US20180235969A1 - Liquid pharmaceutical composition comprising pemetrexed - Google Patents
Liquid pharmaceutical composition comprising pemetrexed Download PDFInfo
- Publication number
- US20180235969A1 US20180235969A1 US15/518,201 US201515518201A US2018235969A1 US 20180235969 A1 US20180235969 A1 US 20180235969A1 US 201515518201 A US201515518201 A US 201515518201A US 2018235969 A1 US2018235969 A1 US 2018235969A1
- Authority
- US
- United States
- Prior art keywords
- composition according
- composition
- present
- pemetrexed
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 229960005079 pemetrexed Drugs 0.000 title claims abstract description 39
- 239000007788 liquid Substances 0.000 title claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 title claims abstract 6
- 239000000203 mixture Substances 0.000 claims abstract description 72
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 51
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 26
- 150000001412 amines Chemical class 0.000 claims abstract description 20
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000012298 atmosphere Substances 0.000 claims abstract description 13
- 239000011261 inert gas Substances 0.000 claims abstract description 7
- 208000006178 malignant mesothelioma Diseases 0.000 claims abstract description 5
- 201000005282 malignant pleural mesothelioma Diseases 0.000 claims abstract description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 5
- 238000007911 parenteral administration Methods 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 238000011282 treatment Methods 0.000 claims abstract description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 5
- 230000001954 sterilising effect Effects 0.000 claims description 20
- 238000004659 sterilization and disinfection Methods 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000002738 chelating agent Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000004475 Arginine Substances 0.000 claims description 11
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 11
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Natural products SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 10
- 239000011521 glass Substances 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000004201 L-cysteine Substances 0.000 claims description 4
- 235000013878 L-cysteine Nutrition 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 3
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 96
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 235000006708 antioxidants Nutrition 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 235000009697 arginine Nutrition 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 235000018417 cysteine Nutrition 0.000 description 4
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 4
- 230000002110 toxicologic effect Effects 0.000 description 4
- 231100000027 toxicology Toxicity 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KNNRKMBDANLMQE-ZBRNBAAYSA-N (2s)-2-amino-4-methylsulfanylbutanoic acid;(2r)-2-amino-3-sulfanylpropanoic acid Chemical compound SC[C@H](N)C(O)=O.CSCC[C@H](N)C(O)=O KNNRKMBDANLMQE-ZBRNBAAYSA-N 0.000 description 1
- IHOWSFVYYZTGSY-FOIRCHMTSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)[C@@H](N)CCCN=C(N)N.OC(=O)CC(O)(C(O)=O)CC(O)=O IHOWSFVYYZTGSY-FOIRCHMTSA-N 0.000 description 1
- IZFHEQBZOYJLPK-SSDOTTSWSA-N (R)-dihydrolipoic acid Chemical compound OC(=O)CCCC[C@@H](S)CCS IZFHEQBZOYJLPK-SSDOTTSWSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 1
- KXUAENBJSSQRHF-AWEZNQCLSA-N NC1=NC2=C(C(=O)C1)C(CCC1=CC=C(C(=O)N[C@@H](CCC(=O)O)C(=O)O)C=C1)=CN2 Chemical compound NC1=NC2=C(C(=O)C1)C(CCC1=CC=C(C(=O)N[C@@H](CCC(=O)O)C(=O)O)C=C1)=CN2 KXUAENBJSSQRHF-AWEZNQCLSA-N 0.000 description 1
- YLUGBQJQQLZZNL-UHFFFAOYSA-N O.O.O.O.O.O.O.[Na].[Na] Chemical compound O.O.O.O.O.O.O.[Na].[Na] YLUGBQJQQLZZNL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940110282 alimta Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000008381 oxidative degradant Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229960003349 pemetrexed disodium Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K47/06—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
- A61K47/16—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
- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- EP432677 is a pharmaceutically active compound used for the treatment of malignant pleural mesothelioma and for second-line treatment of non-small cell lung cancer.
- the compound has been first disclosed in EP432677.
- the disodium heptahydrate salt of pemetrexed is marketed by Eli Lilly under the brand name ALIMTA® and is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials.
- the lyophilized product is available in the strengths of 100 mg and 500 mg per vial and is reconstituted with 0.9% saline solution at a concentration of 25 mg/ml. After further dilution with 0.9% saline solution to 100 ml it is then administered intravenously over 10 minutes.
- pemetrexed It is known that a simple, isotonic saline solution of pemetrexed is not pharmaceutically acceptable for commercial purposes due to degradation into unacceptable related substances.
- the chemical instability of pemetrexed is mainly attributed to oxidative and acidic degradation.
- WO 2012015810 five major degradants of pemetrexed have been detected and identified. Under acidic conditions, decarboxylation of glutamic acid is observed. Under alkaline conditions, degradation proceeds by side chain amide hydrolysis followed by deamination. In the presence of oxygen, two oxidative degradants result.
- WO2012121523 discloses solutions for injection comprising pemetrexed, which are free of antioxidants.
- WO2013144814 discloses stable ready-to-use pharmaceutical compositions comprising pemetrexed, preferably the disodium salt, wherein the composition is free of antioxidants, amino acids and chelating agents.
- Both inventions claim that stability of the solutions is achieved by controlling the oxygen content of drug solution and vial headspace. Although in theory degradation could be prevented by controlling the oxygen content, in practice this is not easy to achieve.
- WO0156575 discloses pharmaceutical compositions suitable for liquid parenteral administration comprising pemetrexed, preferably the disodium salt, at least one antioxidant, selected from monothioglycerol, L-cysteine and thioglycolic acid, and an excipient.
- WO2013179248 discloses liquid compositions, comprising pemetrexed, an organic amine, an inert gas and optionally one or more pharmaceutically acceptable excipients.
- WO2013178214 discloses liquid pharmaceutical solutions comprising pemetrexed, preferably the disodium salt, a solvent and an antioxidant, selected from acetylcysteine and sodium 2-mercaptoethanesulphonate.
- WO2012015810 discloses liquid compositions comprising pemetrexed, preferably the disodium salt, an antioxidant selected from lipoic acid, dihydrolipoic acid and methionine, a chelating agent selected from lactobionic acid and sodium citrate and a fluid.
- the present invention provides a liquid pharmaceutical composition suitable for parenteral administration comprising:
- the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1.
- liquid pharmaceutical composition of the present invention may optionally comprise at least one chelating agent.
