JP7282065B2 - Pemetrexed preparation - Google Patents

Description

の構造を有する。 BACKGROUND OF THE INVENTION Compounds exhibiting 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 formula (1):

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 was reconstituted in sufficient 0.9% sodium chloride injection (preservative-free) to give a solution containing 25 mg/mL of ALIMTA. obtain. This concentrated solution is then further diluted into a solution of 0.9% sodium chloride injection (preservative-free). The prescribing information states that reconstitution and further dilution is recommended with 0.9% Sodium Chloride Injection (preservative-free) only, and that "ALIMTA is Lactated Ringer's Injection, USP and Ringer's Injection. Physically incompatible with calcium-containing diluents, including USP, and therefore should not be used."

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 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 dosage forms suffers from loss of dosage form due to improper reconstitution or dilution, and reconstitution in incompatible diluents. Or would minimize both the risk that the patient could be administered diluted pemetrexed.

In solution, pemetrexed undergoes rapid hydrolysis and degradation. Due to this rapid degradation, pemetrexed formulations must either be lyophilized or contain stabilizers for long-term stability. However, reconstitution of lyophilized formulations requires multiple steps, each of which increases the risk of user error. Additionally, reconstitution of lyophilized formulations is clinically inconvenient and can take up to 30 minutes.

Stable ready-to-use formulations of pemetrexed are known, they include stabilizers such as antioxidants or amino acids as described in US 6,686,365, CN101081305 and WO2012015810 or as described in WO2013144814. Requires as high a level of non-aqueous solvent. It would be advantageous to minimize patient exposure to these additional ingredients.

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

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

SUMMARY OF THE INVENTION In certain embodiments, the present invention is a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration of less than 0.30 ml/mL, wherein , upon dilution to the initial dosage concentration of pemetrexed, after storage at a temperature of 2° C. to 8° C. for at least 24 hours, a pharmaceutical composition comprising at least 90% of the initial dosage concentration of pemetrexed.

In a further embodiment, the invention provides a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol, and water, wherein the initial dosage concentration of pemetrexed in a pharmaceutically acceptable diluent is of 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, upon dilution to 2°C.

In yet a further embodiment, the invention provides 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, wherein of at least 90% of the initial pemetrexed concentration after storage at a temperature of 0° C. for at least 12 months.

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

In certain embodiments, the invention provides a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration of less than 0.30 ml/mL, wherein A pharmaceutical composition containing no more than 8% w/w of total impurities after storage at a temperature of 2° C. to 8° C. for at least 24 hours upon dilution to the initial dosage concentration is intended.

In a further embodiment, the invention provides a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol, and water, wherein the initial dosage concentration of pemetrexed in a pharmaceutically acceptable diluent is A pharmaceutical composition containing no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours, upon dilution to 2°C.

In yet a further embodiment, the invention provides 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, wherein of 8% w/w or less of total impurities after storage for at least 24 hours at a temperature of 0°C.

In a further embodiment, the invention provides a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 μL/mL propylene glycol, and water, wherein after storage at a temperature of 2° C. to 8° C. for at least 24 hours, Pharmaceutical compositions containing 8% w/w or less total impurities are of interest.

