WO2016059238A1 - Pemetrexed formulations - Google Patents
Pemetrexed formulations Download PDFInfo
- Publication number
- WO2016059238A1 WO2016059238A1 PCT/EP2015/074065 EP2015074065W WO2016059238A1 WO 2016059238 A1 WO2016059238 A1 WO 2016059238A1 EP 2015074065 W EP2015074065 W EP 2015074065W WO 2016059238 A1 WO2016059238 A1 WO 2016059238A1
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- WO
- WIPO (PCT)
- Prior art keywords
- pemetrexed
- pharmaceutical composition
- less
- acid
- composition according
- Prior art date
Links
- 229960005079 pemetrexed Drugs 0.000 title claims abstract description 176
- 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 title claims abstract description 160
- 239000000203 mixture Substances 0.000 title claims description 98
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 126
- 238000000034 method Methods 0.000 claims abstract description 47
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 207
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 126
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 80
- 238000003860 storage Methods 0.000 claims description 66
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 65
- 229940035504 Tromethamine Drugs 0.000 claims description 64
- 229960000281 trometamol Drugs 0.000 claims description 64
- 239000000243 solution Substances 0.000 claims description 58
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 53
- 239000012141 concentrate Substances 0.000 claims description 47
- -1 pemetrexed tromethamine salt Chemical class 0.000 claims description 47
- 239000011780 sodium chloride Substances 0.000 claims description 47
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 44
- 239000002253 acid Substances 0.000 claims description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 33
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 31
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 31
- 239000000594 mannitol Substances 0.000 claims description 31
- 235000010355 mannitol Nutrition 0.000 claims description 31
- 239000008215 water for injection Substances 0.000 claims description 31
- 239000002585 base Substances 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 229960003349 pemetrexed disodium Drugs 0.000 claims description 25
- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 claims description 25
- 239000003002 pH adjusting agent Substances 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 23
- OFOBLEOULBTSOW-UHFFFAOYSA-N malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 239000000843 powder Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 16
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 15
- 239000003708 ampul Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000008121 dextrose Substances 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 12
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 12
- 235000010755 mineral Nutrition 0.000 claims description 12
- 239000011707 mineral Substances 0.000 claims description 12
- 238000001802 infusion Methods 0.000 claims description 11
- 239000011975 tartaric acid Substances 0.000 claims description 11
- 229960001367 tartaric acid Drugs 0.000 claims description 11
- 235000002906 tartaric acid Nutrition 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 8
- 239000001103 potassium chloride Substances 0.000 claims description 8
- 235000011164 potassium chloride Nutrition 0.000 claims description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 7
- 230000001082 cryoprotectant Effects 0.000 claims description 7
- 239000002577 cryoprotective agent Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
- 235000011187 glycerol Nutrition 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical group [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 6
- 229920005557 bromobutyl Polymers 0.000 claims description 6
- 239000011778 trisodium citrate Substances 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- 239000004475 Arginine Substances 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 229920005556 chlorobutyl Polymers 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 229940099690 malic acid Drugs 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 229940033654 pemetrexed disodium heptahydrate Drugs 0.000 claims description 4
- 239000000546 pharmaceutic aid Substances 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- 229940095064 tartrate Drugs 0.000 claims description 4
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 claims description 3
- 108009000071 Non-small cell lung cancer Proteins 0.000 claims description 3
- 229960004316 cisplatin Drugs 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- 239000008176 lyophilized powder Substances 0.000 claims description 3
- 201000005282 malignant pleural mesothelioma Diseases 0.000 claims description 3
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 claims description 3
- KLRNMDPLGYEZCJ-AOWDYJTJSA-N (2S,3R)-butane-1,2,3,4-tetrol;(2R,3R,4R,5S)-hexane-1,2,3,4,5,6-hexol Chemical compound OC[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO KLRNMDPLGYEZCJ-AOWDYJTJSA-N 0.000 claims description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N 2,2-bis(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate dihydrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- PKIDNTKRVKSLDB-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;hydrate Chemical compound O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PKIDNTKRVKSLDB-UHFFFAOYSA-K 0.000 claims description 2
- 241000237519 Bivalvia Species 0.000 claims 1
- 235000020639 clam Nutrition 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 235000008504 concentrate Nutrition 0.000 description 39
- 239000012535 impurity Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 12
- 239000003963 antioxidant agent Substances 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 235000014666 liquid concentrate Nutrition 0.000 description 8
- 230000003078 antioxidant Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 229920001971 elastomer Polymers 0.000 description 4
- 239000011261 inert gas Substances 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000006193 liquid solution Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- PJUIMOJAAPLTRJ-GSVOUGTGSA-N (R)-monothioglycerol Chemical compound OC[C@@H](O)CS PJUIMOJAAPLTRJ-GSVOUGTGSA-N 0.000 description 2
- 229960004308 ACETYLCYSTEINE Drugs 0.000 description 2
- 229940110282 Alimta Drugs 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 229940097362 Cyclodextrins Drugs 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 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
- CWERGRDVMFNCDR-UHFFFAOYSA-N Thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000004059 degradation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- NYDXNILOWQXUOF-FFXKMJQXSA-L disodium;(2R)-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)N[C@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-FFXKMJQXSA-L 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003638 reducing agent Substances 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- IZFHEQBZOYJLPK-SSDOTTSWSA-N (R)-dihydrolipoic acid Chemical compound OC(=O)CCCC[C@@H](S)CCS IZFHEQBZOYJLPK-SSDOTTSWSA-N 0.000 description 1
- 229960002433 Cysteine Drugs 0.000 description 1
- 229960000304 Folic Acid Drugs 0.000 description 1
- 229940102223 Injectable Solution Drugs 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N Sodium sulfide Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229920002892 amber Polymers 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000003292 diminished Effects 0.000 description 1
- ZZRCKSSPGJOTEE-UHFFFAOYSA-L disodium;carbamoyl phosphate Chemical compound [Na+].[Na+].NC(=O)OP([O-])([O-])=O ZZRCKSSPGJOTEE-UHFFFAOYSA-L 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M sodium;2-sulfanylethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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 TOILET 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
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET 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
Abstract
Disclosed are pharmaceutical formulations of pemetrexed or pemetrexed salts and processes for their preparation.
