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AU2023202089B2 - Pemetrexed formulations - Google Patents
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AU2023202089B2 - Pemetrexed formulations - Google Patents

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AU2023202089B2
AU2023202089B2 AU2023202089A AU2023202089A AU2023202089B2 AU 2023202089 B2 AU2023202089 B2 AU 2023202089B2 AU 2023202089 A AU2023202089 A AU 2023202089A AU 2023202089 A AU2023202089 A AU 2023202089A AU 2023202089 B2 AU2023202089 B2 AU 2023202089B2
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pemetrexed
pharmaceutical composition
liquid pharmaceutical
impurities
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Feng-Jing Chen
Steven L. Krill
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Eagle Pharmaceuticals Inc
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Eagle Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract

The present invention relates to ready to use, intravenous liquid pharmaceutical compositions comprising pemetrexed, a non-aqueous solvent consisting of propylene glycol, tromethamine, and water which remain stable undiluted for 24 months and after dilution for at least 12 hours when stored at 2C to 8C. The present invention also relates to methods of treating pleural mesothelioma or non-squamous, non-small cell lung cancer comprising administration of said compositions.

Description

PEMETREXED FORMULATIONS BACKGROUND OF THE INVENTION
Compounds exhibiting anti-folate activity have a well known role as chemotherapeutic agents. One such compound is pemetrexed, which has the chemical name N-[4-[2-(2-amino-4,7 dihydro-4-oxo-1H-pyrrolo [2,3-d]pyrimidin-5-yl)ethyli]benzovl]-L-glutamic acid and the structure of formula (1):
o oH
H 2 N- OHH 0
HN
Pemetrexed is used in the treatment of pleural mesothelioma and non-small cell lung cancer. ALIMTA, Eli Lilly's pemetrexed product is presently supplied in 100 mg and 500 mg vials of lyophilized pemetrexed disodium for injection. According to the prescribing information, in order to prepare ALIMTA for infusion the vials are reconstituted in sufficient 0.9% Sodium Chloride Injection (preservative free) to give a solution containing 25 mg/mL of ALIMTA. This concentrated solution is then further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free). The prescribing information cautions that reconstitution and further dilution is only recommended with 0.9% Sodium Chloride Injection (preservative free), and that "ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer's Injection, USP and Ringer's Injection, USP and therefore these should not be used."
Calcium containing diluents, such as Lactated Ringer's Injection and Ringer's Injection, are common solutions used in medical settings for the reconstitution and/or dilution of drug products prior to intravenous administration. There is a need for pemetrexed dosage forms that are chemically stable after reconstitution and/or dilution with diluents containing calcium. In addition to being useful with a wider range of available diluents, the use of such a dosage form would minimize both the loss of dosage forms due to improper reconstitution or dilution and the
I risk that a patient would be administered pemetrexed reconstituted or diluted in anincompatible diluent.
In solution, pemetrexed undergoes hydrolysis and degrades rapidly. Due to this rapid degradation, pemetrexed formulations must either be lyophilized for long term stability or comprise stabilizers. However, reconstitution of a lyophilized formulation requires multiple steps, each of which increases the risk of user error. In addition, reconstitution of a lyophilized formulation is clinically inconvenient and can take up to 30 minutes.
While stable, ready to use formulations of pemetrexed are known, they require stabilizers, such as anti-oxidants or amino acids as described in US6,686,365; CN 101081305; and WO 2012015810, or high levels of non-aqueous solvents, as described in W02013144814. It would be advantageous to minimize patient exposure to these additional ingredients.
As such, there is a need for a stable, non-lyophilized pemetrexed composition with a minimal amount of additional ingredients. To this end, we have developed a stable pemetrexed formulation.
SUMMARY OFTIE INVENTION
In certain embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration less than 0.30ml/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 L/mL propylene glycol, and water, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 24 hours.
In still further embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed at an initial concentration of 10 to 50 mg/mL and a non-aqueous solvent present at a concentration less than 0.30ml/mL, wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 12 months.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 pL/mL propylene glycol, and water, wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 12 months.
In certain embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration less than 0.30ml/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 LIL/mL propylene glycol, and water, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
In still further embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed at an initial concentration of 10 to 50 mg/mL and a non-aqueous solvent present at a concentration less than 0.30ml/mL, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 p.L/mL propylene glycol, and water, the composition comprises no more than 8%ww total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
Additional embodiments of the invention include:
1. A pharmaceutical composition comprising: a) pemetrexed and b) a non-aqueous solvent present at less than 0.30 m/nmL; wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 12 hours.
2. The pharmaceutical composition of embodiment I wherein the composition retains at least 90% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from: a) at least 24 hours, and b) at least 48 hours.