Additional embodiments of the invention include the following.
1. a) pemetrexed and
b) a non-aqueous solvent present at less than 0.30 mL/mL,
Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition is 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. A pharmaceutical composition comprising
2. The pharmaceutical composition of embodiment 1, wherein upon dilution and storage for a period of time selected from a) at least 24 hours, and b) at least 48 hours, said composition retains at least 90% of said initial dosage concentration of pemetrexed. thing.
3. dilution and a) at least 12 hours,
The pharmaceutical composition of embodiment 1, wherein upon storage for a period of time selected from b) at least 24 hours, and c) at least 48 hours, said composition retains at least 95% of said initial dosage concentration of pemetrexed.
4. dilution and a) at least 12 hours,
The pharmaceutical composition of embodiment 1, wherein upon storage for a period of time selected from b) at least 24 hours, and c) at least 48 hours, said composition retains at least 98% of said initial dosage concentration of pemetrexed.
5. 2. The pharmaceutical composition of embodiment 1, wherein said 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. 2. The pharmaceutical composition of embodiment 1, comprising 10 to 50 mg/mL pemetrexed.
7. 7. The pharmaceutical composition of embodiment 6, comprising 25 mg/mL pemetrexed.
8. 2. The pharmaceutical formulation of embodiment 1, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
9. 9. The pharmaceutical formulation of embodiment 8, wherein said non-aqueous solvent is propylene glycol.
10. A pharmaceutical formulation according to embodiment 9, wherein propylene glycol is present at 250 μL/mL.
11. 2. The pharmaceutical composition according to embodiment 1, comprising at least 0.50 mL/mL water.
12. 2. The pharmaceutical composition of embodiment 1, wherein said pemetrexed is in the form of pemetrexed diacid.
13. 2. The pharmaceutical composition of embodiment 1, wherein said pemetrexed is in the form of pemetrexed disodium.
14. 2. The pharmaceutical composition of embodiment 1, substantially free of antioxidants.
15. a) 25 mg/mL pemetrexed and
b) 250 μL/mL propylene glycol;
c) a pharmaceutical composition comprising water,
Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition is 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. A pharmaceutical composition comprising
16. Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition exhibits 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. 16. The pharmaceutical composition according to embodiment 15, comprising
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 of 2°C to 8°C for at least 12 months, said composition comprises at least 90% of the initial pemetrexed concentration.
18. 18. The pharmaceutical composition of embodiment 17, wherein after storage for a period of time selected from a) at least 18 months, and b) at least 24 months, said composition comprises at least 90% of said initial pemetrexed concentration.
19. a) at least 12 months;
18. The pharmaceutical composition of embodiment 17, wherein after storage for a period of time selected from b) at least 18 months, and c) at least 24 months, said composition comprises at least 95% of said initial pemetrexed concentration.
20. a) at least 12 months;
18. The pharmaceutical composition of embodiment 17, wherein after storage for a period of time selected from b) at least 18 months, and c) at least 24 months, said composition comprises at least 98% of said initial pemetrexed concentration.
21. 18. The pharmaceutical composition according to embodiment 17, having an initial pemetrexed concentration of 25 mg/mL.
22. 18. The pharmaceutical formulation of embodiment 17, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
23. 23. The pharmaceutical formulation of embodiment 22, wherein said non-aqueous solvent is propylene glycol.
24. 24. The pharmaceutical formulation of embodiment 23, wherein propylene glycol is present at 250 μL/mL.
25. 18. The pharmaceutical composition according to embodiment 17, comprising at least 0.50 mL/mL water.
26. 18. The pharmaceutical composition of embodiment 17, wherein said pemetrexed is in the form of pemetrexed diacid.
27. 18. The pharmaceutical composition according to embodiment 17, wherein said pemetrexed is in the form of pemetrexed disodium.
28. 18. The pharmaceutical composition according to 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) a pharmaceutical composition comprising water,
A pharmaceutical composition, wherein after storage at a temperature of 2°C to 8°C for at least 12 months, said composition comprises at least 90% of said initial pemetrexed concentration.
30. The pharmaceutical composition according to embodiment 29, wherein after storage at a temperature of 2°C to 8°C for at least 24 months, said composition comprises at least 90% of said initial pemetrexed concentration.
31. a) pemetrexed and
b) a non-aqueous solvent present at less than 0.30 mL/mL,
Upon dilution of pemetrexed to an initial dosage concentration with a pharmaceutically acceptable diluent, the composition exhibits no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 12 hours. A pharmaceutical composition comprising:
32. 2. The pharmaceutical composition of embodiment 1, wherein after dilution and storage for a period of time selected from a) at least 24 hours, and b) at least 48 hours, said composition comprises 8% w/w or less total impurities.
33. dilution and a) at least 12 hours,
The pharmaceutical composition of embodiment 1, wherein after storage for a period of time selected from b) at least 24 hours, and c) at least 48 hours, said composition comprises 5% w/w or less of total impurities.
34. dilution and a) at least 12 hours,
The pharmaceutical composition of embodiment 1, wherein after storage for a period of time selected from b) at least 24 hours, and c) at least 48 hours, said composition comprises no more than 2% w/w total impurities.
35. 32. The pharmaceutical composition of embodiment 31, wherein said 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. 32. The pharmaceutical composition according to embodiment 31, comprising 10-50 mg/mL pemetrexed.
37. 37. A pharmaceutical composition according to embodiment 36, comprising 25 mg/mL pemetrexed.
38. 32. The pharmaceutical formulation of embodiment 31, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
39. 39. The pharmaceutical formulation of embodiment 38, wherein said non-aqueous solvent is propylene glycol.
40. 40. A pharmaceutical formulation according to embodiment 39, wherein propylene glycol is present at 250 [mu]L/mL.
41. 32. The pharmaceutical composition according to embodiment 31, comprising at least 0.50 mL/mL water.
42. 32. The pharmaceutical composition of embodiment 31, wherein said pemetrexed is in the form of pemetrexed diacid.
43. 32. The pharmaceutical composition of embodiment 31, wherein said pemetrexed is in the form of pemetrexed disodium.
44. 32. The pharmaceutical composition according to embodiment 31, which is substantially free of antioxidants.
45. a) 25 mg/mL pemetrexed and
b) 250 μL/mL propylene glycol;
c) a pharmaceutical composition comprising water,
Upon dilution of pemetrexed to an initial dosage concentration with a pharmaceutically acceptable diluent, the composition exhibits no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours. A pharmaceutical composition comprising:
46. Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition exhibits no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 48 hours. 46. The pharmaceutical composition of embodiment 45, comprising:
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 said composition contains no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
48. 48. The pharmaceutical composition of embodiment 47, wherein after storage for a period of time selected from a) at least 18 months, and b) at least 24 months, said composition comprises 8% w/w or less total impurities.
49. a) at least 12 months;
48. The pharmaceutical composition of embodiment 47, wherein after storage for a period of time selected from b) at least 18 months, and c) at least 24 months, said composition comprises 5% w/w or less of total impurities.
50. a) at least 12 months;
48. The pharmaceutical composition of embodiment 47, wherein after storage for a period of time selected from b) at least 18 months, and c) at least 24 months, said composition comprises no more than 2% w/w total impurities.
51. 48. The pharmaceutical composition according to embodiment 47, comprising 25 mg/mL pemetrexed.
52. 48. The pharmaceutical formulation of embodiment 47, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
53. 53. The pharmaceutical formulation of embodiment 52, wherein said non-aqueous solvent is propylene glycol.
54. 54. The pharmaceutical formulation of embodiment 53, wherein propylene glycol is present at 250 μL/mL.
55. 48. The pharmaceutical composition according to embodiment 47, comprising at least 0.50 mL/mL water.
56. 48. The pharmaceutical composition according to embodiment 47, wherein said pemetrexed is in the form of pemetrexed diacid.
57. 48. The pharmaceutical composition according to embodiment 47, wherein said pemetrexed is in the form of pemetrexed disodium.
58. 48. The pharmaceutical composition according to 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) a pharmaceutical composition comprising water,
A pharmaceutical composition, wherein said composition contains no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
60. 60. The pharmaceutical composition according to embodiment 59, wherein after storage at a temperature of 2[deg.]C to 8[deg.]C for at least 24 months, said composition contains no more than 8% w/w total impurities.