- It also provides a process for preparing said liquid pharmaceutical composition comprising dissolving the organic amine(s), pemetrexed diacid, the antioxidant(s), optionally the chelating agent(s) and propylene glycol in the solvent(s), making up the volume using water (for injection), filtrating and filling the glass vials.
- Said liquid pharmaceutical composition may be used as medicament in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
- the present invention provides a liquid pharmaceutical composition suitable for parenteral administration comprising:
- the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1.
- the pharmaceutical composition of the present invention is free from pemetrexed disodium or sodium ions.
- the solubility of pemetrexed diacid is very low in aqueous solutions with neutral or acidic pH.
- one or more organic amines are added to the composition.
- the organic amine is arginine.
- the arginine used in the present invention is preferably, but not limited to, the naturally occurring aminoacid L-arginine, which is cheap and readily available.
- the organic amine is present in at least 2.5 equivalents (mole/mole) with respect to pemetrexed diacid.
- addition of the organic amine(s) serves the purpose of dissolving pemetrexed diacid.
- by using an excess of organic amine over pemetrexed diacid it also has the function of obtaining and maintaining the pH of the composition in the desired range.
- the pH of the liquid pharmaceutical composition of the present invention is in the range from 8.3 to 9.1.
- the pH is between 8.5 and 8.8.
- the lower limit of the pH range suitable for the composition of the present invention is 8.3; below this value, precipitation was observed.
- the upper limit of the pH range for the composition of the present invention is 9.1. Above this pH value, the safety of administration of parenteral compositions into peripheral veins cannot be guaranteed.
- the organic amine(s) is present in an amount sufficient to reach the desired pH range of the liquid pharmaceutical composition.
- arginine is present in an amount sufficient to reach a pH of the liquid pharmaceutical composition in the range from 8.3 to 9.1.
- Suitable antioxidants are those compounds which are pharmaceutically acceptable for use in human liquid pharmaceutical compositions. Common antioxidants, such as BHT (butylhydroxytoluene) and methionine do not provide the desired stability for the claimed composition. In fact, the compositions comprising these antioxidants gave rise to precipitation after 2 months of storage at 25° C. Surprisingly, the antioxidants most effective in the claimed composition are monothiolic antioxidants, viz. antioxidants containing one single thiol-functionality. Examples of such antioxidants are L-cysteine, monothioglycerol and thioglycolic acid. Most preferably, the antioxidant is L-cysteine.
- the antioxidant is present in the composition of the present invention in concentrations of 0.5-10 mg/ml.
- the concentration is 0.5-4 mg/ml, preferably 1-2 mg/ml.
- the liquid pharmaceutical composition of the present invention 10-200 mg/ml of propylene glycol is added to the composition.
- the water-soluble propylene glycol is present in concentrations of 20-50 mg/ml. These concentrations of propylene glycol are considered safe from a toxicological point of view, hereby also taking into account the relatively short administration time of the pemetrexed comprising liquid composition.
- the propylene glycol likely by increasing the viscosity of the composition, surprisingly prevents to a certain extent exposure of pemetrexed to oxygen and therefore contribute to enhancement of the stability of the composition towards oxidation.
- the parenteral solvents used in the present invention are those solvents which are pharmaceutically acceptable for use in human liquid pharmaceutical compositions.
- the parenteral solvent of the present invention is selected from ethanol, isopropanol, dimethylsulfoxide, dimethylformamide, dimethylacetamide, glycerol and water or mixtures thereof.
- the parenteral solvent is selected from ethanol, isopropanol, dimethylsulfoxide and water or a mixture thereof.
- the parenteral solvent is water or a mixture of alcohol and water. Water must be of pharmaceutically acceptable quality. Typically, water with the qualification “for injections”, as defined in acknowledged Pharmacopoeias, is used.
- water may comprise conventional tonicity agents assuring proper osmolarity, for instance sodium chloride, dextrose, mannitol, etc, in suitable non-limiting concentrations, e.g. an aqueous saline solution.
- tonicity agents assuring proper osmolarity, for instance sodium chloride, dextrose, mannitol, etc, in suitable non-limiting concentrations, e.g. an aqueous saline solution.
- a chelating agent may be added optionally. It is common knowledge that metal ions induce oxidation. Without meaning to be bound by any theory or hypothesis, oxidation can be induced by metal ions leached from the surface of the glass vial or from the elastomeric composition of the stopper in which the pemetrexed composition is stored, or by metal ions already present in the solvents and/or additives used. The presence of a chelating agent stabilizes the pemetrexed solution during long-term storage. Suitable chelating agents include those which are pharmaceutically acceptable for use in human formulations.
- the chelating agent used in the present invention is citric acid or tartaric acid. Most preferably, the chelating agent is citric acid. Due to the presence of arginine in the composition, arginine citrate will be formed in situ. Typically, the concentration of the chelating agent in the liquid composition is 1 mg/ml.
- the present invention further provides a process for preparing the liquid pharmaceutical composition comprising dissolving the organic amine(s), pemetrexed diacid, the antioxidant(s), optionally the chelating agent(s) and propylene glycol in the solvent(s), making up the volume using water (for injection), filtrating and filling the glass vials.
- the process of the present invention is simple, reliable and cheap.
- the liquid pharmaceutical composition of the present invention may optionally be sterilized using methods known to the artisan. Typically, the sterilization is carried out in an autoclave at 121° C. for 15 minutes. It is especially beneficial that the presently claimed liquid composition is stable during heat sterilization.
- the liquid pharmaceutical composition is prepared by dissolving arginine in water for injection, followed by addition of successively pemetrexed diacid, L-cysteine, optionally citric acid, and propylene glycol. The total volume is made up with water for injection. The obtained solution is then filtered, filled into glass vials and sterilized.
- the process for preparing the liquid composition of the present invention is conducted in an atmosphere of inert gas to minimize oxidation of pemetrexed.
- inert gas to minimize oxidation of pemetrexed.
- headspace oxygen and moisture from the sealable vessel have to be removed.
- This can be established by purging the sealable container with an inert gas.
- inert gasses are for example nitrogen, argon or helium, or mixtures thereof.
- the preferred gas is nitrogen.
- the suitability of the composition of the present invention has been studied and confirmed in stability studies.
- the impurities present in the pemetrexed-comprising formulations during stability studies were detected by high performance liquid chromatography (HPLC) equipped with a UV detector operating at a suitable wavelength (typically 227 nm).
