharma- ceutical acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains at least 90% of said initial dosage concentration of pemetrexed after storage for at least 12 hours at a temperature between 2°C and 8°C.
(Item 2)
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.
(Item 3)
Dilution and a) at least 12 hours;
2. The pharmaceutical composition of claim 1, wherein the composition retains at least 95% of the initial dosage concentration of pemetrexed upon storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
(Item 4)
Dilution and a) at least 12 hours;
2. The pharmaceutical composition of claim 1, wherein the composition retains at least 98% of the initial dosage concentration of pemetrexed upon storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
(Item 5)
2. The pharmaceutical composition of claim 1, wherein the pharma- ceutically 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.
(Item 6)
2. The pharmaceutical composition of claim 1, comprising 10 to 50 mg/mL of pemetrexed.
(Item 7)
7. The pharmaceutical composition of claim 6, comprising 25 mg/mL pemetrexed.
(Item 8)
2. The pharmaceutical formulation of claim 1, wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or a combination thereof.
(Item 9)
9. The pharmaceutical formulation of claim 8, wherein the non-aqueous solvent is propylene glycol.
(Item 10)
10. The pharmaceutical formulation of item 9, wherein propylene glycol is present at 250 μL/mL.
(Item 11)
2. The pharmaceutical composition of claim 1, comprising at least 0.50 mL/mL of water.
(Item 12)
2. The pharmaceutical composition of claim 1, wherein the pemetrexed is in the form of pemetrexed diacid.
(Item 13)
2. The pharmaceutical composition of claim 1, wherein the pemetrexed is in the form of pemetrexed disodium.
(Item 14)
13. The pharmaceutical composition of claim 1, which is substantially free of antioxidants.
(Item 15)
a) 25 mg/mL pemetrexed;
b) 250 μL/mL propylene glycol;
c) water,
A pharmaceutical composition, which upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains at least 90% of said initial dosage concentration of pemetrexed after storage for at least 24 hours at a temperature between 2°C and 8°C.
(Item 16)
16. The pharmaceutical composition of claim 15, wherein upon dilution with a pharma- ceutical acceptable diluent to an initial dosage concentration of pemetrexed, the composition contains at least 90% of the initial dosage concentration of pemetrexed after storage for at least 48 hours at a temperature between 2° C. and 8° C.
(Item 17)
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,
A pharmaceutical composition, wherein after storage for at least 12 months at a temperature between 2°C and 8°C, said composition comprises at least 90% of its initial pemetrexed concentration.
(Item 18)
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.
(Item 19)
a) at least 12 months;
18. 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: b) at least 18 months; and c) at least 24 months.
(Item 20)
a) at least 12 months;
18. 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: b) at least 18 months; and c) at least 24 months.
(Item 21)
18. The pharmaceutical composition of item 17, having an initial pemetrexed concentration of 25 mg/mL.
(Item 22)
18. The pharmaceutical formulation of claim 17, wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or a combination thereof.
(Item 23)
23. The pharmaceutical formulation of claim 22, wherein the non-aqueous solvent is propylene glycol.
(Item 24)
24. The pharmaceutical formulation of claim 23, wherein propylene glycol is present at 250 μL/mL.
(Item 25)
18. The pharmaceutical composition of claim 17, comprising at least 0.50 mL/mL of water.
(Item 26)
18. The pharmaceutical composition of claim 17, wherein the pemetrexed is in the form of pemetrexed diacid.
(Item 27)
18. The pharmaceutical composition of claim 17, wherein the pemetrexed is in the form of pemetrexed disodium.
(Item 28)
18. The pharmaceutical composition of claim 17, which is substantially free of antioxidants.
(Item 29)
a) an initial pemetrexed concentration of 25 mg/mL;
b) 250 μL/mL propylene glycol;
c) water,
A pharmaceutical composition, wherein after storage for at least 12 months at a temperature between 2°C and 8°C, said composition comprises at least 90% of said initial pemetrexed concentration.
(Item 30)
30. The pharmaceutical composition of item 29, wherein after storage at a temperature between 2° C. and 8° C. for at least 24 months, the composition contains at least 90% of the initial pemetrexed concentration.
(Item 31)
a) pemetrexed,
b) a non-aqueous solvent present at less than 0.30 mL/mL,
A pharmaceutical composition, wherein upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains 8% w/w or less of total impurities after storage for at least 12 hours at a temperature between 2°C and 8°C.
(Item 32)
2. The pharmaceutical composition according to item 1, wherein after dilution and storage for a period selected from a) at least 24 hours, and b) at least 48 hours, the composition contains less than or equal to 8% w/w of total impurities.
(Item 33)
Dilution and a) at least 12 hours;
2. The pharmaceutical composition according to claim 1, wherein the composition contains less than or equal to 5% w/w of total impurities after storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
(Item 34)
Dilution and a) at least 12 hours;
2. The pharmaceutical composition according to claim 1, wherein the composition contains less than or equal to 2% w/w of total impurities after storage for a period selected from: b) at least 24 hours; and c) at least 48 hours.
(Item 35)
32. The pharmaceutical composition of claim 31, wherein said pharma- ceutically 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.
(Item 36)
32. The pharmaceutical composition of claim 31, comprising 10 to 50 mg/mL of pemetrexed.
(Item 37)
37. The pharmaceutical composition of claim 36, comprising 25 mg/mL pemetrexed.
(Item 38)
32. The pharmaceutical formulation of claim 31, wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or a combination thereof.