Figures 1A-1D depict the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations. Figures 1A-1D depict the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations. Figures 1A-1D depict the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations. Figures 1A-1D depict 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 commonly understood by one of ordinary skill in the art to which this invention belongs. Where there are multiple definitions for terms used in this specification, the definitions in this section take precedence unless otherwise stated.

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

As used herein, "initial dosage concentration of pemetrexed" refers to 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 from about 20°C to about 25°C.

Pemetrexed, or a pharmaceutically 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 pemetrexed diacid anhydride. In certain embodiments of the invention, pemetrexed is from about 10 mg/mL to about 40 mg/mL, from about 10 mg/mL to about 30 mg/mL, from about 10 mg/mL to about 20 mg/mL, from about 20 mg/mL from about 50 mg/mL, from about 20 mg/mL to about 40 mg/mL, from about 20 mg/mL to about 30 mg/mL, from about 30 mg/mL to about 50 mg/mL, from about 30 mg/mL to about 40 mg/mL , or from about 40 mg/mL to about 50 mg/mL. In further embodiments of the invention, pemetrexed is 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, monoacid, pharmaceutically 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 a still further embodiment of the invention pemetrexed is present as pemetrexed meglumine. In a still further embodiment of the invention the pemetrexed is present as pemetrexed tromethamine.
non-aqueous solvent

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. Not limited. Useful alcohols are, 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 a further embodiment of the invention the non-aqueous solvent is a polyhydroxy alcohol. In yet a further embodiment of the invention the non-aqueous solvent is propylene glycol. In yet a further embodiment of the invention the non-aqueous solvent is polyethylene glycol. In certain 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, prior to dilution, is 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, Present at 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 do.

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 a further embodiment, 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 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, prior to dilution, is 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 mL to 300 μL/mL, or 250 μL/mL to 300 μL/mL.

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 a further embodiment of the invention, water is present at a concentration of about 500 μL/mL to 950 μL/mL prior to dilution. In still further embodiments of the invention, the water is 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 before dilution. /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.

In certain embodiments, water comprises at least about 50 wt. % concentration. In a further embodiment, the water is at least about 60 wt. %, 75 wt % or 95 wt. % concentration. In certain embodiments of the invention, water is at least about 50-95 wt. % concentration. In accordance with the present invention, water should be 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. % concentration.

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 a further embodiment 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 contains one or more antioxidants, amino acids and/or chelating agents to stabilize It means that it is not present in sufficient concentration to have an effect.

In certain embodiments, the formulation comprises ascorbic acid and derivatives, tocopherols and derivatives, propyl gallate, thioglycerol, lactobionic acid, methionine, tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxy Toluene (BHT), sodium formaldehyde sulfoxylate, sodium bisulfite, Eethylenediaminetetraacetic acid (EDTA) and derivatives, monoethanolamine gentisate, 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 sufficient concentrations 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 12-24 mg/mL tromethamine. In a further embodiment 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 16-20 mg/mL tromethamine, about 17-19 mg/mL tromethamine, about 17-21 mg/mL tromethamine, about 18-20 mg/mL tromethamine, about 18-22 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 still further embodiments of the invention, the formulation comprises about 18 mg/mL tromethamine.

In certain embodiments of the invention, the formulation does not substantially degrade after storage at room temperature for at least about 6 months. In certain embodiments of the invention, the formulation does not substantially degrade after storage at room temperature for at least about 1 year. In a further embodiment of the invention, the formulation does not substantially degrade after storage at room temperature for at least about 18 months. In still further embodiments of the invention, the formulation does not substantially degrade after storage at room temperature for at least about 2 years.