- HPLC high performance liquid chromatography
- the amount of impurities was calculated on a normalized peak area response (“PAR”) basis.
- PAR peak area response
- the sum of peaks of all individual impurities in the invention compositions should not exceed 2% of the total PAR.
- the peak size of any individual impurity should not exceed 1% of the total PAR.
- the preferred compositions of the present invention are characterized in that they exhibit, after 6 months of storage in a closed container at 25° C., less than 3% of total impurities.
- the preferred compositions of the present invention are characterized in that they exhibit, after 18 months of storage in a closed container at 2-8° C., less than 2 per cent of total impurities.
- the temperatures at which the compositions of the present invention are kept for routine storage, within the period of the pharmaceutical shelf-life of the composition are preferably between 2 and 8° C.
- the compositions are preferably stored in tightly stoppered original containers, typically closed glass vials. Under such conditions, the expected shelf-life of the compositions of the present invention is at least 18 months. It should be understood that the pemetrexed-comprising solutions remain in the temperature range described herein for substantially the entire period of storage before dilution and/or administration to the patient in need thereof.
- the liquid pharmaceutical composition in accordance with the present invention may be used as a medicament.
- the pharmaceutical composition typically may be used in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
- the organic amine was added to the appropriate amount of water under stirring.
- Pemetrexed diacid was added to the solution and the resulting mixture was stirred until complete dissolution was obtained.
- the antioxidant was added.
- BHT butylhydroxytoluene
- a solution of BHT in ethanol was added.
- the chelating agent was added.
- Propylene glycol was added and the mixture was stirred for 10 minutes.
- the volume of the obtained solution was made up to 1 ml with water for injection.
- the whole process of dissolving was carried out under a protective atmosphere of nitrogen (except for the procedure of example 4).
- the solution was filtered over a 0.22 microns Durapore membrane filter, filled into glass vials under nitrogen atmosphere and the vials were closed.
- the prepared injection solutions were sterilized in an autoclave at 121° C. for 15 minutes.
- compositions were tested in a stability study at 25 and 40° C. in closed glass vials. Impurities were detected by high performance liquid chromatography (HPLC) equipped with a UV detector operating at 227 nm. The amount of impurities was calculated on a normalized peak area response (“PAR”) basis.
- HPLC high performance liquid chromatography
- UV detector operating at 227 nm.
- PAR peak area response
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Abstract
The present invention relates to a liquid pharmaceutical composition suitable for parenteral administration comprising: a) pemetrexed diacid; b) at least one organic amine; c) at least one antioxidant; d) 10-200 mg/ml of propylene glycol; and e) one or more parenteral solvents, wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1 The invention further relates to the use of said liquid pharmaceutical composition as medicament in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
Description
- Pemetrexed, chemically N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid of formula (I),
- is a pharmaceutically active compound used for the treatment of malignant pleural mesothelioma and for second-line treatment of non-small cell lung cancer. The compound has been first disclosed in EP432677.
- The disodium heptahydrate salt of pemetrexed is marketed by Eli Lilly under the brand name ALIMTA® and is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials. The lyophilized product is available in the strengths of 100 mg and 500 mg per vial and is reconstituted with 0.9% saline solution at a concentration of 25 mg/ml. After further dilution with 0.9% saline solution to 100 ml it is then administered intravenously over 10 minutes.
- It would be an advantage to have a stable, ready to use reconstituted solution that only has to be further diluted before administration. Particularly with potentially toxic pharmaceuticals like pemetrexed this would be desired, wherein such solution provides easier and safer handling for the caregiver. In addition, it would be particularly desirable if the stable formulation can be prepared without the use of freeze drying techniques.
- It is known that a simple, isotonic saline solution of pemetrexed is not pharmaceutically acceptable for commercial purposes due to degradation into unacceptable related substances. The chemical instability of pemetrexed is mainly attributed to oxidative and acidic degradation. According to WO 2012015810, five major degradants of pemetrexed have been detected and identified. Under acidic conditions, decarboxylation of glutamic acid is observed. Under alkaline conditions, degradation proceeds by side chain amide hydrolysis followed by deamination. In the presence of oxygen, two oxidative degradants result.
- In literature, several examples are given of stable solutions comprising pemetrexed. WO2012121523 discloses solutions for injection comprising pemetrexed, which are free of antioxidants. WO2013144814 discloses stable ready-to-use pharmaceutical compositions comprising pemetrexed, preferably the disodium salt, wherein the composition is free of antioxidants, amino acids and chelating agents. Both inventions claim that stability of the solutions is achieved by controlling the oxygen content of drug solution and vial headspace. Although in theory degradation could be prevented by controlling the oxygen content, in practice this is not easy to achieve.
- WO0156575 discloses pharmaceutical compositions suitable for liquid parenteral administration comprising pemetrexed, preferably the disodium salt, at least one antioxidant, selected from monothioglycerol, L-cysteine and thioglycolic acid, and an excipient. WO2013179248 discloses liquid compositions, comprising pemetrexed, an organic amine, an inert gas and optionally one or more pharmaceutically acceptable excipients. WO2013178214 discloses liquid pharmaceutical solutions comprising pemetrexed, preferably the disodium salt, a solvent and an antioxidant, selected from acetylcysteine and sodium 2-mercaptoethanesulphonate. WO2012015810 discloses liquid compositions comprising pemetrexed, preferably the disodium salt, an antioxidant selected from lipoic acid, dihydrolipoic acid and methionine, a chelating agent selected from lactobionic acid and sodium citrate and a fluid.
- Repetition of the examples cited in the prior art show that the long term stability of the disclosed compositions is insufficient. Moreover, some of the compositions are not desirable from a toxicological point of view.
- Thus, in view of the prior art cited above, there is still a need for a ready to use reconstituted solution comprising pemetrexed, which is safe and exhibits excellent long term stability.
- The present invention provides a liquid pharmaceutical composition suitable for parenteral administration comprising:
- a) pemetrexed diacid;
- b) at least one organic amine;
- c) at least one antioxidant;
- d) 10-200 mg/ml of propylene glycol; and
- e) one or more parenteral solvents,
- wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1.
- In addition, the liquid pharmaceutical composition of the present invention may optionally comprise at least one chelating agent.