3. The pharmaceutical composition of embodiment I wherein the composition retains at least 95% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from: a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.
4. The pharmaceutical composition of embodiment I wherein the composition retains at least 98% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from: a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.
5. The pharmaceutical composition of embodiment I wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer's Injection, and Lactated Ringer's Injection.
6. The pharmaceutical composition of embodiment I comprising 10 to 50 mg/mL pemetrexed.
The pharmaceutical composition of embodiment6comprising25mg/nL pemetrexed.
8. The pharmaceutical formulation of embodiment 1 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
9. The pharmaceutical formulation of embodiment 8 wherein the non-aqueous solvent is propylene glycol.
10. The pharmaceutical formulation of embodiment 9 wherein propylene glycol is presentat 250 pL/mL.
11. The pharmaceutical composition of embodiment I comprising at least 0.50mL/mL water.
12. The pharmaceutical composition of embodiment I wherein the pemetrexed is in the form of pemetrexed diacid.
13. The pharmaceutical composition of embodiment I wherein the pemetrexed is in the form of pemetrexed disodium.
14. The pharmaceutical composition of embodiment I substantially free of an anti-oxidant.
15. A pharmaceutical composition comprising a) 25 mg/mL pemetrexed, and b) propylene glycol at 250 tL/mL c) water wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 24 hours.
16. The pharmaceutical composition of embodiment 15 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 48 hours.
17. A pharmaceutical composition comprising: a) pemetrexed at an initial concentration of 10 to 50 mg/mL and b) a non-aqueous solvent present at less than 0.30 nL/mL, wherein the composition comprises at least 90% of the initial pernetrexed concentration after storage at a temperature of 2°C to 8°C for at least 12 months.
18. The pharmaceutical composition of embodiment 17 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage for a period selected from: a) at least 18 months, and b) at least 24 months.
19. The pharmaceutical composition of embodiment 17 wherein the composition comprises at least 95% of the initial pemetrexed concentration after storage for a period selected from: a) at least 12 months, b) at least 18 months, and c) at least 24 months.
20. The pharmaceutical composition of embodiment 17wherein the composition comprises at least 98% of the initial pemetrexed concentration after storage for a period selected from: a) at least 12 months, b) at least 18 months, and c) at least 24 months.
21. The pharmaceutical composition of embodiment 17 having an initial pemetrexed concentration of 25 mg/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 combinations thereof.
23. The pharmaceutical formulation of embodiment 22 wherein the non-aqueous solvent is propylene glycol.
24. The pharmaceutical formulation of embodiment 23 wherein propylene glycol is present at 250 [L/imL.
25. The pharmaceutical composition of embodiment 17 comprising at least 0.50mL/mL water.
26. The pharmaceutical composition of embodiment 17 wherein the pemetrexed is in the form of pemetrexed diacid.
27. The pharmaceutical composition of embodiment 17 wherein the pemetrexed is in the form of pemetrexed disodium.
28. The pharmaceutical composition of embodiment 17 substantially free of an anti-oxidant.
29. A pharmaceutical composition comprising a) an initial pemetrexed concentration of 25 mg/mL, b) propylene glycol at 250 L/mL, and c) water; wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 12 months.
30. The pharmaceutical composition of embodiment 29 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 24 months.
31. A pharmaceutical composition comprising: a) pemetrexed and b) a non-aqueous solvent present at less than 0.30 mL/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8C for at least 12 hours.
32. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 8% w/w total impurities after dilution and storage for a period selected from: a) at least 24 hours, and b) at least 48 hours.
33. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 5% w/w total impurities after dilution and storage for a period selected from: a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.
34. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 2% w/w total impurities after dilution and storage for a period selected from: a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.
35. The pharmaceutical composition of embodiment 31 wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer's Injection, and Lactated Ringer's Injection.
36. The pharmaceutical composition of embodiment 31 comprising 10 to 50 mg/mL pemetrexed.
37. The pharmaceutical composition of embodiment 36 comprising 25 mg/mL pemetrexed.
38. The pharmaceutical formulation of embodiment 31 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
39. The pharmaceutical formulation of embodiment 38 wherein the non-aqueous solvent is propylene glycol.
40. The pharmaceutical formulation of embodiment 39 wherein propylene glycol is present at 250 jL/mL.
41 The pharmaceutical composition of embodiment 31 comprising at least 0.50m/mL water.
42. The pharmaceutical composition of embodiment 31 wherein the pemetrexed is in the form of pemetrexed diacid.
43. The pharmaceutical composition of embodiment 31 wherein the pemetrexed is in the form of pemetrexed disodium.
44. The pharmaceutical composition of embodiment 31 substantially free of an anti-oxidant.
45. A pharmaceutical composition comprising a) 25 mg/mL pemetrexed, b) propylene glycol at 250 L/mL, and c) water; wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
46. The pharmaceutical composition of embodiment 45 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8C for at least 48 hours.