In a further embodiment of the invention, the formulation does not substantially degrade after storage at 2-8° C. for at least about 6 months. In certain embodiments of the invention, the formulation does not substantially degrade after storage at 2-8° C. for at least about 1 year. In a further embodiment of the invention, the formulation does not substantially degrade after storage at 2-8°C for at least about 18 months. In still further embodiments of the invention, the formulation is substantially non-degradable after storage at 2-8° C. for at least about 2 years.

In other embodiments of the invention, the formulation has no more than about 10% w/w impurities, about 8% w/w or less impurities, about 6% w/w or less impurities, about 5% w/w or less impurities, about 4% w/w or less impurities, about 3.5% w/w or less impurities , about 3% w/w or less impurities, about 2.5% w/w or less impurities, about 2% w/w or less impurities, about 1.5% w/w or less impurities, about 1% w/w w impurities or less, about 0.5% w/w impurities or less, about 0.2% w/w impurities or less, about 0.1% w/w impurities or less.

In a further embodiment of the invention, the formulation has no more than about 10% 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. , 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. up to about 3% w/w impurities up to about 2.5% w/w impurities up to about 2% w/w impurities up to about 1.5% w/w impurities about 1% w/w or less impurities, about 0.5% w/w or less impurities, about 0.2% w/w or less impurities, about 0.1% w/w or less impurities.

In still further embodiments of the present invention, the formulation has a single maximal single largest impurity no greater than about 8% w/w; single largest impurity no greater than about 6% w/w; single largest impurity no greater than about 5% w/w; single largest impurity no greater than about 4% w/w; one largest impurity, a single largest impurity no greater than about 3.5% w/w, a single largest impurity no greater than about 3% w/w, a single largest impurity no greater than about 2.5% w/w, about 2% w/w or less single largest impurity, about 1.5% w/w or less single largest impurity, about 1% w/w or less single largest impurity, about 0.5% w/w or less single including the largest impurity, the single largest impurity less than or equal to about 0.2% w/w, and the single largest impurity less than or equal to about 0.1% w/w.

In still further embodiments of the invention, the formulation has no more than about 10% w/w after storage at 2-8° C. for at least about 6 months, about 12 months, about 18 months, or about 24 months. single largest impurity, about 8% w/w or less single largest impurity, about 6% w/w or less single largest impurity, about 5% w/w or less single largest impurity, about 4% w/w the following single largest impurity, about 3.5% w/w or less single largest impurity, about 3% w/w or less single largest impurity, about 2.5% w/w or less single largest impurity, single largest impurity no greater than about 2% w/w, single largest impurity no greater than about 1.5% w/w, single largest impurity no greater than about 1% w/w, no greater than about 0.5% w/w a single largest impurity of about 0.2% w/w or less, a single largest impurity of about 0.1% w/w or less.

In certain embodiments of the invention, the formulation, after storage at room temperature for at least about 6 months, about 12 months, about 18 months, or about 24 months, is 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, and the formulation retains at least about 97% of its initial pemetrexed concentration , retains at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, and at least about 99.5% of its initial pemetrexed concentration.

In further embodiments of the invention, the formulation exhibits at least about 85% 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. , the formulation retains at least about 90% of its initial pemetrexed concentration, the formulation retains at least about 92% of its initial pemetrexed concentration, the formulation retains at least about 95% of its initial pemetrexed concentration, and the formulation retains at least about 90% of its initial pemetrexed concentration 97%, 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.

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 may 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 to a suitable initial dosage concentration of pemetrexed in a pharmaceutically acceptable diluent. In certain embodiments of the invention, the initial dosage concentration of pemetrexed is determined by a physician or one skilled in the art based on a variety of factors including, but not limited to, patient weight, age and condition and volume of diluent. be able to. 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, after dilution and storage at about 2° C. to about 8° C. for at least about 12 hours, is at least about 85% of its initial dosage concentration of pemetrexed, at least about 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, and at least about 99.5% of its initial dosage concentration of pemetrexed.

In still other embodiments of the invention, the formulation, after dilution and storage at about 2° C. to about 8° C. for at least about 24 hours, is 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 95% of its initial dosage concentration of pemetrexed; at least about 97% of its initial dosage concentration of pemetrexed; 98%, at least about 99% of its initial dosage level of pemetrexed, and at least about 99.5% of its initial dosage level of pemetrexed.

In still other embodiments of the invention, the formulation, after dilution and storage at about 2° C. to about 8° C. for at least about 48 hours, is 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 95% of its initial dosage concentration of pemetrexed; at least about 97% of its initial dosage concentration of pemetrexed; 98%, at least about 99% of its initial dosage level of pemetrexed, and at least about 99.5% of its initial dosage level of pemetrexed.

In a further embodiment of the invention, the formulation has no more than about 10% w/w impurities, no more than about 8% w/w impurities, about 6% w/w or less impurities, about 5% w/w or less impurities, about 4% w/w or less impurities, about 3.5% w/w or less impurities, about 3% w/w or less impurities , about 2.5% w/w or less impurities, about 2% w/w or less impurities, about 1.5% w/w or less impurities, about 1% w/w or less impurities, about 0.5% w/w or less impurities, about 0.2% w/w or less impurities, about 0.1% w/w or less impurities.