- It also provides a process for preparing said liquid pharmaceutical composition comprising dissolving the organic amine(s), pemetrexed diacid, the antioxidant(s), optionally the chelating agent(s) and propylene glycol in the solvent(s), making up the volume using water (for injection), filtrating and filling the glass vials.
- Said liquid pharmaceutical composition may be used as medicament in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
- As mentioned above, in literature, several examples are given of so-called stable solutions comprising pemetrexed. However, we experienced that none of the disclosed compositions cited in the prior art exhibit sufficient long term stability and that in addition, some of the compositions are not desirable from a toxicological point of view. Experiments in our laboratory have led to the development of a ready to use reconstituted solution comprising pemetrexed, wherein a particular combination of components within a specific pH range results in a toxicological safe composition exhibiting excellent long term stability.
- The present invention provides a liquid pharmaceutical composition suitable for parenteral administration comprising:
- a) pemetrexed diacid;
- b) at least one organic amine;
- c) at least one antioxidant;
- d) 10-200 mg/ml of propylene glycol, and
- e) one or more parenteral solvents,
- wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1.
- The pharmaceutical composition of the present invention is free from pemetrexed disodium or sodium ions.
- The solubility of pemetrexed diacid is very low in aqueous solutions with neutral or acidic pH. In order to obtain an aqueous solution wherein pemetrexed diacid is completely dissolved, one or more organic amines are added to the composition. Preferably, the organic amine is arginine. The arginine used in the present invention is preferably, but not limited to, the naturally occurring aminoacid L-arginine, which is cheap and readily available. The organic amine is present in at least 2.5 equivalents (mole/mole) with respect to pemetrexed diacid. In the first place, addition of the organic amine(s) serves the purpose of dissolving pemetrexed diacid. Furthermore, by using an excess of organic amine over pemetrexed diacid it also has the function of obtaining and maintaining the pH of the composition in the desired range.
- In order to prevent acidic degradation of the composition of pemetrexed as much as possible, the pH of the liquid pharmaceutical composition of the present invention is in the range from 8.3 to 9.1. Preferably, the pH is between 8.5 and 8.8. The lower limit of the pH range suitable for the composition of the present invention is 8.3; below this value, precipitation was observed. The upper limit of the pH range for the composition of the present invention is 9.1. Above this pH value, the safety of administration of parenteral compositions into peripheral veins cannot be guaranteed.
- The organic amine(s) is present in an amount sufficient to reach the desired pH range of the liquid pharmaceutical composition. In a preferred embodiment of the present invention, arginine is present in an amount sufficient to reach a pH of the liquid pharmaceutical composition in the range from 8.3 to 9.1.
- Suitable antioxidants are those compounds which are pharmaceutically acceptable for use in human liquid pharmaceutical compositions. Common antioxidants, such as BHT (butylhydroxytoluene) and methionine do not provide the desired stability for the claimed composition. In fact, the compositions comprising these antioxidants gave rise to precipitation after 2 months of storage at 25° C. Surprisingly, the antioxidants most effective in the claimed composition are monothiolic antioxidants, viz. antioxidants containing one single thiol-functionality. Examples of such antioxidants are L-cysteine, monothioglycerol and thioglycolic acid. Most preferably, the antioxidant is L-cysteine.
- The antioxidant is present in the composition of the present invention in concentrations of 0.5-10 mg/ml. When the antioxidant used is L-cysteine, the concentration is 0.5-4 mg/ml, preferably 1-2 mg/ml.
- To further increase the stability of the liquid pharmaceutical composition of the present invention, 10-200 mg/ml of propylene glycol is added to the composition. In a preferred embodiment of the present invention, the water-soluble propylene glycol is present in concentrations of 20-50 mg/ml. These concentrations of propylene glycol are considered safe from a toxicological point of view, hereby also taking into account the relatively short administration time of the pemetrexed comprising liquid composition.
- Without meaning to be bound by any theory or hypothesis, the propylene glycol, likely by increasing the viscosity of the composition, surprisingly prevents to a certain extent exposure of pemetrexed to oxygen and therefore contribute to enhancement of the stability of the composition towards oxidation.
- The parenteral solvents used in the present invention are those solvents which are pharmaceutically acceptable for use in human liquid pharmaceutical compositions. The parenteral solvent of the present invention is selected from ethanol, isopropanol, dimethylsulfoxide, dimethylformamide, dimethylacetamide, glycerol and water or mixtures thereof. Preferably, the parenteral solvent is selected from ethanol, isopropanol, dimethylsulfoxide and water or a mixture thereof. Most preferably, the parenteral solvent is water or a mixture of alcohol and water. Water must be of pharmaceutically acceptable quality. Typically, water with the qualification “for injections”, as defined in acknowledged Pharmacopoeias, is used.
- For administration, water may comprise conventional tonicity agents assuring proper osmolarity, for instance sodium chloride, dextrose, mannitol, etc, in suitable non-limiting concentrations, e.g. an aqueous saline solution.
- To further protect the composition of the present invention from oxidation, a chelating agent may be added optionally. It is common knowledge that metal ions induce oxidation. Without meaning to be bound by any theory or hypothesis, oxidation can be induced by metal ions leached from the surface of the glass vial or from the elastomeric composition of the stopper in which the pemetrexed composition is stored, or by metal ions already present in the solvents and/or additives used. The presence of a chelating agent stabilizes the pemetrexed solution during long-term storage. Suitable chelating agents include those which are pharmaceutically acceptable for use in human formulations. Preferably, the chelating agent used in the present invention is citric acid or tartaric acid. Most preferably, the chelating agent is citric acid. Due to the presence of arginine in the composition, arginine citrate will be formed in situ. Typically, the concentration of the chelating agent in the liquid composition is 1 mg/ml.
- The present invention further provides a process for preparing the liquid pharmaceutical composition comprising dissolving the organic amine(s), pemetrexed diacid, the antioxidant(s), optionally the chelating agent(s) and propylene glycol in the solvent(s), making up the volume using water (for injection), filtrating and filling the glass vials. The process of the present invention is simple, reliable and cheap.
- The liquid pharmaceutical composition of the present invention may optionally be sterilized using methods known to the artisan. Typically, the sterilization is carried out in an autoclave at 121° C. for 15 minutes. It is especially beneficial that the presently claimed liquid composition is stable during heat sterilization.