47. A pharmaceutical composition comprising: a) pemetrexed at an initial concentration of 10 to 50 mg/mL and b) a non-aqueous solvent present at less than 0.30 mL/mL, wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
48. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 8% w/w total impurities after storage for a period selected from: a) at least 18 months, and b) at least 24 months.
49. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 5% w/w total impurities after storage for a period selected from: a) at least 12 months, b) at least 18 months, and c) at least 24 months.
50. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 2% w/w total impurities after storage for a period selected from: a) at least 12 months, b) at least 18 months, and c) at least 24 months.
51 The pharmaceutical composition of embodiment 47 comprising 25 mg/mL pemetrexed.
52. The pharmaceutical formulation of embodiment 47 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
53. The pharmaceutical formulation of embodiment 52 wherein the non-aqueous solvent is propylene glycol.
54. The pharmaceutical formulation of embodiment 53 wherein propylene glycol is present at 250 L/mL.
55. The pharmaceutical composition of embodiment 47 comprising at least 0.50mL/mL water.
56. The pharmaceutical composition of embodiment 47 wherein the pemetrexed is in the form of pemetrexed diacid.
57. The pharmaceutical composition of embodiment 47 wherein the pemetrexed is in the form of pemetrexed disodium.
58. The pharmaceutical composition of embodiment 47 substantially free of an anti-oxidant.
59. A pharmaceutical composition comprising a) an initial pemetrexed concentration of 25 mg/mL, b) propylene glycol at 250 uL/mL, and c) water; wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
60. The pharmaceutical composition of embodiment 59 wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 months.
II BRIEF DESCRIPTION OFTHE FIGURES
FIGS 1A-ID: Depicts the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations.
DETAILED DESCRIPTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art towhich this invention belongs. In the event that there is a plurality of definitions for a term used herein, those definitions in this section prevail unless stated otherwise.
As used herein "single largest impurity" refers to the impurity with the largest HPLC peak by percentage.
As used herein "initial dosage concentration of pemetrexed" refers the concentration of pemetrexed at the time of diIution, prior to storage.
As used herein "initial pernetrexed concentration" refers to the concentration of pemetrexed at the time of formulation, prior to dilution and/or storage.
As used herein "room temperature" is about 20°C to about 25°C.
Pemetrexed or a pharmaceutically acceptable salt thereof is present in the compositions of the present invention at concentrations of between about 10 mg/mIL to about 50mg/L when calculated as anhydrous pemetrexed diacid. In certain embodiments of the invention, pemetrexed is present at about 10 mg/mi. to about 40 mg/mL, at about 10 mg/mL to about 30 mg/mL, at about 10 mg/mL to about 20 mg/IL, at about 20 mg/mL to about 50 mg/mL, at about 20 mg/iL to about 40 mg/mI, at about 20 mg/iL to about 30 mg/mL, at about 30 mg/mL to about 50 mg/rmL,at about 30 mg/mL to about 40 mg/mL, or at about 40 mg/mL to about 50 mg/mL. In further embodiments of the invention, pemetrexed is available at about 10mg/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/mor at about 50mg/mL.
Pemetrexed is present in the composition as the diacid, monoacid, a pharmaceutically acceptable salt, or as combinations thereof. In certain embodiments of the invention, pemetrexed is present as pemetrexed disodium, in further embodiments of the invention, pemetrexed is present as pemetrexed dipotassium. In yet further embodiments of the invention, pemetrexed is present as pemetrexed meglumine. In still further embodiments of the invention, pemetrexed is present as pemetrexed tromethamine.
Non-Aqueous Solvents
Suitable non-aqueous solvents include, but are not limited to alcohols, ketones, esters, ethers, aromatic hydrocarbons, nitriles, aprotic polar solvents, acidic solvents, and mixtures of any two or more thereof. Useful alcohols include, for example, methanol, ethanol, denatured spirits, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, polyhydroxy alcohols example glycerin, propylene glycol, polyethylene glycol, diethylene glycol, diglycerin, triethylene glycol, tetraethylene glycol, trimethylolpropane and the like. Useful ketones include propanone, 2 butanone, and the like. Useful esters include, for example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, and the like. Useful ethers include, for example, dimethyl ether, diethyl ether, methyl t-butyl ether, ethyl methyl ether, diisopropyl ether, and the like. Useful aromatic hydrocarbons include, for example, and the like. Useful nitriles include acetonitrile, propionitrile, and the like. Useful aprotic polar solvents include N,N dimethylformide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like.