Description
PEMETREXED FORMULATIONS
FIELD OF THE INVENTION The present invention is directed to formulations of pemetrexed. In particular, the invention relates to stable formulations of pemetrexed and its salts. The invention is particularly useful for the preparation of liquid formulations, and preferably aqueous formulations of pemetrexed and its salts. The formulations may be prepared as solid formulations, or as liquid formulations in the form of a liquid concentrate or as a ready-to- use (RTU) liquid formulation.
BACKGROUND OF THE INVENTION
Pemetrexed, in its diacid form has the following formula:
Pemetrexed or pemetrexed disodium is currently not commercially available as a ready to use formulation. The preparation of a solution form of pemetrexed or its salts is particularly challenging because of the propensity of pemetrexed and it salts to degrade. This problem is especially exacerbated when pemetrexed or its salts are present in
solution, as its degradation or discolouration by oxidation or hydrolysis occurs much more readily. The degradation or storage of pemetrexed or pemetrexed salts such as pemetrexed disodium can lead to a significant visible colour change. Typically, the pure product is colourless, and upon storage of the solution, the product can change in colour from yellow to green-yellow. Such a colour change is undesirable and may lead to acceptance problems for the clinician or patient. When present in solution,
pemetrexed/pemetrexed disodium typically develops a yellow or green-yellow
colouration. For example, solutions prepared by reconstitution of the lyophilised product are also prone to discolouration upon storage. Even in the absence of water, upon storage, pemetrexed/pemetrexed disodium API in solid form is also prone to oxidation and readily develops a yellow/green discolouration due to oxidation. Over time, the increased concentration of degradation products leads to a diminished activity and quality of the product.
Methods of stabilizing pemetrexed and pemetrexed salts are disclosed in the art.
EP2666463 discloses the use of a monothioglycerol as an antioxidant together with a co-stabilizer such as non-ionogenic water soluble polymer and /or an edetate.
WO2001056575 discloses the use of thioglycolic acid and at least one antioxidant selected from monothioglycerol, L-cysteine and thioglycolic acid.
WO2013144814 discloses the use of controlled oxygen and antimicrobial agents. The use of acetyl cysteine and sodium 2-mercaptoethanesulfonate is proposed in
WO2013178214.
Use of an organic amine, which is free from sodium ions and an inert gas is disclosed in WO2013179248.
Stability enhancing adjuvants such as cyclodextrins are proposed in WO2013179310. WO2012121523 discloses the use of antioxidant free solution, which involves controlling the dissolved oxygen concentration, and a closed system with an upper limit of oxygen partial pressure.
According to WO2012015810, antioxidants such as lipoic acid, dihydrolipoic acid, methionine, and a chelating agent can be used.
WO2013165130 discloses the use of sodium sulfide and sodium sulfite as stabilising agents.
WO2014084651 discloses an injectable solution containing both an acetylcysteine (antioxidant) and citrate salt (as buffer). WO2014122460 proposes the use of pemetrexed or pemetrexed salt complexed with a co-former such as a carbohydate.
The prior art attempts to stabilise pemetrexed do not provide universally applicable methods to prepare stable formulations of pemetrexed and its salts. For example, reducing agents such as sodium sulfite, and cyclodextrins are not particularly desirable. None of these prior art disclosures provide a satisfactory solution to the problem of providing a simple formulation of pemetrexed or pemetrexed salts.
There is therefore a need to provide further stable formulations of pemetrexed or pemetrexed salts. It is therefore an object of the present invention to provide formulations of pemetrexed or its salts, that are stable and which can be easily manufactured without the need for special excipients.
SUMMARY OF THE INVENTION
The present invention provides stable pemetrexed formulations. Thus, in one aspect of the present invention, there is provided a pharmaceutical formulation comprising:
(a) at least one of the following:
(i) pemetrexed disodium,
(ii) pemetrexed diacid and sodium hydroxide,
(iii) pemetrexed tromethamine salt, or
(iv) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein when (a) is (iii) or (iv), the composition further comprises a sugar alcohol.
The applicant has unexpectedly found that citric acid or a citrate such as sodium citrate e.g. trisodium citrate) can stabilise formulations of pemetrexed diacid, pemetrexed disodium and pemetrexed tromethamine salt. In particular, it has been found that citric acid alone is sufficient to stabilise the formulations, especially formulations containing
tromethamine or pemetrexed tromethamine salt, thereby avoiding the need to use the expensive, and potentially undesirable, stabilising agents proposed in prior art compositions. A further aspect of the present invention provides a process for preparing a
pharmaceutical composition as defined above, wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide or tromethamine
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine.
Tromethamine is a particularly preferred base. A particularly preferred combination of acid and base for use to adjust the pH is hydrochloric acid and tromethamine. Other suitable acids include malic acid. The pH adjusting agent may also be a salt of a mineral or organic acid. Suitable such salts include: acetate, citrate, malonate, tartrate, maleate and phosphate. The invention further provides a pharmaceutical composition obtainable by such a process.