In other embodiments of the invention, the formulation has no more than about 10% w/w impurities, no more than about 8% w/w impurities, after dilution and storage at about 2°C to about 8°C for at least about 24 hours. about 6% w/w or less impurities, about 5% w/w or less impurities, about 4% w/w or less impurities, about 3.5% w/w or less impurities, about 3% w/w or less impurities Impurities, up to about 2.5% w/w impurities, up to about 2% w/w impurities, up to about 1.5% w/w impurities, up to about 1% w/w impurities, about 0.5 % w/w impurities, up to about 0.2% w/w impurities, up to about 0.1% w/w impurities.

In still other embodiments of the invention, the formulation has no more than about 10% w/w impurities, no more than about 8% w/w impurities after dilution and storage at about 2° C. to about 8° C. for at least about 48 hours. , 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. of impurities, up to about 2.5% w/w impurities, up to about 2% w/w impurities, up to about 1.5% w/w impurities, up to about 1% w/w impurities, about 0. 5% w/w or less impurities, about 0.2% w/w or less impurities, about 0.1% w/w or less impurities.

In still other embodiments of the invention, the formulation has a single largest impurity of about 10% w/w or less, about 8% w/w after dilution and storage at about 2° C. to about 8° C. for at least about 12 hours. The single largest impurity of less than or equal to about 6% w/w, the single largest impurity of less than or equal to about 5% w/w, the single largest impurity of less than or equal to about 4% w/w, about 3.5 % w/w or less single largest impurity, about 3% w/w or less single largest impurity, about 2.5% w/w or less single largest impurity, about 2% w/w or less single largest impurity Impurity, single largest impurity less than or equal to about 1.5% w/w, single largest impurity less than or equal to about 1% w/w, single largest impurity less than or equal to about 0.5% w/w, about 0.2% W/w or less single largest impurity, including about 0.1% w/w or less single largest impurity.

In a further embodiment of the invention, the formulation has a single largest impurity of no more than about 10% w/w, no more than about 8% w/w after dilution and storage at about 2°C to about 8°C for at least about 24 hours. single largest impurity, about 6% w/w or less single largest impurity, about 5% w/w or less single largest impurity, about 4% w/w or less single largest impurity, about 3.5% w /w, the single largest impurity no greater than about 3% w/w, the single largest impurity no greater than about 2.5% w/w, the single largest impurity no greater than about 2% w/w, single largest impurity less than or equal to about 1.5% w/w, single largest impurity less than or equal to about 1% w/w, single largest impurity less than or equal to about 0.5% w/w, about 0.2% w/w w or less single largest impurity, including about 0.1% w/w or less single largest impurity.

In still further embodiments of the invention, the formulation has a single largest impurity of no more than about 10% w/w, no more than about 8% w/w after dilution and storage at about 2°C to about 8°C for at least about 48 hours. single largest impurity of about 6% w/w or less single largest impurity of about 5% w/w or less single largest impurity of about 4% w/w or less about 3.5% w/w or less single largest impurity, about 3% w/w or less single largest impurity, about 2.5% w/w or less single largest impurity, about 2% w/w or less single largest impurity , about 1.5% w/w or less single largest impurity, about 1% w/w or less single largest impurity, about 0.5% w/w or less single largest impurity, about 0.2% w /w or less, and about 0.1% w/w or less single largest impurity.

In other embodiments of the invention, the formulation comprises, after dilution and storage at room temperature for at least about 12 hours, 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, 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 98% of its dosage concentration of pemetrexed Retains about 99%, at least about 99.5% of its dosage concentration of pemetrexed.

In still other embodiments of the present invention, the formulation comprises, after dilution and storage at room temperature for at least about 24 hours, 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 It retains at least about 99% and at least about 99.5% of its dosage level of pemetrexed.

In still other embodiments of the invention, the formulation, after dilution and storage at about room temperature for at least about 48 hours, has at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, Retaining 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 98% of its initial pemetrexed concentration, Retain at least about 99% of the pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration.

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

In another embodiment of the invention, the formulation has no more than about 10% w/w impurities, no more than about 8% w/w impurities, about 6% w/w impurities after dilution and storage at room temperature for at least about 24 hours. Impurities up to about 5% w/w Impurities up to about 4% w/w Impurities up to about 3.5% w/w Impurities up to about 3% w/w Impurities up to about 2.5 % w/w or less impurities, about 2% w/w or less impurities, about 1.5% w/w or less impurities, about 1% w/w or less impurities, about 0.5% w/w or less impurities Impurities, up to about 0.2% w/w impurities, up to about 0.1% w/w impurities.

In still other embodiments of the invention, the formulation has no more than about 10% w/w impurities, no more than about 8% w/w impurities, about 6% w/w impurities after dilution and storage at room temperature for at least about 48 hours. w impurities or less, about 5% w/w impurities or less, about 4% w/w impurities or less, about 3.5% w/w impurities or less, about 3% w/w impurities or less, about 2. 5% w/w or less impurities, about 2% w/w or less impurities, about 1.5% w/w or less impurities, about 1% w/w or less impurities, about 0.5% w/w or less impurities impurities, up to about 0.2% w/w impurities, up to about 0.1% w/w impurities.