In certain embodiments of the invention, the non-aqueous solvent is an alcohol. In further embodiments of the invention, the non-aqueous solvent is a polyhydroxy alcohol. In still further embodiments of the invention, the non-aqueous solvent is propylene glycol. In yet further embodiments of the invention, the non-aqueous solvent is polyethylene glycol. In particular embodiments of the invention, the non-aqueous solvent is low molecular weight polyethylene glycol. In other embodiments of the invention, the non-aqueous solvent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, or combinations thereof In certain embodiments of the invention, more than one non-aqueous solvent is present, such as, but not limited to polyethylene glycol and propyleneglycol.
In certain embodiments of the invention, the non-aqueous solvent is present at a concentration of about 50 mg/nL to 300 mg/mL prior to dilution. In further embodiments of the invention, the non-aqueous solvent is present at about 50 mg/mL to 100 mg/niL, 50 mg/mL to 200 mg/ni, 50 mg/mL to 250 mg/mL,50mg/nto300mg'L,100mg/mLto200mg/mL, 100 mg/mL to 250 mg/mL, 100 mg/mL to 300 mg/mL, 200 mg/miL to 250 mg/mL, 200 mg/mL to 300 mg/mL, or 250 mg/n to.300 mg/nL prior to dilution.
In particular embodiments, the non-aqueous solvent is present at a concentration of no more than 30 weight percent (wt.%) of the formulation prior to dilution. In further embodiments, the non-aqueous solvent is present at a concentration of at least 5 weight percent (wt.%) of the formulation prior to dilution. In certain embodiments of the invention the non-aqueous solvent is present at 5-30 weight percent (wt.%) of the formulation prior to dilution. In particular embodiments of the invention the non-aqueous solvent is present at about 10-30 vt.%., 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.%, 520%, 10-20 wt.%, 15-20 wt.%, 5 15%, 10-15 wt.%, or 5-10 wt% prior to dilution.
In particular embodiments, the non-aqueous solvent is present at a concentration of no more than 300 aL/mL prior to dilution. In further embodiments, the non-aqueous solvent is present at a concentration of at least 50 pL/mL prior to dilution. In certain embodiments of the invention, the non-aqueous solvent is present at a concentration of about 50 IL/mL to 300 pL/mL. In further embodiments of the invention, the non-aqueous solvent is present at about 50 pL/mL to 100 pL/mL,50 L/mLto 200 pL/nL, 50 pL/mL to 250 pL/iL, 50 L/mL to 275 pL/mL, 50 LmLto 300 L/ni, 100 uL/mL to 200 L/ni., 100 LmLto 250 pL/ni., 100 pL/mL to 275 pL/mL, 100 pL/mL to 300 L/mL,200 pL/mL to 250 uL/iL, 200 pmLto 300 pL/mL, or 250 L/mLto 300pL/mL prior to dilution.
In certain embodiments, water is present at a concentration of at least about 500 L/mL prior to dilution. In other embodiments of the invention, water is present at a concentration of at least about 600 tL/i[L, 750 L/mL, or 950 pL/mL prior to dilution. In further embodiments of the invention, water is present at a concentration of about. 500 L/mL to 950 L/IL prior to dilution. In still further embodiments of the invention, water is present at about 500 uL/mL to
800 pL/mL, 500 iL/rnL to 700 pL/mL, 500 L/rnL to 600 iL/n, 600 pL/mL to 750 tL/m, 600 iL/mL to 800 p/mL, 600 iL/mL to 950 L/rnL, 700 iL/mL to 800 L/mL, 700 L/mL to 950 pL/mL, or 750 L/rnL to 950 L/mL prior to dilution.
In particular embodiments, water is present at a concentration of at least about 50 wt.% of the formulation prior to dilution. In further embodiments, water is present at a concentration of at least about 60 wt.%, 75 w t%, or 95 wt.% prior to dilution. In certain embodiments of the invention water is present at a concentration of at least about 50-95 wt.% prior to dilution. of the invention water is present at a concentration of at least about 50-60 wt.%, 50-70 wt.%, 50-80 wt.%, 60-70 wt.%, 60-80 wt.%, 60-95 wt.%, 70-80 wt.%, or 70-95 wt.% prior to dilution
In certain embodiments of the invention the formulation is substantially free of anti oxidants and/or amino acids. In particular embodiments of the invention, the formulation is substantially free of anti-oxidants. In further embodiments of the invention, the formulation is substantially free of chelating agents. As used herein, substantially free of anti-oxidants, amino acids, and/or chelating agents means the formulation does not comprise one or more anti oxidants,aminoacids, and/or chelating agents, at a concentration sufficientto have a stabilizing effect.