The compositions of the present invention, when in the form of a liquid concentration, preferably an aqueous concentrate for dilution or a powder for reconstitution, may be diluted with water for injection or reconstituted in water for injection to provide an aqueous solution for injection or infusion. The dilution or reconstitution may also be done in saline for injection, preferably 0.9% aqueous sodium chloride (9 mg sodium chloride/ml water for injection) for injection. Preferably the dilution of the liquid or aqueous concentrate compositions, or the reconstitution of the powder is done in saline for injection, preferably 0.9% (9 mg/ml) for injection. The pharmaceutical compositions of the present invention particularly when in the form of an aqueous concentrate or a powder can be packaged into a vial or ampoule, which is preferably sealed with an inert gas such as nitrogen to provide a convenient product with good storage stability. A
preferred pharmaceutical composition of the present invention is in the form of liquid concentrate, preferably an aqueous concentrate, for dilution. Preferably such a composition is packaged into a vial or ampoule, which is sealed with an inert gas such as nitrogen to provide a convenient, ready-to-dilute product having good storage stability.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term De-Glu pemetrexed refers the following compound, which is a potential impurity of pemetrexed:
As used herein the term pemetrexed diethylester refers the following compound, which is a potential impurity of pemetrexed:
As used herein the term L-Glu pemetrexed refers to pemetrexed wherein the glutamic acid substituent has L-configuration, and which is a potential impurity of pemetrexed.
As used herein the term D-pemetrexed refers to the following compound, which is a potential impurity of pemetrexed (enantiomeric impurity):
The provision of stable pemetrexed formulations, particularly in the form of solutions (e.g. concentrate for dilution or ready-to-use aqueous solutions) presents a difficult challenge due to the tendency of pemetrexed and its salts to oxidise and/or hydrolyse and/or discolour. A particular concern is the speed at which aqueous pharmaceutical compositions of pemetrexed or its salts can discolour, including those formed by reconstitution of the marketed Alimta® lyophilised product, forming a yellow to green- yellow solution, which although acceptable from a regulatory view, is not desirable from a physician's or patient's perspective. Previous attempts to address the stability problem typically involve the use of a number of special antioxidants, complexing agents, reducing agents and other additives. However, not all of these are suitable for inclusion into concentrates or ready-to-use solutions. Moreover, many of the additives are expensive and their presence in infusion formulations are not especially desirable. In contrast, the stable formulations of the present invention contain simple and relatively inexpensive excipients which are well-tolerated and which do not require special manufacturing methods. In particular, the liquid formulations of the present invention provide a further advantage in that they do not require labour- and energy-intensive processes such as lyophilisation. Moreover, the ready-to-use formulations of the present invention do not require reconstitution, thus making these formulations particularly easy to use. For example, the ready-to-use formulations are liquid formulations, which may comprise an aqueous concentrate, which can be used without reconstitution (such as required in lyophilized products), but can be simply diluted with saline prior to use.
Accordingly, in a first aspect, there is provided a pharmaceutical formulation comprising: (a) at least one of the following:
(i) pemetrexed disodium,
(ii) pemetrexed diacid and sodium hydroxide,
(iii) pemetrexed tromethamine salt, or
(iv) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein when (a) is (iii) or (iv), the composition further comprises a sugar alcohol.
Preferably, the pharmaceutical formulation comprises:
(a) at least one of the following:
(i) pemetrexed tromethamine salt, or
(ii) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate, and
(c) a sugar alcohol.
More preferably, the pharmaceutical formulation comprises a combination of pemetrexed diacid and tromethamine, citric acid or a citrate and a sugar alcohol. Preferably, the weight ratio of tromethamine to pemetrexed diacid is from 0.6 to 1 .2, preferably 0.7 to 1 and more preferably 0.8 to 0.9. The composition may be in the form of a lyophilized powder, or a liquid concentrate or liquid solution. Preferably, the composition is an aqueous concentrate or an aqueous solution. In preferred embodiments, the compositions are in the form of a liquid concentrate or a liquid ready-to-use solution, more preferably the compositions are in the form of an aqueous concentrate or an aqueous ready-to-use solution. Preferably the compositions of any aspect or embodiment of the present invention are in the form of a liquid, preferably an aqueous concentrate. Preferably, the liquid compositions, more preferably an aqueous concentrate, is ready-to-use in that it does not require
reconstitution, and can simply be diluted with water before use. The liquid or aqueous concentrate may be diluted with saline (e.g. 0.9%, i.e. 9 mg/ml) for injection.
In one embodiment, the composition contains: (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide, or a mixture thereof. Preferably, the composition contains either: (i) pemetrexed disodium or (ii) pemetrexed diacid and sodium hydroxide. Preferably, the composition contains a combination of pemetrexed diacid with sodium hydroxide. Preferably, the composition is a liquid concentrate or a liquid ready-to-use solution, and more preferably, an aqueous concentrate or a ready-to- use aqueous solution.
According to one embodiment, there is provided a pharmaceutical composition comprising:
(a) (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
(b) citric acid or a citrate,
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), an antioxidant and water for injection or infusion (preferably wherein the water is water for injection).
Suitable tonicity adjusting agents are selected from one or more of: a sugar (such as dextrose), arginine, glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride, preferably potassium chloride or sodium chloride, and more preferably sodium chloride. Preferably, suitable tonicity adjusting agents are selected from one or more of: a sugar (such as dextrose), glycerin, a sugar alcohol (such as mannitol) or sodium chloride, with sodium chloride being particularly preferred.