In a further embodiment of the invention, the formulation, after dilution and storage at room temperature for at least about 12 hours, has a single largest impurity of about 10% w/w or less, a single largest impurity of about 8% w/w or less, about single largest impurity no greater than 6% w/w, single largest impurity no greater than about 5% w/w, single largest impurity no greater than about 4% w/w, single largest impurity no greater than about 3.5% w/w largest impurity, single largest impurity less than or equal to about 3% w/w, single largest impurity less than or equal to about 2.5% w/w, single largest impurity less than or equal to about 2% w/w, about 1.5% w /w, single largest impurity no greater than about 1% w/w, single largest impurity no greater than about 0.5% w/w, single largest impurity no greater than about 0.2% w/w Impurities, including the single largest impurity less than or equal to about 0.1% w/w.

In still further embodiments of the invention, the formulation has a single largest impurity of no more than about 10% w/w, a single largest impurity of no more than about 8% w/w, after dilution and storage at room temperature for at least about 24 hours, single largest impurity no greater than about 6% w/w; single largest impurity no greater than about 5% w/w; single largest impurity no greater than about 4% w/w; single largest impurity no greater than about 3.5% w/w; one largest impurity, no more than about 3% w/w, no more than about 2.5% w/w, no more than about 2% w/w, no more than about 1.5% w/w or less single largest impurity, about 1% w/w or less single largest impurity, about 0.5% w/w or less single largest impurity, about 0.2% w/w or less single Largest impurity, including a single largest impurity of less than or equal to about 0.1% w/w.

In still further embodiments of the invention, the formulation, after dilution and storage at room temperature for at least about 48 hours, has a single largest impurity of no more than about 10% w/w, a single largest impurity of no more than about 8% w/w, single largest impurity no greater than about 6% w/w; single largest impurity no greater than about 5% w/w; single largest impurity no greater than about 4% w/w; single largest impurity no greater than about 3.5% w/w; one largest impurity, no more than about 3% w/w, no more than about 2.5% w/w, no more than about 2% w/w, no more than about 1.5% w/w or less single largest impurity, about 1% w/w or less single largest impurity, about 0.5% w/w or less single largest impurity, about 0.2% w/w or less single Largest impurity, including a single largest impurity of less than or equal to about 0.1% w/w.

In certain embodiments of the invention, the formulation contains 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 % in vials with a headspace oxygen concentration of less than v%, 5v/v%, 4v/v%, 3v/v%, 2v/v% or 1v/v% oxygen.

In certain embodiments of the invention, the formulation is in a single dose vial. In a further embodiment of the invention, the formulation is in multi-dose vials. In yet a further embodiment of the invention, the formulation is in multiple dose vials intended for use by the same patient. In yet a further embodiment of the invention, the formulation is in multi-dose vials intended for use by different patients.

In another embodiment, the invention provides a method of administering pemetrexed to a patient in need thereof, comprising administering an effective amount of a formulation as described herein. including, relating to methods. In a further embodiment, the present invention provides a method of administering pemetrexed to a patient in need thereof, comprising a formulation comprising an effective amount of pemetrexed and a non-aqueous solvent present at less than 30 wt%. It relates to a method comprising the step of administering. In a further embodiment, the invention provides 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 between 5 and 30 wt% for the method.

(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 obtain a visually homogeneous mixture. Pemetrexed diacid was slowly added to the mixture with continuous stirring and the resulting homogenous suspension was stirred 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 homogeneous mixture was obtained. The pH of the solution was adjusted to 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)) prior to testing. Impurities were determined by HPLC.

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

Long-term stability of Formulations B, I and K (see Table 4, prepared as described above) was also measured in real-time and predictive. Table 3 shows the results.

(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 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 mixture was stored at 2-8°C and tested for appearance, assay, impurities and pH at 12, 24 and 48 hours. A sample was taken immediately after dilution to provide a 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 treated with HPLC diluent (60:40 (v/v, water:ACN )). Results are shown in Tables 6 and 7 (each table representing a separate study).

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

Although the present invention has been described in relation to specific embodiments thereof, further modifications are possible and the present application generally conforms to the principles of the invention, including such departures from the present disclosure. Any variation, use or adaptation of the invention as falling within known or conventional practice within the technical field to which the invention pertains is described above and in the appended claims as follows: It will be understood that it is intended to be inclusive as applicable to any essential feature.