In particular embodiments, the formulation is substantially free of additives selected from the group consisting of ascorbic acid and derivatives, tocopherols and derivatives, propyl gallate, thioglycerol., lactobionic acid, methionine, tertiary butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT). sodium formaldehyde sulfoxylate, sodium hydrogen sulfite., Eethylenediaminetetraacetic acid (EDTA) and derivatives, monoethanolamine gentisate, glutathione, propionic acid, acetone sodium bisulfite, sodium dithionite, citric acid and derivatives, tribasic (tri sodium citrate dehydrate), or suitable mixtures thereof. As used herein, substantially free means the formulation does not comprise one or more additives listed above at a concentration sufficient to have a stabilizing effect.
In particular embodiments of the invention, the formulation comprises tromethamine. In certain embodiments of the invention, the formulation comprises about 12 to 24 mg/mL tromethamine. In further embodiments of the invention, the formulation comprises about 12 to
14 mg/mL tromethamine, about 12 to 16 mg/mL tromethamine, about 14 to 16 mg/mL tromethamine, about 14 to 18 mg/mL tromethamine, about 16 to 18 mg/mL tromethamine, about 16 to 20 mg/mL tromethamine, about 17 to 19 mg/mL tromethamine, about 17 to 21 mg/mL tromethamine, about 18 to 20 mg/mL tromethamine, about 18 to 22 mg/mL tromethamine, about 20 to 22 mg/mL tromethamine, about 20 to 24 mg/nL tromethamine, or about 22 to 24 mg/mL tromethamine. In yet further embodiments of the invention, the formulation comprises about 18 mg/mL tromethamine.
In certain embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 6 months. In particular embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 1 year. In further embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 18 months. In still further embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 2 years.
In further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 6 months. In certain embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 1 year. In further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 18 months. In still further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 2 years.
In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5%w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after storage at 2-8°C for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w
of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In yet further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after storage at 2-8°C for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In particular embodiments of the invention, the formulation retains at least about 85% of its initial pemetrexed concentration, at least about 90% of its initial pemetrexed concentration, the formulation retains at least about 92% of its initial pemetrexed concentration, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In further embodiments of the invention, the formulation retains at least about 85% of its initial pemetrexed concentration, at least about 90% of its initial pemetrexed concentration, the formulation retains at least about 92% of its initial pemetrexed concentration, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration, after storage at 2-8°C for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In certain embodiments of the invention, the formulation is further diluted in a pharmaceutically acceptable diluent. Suitable diluents include, but are not limited to saline, dextrose, water, Ringer's Injection, and Lactated Ringer's Injection. In certain embodiments of the invention, the formulation can be diluted in a calcium containing diluent, such as Ringer's Injection or Lactated Ringer's Injection.
In particular embodiments of the invention, the formulation is diluted in a pharmaceutically acceptable diluent to a suitable initial dosage concentration of pemetrexed. In certain embodiments of the invention the initial dosage concentration of pemetrexed is based on various factors, such as, but not limited to the patient's weight, age, and condition as well as the volume of diluent and can be determined by a practitioner or one of skill in the art. In further embodiments, pemetrexed is diluted to an initial dosage concentration and can be further diluted prior to administration.
In other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2°C to about 8°C for at least about 12 hours.
In still other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2°C to about 8°C for at least about24 hours.
In yet other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2°C to about 8C for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at about 2°C to about 8°C for at least about 12 hours.
In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at about 2°C to about 8°C for at least about 24 hours.
In yet other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at about 2°C to about 8°C for at least about 48 hours.
In still other embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/wof the single largestimpurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2°C to about 8°C for at least about 12 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8%w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2°C to about 8°C for at least about 24 hours.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of thesinglelargest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2°C to about 8°C for at least about 48 hours.
In other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its dosage concentration of pemetrexed, at least about 97% of its dosage concentration of pemetrexed, at least about 98% of its dosage concentration of pemetrexed, at least about 99% of its dosage concentration of pemetrexed, at least about 99.5% of its dosage concentration of pemetrexed, after dilution and storage at room temperature for at least about 12 hours.
In still other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its dosage concentration of pemetrexed, at least about 97% of its dosage concentration of pemetrexed, at least about 98% of its dosage concentration of pemetrexed, at least about 99% of its dosage concentration of pemetrexed, at least about 99.5% of its dosage concentration of pemetrexed, after dilution and storage at room temperature for at least about 24 hours.
In yet other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration, after dilution and storage at about room temperature for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/W impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at room temperature for at least about 12 hours.
In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5%w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at room temperature for at least about 24 hours.