Suitable pH adjusting agents are an acid and/or base. Preferred acids include mineral acids (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine. Preferably, the pH adjusting agent comprises hydrochloric acid and/or sodium hydroxide, preferably both. Alternatively, the base is preferably tromethamine. A preferred acid and base combination for the pH adjusting agent may be tromethamine and citric acid, or tromethamine and hydrochloric acid. Particularly preferred is tromethamine and hydrochloric acid.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising:
- one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
- citric acid or a citrate
- a tonicity adjusting agent
- one or more pH adjusting agents and
- water for injection.
Preferably, the pharmaceutical composition comprises a combination of pemetrexed diacid and sodium hydroxide.
Another embodiment of the present invention provides a pharmaceutical composition comprising:
- one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
- citric acid or a citrate
- sodium chloride
- one or more pH adjusting agents, preferably selected from sodium hydroxide and/or hydrochloric acid, and
- water for injection
in the form of a concentrate or a ready-to-use solution. Preferably, the pharmaceutical composition comprises a combination of pemetrexed diacid and sodium hydroxide, citric acid or a citrate, sodium chloride, and one or more pH adjusting agents, preferably selected from sodium hydroxide and/or hydrochloric acid, and water for injection.
Preferably in these embodiments of the present invention the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25.
It will be appreciated that depending on the final formulation and process, the
pemetrexed diacid may react with the sodium hydroxide to form the disodium salt of pemetrexed, i.e. a combination of pemetrexed diacid with sodium hydroxide may comprise pemetrexed disodium. Similarly, pemetrexed diacid may react with the tromethamine to form a tromethamine salt of pemetrexed, i.e. a combination of pemetrexed diacid with tromethamine may comprise pemetrexed tromethamine salt. The weight ratios and concentrations of pemetrexed used throughout refer to the weight ratios and concentrations relative to pemetrexed diacid.
Preferably, when the pharmaceutical composition is in the form of an aqueous solution, the concentration of citric acid or citrate (based on citric acid) in the solution may be from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml or about 0.75 to about 1 .25 mg/ml, and most preferably about 1 mg/ml.
It will be appreciated that depending on the final formulation and process, the citric acid may react with the sodium hydroxide to form the sodium citrate (e.g. trisodium citrate). The weight ratios and concentrations of citric acid or citrate throughout refer to the weight ratios and concentrations relative to citric acid.
Preferably, the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml. In preferred embodiments of the present invention the pharmaceutical composition is in the form of an aqueous concentrate. The aqueous concentrate may be packaged into a pharmaceutical product, preferably the pharmaceutical product is packaged in a stoppered vial. In use, the aqueous concentrate may be diluted with saline (e.g. 0.9% saline - i.e. 0.9 mg/ml). The stopper can be a bromobutyl or chlorobutyl stopper.
In another embodiment of the present invention, the pharmaceutical composition comprises pemetrexed tromethamine salt, or pemetrexed diacid and tromethamine, or a mixture thereof. Preferably, the composition contains either pemetrexed tromethamine salt, or pemetrexed diacid and tromethamine,. More particularly, the composition contains a combination of pemetrexed diacid and tromethamine. In these embodiments, the composition may be in the form of a powder for reconstitution, a liquid concentrate or a liquid ready-to-use solution or an aqueous concentrate or a ready-to-use aqueous solution. Preferably, the composition may be in the form of a powder for reconstitution, such as a lyophilisate, or in the form of a liquid concentrate, preferably an aqueous concentrate. Most preferably, the composition is in the form of an aqueous concentrate.
A further embodiment of the present invention provides a pharmaceutical composition comprising:
(a) (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and
tromethamine,
(b) citric acid or a citrate,
(c) a sugar alcohol
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), a cryoprotectant and
water for injection or infusion. Preferably the pharmaceutical composition comprises a combination of pemetrexed diacid and tromethamine. Suitable sugar alcohols include those selected from the group consisting of mannitol, sorbitol, and pentaerythritol, preferably mannitol. Suitable tonicity adjusting agent for use in formulations is selected from one or more of: a sugar (such as dextrose), arginine, glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride. Alternatively, the tonicity adjusting agent for use in the formulations is selected from one or more of: a sugar (such as dextrose), glycerin, a sugar alcohol (such as mannitol), or sodium chloride. More preferably, the tonicity adjusting agents are potassium chloride or sodium chloride, and most preferably sodium chloride.
Preferred pH adjusting agents for use in compositions containing (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine, are acids and/or bases. Preferably, the acid is selected from the group consisting of mineral acids (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid. Preferred bases are selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine. Preferred combinations of pH adjusting agent comprises sodium hydroxide and/or hydrochloric acid, preferably both or tromethamine and/or hydrochloric acid, preferably both.
In preferred embodiments, the composition containing at least one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and/or tromethamine, is in the form of a lyophilisate for reconstitution, and wherein the cryoprotectant is selected from the group consisting of sucrose, dextrose, mannitol, glucose, and preferably is mannitol.
Another embodiment of the present invention provides a pharmaceutical composition comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and tromethamine,
- citric acid or a citrate
- a tonicity adjusting agent
- a sugar alcohol
- one or more pH adjusting agents and optionally
- water for injection.
A further embodiment provides a pharmaceutical composition comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and tromethamine,
- citric acid or a citrate
- a sugar alcohol, preferably mannitol
- pH adjusting agents, preferably selected from a combination of either: sodium hydroxide and hydrochloric acid; or tromethamine and hydrochloric acid, and optionally
- sodium chloride
in the form of a powder for reconstitution, preferably in the form of a lyophilisate.