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 and
b) a non-aqueous solvent present at less than 0.30 mL/mL;
A pharmaceutical composition comprising
Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition is 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. A pharmaceutical composition comprising
(Item 2)
dilution and
a) at least 24 hours, and
b) at least 48 hours
2. The pharmaceutical composition of item 1, wherein said composition retains at least 90% of said initial dosage concentration of pemetrexed upon storage for a period of time selected from:
(Item 3)
dilution and
a) at least 12 hours,
b) at least 24 hours, and
c) at least 48 hours
2. The pharmaceutical composition of item 1, wherein said composition retains at least 95% of said initial dosage concentration of pemetrexed upon storage for a period of time selected from:
(Item 4)
dilution and
a) at least 12 hours,
b) at least 24 hours, and
c) at least 48 hours
2. The pharmaceutical composition of item 1, wherein said composition retains at least 98% of said initial dosage concentration of pemetrexed upon storage for a period of time selected from:
(Item 5)
The pharmaceutical composition according to item 1, wherein said 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.
(Item 6)
A pharmaceutical composition according to item 1, comprising 10 to 50 mg/mL pemetrexed.
(Item 7)
A pharmaceutical composition according to item 6, comprising 25 mg/mL pemetrexed.
(Item 8)
The pharmaceutical formulation of item 1, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
(Item 9)
9. Pharmaceutical formulation according to item 8, wherein the non-aqueous solvent is propylene glycol.
(Item 10)
Pharmaceutical formulation according to item 9, wherein the propylene glycol is present at 250 μL/mL.
(Item 11)
A pharmaceutical composition according to item 1, comprising at least 0.50 mL/mL of water.
(Item 12)
A pharmaceutical composition according to item 1, wherein the pemetrexed is in the form of pemetrexed diacid.
(Item 13)
A pharmaceutical composition according to item 1, wherein the pemetrexed is in the form of pemetrexed disodium.
(Item 14)
A pharmaceutical composition according to item 1, which is substantially free of antioxidants.
(Item 15)
a) 25 mg/mL pemetrexed and
b) 250 μL/mL propylene glycol;
c) water and
A pharmaceutical composition comprising
Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition is 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. A pharmaceutical composition comprising
(Item 16)
Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition exhibits 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. 16. The pharmaceutical composition according to item 15, comprising
(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 comprising
A pharmaceutical composition, wherein after storage at a temperature of 2°C to 8°C for at least 12 months, said composition comprises at least 90% of the initial pemetrexed concentration.
(Item 18)
a) at least 18 months, and
b) at least 24 months
18. The pharmaceutical composition of item 17, wherein after storage for a period of time selected from, said composition comprises at least 90% of said initial pemetrexed concentration.
(Item 19)
a) at least 12 months;
b) at least 18 months, and
c) at least 24 months
18. The pharmaceutical composition of item 17, wherein after storage for a period of time selected from, said composition comprises at least 95% of said initial pemetrexed concentration.
(Item 20)
a) at least 12 months;
b) at least 18 months, and
c) at least 24 months
18. The pharmaceutical composition of item 17, wherein after storage for a period of time selected from, said composition comprises at least 98% of said initial pemetrexed concentration.
(Item 21)
18. Pharmaceutical composition according to item 17, having an initial pemetrexed concentration of 25 mg/mL.
(Item 22)
18. The pharmaceutical formulation of item 17, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
(Item 23)
23. Pharmaceutical formulation according to item 22, wherein said non-aqueous solvent is propylene glycol.
(Item 24)
24. Pharmaceutical formulation according to item 23, wherein the propylene glycol is present at 250 [mu]L/mL.
(Item 25)
18. Pharmaceutical composition according to item 17, comprising at least 0.50 mL/mL of water.
(Item 26)
18. Pharmaceutical composition according to item 17, wherein said pemetrexed is in the form of pemetrexed diacid.
(Item 27)
18. A pharmaceutical composition according to item 17, wherein said pemetrexed is in the form of pemetrexed disodium.
(Item 28)
18. Pharmaceutical composition according to item 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 and
A pharmaceutical composition comprising
A pharmaceutical composition, wherein after storage at a temperature of 2°C to 8°C for at least 12 months, 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 of 2[deg.]C to 8[deg.]C for at least 24 months, said composition comprises at least 90% of said initial pemetrexed concentration.
(Item 31)
a) pemetrexed and
b) a non-aqueous solvent present at less than 0.30 mL/mL;
A pharmaceutical composition comprising
Upon dilution of pemetrexed to an initial dosage concentration with a pharmaceutically acceptable diluent, the composition exhibits no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 12 hours. A pharmaceutical composition comprising:
(Item 32)
dilution and
a) at least 24 hours, and
b) at least 48 hours
2. The pharmaceutical composition of item 1, wherein after storage for a period of time selected from said composition comprises 8% w/w or less of total impurities.
(Item 33)
dilution and
a) at least 12 hours,
b) at least 24 hours, and
c) at least 48 hours
2. The pharmaceutical composition of item 1, wherein after storage for a period of time selected from, said composition comprises 5% w/w or less of total impurities.
(Item 34)
dilution and
a) at least 12 hours,
b) at least 24 hours, and
c) at least 48 hours
2. The pharmaceutical composition of item 1, wherein after storage for a period of time selected from, said composition comprises 2% w/w or less of total impurities.
(Item 35)
32. The pharmaceutical composition of item 31, wherein said 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.
(Item 36)
32. A pharmaceutical composition according to item 31, comprising 10 to 50 mg/mL pemetrexed.
(Item 37)
37. Pharmaceutical composition according to item 36, comprising 25 mg/mL pemetrexed.
(Item 38)
32. The pharmaceutical formulation of item 31, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
(Item 39)
39. Pharmaceutical formulation according to item 38, wherein said non-aqueous solvent is propylene glycol.
(Item 40)
40. Pharmaceutical formulation according to item 39, wherein the propylene glycol is present at 250 [mu]L/mL.
(Item 41)
32. Pharmaceutical composition according to item 31, comprising at least 0.50 mL/mL of water.
(Item 42)
32. A pharmaceutical composition according to item 31, wherein said pemetrexed is in the form of pemetrexed diacid.
(Item 43)
32. A pharmaceutical composition according to item 31, wherein said pemetrexed is in the form of pemetrexed disodium.
(Item 44)
32. A pharmaceutical composition according to item 31, which is substantially free of antioxidants.
(Item 45)
a) 25 mg/mL pemetrexed and
b) 250 μL/mL propylene glycol;
c) water and
A pharmaceutical composition comprising
Upon dilution of pemetrexed to an initial dosage concentration with a pharmaceutically acceptable diluent, the composition exhibits no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours. A pharmaceutical composition comprising:
(Item 46)
Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition exhibits no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 48 hours. 46. The pharmaceutical composition of item 45, comprising:
(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 comprising
A pharmaceutical composition, wherein said composition contains no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
(Item 48)
a) at least 18 months, and
b) at least 24 months
48. The pharmaceutical composition of item 47, wherein after storage for a period of time selected from, said composition comprises 8% w/w or less of total impurities.
(Item 49)
a) at least 12 months;
b) at least 18 months, and
c) at least 24 months
48. The pharmaceutical composition of item 47, wherein after storage for a period of time selected from, said composition comprises 5% w/w or less of total impurities.
(Item 50)
a) at least 12 months;
b) at least 18 months, and
c) at least 24 months
48. The pharmaceutical composition of item 47, wherein after storage for a period of time selected from, said composition comprises 2% w/w or less of total impurities.
(Item 51)
48. Pharmaceutical composition according to item 47, comprising 25 mg/mL pemetrexed.
(Item 52)
48. The pharmaceutical formulation of item 47, wherein said non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
(Item 53)
53. Pharmaceutical formulation according to item 52, wherein said non-aqueous solvent is propylene glycol.
(Item 54)
54. Pharmaceutical formulation according to item 53, wherein the propylene glycol is present at 250 [mu]L/mL.
(Item 55)
48. Pharmaceutical composition according to item 47, comprising at least 0.50 mL/mL of water.
(Item 56)
48. Pharmaceutical composition according to item 47, wherein said pemetrexed is in the form of pemetrexed diacid.
(Item 57)
48. A pharmaceutical composition according to item 47, wherein said pemetrexed is in the form of pemetrexed disodium.
(Item 58)
48. Pharmaceutical composition according to item 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 and
A pharmaceutical composition comprising
A pharmaceutical composition, wherein said composition contains no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
(Item 60)
60. The pharmaceutical composition according to item 59, wherein after storage at a temperature of 2[deg.]C to 8[deg.]C for at least 24 months, said composition contains no more than 8% w/w of total impurities.