In yet other embodiments of the invention, the formulation comprises no more than about 10% xw impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5%w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at room temperature for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0,1% w/w of the single largest impurity, after dilution and storage at room temperature for at least about 12 hours.
In yet further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% wv of the single largest impurity, no more than about 5%w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, nomore than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0. 1% w/w of the single largest impurity, after dilution and storage at room temperature for at least about 24 hours.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at a room temperature for at least about 48 hours.
In particular embodiments of the invention the formulation is in a vial with a headspace oxygen concentration of less than about 20 v/v%, 18 v/v%, 16 v/v%, 14 v/v%, 12 v/v%, 10 v/v%, 8 v/v%,6v/v%, 5 v/v%, 4 v/v%, 3 v/v%, 2 v/v%, or I v/v% oxygen.
In certain embodiments of the invention, the formulation is in a single-dose vial. In further embodiments of the invention, the formulation is in a multi-dose vial. In yet further embodiments of the invention, the formulation is in a multi-dose vial intended for use by the same patient. In still further embodiments of the invention, the formulation is in a multi-dose vial intended for use by different patients.
In another embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation as described herein. In a further embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation comprising pemetrexed and a non-aqueous solvent present at less than 30 wt%. In a further embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation comprising pemetrexed and propylene glycol wherein the propylene glycol is present at 5-30 wt%.
EXAMPLES
Example 1: E'ffectofANon-Aqueous.Solvents on Pemerexed Stability
Formulations as described in Table I were prepared as follows:
Water for Injection, a suitable base solution (0.1 - N NaOI-I or KOH), and citric acid, if present, were combined and mixed to yield a visually uniform mixture. Pemetrexed diacid was incrementally added to the mixture under continuous agitation, and the resulting homogenous suspension was agitated until all solids were completely dissolved. The pH of the solution was adjusted to about 7.4-7.6. Propylene glycol, if present, was then added to the pemetrexed solution, and the mixture was agitated until a visually uniform mixture was obtained. The p1 of the solution was adjusted to 7.4-7.6.
Ci.lec d - 13.2 13.2 - H.O.mg mL) Propykne 250 - - 250 5 p:. p25 p25 pH5 NaOHl qs to qs to qs to qs to pH17.5 pH-17.5 pH-I7.5 p117.5 Hvdonchtoric Acd qsto qsto qsto qsto
WEI qs qs qs qs
The stability of FormulationsB, CFandIwas tested under accelerated conditions at
60°C and 40°C/75% RH over the course of several days. Samples were taken at various time points and diluted with HPLC diluents (60:40 (v/v, Water:ACN)) prior to testing. Impurities were measured by HPLC.
The results are shown in'Tables 2A-2D and Figures IA-1D.
Table 2A: Single Largest Impurity (% w/w) after storage at 60°C
B C F I Initial 0.09 0.15 0.10 0.07 I day 0.61 1.26 1.00 0.56 2 day 116 2.56 1.97 1.04 day 1.68 4.01 2.91 1.50
Table 2B: Total Impurities (% w/w) after storage at 60°C
Total B C F I Impurity BCFI initial 0 69 0.92 0.74 0700 I day 1.50 2.35 2.02 1.39 2 dav 2.20 3.93 3.31 2.04 3 day 2.86 5.63 4.54 2.65
Table 2C: Single Largest Impurity (% w/w) after storage at 40°C/75% RH
RRT 0.87 B C F I Initial 0.09 0.15 0.10 0.07 2 days 1.70 6.36 3.36 133
[4 days - 329 13.44 9.24 235
Table 2D: Total Impurities after (% w/w) storage at 40°C/75% RH
Total B C F I Impurity Initial 0.69 0.92 0.74 0.70 2 days 3.63 11.75 7.28 2.75 4 days 6.05 20.94 16.71 4.31
The long term stability, real-time, and projected, of formulations B, I, and K (See Table 4, prepared as described above) were also measured. Results are shown in'Table 3
Table 3: LongTerm Stability of Pemetrexed Formulations B, I, and K
Storage Single Total Projected Projected Head at 2-8C Largest . TI in SLI in 24 Assay (Month Impurity 24 M M (% (%LC) PH ( 1(%w/w) oxygen
Fonnulation B 15 0.57 4.70 7.52 0.91 93.6 7.59 18.1 FornulationI 15 0.31 1.70 2 72 0.50 978 7.50 20.9 Fornulation K 14 0.42 2.96 507 0.72 95.2 7.47 19.6
Table 4: Penetrexed Formulation K
Pemetrexed diacid 25.0 mg Propylene Glycol 250 pL Tromnethamnine qs topH-74-7.6 Hydrochloric Acid qs to pH7.4-7.6 Water for Injection qs to 1mL
Example: Stability fPemetrexed FormulationKafer dilution.