Where the compositions contain (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine, the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25. The liquid or aqueous solution formulations, preferably aqueous solution formulations, of the present invention containing (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine preferably have a concentration of citric acid or citrate (based on citric acid) in the solution of from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
The liquid or aqueous solution formulations, preferably aqueous solution formulations, of the present invention containing (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine preferably have a concentration of pemetrexed acid in the solution of from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
Preferably these aqueous solutions are in the form of an aqueous concentrate.
The citric acid employed in the compositions of the invention may preferably be anhydrous. The citrate component may be sodium citrate, preferably trisodium citrate or trisodium citrate dihydrate.
The pemetrexed disodium may preferably be in the form of the pemetrexed disodium heptahydrate.
According to a further aspect of the present invention, there is provided a process for preparing a pharmaceutical composition comprising
(a) at least one of the following:
(i) pemetrexed disodium,
(ii) pemetrexed diacid and sodium hydroxide,
(iii) pemetrexed tromethamine salt, or
(iv) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide or tromethamine
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally .
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine. Alternatively, the acid may also be selected from the group consisting of a mineral acid (preferably hydrochloric acid, acetic acid, citric acid, malonic acid, tartaric acid, or malic acid), or a salt of a mineral acid, such as acetate, citrate, malonate, tartrate, maleate or phosphate, and more preferably wherein the acid is hydrochloric acid
The step (1 ) of dissolving (A), (B), (C) and (D) can be carried out in any suitable order which enables the preparation of a solution of the four components. For example, the
pemetrexed diacid (A) may be added to an aqueous solution containing at least a portion of component (B). Then the remaining (B), along with (C) and, where necessary, (D) can be added. Preferably, pemetrexed diacid is added to an aqueous solution containing (B), (C) and (D). Thus, preferably pemetrexed diacid is added to a solution of citric acid, mannitol and tromethamine.
In any embodiment of the process, the dissolution of pemetrexed is preferably carried out in an inert atmosphere. Preferably the inert atmosphere is one which minimizes the exposure of the pemetrexed to oxygen. More preferably, the dissolution of pemetrexed is carried out under a nitrogen atmosphere. In addition, it is also preferred that operations involving the handling of pemetrexed, such as weighing, mixing, filtration, filling (e.g. into vials or ampoules) and stoppering, are carried out under such an inert atmosphere, i.e. preferably under a nitrogen atmosphere.
Preferably, the pH is adjusted to between about 6.0 to about 9.0, preferably about 6.0 to about 8.5, more preferably about 6.5 to about 8.0 and most preferably about 6.6 to about 7.8.
The order of dissolution is preferably (A), (B), (C) and where necessary, (D).
Alternatively, the order of dissolution may be (B), (A), and then, in either order, (C) or (D) (when present). Where the pharmaceutical composition is an aqueous concentrate or an aqueous ready- to-use solution, the process may further comprise a step of adding water to obtain the final volume/weight.
Where the pharmaceutical composition is a powder for reconstitution, the process may further comprise a step of removal of the water. For example, where the pharmaceutical composition is a lyophilizate for reconstitution, the process typically comprises: optionally adding a cryoprotectant (preferably selected from the group consisting of: sucrose, dextrose, mannitol, glucose, and more preferably mannitol) prior to removal of the water
by lyophilization.
The invention further provides a pharmaceutical composition obtainable by any of the above described processes, as well as a pharmaceutical composition prepared by dilution or reconstitution of a liquid concentrate, an aqueous concentrate or a powder for reconstitution, more preferably, an aqueous concentrate or powder for reconstitution. A preferred pharmaceutical composition is one prepared by dilution of an aqueous concentrate of any embodiment or aspect of the present invention. Preferably, the dilution liquid is saline (e.g. 0.9%, i.e. 0.9 mg/ml).
Further provided is a pharmaceutical product comprising a pharmaceutical composition as defined herein packaged in a vial or ampoule, preferably under an inert gas, such as nitrogen. The pharmaceutical compositions and products of the present invention are stable, and preferably show no significant colour change, or in some cases may show no visible colour change, upon storage:
- at 2-8eC, for 3 months or
- at 2-8eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably show no significant colour change, or in some cases may show no visible colour change, upon storage:
- at 25eC, for 3 months, or
- at 25eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably show no significant colour change, or in some cases may show no visible colour change, upon storage:
- at 40eC, for 3 months, or
- at 40eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and
more preferably 99.5-100% relative to the initial amount before storage, following storage:
- at 2-8eC, for 3 months, or
- at 2-8eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage:
- at 25eC, for 3 months, or
- at 25eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage:
- at 40eC, for 3 months, or
- at 40eC for 6 months. Whilst the invention has been described herein with reference to specific and preferred embodiments, it will be appreciated that many variations, combinations, equivalents and modifications can be made while remaining within the spirit and scope of the invention. The invention is therefore not limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.
Examples of compositions according to the invention are set out below: Example 1
Osmolality adjusted with NaCI
Example 2
Example 3
* present in headspace of the vials
Example 4 - Preparation of pemetrexed concentrate for solution for infusion
A pemetrexed concentrate for solution for infusion containing: a combination of pemetrexed diacid, tromethamine, citric acid, mannitol and water for injection is prepared as follows (the process is carried out at 20 ± 5°C): 1 ) A portion (e.g. 25-90%, preferably 50-80%, more preferably 65-80%, or about
75%) of the total amount of water for injection is added to a vessel. The water for injection is preferably previously purged with nitrogen for a minimum of 10 minutes.