- Advantageously, the liquid pharmaceutical composition is prepared by dissolving arginine in water for injection, followed by addition of successively pemetrexed diacid, L-cysteine, optionally citric acid, and propylene glycol. The total volume is made up with water for injection. The obtained solution is then filtered, filled into glass vials and sterilized.
- The process for preparing the liquid composition of the present invention is conducted in an atmosphere of inert gas to minimize oxidation of pemetrexed. In addition, headspace oxygen and moisture from the sealable vessel have to be removed. This can be established by purging the sealable container with an inert gas. Such inert gasses are for example nitrogen, argon or helium, or mixtures thereof. The preferred gas is nitrogen.
- The suitability of the composition of the present invention has been studied and confirmed in stability studies. For purposes of the present invention, the impurities present in the pemetrexed-comprising formulations during stability studies were detected by high performance liquid chromatography (HPLC) equipped with a UV detector operating at a suitable wavelength (typically 227 nm). The amount of impurities was calculated on a normalized peak area response (“PAR”) basis. As an acceptable limit demonstrating sufficient stability at the corresponding sampling point, the sum of peaks of all individual impurities in the invention compositions should not exceed 2% of the total PAR. The peak size of any individual impurity should not exceed 1% of the total PAR.
- A sum of peaks of all individual impurities of below 3% of the total PAR after 6 months at 25° C. indicates sufficient stability for at least 18 months at 2-8° C.
- Thus, the preferred compositions of the present invention are characterized in that they exhibit, after 6 months of storage in a closed container at 25° C., less than 3% of total impurities. Alternatively, the preferred compositions of the present invention are characterized in that they exhibit, after 18 months of storage in a closed container at 2-8° C., less than 2 per cent of total impurities.
- Accordingly, the temperatures at which the compositions of the present invention are kept for routine storage, within the period of the pharmaceutical shelf-life of the composition, are preferably between 2 and 8° C. The compositions are preferably stored in tightly stoppered original containers, typically closed glass vials. Under such conditions, the expected shelf-life of the compositions of the present invention is at least 18 months. It should be understood that the pemetrexed-comprising solutions remain in the temperature range described herein for substantially the entire period of storage before dilution and/or administration to the patient in need thereof.
- The liquid pharmaceutical composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
- The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.
- General Procedure for the Preparation of the Liquid Pharmaceutical Composition
- The liquid pharmaceutical compositions of examples 1-23, as described below, were prepared by using the following procedure.
- Nitrogen was bubbled through water for injection for about 20 minutes. The organic amine was added to the appropriate amount of water under stirring. Pemetrexed diacid was added to the solution and the resulting mixture was stirred until complete dissolution was obtained. The antioxidant was added. In case of BHT (butylhydroxytoluene), a solution of BHT in ethanol was added. Optionally, the chelating agent was added. Propylene glycol was added and the mixture was stirred for 10 minutes. The volume of the obtained solution was made up to 1 ml with water for injection. The whole process of dissolving was carried out under a protective atmosphere of nitrogen (except for the procedure of example 4). The solution was filtered over a 0.22 microns Durapore membrane filter, filled into glass vials under nitrogen atmosphere and the vials were closed. Optionally, the prepared injection solutions were sterilized in an autoclave at 121° C. for 15 minutes.
- Stability Study
- The compositions were tested in a stability study at 25 and 40° C. in closed glass vials. Impurities were detected by high performance liquid chromatography (HPLC) equipped with a UV detector operating at 227 nm. The amount of impurities was calculated on a normalized peak area response (“PAR”) basis.
- Results
- Cysteine Concentration
-
Composition PXD Arginine Propylene Glycol Cysteine mg/ml mg/ml mg/ml mg/ml Example 1 50 60 200 1 Example 2 50 60 200 2 Samples were prepared in an atmosphere of nitrogen -
-
Name Zero 1 m/25° C. 3 m/25° C. 6 m/25° C. Appearance Pale yellow Pale yellow Pale yellow Yellow solution solution solution solution pH 8.99 8.90 8.92 8.85 Color GY4-GY5 <Y3-<GY3 <Y4 GY2-GY3 Clarity <I <I <I <I PXD (mg/ml) 53.05 50.04 50.52 49.64 ΣIMP (% IN) 0.34 0.58 0.37 0.41 -
-