The stability of pemetrexed for upto48 hours after dilution of Formulation Kwas evaluated. . Normal salinewater for injection and 5% dextrose in waterRinger's Injection, and Lactated Ringer's Injection were purchased directly and used as is. The pH ofeach diluent was tested and recorded in Table 6.
Table 6:pH of diluents
Normal Saline(NS) 6.8 Wa ter for Injecti on (WI) 7.01 Ringer's Injection(LR) 6.6 Lactated Ringer'sInjection (LRS) 6.5 5% Dextrose ind atern(D5W) 7.5
Formulation K (25 mg/mL) was diluted to 0.15, 1.5, and 15 mg/n in the diluents listed above. The mixtures were stored at 2-8° C and tested at 12, 24, and 48 hours for appearance, assay, impurities, and pH. A sample was taken immediately after dilution for the time zero sample. The 0.15 mg/mL samples were analyzed as is without further dilution, while the 1.5 mg/mL and 15 mg/mL samples were diluted withHPLC diluents (60:40 (v/v, Water:ACN)) prior to testing. Results are in Tables 6 & 7 (each Table represents separate studies).
Table 6: Stability of Formulation K after dilution in Normal Saline or Water for Injection
Theoretical *Percentage of Total Assay p) Diluents Time (hrs) Pemetrexed cone Theoretical H Impurity (mg/mL) ( mng/g)H Pemetrexed % (% w/w) Bulk - 25.0 2480 99.2 7.50 0.16 Solution
NS 04.598.8 74 0.08 2151.199.25 7.40.19 481.199.93 7.80.17
WI014.60 99.18 7.52 0.14
24 14 40 97 82 7.58! 0.16 48 1514.70 99.86 7.59 0.11
Table7.:Stability of Formulation Kafter dilution in Ringer's Injection,Lactated Ringer's Injection, or 5%Dextrose
.Theoretical (/ *Percentage of ime Asy(%.Total Diluents ' Pemetrexed conc L)Theoretical pH i ~rs(mg/miL) Pemetrexed %
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- - - 8 : ,,,,,,,,,, ,............... ,,,,,,,,,,,,,,,,,,,,,,,,,........... ,,,,,,,,,,,,,,,,,,,",,......... - , : :: : :;6 ................... 6 ---- -, -it;, ,--,:....... , q,:::::::::: ,,,,,,,,,..... ,,,,,,,,4 ,,,,,,,, - - -- --- ,,,,,,,,.... ,,,,,,,,,,,......... ,.... ,....,,,,,, --- ....... ....... ,,,- ,,........ ,,,,, --- ........... ...... ::::::::::9 7 , 2: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : ,: :9....................... --,-, - - -- ...... V :- ---- , :............ ,,,,,, ..........() ,31-- ...... , ,
......... ----------0---------- ------------97. 7 100.1 ----7.47 ----------- -----------0,31 12 15 99.0 100.3 17. 6 1 034 24 97.9 1 100.3 7.40 0.321 ---------------------------------I---------4-, -------- ----------------------------------- -------- 98.0------------1 100A ----------L------- 7. 5 9 0,34 ----------
The foregoirt'g, detailed description has been Z:given for clearness of understanding only I and no unnecessary limitations should be understood there from as modifications will be obvious
to those skilled in the art.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.
The disclosures, including the claims, figures and/or drawings, of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entireties.

Claims (28)

CLAIMS What is claimed is:
1. A ready to use, liquid pharmaceutical composition comprising: 20 mg/mL to 30 mg/mL of pemetrexed; a non-aqueous solvent consisting of 200 mg/mL to 300 mg/mL of propylene glycol; 12 mg/mL to 24/mL mg of tromethamine; and at least 0.50 mL/mL water; wherein the pH of the composition is from 7.4 to 7.6.
2. The ready to use, liquid pharmaceutical composition of claim 1, further comprising: 25 mg/mL of the pemetrexed; 250 mg/mL to 300 mg/mL of the propylene glycol; and 17 mg/mL to 21 mg/mL of tromethamine.
3. The ready to use, liquid pharmaceutical composition of claim 1, further comprising: 25 mg/mL of the pemetrexed; 250 mg/mL to 300 mg/mL of the propylene glycol; and 18 mg/mL to 20 mg/mL of tromethamine.
4. The ready to use, liquid pharmaceutical composition of claim 1, further comprising HCl.
5. The ready to use, liquid pharmaceutical composition of claim 1, wherein the pemetrexed is present as pemetrexed diacid, pemetrexed monoacid, a pharmaceutically acceptable salt of pemetrexed, or a combination thereof.