Claims (7)

An anti-oxidant-free liquid pharmaceutical composition, the liquid pharmaceutical composition comprising:
20 mg/mL to 30 mg/mL pemetrexed;
Propylene glycol from 250 μL /mL to 275 μL /mL;
12 mg/mL to 24 mg/mL tromethamine; and at least 0.50 mL/mL water
wherein said composition has a pH of about 7.4-7.6 and said composition contains no more than 4% w/w impurities. 2. The antioxidant-free liquid pharmaceutical composition of claim 1, comprising 25 mg/mL of said pemetrexed; and 250 μL /mL to 275 μL /mL of said propylene glycol. 25 mg/mL of said pemetrexed, which is pemetrexed diacid; and 250 μL /mL to 275 μL /mL of said propylene glycol. 2. The antioxidant-free liquid pharmaceutical composition of claim 1, wherein the pemetrexed is pemetrexed diacid. Upon dilution to the initial dosage concentration of pemetrexed with a pharmaceutically acceptable diluent, the composition reduces the initial dosage concentration of pemetrexed by at least 90% after storage at a temperature of 2°C to 8°C for at least 12 hours. The antioxidant-free liquid pharmaceutical composition of claim 1, comprising: Upon dilution of pemetrexed with a pharmaceutically acceptable diluent to the initial dosage concentration, the composition contains no more than 8% w/w of total impurities after storage at a temperature of 2°C to 8°C for at least 12 hours. The antioxidant-free liquid pharmaceutical composition of claim 1, comprising: Antioxidant according to claim 1 for use in a method of treating pleural mesothelioma or non-squamous non-small cell lung cancer in a patient in need of treatment for pleural mesothelioma or non-squamous non-small cell lung cancer an agent-free liquid composition, the method comprising:
providing said antioxidant-free liquid composition;
storing the antioxidant-free liquid composition at a temperature of 2° C. to 8° C., wherein the antioxidant-free liquid composition has no more than 4% w/w of total impurities after storage; including a step;
diluting the antioxidant-free liquid composition with normal saline, water for injection, 5% dextrose in water, Ringer's injection, or lactated Ringer's injection to form a diluted liquid composition. and an antioxidant-free liquid composition comprising administering said diluted liquid composition intravenously to said patient.

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