2) Tromethamine is dissolved into the water to form a solution 3) Citric acid anhydrous is dissolved into the Tromethamine solution
4) Mannitol is then dissolved into the tromethamine/citric acid solution
The following steps 4)-7) are preferably carried out in an inert atmosphere of nitrogen (target: 02≤ 1.5%; RH < 2.0), in the absence of UV light. For example, these steps may be conducted in red or yellow light. 5) Pemetrexed diacid is weighed and added to the solution of step 3) and the
solution is mixed until complete dissolution of the API
6) The pH is checked, and if necessary, adjusted to pH 6.0 to 8.5, preferably 6.5 to 8, more preferably 6.6 to 7.8, or about 7.2) using tromethamine solution (10 w/V% in water for injection) and/or 1 M hydrochloric acid solution in water for injection.
7) The solution is completed with water for injection to the final volume/final weight.
8) The solution is homogenized, filtered, filled into vials and stoppered.
Example 5 - Preparation of pemetrexed concentrate for solution for infusion
A pemetrexed concentrate for solution for infusion containing: a combination of pemetrexed diacid, tromethamine, citric acid, mannitol and water for injection is prepared as follows (the process is carried out at 20 ± 5°C):
1 ) A portion (e.g. 25-90%, preferably 50-80%, more preferably 65-80%, or about
75%) of the total amount of water for injection is added to a vessel. The water for injection is preferably previously purged with nitrogen for a minimum of 10 minutes. 2) Citric acid anhydrous and Mannitol is dissolved into the water to form a solution
3) Tromethamine is then dissolved into the Mannitol/citric acid solution
The following steps 4)-7) are preferably carried out in an inert atmosphere of nitrogen (target: 02≤ 1.5%; RH < 2.0%), in the absence of UV light. For example, these steps may be conducted in red or yellow light. 4) Pemetrexed diacid is weighed and added to the solution of step 3) and the
solution is mixed until complete dissolution of the API
5) The pH is checked, and if necessary, adjusted to pH 6.0 to 8.5, preferably 6.5 to 8, more preferably 6.6 to 7.8, or about 7.2) using tromethamine solution (10 w/V% in water for injection) and/or 1 M hydrochloric acid solution in water for injection.
6) The solution is completed with water for injection to the final volume/final weight.
7) The solution is homogenized, filtered with a 0.2 μηι sterilizing grade filter (PVDF Fluorodyne), filled into vials and stoppered.
Example 6 - Storage Stability The finished bulk solution was filled into two amber glass bottles and kept at 2-8 °C and room temperature for 168 hours. Samples were taken after 24, 48, 72, 96 and 168 hours. After storage the following parameters were tested:
Tests Requirements
Clear solution,
Description practically free from
visible particles
Color > GY5 or Y5
PH 6.6 - 7.8
Assay of active ingredient 95.0 - 105.0 %
Any unknown impurity NMT 0.2 %
Impurities / Related substances
Total impurities NMT 1.0 %
* tested in accordance with European Pharmacopoeia 8.0, 2.2.2. "Degree of Coloration of Liquids"
GY = green-yellow
Y = yellow
Tests
Impurities/related Assay substances of Any
Temperature Description Color PH active unTotal ingreknown impdient impurit urities y
Initial Conforms GY7 7.1 101.0 % < 0.1 % < 0.1 % room temp. % < 0.1 %
After 24 CoHforms GY7 7.1 99.6 % < 0. l
hours 2 - 8 °C Conforms GY7 7.1 100.0 % < 0.1 % < 0.1 % room temp. %
After 48 Conforms GY? 7.1 101.2 % < 0.1 % < 0.1 hours 2 - 8 °C Conforms GY7 7.1 100.2 % < 0.1 % < 0.1 % room temp.
After 72 Conforms GY7 7.1 100.6 % < 0.1 % < 0.1 % hours 2 - 8 °C Conforms GY7 7.1 100.5 % < 0.1 % < 0.1 % room temp.
After 96 Conforms GY7 7.1 101.2 % < 0.1 % < 0.1 % hours 2 - 8 °C Conforms GY7 7.1 100.6 % < 0.1 % < 0.1 % room temp.
After 168 Conforms GY7 7.1 101.2 % < !).1 % < 0.1 % hours 2 - 8 °C Conforms GY7 7.1 101.2 % < 0.1 % < 0.1 %
Example 7 - Stability under oxygen
After filling the filtered solution into vials, the headspace (i.e. the air in the vial between the product and the stopper) of the vials are set in the freeze-dryer to approx. 2 %, approx. 5 % and approx.10 % oxygen levels. Then the vials are stoppered by the freeze- dryer and capped with automatic capper. Headspace oxygen analyzer was measured using Lighthouse FMS-760. Then the vials are put on the different stability parameters:
Test methods and specifications:
Tests Requirements
Color* > GY5 or Y5
Assay of active ingredient 95.0 - 105.0 %
Any unknown
Impurities / Related NMT 0.2 %
impurity
substances
Total impurities NMT 1.0 %
For monitoring
Headspace oxygen**
purpose
* tested in accordance with European Pharmacopoeia 8.0, 2.2.2. "Degree of Coloration of Liquids"
** tested from filled product at initial and stability time points
GY = green-yellow
Y = yellow
Storage conditions tested:
1 ) 5°C ± 3°C, not controlled relative humidity (NC RH)
2) 25°C ± 2°C, 60 ± 5% RH
3) 40°C ± 2°C, 60 ± 5% RH
Results:
Vials having about 2% or about 5% headspace oxygen content have all results conforming to the above requirements under all 3 storage conditions after 1 month. Vials having a headspace oxygen content of about 10% conformed to the above requirements under storage conditions 1 ) and 2), but the any unknown impurity and total impurities content were at 0.4% and 1 .1 % respectively
Example 8 - Storage Stability with different stoppers
Colour changes were observed and impurity/related substances were determined in vials having chlorobutyl and bromobutyl stoppers:
Chlorobutvl rubber stopper
Container: 6R Type I vial
20 mm Datwvler FM140/0 V9025 ISAF1
Closure: chlorobutvl rubber stopper, qrev
20 mm flip-off cap (red)
Bromobutvl rubber stopper
Container: 6R Type 1 vial
20 mm Datwvler FM457/0 V9047
Closure: bromobutvl rubber stopper, FLCO, qrev
20 mm flip-off cap (dark qreen)
The vials were stored at 5 ± 3°C NC RH (i.e. uncontrolled relative humidity) ± 2°C and 60 ± 5% RH, for 3 months at upright and inverted positions. In the formulation comprising pemetrexed disodium (pemetrexed and sodium hydroxide), the stability was found to be dependent on the stopper used. In contrast all formulations comprising pemetrexed tromethamine (or pemetrexed and tromethamine) showed no colour change and met the impurity/related substances requirements independent of the stopper used.