6. The ready to use, liquid pharmaceutical composition of claim 1, wherein the pH is 7.4, 7.5 or 7.6.
7. The ready to use, liquid pharmaceutical composition of claim 1, wherein the composition comprises no more than 3% w/w impurities after storage for 2 days at 40 °C and 75% relative humidity
8. The ready to use, liquid pharmaceutical composition of claims 1-7, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed diacid, the composition comprises at least 90% of the initial dosage concentration of pemetrexed diacid after storage for at least 12 hours at a temperature of 2 °C to 8 °C.
9. The ready to use, liquid pharmaceutical composition of claims 1-7, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed diacid, the composition comprises no more than 8% w/w total impurities after storage for at least 12 hours at a temperature of 2 °C to 8 °C.
10. A method of treating pleural mesothelioma or non-squamous, non-small cell lung cancer in a patient in need thereof comprising: providing ready to use, liquid composition according to claims 1-7; diluting the composition according to claims 8 or 9 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 intravenously administering the diluted liquid composition to the patient.
11. The method of claim 10, wherein the diluted liquid composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage for 48 hours.
12. The method of claim 10, wherein the diluted liquid composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of from 2 °C to 8 °C for 48 hours.
13. A method of treating pleural mesothelioma or non-squamous, non-small cell lung cancer in patient in need thereof comprising the steps of: providing the liquid pharmaceutical composition comprising: 20 mg/mL to 30 mg/mL of pemetrexed; 200 mg/mL to 300 mg/mL of propylene glycol; and water; wherein the pH of the composition is from 7.4 to 7.6 and the composition is ready to dilute; diluting the liquid pharmaceutical composition with a pharmaceutically acceptable diluent to form a diluted liquid pharmaceutical composition at a dosage concentration; administering the diluted liquid pharmaceutical composition to the patient.
14. The method of claim 13, wherein the liquid pharmaceutical composition comprises 25 mg/mL of pemetrexed.
15. The method of claim 13 or claim 14, wherein the liquid pharmaceutical composition comprises 250 mg/mL to 300 mg/mL of propylene glycol.
16. The method of any one of claims 13-15, wherein the liquid pharmaceutical composition comprises at least 0.50 mL/mL water.
17. The method of any one of claims 13-16, wherein the pemetrexed is present as pemetrexed diacid, pemetrexed monoacid, a pharmaceutically acceptable salt of pemetrexed, or a combination thereof.
18. The method of claim 17, wherein the pemetrexed is in the form of pemetrexed diacid or pemetrexed disodium.
19. The method of any one of claims 13-18, wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer's Injection, and Lactated Ringer's Injection.
20. The method of any one of claims 13-19, wherein the pharmaceutically acceptable diluent is 5% dextrose in water.
21. The method of any one of claims 13-20, wherein the diluted liquid pharmaceutical composition is administered in less than 30 minutes.
22. The method of any one of claims 13-21, wherein before administration, the diluted liquid pharmaceutical composition is stored at room temperature for up to 48 hours.
23. The method of any one of claims 13-21, wherein before administration, the diluted liquid pharmaceutical composition is stored at room temperature for 12 to 48 hours.
24. The method of any one of claims 13-21, wherein before administration, the diluted liquid pharmaceutical composition is stored at 2-8°C for up to 48 hours.
25. The method of any one of claims 13-21, wherein before administration, the diluted liquid pharmaceutical composition is stored at 2-8°C for 12 to 48 hours.
26. The liquid pharmaceutical composition or method of any one of claims 3-25, wherein the liquid pharmaceutical composition further comprises 12 mg/mL to 24 mg/mL of tromethamine.
27. The liquid pharmaceutical composition or method of claim 26, wherein the liquid pharmaceutical composition further comprises 18/mL mg to 20 mg/mL of tromethamine.
28. Use of the liquid pharmaceutical composition of any one of claims 1-9, in the manufacture of a medicament for treating pleural mesothelioma or non-squamous, non small cell lung cancer in a patient in need thereof.
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WO2013179310A1 (en) * 2012-05-31 2013-12-05 Mylan Laboratories Limited Stable aqueous compositions of pemetrexed
JP6099557B2 (en) * 2013-12-27 2017-03-22 富士フイルム株式会社 Injection solution preparation and method for producing the same
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EP2666463A1 (en) * 2012-05-21 2013-11-27 Synthon BV Stabilized liquid composition comprising pemetrexed
WO2013179248A1 (en) * 2012-05-30 2013-12-05 Fresenius Kabi Oncology Ltd. Pharmaceutical compositions of pemetrexed
WO2015193517A2 (en) * 2014-10-16 2015-12-23 Synthon B.V. Liquid pharmaceutical composition comprising pemetrexed

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