Name Zero 1 m/25° C. 6 m/25° C. Appearance Pale yellow Pale yellow Dark yellow solution solution solution pH 8.97 8.92 8.86 Color GY4-GY5 <Y6 out of scale Clarity <I <I <I PXD (mg/ml) 53.74 49.97 50.26 ΣIMP (% IN) 0.52 0.40 0.94 -
-
Name Zero 1 m/25° C. 3 m/25° C. 6 m/25° C. Appearance Pale yellow Pale yellow Pale yellow Pale yellow solution solution solution solution pH 8.98 8.91 8.88 8.86 Color GY4-GY5 <Y7 <Y6 <Y6 Clarity <I <I <I <I PXD (mg/ml) 52.82 50.59 51.91 50.51 ΣIMP (% IN) 0.34 0.37 0.30 0.26 -
-
Name Zero 1 m/25° C. 6 m/25° C. Appearance Pale yellow Pale yellow Colorless solution solution solution pH 8.96 8.90 8.84 Color GY4-GY5 <Y7 <Y7 Clarity <I <I <I PXD (mg/ml) 54.32 50.63 51.13 ΣIMP (% IN) 0.47 0.38 0.27 -
-
Composition Propyl- Tar- Argi- ene Cyste- taric PXD nine Glycol ine Acid NITRO- mg/ml mg/ml mg/ml mg/ml mg/ml GEN Example 3 25 30 100 1 1 YES Example 4 25 30 100 1 1 NO -
-
Name Zero 1 m/40° C. 2 m/40° C. Appearance Colorless Colorless Colorless solution solution solution pH 8.99 8.93 not measured Color <B9 <B9 <B9 Clarity <I <I <I PXD (mg/ml) 25.85 25.87 25.09 ΣIMP (% IN) 0.18 0.30 0.26 -
-
Name Zero 1 m/40° C. 2 m/40° C. Appearance Colorless Yellow Dark yellow solution solution solution pH 8.99 8.89 not measured Color <B9 Y3 out of scale Clarity <I <I <I PXD (mg/ml) 25.36 25.02 23.70 ΣIMP (% IN) 0.16 2.72 4.19
pH/Varying Amounts of Arginine -
Composition Propyl- Cit- Argi- ene Cyste- ric PXD nine Glycol ine Acid mg/ml mg/ml mg/ml mg/ml mg/ml pH* Example 5 25 30 100 2 1 8.5 Example 6 25 40 100 2 1 8.9 Example 7 25 40 100 2 1 9.4 *At pH values below 8.3, precipitation occurred Samples were prepared in an atmosphere of nitrogen Value of pH = 9.4 was adjusted by addition of extra amount of L-arginine -
-
Name Zero 1 m/25° C. 2 m/25° C. 3 m/25° C. Appearance Colorless Colorless Colorless Colorless solution solution solution solution pH 8.46 8.52 8.52 8.55 Color <BY9 <BY9 <BY9 <BY9 Clarity <I <I <I <I PXD(mg/ml) 25.39 25.86 25.69 25.76 ΣIMP (% IN) 0.21 0.20 0.24 0.26 -
-
Name Zero 1 m/25° C. 2 m/25° C. 3 m/25° C. Appearance Colorless Colorless Colorless Colorless solution solution solution solution pH 8.89 8.92 8.88 8.91 Color <BY9 <BY9 <BY9 <BY9 Clarity <I <I <I <I PXD (mg/ml) 24.94 25.25 25.83 25.84 ΣIMP (% IN) 0.16 0.23 0.20 0.18 -
-
Name Zero 1 m/25° C. 2 m/25° C. 3 m/25° C. Appearance Colorless Colorless N/A Colorless solution solution solution pH 9.39 9.41 N/A 9.42 Color <BY9 <BY9 N/A <BY9 Clarity <I <I N/A <I PXD (mg/ml) 24.32 25.69 N/A 24.91 ΣIMP (% IN) 0.23 0.26 N/A 0.28 -
-
Composition PXD Arginine Propylene Glycol Cysteine mg/ml mg/ml mg/ml mg/ml Example 8 25 30 — 1 Example 9 25 30 50 1 Example 10 25 30 100 1 Samples were prepared in an atmosphere of nitrogen -
-
Name Zero 1 m/40° C. 2 m/40° C. Appearance Almost colorless Pale yellow Pale yellow solution solution solution pH 8.85 8.95 8.95 Color <BY7 <Y4 Y3-Y4 Clarity <I <I <I PXD (mg/ml) 25.01 24.25 24.64 ΣIMP (% IN) 0.22 1.66 2.75 -
-
Name Zero 1 m/40° C. 2 m/40° C. Appearance Almost colorless N/A Yellowish solution solution pH 8.86 N/A 8.87 Color <BY7 N/A GY2-GY3 Clarity <I N/A <I PXD (mg/ml) 25.31 N/A 24.74 ΣIMP (% IN) 0.19 N/A 1.91 -
-
Name Zero 1 m/40° C. 2 m/40° C. Appearance Almost colorless Pale green-yellow Pale yellow solution solution solution pH 8.85 8.91 8.93 Color <BY7 <Y5 GY2-GY3 Clarity <I <I <I PXD (mg/ml) 25.18 25.23 24.98 ΣIMP (% IN) 0.18 0.55 1.13 -
-
Composition Propyl- Tar- Cit- Argi- ene Cyste- taric ric PXD nine Glycol ine acid acid mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml Example 11 25 30 100 1 — — Example 12 25 30 100 1 1 — Example 13 25 30 100 1 — 1 Samples were prepared in an atmosphere of nitrogen -
-
Name Zero 1 m/40° C. 2 m/40° C. Appearance Colorless Pale yellow green Pale yellow solution solution solution pH 8.85 8.91 8.93 Color <BY7 <Y5 GY2-GY3 Clarity <I <I <I PXD (mg/ml) 25.18 25.23 24.98 ΣIMP (% IN) 0.18 0.55 1.13 -
-
Name Zero 1 m/40° C. 2 m/40° C. Appearance Colorless Colorless Colorless solution solution solution pH 8.99 8.93 N/A Color <B9 <B9 <B9 Clarity <I <I <I PXD (mg/ml) 25.85 25.87 25.09 ΣIMP (% IN) 0.18 0.30 0.26 -
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Name Zero 1 m/40° C. 2 m/40° C. Appearance Colorless Pale yellow Pale yellow solution solution solution pH 8.99 9.03 9.09 Color <B9 Y4 Y4 Clarity <I <I <I PXD (mg/ml) 25.93 25.14 25.49 ΣIMP (% IN) 0.17 0.77 0.56 - Antioxidant
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Composition Propylene N-acetyl- PXD Arginine Glycol Cysteine L-cysteine Methionine BHT mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml Ex. 14 50 50 200 0.15 Ex. 15 50 60 200 1 Ex. 16 50 60 200 2 Ex. 17 50 60 200 1 Ex. 18 50 60 200 2 Ex. 19 25 30 100 5 Samples were prepared in an atmosphere of nitrogen -
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Name Zero 1 m/25° C. 2 m/25° C. Appearance Pale yellow Pale yellow Stability solution solution testing pH 8.56 8.53 terminated due to Color BY6 <Y3 precipitation Clarity <I <I PXD (mg/ml) 51.88 53.36 ΣIMP (% IN) 0.25 1.01 -