(Item 39)
39. The pharmaceutical formulation of claim 38, wherein the non-aqueous solvent is propylene glycol.
(Item 40)
41. The pharmaceutical formulation of claim 39, wherein propylene glycol is present at 250 μL/mL.
32. The pharmaceutical composition of claim 31, comprising at least 0.50 mL/mL of water.
(Item 42)
32. The pharmaceutical composition of claim 31, wherein the pemetrexed is in the form of pemetrexed diacid.
(Item 43)
32. The pharmaceutical composition of claim 31, wherein the pemetrexed is in the form of pemetrexed disodium.
(Item 44)
32. The pharmaceutical composition of claim 31, which is substantially free of antioxidants.
(Item 45)
a) 25 mg/mL pemetrexed;
b) 250 μL/mL propylene glycol;
c) water,
A pharmaceutical composition, wherein upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains 8% w/w or less of total impurities after storage for at least 24 hours at a temperature between 2°C and 8°C.
(Item 46)
46. The pharmaceutical composition of item 45, wherein upon dilution with a pharma- ceutically acceptable diluent to an initial dosage concentration of pemetrexed, said composition contains 8% w/w or less of total impurities after storage for at least 48 hours at a temperature between 2° C. and 8° C.
(Item 47)
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,
A pharmaceutical composition, wherein after storage for at least 12 months at a temperature between 2°C and 8°C, said composition contains less than 8% w/w of total impurities.
(Item 48)
48. The pharmaceutical composition according to item 47, wherein the composition contains less than or equal to 8% w/w of total impurities after storage for a period selected from a) at least 18 months, and b) at least 24 months.
(Item 49)
a) at least 12 months;
48. The pharmaceutical composition according to item 47, wherein said composition contains less than or equal to 5% w/w of total impurities after storage for a period selected from: b) at least 18 months, and c) at least 24 months.
(Item 50)
a) at least 12 months;
48. The pharmaceutical composition according to item 47, wherein said composition contains less than or equal to 2% w/w of total impurities after storage for a period selected from: b) at least 18 months, and c) at least 24 months.
(Item 51)
48. The pharmaceutical composition of claim 47, comprising 25 mg/mL pemetrexed.
(Item 52)
48. The pharmaceutical formulation of claim 47, wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or a combination thereof.
(Item 53)
53. The pharmaceutical formulation of claim 52, wherein the non-aqueous solvent is propylene glycol.
(Item 54)
55. The pharmaceutical formulation of claim 53, wherein propylene glycol is present at 250 μL/mL.
48. The pharmaceutical composition of claim 47, comprising at least 0.50 mL/mL of water.
(Item 56)
48. The pharmaceutical composition of claim 47, wherein the pemetrexed is in the form of pemetrexed diacid.
(Item 57)
48. The pharmaceutical composition of claim 47, wherein the pemetrexed is in the form of pemetrexed disodium.
(Item 58)
48. The pharmaceutical composition of claim 47, which is substantially free of antioxidants.
(Item 59)
a) an initial pemetrexed concentration of 25 mg/mL;
b) 250 μL/mL propylene glycol;
c) water,
A pharmaceutical composition, wherein after storage for at least 12 months at a temperature between 2°C and 8°C, said composition contains less than 8% w/w of total impurities.
(Item 60)
60. The pharmaceutical composition according to item 59, wherein after storage at a temperature of 2° C. to 8° C. for at least 24 months, the composition contains 8% w/w or less of total impurities.

Claims (9)

20 mg/mL to 30 mg/mL pemetrexed diacid;
200 mg/mL to 300 mg/mL propylene glycol;
12 mg/mL to 24 mg/mL tromethamine;
Optionally, a liquid pharmaceutical composition consisting of HCl; and water, wherein said composition has a pH of about 7.4-7.6, said composition is suitable for multiple dose administration, and wherein said composition remains stable when stored for about 14 months at a temperature of 2°C to 8°C in a container having a headspace oxygen content of about 20% v/v, such that said composition contains 3% w/w or less total impurities after said storage. The composition,
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of said propylene glycol;
17 mg/mL to 21 mg/mL of said tromethamine;
10. The liquid pharmaceutical composition of claim 1, consisting of optionally HCl; and water, wherein the pH of said composition is about 7.4 to 7.6. The composition,
25 mg/mL of the pemetrexed diacid;
250 mg/mL to 300 mg/mL of said propylene glycol;
18 mg/mL to 20 mg/mL of said tromethamine;
10. The liquid pharmaceutical composition of claim 1, consisting of optionally HCl; and water, wherein the pH of said composition is about 7.4 to 7.6. 20 mg/mL to 30 mg/mL pemetrexed diacid;
200 mg/mL to 300 mg/mL propylene glycol;
12 mg/mL to 24 mg/mL tromethamine;
Optionally, a vial containing a liquid pharmaceutical composition consisting of: HCl; and water, wherein said composition has a pH of about 7.4-7.6 and remains stable when stored for about 14 months at a temperature of 2° C. to 8° C. in a container having a headspace oxygen content of about 20% v/ v , such that said composition contains 3% w/w or less total impurities after said storage. The vial is
25 mg/mL of the pemetrexed diacid;
5. The vial of claim 4, containing: 250 mg/mL to 300 mg/mL of said propylene glycol; and 17 mg/mL to 21 mg/mL of said tromethamine. The vial is
25 mg/mL of the pemetrexed diacid;
5. The vial of claim 4, containing: 250 mg/mL to 300 mg/mL of said propylene glycol; and 18 mg/mL to 20 mg/mL of said tromethamine. The vial of claim 4, wherein the vial is a multi-dose vial. The vial of claim 5, wherein the vial is a multi-dose vial. The vial of claim 6, wherein the vial is a multi-dose vial.