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Name Zero 1 m/25° C. 2 m/25° C. Appearance Pale yellow Pale yellow Stability solution solution testing pH 8.93 8.84 terminated due to Color BY6 Y4 precipitation Clarity <I <I PXD (mg/ml) 49.74 49.55 ΣIMP (% IN) 0.33 1.26 -
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Name Zero 1 m/25° C. 2 m/25° C. Appearance Pale yellow Pale yellow Stability solution solution testing pH 8.92 8.93 terminated due to Color BY5 Y4 precipitation Clarity <I <I PXD (mg/ml) 49.14 49.27 ΣIMP (% IN) 0.41 1.35 -
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Name Zero 1 m/25° C. 3 m/25° C. Appearance Pale yellow Pale yellow Pale yellow solution solution solution pH 8.99 8.90 8.92 Color GY4-GY5 <Y3-GY3 <Y4 Clarity <I <I <I PXD (mg/ml) 53.05 50.04 50.52 ΣIMP (% IN) 0.34 0.58 0.37 - Without Steam Sterilization
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Name Zero 1 m/25° C. 3 m/25° C. Appearance Pale yellow Pale yellow Pale yellow solution solution solution pH 8.98 8.91 8.88 Color GY4-GY5 <Y7 <Y6 Clarity <I <I <I PXD (mg/ml) 52.82 50.59 51.91 ΣIMP (% IN) 0.38 0.37 0.30 -
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Name Zero 1 m/25° C. 3 m/25° C. Appearance Almost colorless Almost colorless N/A solution solution pH 8.39 8.43 N/A Color <BY7 <BY7 N/A Clarity <I <I N/A PXD (mg/ml) 25.70 25.33 N/A ΣIMP (% IN) 0.22 1.43 N/A -
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Composition Propyl- Argi- ene Cyste- Citric Steam PXD nine Glycol ine acid sterili- mg/ml mg/ml mg/ml mg/ml mg/ml zation Example 20 25 40 50 2 1 Without Example 21 25 40 50 2 1 121° C./ 15 min Example 22 25 30* 50 2 — Without Example 23 25 30* 50 2 — 121° C./ 15 min Samples were prepared in an atmosphere of nitrogen -
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Name Zero 1 m/25° C. 2 m/25° C. 3 m/25° C. Appearance Colorless Colorless Colorless Colorless solution solution solution solution pH 8.99 9.04 9.01 8.97 Color <BY9 <BY9 <BY9 <BY9 Clarity <I <I <I <I PXD (mg/ml) 24.93 24.67 24.97 24.62 ΣIMP (% IN) 0.21 0.22 0.24 0.22 -
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Name Zero 1 m/25° C. 2 m/25° C. 3 m/25° C. Appearance Colorless Colorless Colorless Colorless solution solution solution solution pH 8.98 9.01 9.00 8.96 Color <BY9 <BY9 <BY9 <BY9 Clarity <I <I <I <I PXD (mg/ml) 24.81 24.59 24.75 24.96 ΣIMP (% IN) 0.20 0.24 0.25 0.29 -
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Name Zero 1 m/25° C. 2 m/25° C. 3 m/25° C. Appearance Colorless Colorless Colorless Colorless solution solution solution solution pH 8.94 8.91 8.95 8.97 Color <BY9 <BY9 <BY9 <BY9 Clarity <I <I <I <I PXD (mg/ml) 24.80 24.34 25.05 25.02 ΣIMP (% IN) 0.24 0.25 0.24 0.29 -
-
Name Zero 1 m/25° C. 2 m/25° C. 3 m/25° C. Appearance Colorless Colorless Colorless Colorless solution solution solution solution pH 8.92 8.89 8.95 8.94 Color <BY9 <BY9 <BY9 <BY9 Clarity <I <I <I <I PXD (mg/ml) 24.73 25.01 24.94 24.99 ΣIMP (% IN) 0.29 0.28 0.29 0.30
Claims (15)
1. A liquid pharmaceutical composition suitable for parenteral administration comprising:
a. pemetrexed diacid;
b. at least one organic amine;
c. at least one antioxidant;
d. 10-200 mg/ml of propylene glycol, and
e. one or more parenteral solvents,
wherein the preparation thereof is conducted in an atmosphere of inert gas and wherein the organic amine(s) is present in an amount sufficient to reach a pH of the composition in the range from 8.3 to 9.1.
2. The composition according to claim 1 , wherein the antioxidant is a monothiol compound.
3. The composition according to claim 1 , wherein the antioxidant is L-cysteine.
4. The composition according to claim 3 , wherein L-cysteine is present in a concentration of 0.5-4 mg/ml.
5. The composition according to claim 1 , wherein the concentration of propylene glycol is in the range of 20-50 mg/ml.
6. The composition according to claim 1 , wherein the parenteralsolvent is selected from: ethanol, isopropanol, dimethylsulfoxide, dimethylformamide, dimethylacetamide, glycerol and water (for injection) or mixtures thereof.
7. The composition according to claim 1 , wherein the parenteral solvent is water (for injection).
8. The composition according to claim 1 , wherein the organic amine is arginine.
9. The composition according to claim 1 , wherein arginine is present in at least 2.5 equivalents (mole/mole) with respect to pemetrexed diacid.
10. The composition according to claim 1 comprising optionally at least one chelating agent.
11. The composition according to claim 10 , wherein the chelating agent is citric acid.
12. The composition according to claim 1 , wherein the pemetrexed diacid concentration is 25-50 mg/ml.
13. A process for preparing the composition according to claim 1 comprising dissolving the organic amine(s), pemetrexed diacid, the antioxidant(s), optionally the chelating agent(s) and propylene glycol in the solvent(s), making up the volume using water (for injection), filtrating and filling the glass vials.
14. The process according to claim 13 comprising the step of terminal sterilization.
15. The composition according to claim 1 for use in the treatment of malignant pleural mesothelioma and non-small cell lung cancer.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/990,035 US10188655B2 (en) | 2014-10-16 | 2018-05-25 | Liquid pharmaceutical composition comprising pemetrexed |
US16/215,029 US10272090B1 (en) | 2014-10-16 | 2018-12-10 | Liquid pharmaceutical composition comprising pemetrexed |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14189222.4 | 2014-10-16 | ||
EP14189222 | 2014-10-16 | ||
PCT/EP2015/073385 WO2015193517A2 (en) | 2014-10-16 | 2015-10-09 | Liquid pharmaceutical composition comprising pemetrexed |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2015/073385 A-371-Of-International WO2015193517A2 (en) | 2014-10-16 | 2015-10-09 | Liquid pharmaceutical composition comprising pemetrexed |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/990,035 Continuation US10188655B2 (en) | 2014-10-16 | 2018-05-25 | Liquid pharmaceutical composition comprising pemetrexed |
Publications (1)
Publication Number | Publication Date |
---|---|
US20180235969A1 true US20180235969A1 (en) | 2018-08-23 |
Family
ID=51844505
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/518,201 Abandoned US20180235969A1 (en) | 2014-10-16 | 2015-10-09 | Liquid pharmaceutical composition comprising pemetrexed |
US15/990,035 Active US10188655B2 (en) | 2014-10-16 | 2018-05-25 | Liquid pharmaceutical composition comprising pemetrexed |
US16/215,029 Active US10272090B1 (en) | 2014-10-16 | 2018-12-10 | Liquid pharmaceutical composition comprising pemetrexed |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/990,035 Active US10188655B2 (en) | 2014-10-16 | 2018-05-25 | Liquid pharmaceutical composition comprising pemetrexed |
US16/215,029 Active US10272090B1 (en) | 2014-10-16 | 2018-12-10 | Liquid pharmaceutical composition comprising pemetrexed |
Country Status (12)
Country | Link |
---|---|
US (3) | US20180235969A1 (en) |
EP (1) | EP3206666B1 (en) |
EA (1) | EA034559B1 (en) |
ES (1) | ES2775582T3 (en) |
HR (1) | HRP20200387T1 (en) |
HU (1) | HUE048357T2 (en) |
LT (1) | LT3206666T (en) |
PL (1) | PL3206666T3 (en) |
PT (1) | PT3206666T (en) |
RS (1) | RS60183B1 (en) |
SI (1) | SI3206666T1 (en) |
WO (1) | WO2015193517A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020222151A1 (en) * | 2019-05-01 | 2020-11-05 | Intas Pharmaceuticals Ltd. | A stable, ready to use aqueous pharmaceutical composition of pemetrexed |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3014755C (en) * | 2016-02-19 | 2023-11-14 | Eagle Pharmaceuticals, Inc. | Stable pemetrexed formulations comprising propylene glycol |
US20170239250A1 (en) | 2016-02-19 | 2017-08-24 | Eagle Pharmaceuticals, Inc. | Pemetrexed formulations |
JP6854710B2 (en) * | 2017-06-14 | 2021-04-07 | 日本化薬株式会社 | Injectable solution formulation containing pemetrexed |
JP2019094284A (en) * | 2017-11-21 | 2019-06-20 | 日本化薬株式会社 | Injection solution formulation containing pemetrexed |
JP7282065B2 (en) * | 2020-10-05 | 2023-05-26 | イーグル ファーマシューティカルズ, インコーポレイテッド | Pemetrexed preparation |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL96531A (en) | 1989-12-11 | 1995-08-31 | Univ Princeton | N-(disubstituted-1h-pyrrolo [2,3-d] pyrimidin-3-ylacyl)-glutamic acid derivatives their preparation and pharmaceutical compositions containing them |
SK10982002A3 (en) | 2000-02-04 | 2003-03-04 | Eli Lilly And Company | Pharmaceutical composition comprising pemetrexed together with monothioglycerol L-cystein or thioglycolic acid |
US6686365B2 (en) * | 2000-02-04 | 2004-02-03 | Eli Lilly And Company | Pharmaceutical composition |
CN101081301A (en) * | 2006-05-29 | 2007-12-05 | 海南天源康泽医药科技有限公司 | Medicinal composition containing pemetrexed |
CN100522173C (en) | 2006-07-28 | 2009-08-05 | 南京依诺维医药科技有限公司 | Pharmaceutical composition containing pemetrexed |
WO2012015810A2 (en) * | 2010-07-28 | 2012-02-02 | Eagle Pharmaceuticals, Inc. | Pharmaceutical compositions containing pemetrexed having extended storage stability |
KR101069128B1 (en) | 2011-03-10 | 2011-09-30 | 건일제약 주식회사 | Process for preparing pharmaceutical formulation in form of antioxidant-free solution for injection comprising pemetrexed or its salt |
IN2012DE00912A (en) | 2012-03-27 | 2015-09-11 | Fresenius Kabi Oncology Ltd | |
EP2666463A1 (en) * | 2012-05-21 | 2013-11-27 | Synthon BV | Stabilized liquid composition comprising pemetrexed |
SI2854768T1 (en) * | 2012-05-30 | 2017-08-31 | Fresenius Kabi Oncology Limited | Pharmaceutical compositions of pemetrexed |
DE102012010774A1 (en) | 2012-05-31 | 2013-12-05 | Stada Arzneimittel Ag | Pharmaceutical pemetrexed solution |
EP3008064B1 (en) | 2013-06-14 | 2017-11-22 | Synthon B.V. | Stable pemetrexed arginine salt and compositions comprising it |
-
2015
- 2015-10-09 US US15/518,201 patent/US20180235969A1/en not_active Abandoned
- 2015-10-09 HU HUE15778927A patent/HUE048357T2/en unknown
- 2015-10-09 EP EP15778927.2A patent/EP3206666B1/en active Active
- 2015-10-09 ES ES15778927T patent/ES2775582T3/en active Active
- 2015-10-09 RS RS20200261A patent/RS60183B1/en unknown
- 2015-10-09 EA EA201790788A patent/EA034559B1/en not_active IP Right Cessation
- 2015-10-09 LT LTEP15778927.2T patent/LT3206666T/en unknown
- 2015-10-09 SI SI201531124T patent/SI3206666T1/en unknown
- 2015-10-09 WO PCT/EP2015/073385 patent/WO2015193517A2/en active Application Filing
- 2015-10-09 PL PL15778927T patent/PL3206666T3/en unknown
- 2015-10-09 PT PT157789272T patent/PT3206666T/en unknown
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2018
- 2018-05-25 US US15/990,035 patent/US10188655B2/en active Active
- 2018-12-10 US US16/215,029 patent/US10272090B1/en active Active
-
2020
- 2020-03-09 HR HRP20200387TT patent/HRP20200387T1/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020222151A1 (en) * | 2019-05-01 | 2020-11-05 | Intas Pharmaceuticals Ltd. | A stable, ready to use aqueous pharmaceutical composition of pemetrexed |
Also Published As
Publication number | Publication date |
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US20190105325A1 (en) | 2019-04-11 |
EA034559B1 (en) | 2020-02-20 |
WO2015193517A3 (en) | 2016-03-10 |
EP3206666A2 (en) | 2017-08-23 |
ES2775582T3 (en) | 2020-07-27 |
HUE048357T2 (en) | 2020-08-28 |
US10272090B1 (en) | 2019-04-30 |
WO2015193517A2 (en) | 2015-12-23 |
SI3206666T1 (en) | 2020-04-30 |
HRP20200387T1 (en) | 2020-06-12 |
PT3206666T (en) | 2020-03-11 |
PL3206666T3 (en) | 2020-09-21 |
US10188655B2 (en) | 2019-01-29 |
LT3206666T (en) | 2020-03-10 |
EA201790788A1 (en) | 2017-08-31 |
RS60183B1 (en) | 2020-06-30 |
US20180271872A1 (en) | 2018-09-27 |
EP3206666B1 (en) | 2019-12-11 |
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