Further aspects and embodiments of the present invention are set out in the following numbered paragraphs:
1 . A pharmaceutical formulation comprising:
(a) at least one of the following:
(i) pemetrexed disodium, or
(ii) pemetrexed diacid and sodium hydroxide,
(b) citric acid or a citrate.
2. A pharmaceutical composition according to paragraph 1 in the form of a lyophilized powder, an aqueous concentrate or an aqueous solution.
3. A pharmaceutical composition according to paragraphs 1 or 2 in the form of an aqueous concentrate or an aqueous ready-to-use solution, preferably wherein the composition is in the form of an aqueous concentrate.
4. A pharmaceutical composition according to any of paragraphs 1 to 3, wherein (a) is (i) or (ii) or a mixture thereof.
5. A pharmaceutical composition according to paragraph 4 wherein (a) is (i) or (ii).
6. A pharmaceutical composition according to any of paragraphs 1 -5 wherein the composition is an aqueous concentrate or a ready-to-use aqueous solution, preferably wherein the composition is in the form of an aqueous concentrate. 7. A pharmaceutical composition according to paragraph 6 comprising:
(a) (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
(b) citric acid or a citrate,
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), an antioxidant and water for injection or infusion.
8. A pharmaceutical composition according to paragraph 7 wherein the tonicity adjusting agent is selected from one or more of: a sugar (such as dextrose), arginine,
glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride, preferably potassium chloride or sodium chloride, and more preferably sodium chloride.
9. A pharmaceutical composition according to any of paragraphs 7 and 8 wherein the pH adjusting agent is an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine.
10. A pharmaceutical composition according to paragraph 9 wherein the pH adjusting agent comprises hydrochloric acid and/or sodium hydroxide, preferably both.
1 1 . A pharmaceutical composition according to any of paragraphs 1 -10 comprising: - one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
- citric acid or a citrate
- a tonicity adjusting agent
- one or more pH adjusting agents and
- water for injection.
12. A pharmaceutical composition according to paragraph 1 1 comprising:
- one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide, - citric acid or a citrate
- sodium chloride
- one or more pH adjusting agents, preferably selected from sodium hydroxide and/or hydrochloric acid, and
- water for injection
in the form of a concentrate or a ready-to-use solution. 13. A pharmaceutical composition according to any of paragraphs 1 -12 wherein the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25.
14. A pharmaceutical composition according to any of paragraphs 1 -13 in the form of an aqueous solution wherein the concentration of citric acid or citrate (based on citric acid) in the solution is from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
15. A pharmaceutical composition according to any of paragraphs 1 -14 in the form of an aqueous solution wherein the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
16. A pharmaceutical composition according to any of paragraphs 13-15 in the form of an aqueous concentrate. 17. A pharmaceutical composition according to any of paragraphs 1 -16 wherein the pemetrexed disodium is in the form of the pemetrexed disodium heptahydrate.
18. A process for preparing a pharmaceutical composition comprising
(a) at least one of the following:
(i) pemetrexed disodium, or
(ii) pemetrexed diacid and sodium hydroxide,
and
(b) citric acid or a citrate,
wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally:
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine.
19. A process according to paragraph 18 wherein the pH is adjusted to between about 6.0 to about 9.0, preferably about 6.0 to about 8.5, more preferably about 6.5 to about 8.0 and most preferably about 6.6 to about 7.8.
20. A process according to any of paragraphs 18 and 19 wherein the order of dissolution is (A), (B), (C) and where necessary, (D), or wherein the order of dissolution is (A) added to a solution containing (B), (C) and (D). 21 . A process according to any of paragraphs 18-20 wherein the pharmaceutical composition is an aqueous concentrate or an aqueous ready-to-use solution, the process further comprising a step of adding water to obtain the final volume.
22. A process according to any of paragraphs 18-20 or 21 wherein the
pharmaceutical composition is a powder for reconstitution, the process further comprising a step of removal of the water.
23. A process according to paragraph 22 wherein the pharmaceutical composition is a lyophilizate for reconstitution, wherein the process further comprises: optionally adding a cryoprotectant (preferably selected from the group consisting of: sucrose, dextrose, mannitol, glucose, and more preferably mannitol) prior to removal of the water by lyophilization.
24. A pharmaceutical composition obtainable by a process according to any of paragraphs 18-23.
25. A pharmaceutical composition prepared by reconstitution of an aqueous concentrate or powder for reconstitution according to any of paragraphs 1 -17. 26. A pharmaceutical product comprising a pharmaceutical composition according to any of paragraphs 1 -17 or 24 in a vial or ampoule.
27. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-26 which shows no significant colour change, or no visible colour change,
following storage at 2-8eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 2-8eC for 6 months.
28. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-27 which show no significant colour change, or no visible colour change, following storage at 25eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 25eC for 6 months.
29. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-28 which shows significant colour change, or no visible colour change, following storage at 40eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 40eC for 6 months.
30. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-29 wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98-
100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 2-8eC, for 3 months, and preferably following storage at 2-8eC for 6 months. 31 . A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-30 wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98- 100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 25eC, for 3 months, and preferably following storage at 25eC for 6 months.
32. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-31 wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98- 100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 40eC, for 3 months, and preferably following storage at 40eC for 6 months.
33. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-32 for use as a medicament.
34. A pharmaceutical composition or product according to paragraph 33 for use in the treatment of malignant pleural mesothelioma or non-small cell lung cancer, optionally in combination with cisplatin.
Claims
1 . A pharmaceutical formulation comprising:
(a) at least one of the following:
(i) pemetrexed tromethamine salt, or
(ii) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein the composition further comprises a sugar alcohol.
2. A pharmaceutical composition according to Claim 1 in the form of a lyophilized powder, an aqueous concentrate or an aqueous solution.
3. A pharmaceutical composition according any of Claims 1 or 2 in the form of an aqueous concentrate or an aqueous ready-to-use solution, preferably wherein the composition is in the form of an aqueous concentrate.
4. A pharmaceutical composition according to any preceding claim wherein the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25.
5. A pharmaceutical composition according to any preceding claim in the form of an aqueous solution wherein the concentration of citric acid or citrate (based on citric acid) in the solution is from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
6. A pharmaceutical composition according to any preceding claim in the form of an aqueous solution wherein the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
7. A pharmaceutical composition according to any of Claims 4-6 in the form of an aqueous concentrate.
8. A pharmaceutical composition according to any of Claims 1 -3 wherein (a) is (i) or (ii).
9. A pharmaceutical composition according to Claim 8 wherein the composition is in the form of a powder for reconstitution, an aqueous concentrate or a ready-to-use aqueous solution.
10. A pharmaceutical composition according to Claim 9 wherein the composition is in the form of a powder for reconstitution (such as a lyophilisate).
1 1 . A pharmaceutical composition according to any of Claims 9 or 10 comprising:
(a) (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and
tromethamine,
(b) citric acid or a citrate,
(c) a sugar alcohol
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), a cryoprotectant and water for injection or infusion.
12. A pharmaceutical composition according to any of Claims 8-1 1 wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, and pentaerythritol, preferably mannitol.
13. A pharmaceutical composition according to any of Claims 1 1 -12 wherein the tonicity adjusting agent is selected from one or more of: a sugar (such as dextrose), arginine, glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride, preferably potassium chloride or sodium chloride, and more preferably sodium chloride.
14. A pharmaceutical composition according to any of Claims 1 1 -12 wherein the tonicity adjusting agent is selected from one or more of: a sugar (preferably dextrose),
glycerin, a sugar alcohol (preferably mannitol) or sodium chloride, preferably sodium chloride.
15. A pharmaceutical composition according to any of Claims 1 1 -13 or 14 wherein the pH adjusting agent is an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; , or alternatively, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, citric acid, malonic acid, tartaric acid, or malic acid), or a salt of a mineral acid, such as acetate, citrate, malonate, tartrate, maleate or phosphate, and more preferably wherein the acid is hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine
16. A pharmaceutical composition according to Claim 15 wherein the pH adjusting agent comprises sodium hydroxide and/or hydrochloric acid, preferably both.
17. A pharmaceutical composition according to Claim 15 wherein the pH adjusting agent comprises tromethamine and/or hydrochloric acid, preferably both.
18. A pharmaceutical composition according to any of Claims 1 1 -13, or 14, or 15-17, wherein the composition is a lyophilisate for reconstitution, and wherein the
cryoprotectant is selected from the group consisting of sucrose, dextrose, mannitol, glucose, and preferably is mannitol.
19. A pharmaceutical composition according to any of Claims 1 -3 and 8-1 1 comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and tromethamine,
- citric acid or a citrate
- a tonicity adjusting agent
- a sugar alcohol
- one or more pH adjusting agents and optionally
- water for injection.
20. A pharmaceutical composition according to Claim 19 comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and trometh amine,
- citric acid or a citrate
- a sugar alcohol, preferably mannitol
- pH adjusting agents, preferably selected from a combination of either: sodium hydroxide and hydrochloric acid; or tromethamine and hydrochloric acid, and optionally
- sodium chloride
in the form of a powder for reconstitution, preferably in the form of a lyophilisate.
21 . A pharmaceutical composition according to any of Claims 8-20 wherein the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25.
22. A pharmaceutical composition according to any of Claims 8-21 the form of an aqueous solution wherein the concentration of citric acid or citrate (based on citric acid) in the solution is from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
23. A pharmaceutical composition according to any of Claims 8-22 in the form of an aqueous solution wherein the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
24. A pharmaceutical composition according to any of Claims 22 or 23 in the form of an aqueous concentrate.
25. A pharmaceutical composition according to any preceding claim wherein the citric acid is anhydrous.
26. A pharmaceutical composition according to any of Claims 1 -24 wherein the citrate is sodium citrate, preferably trisodium citrate or trisodium citrate dihydrate.
27. A pharmaceutical composition according to any preceding claim wherein the pemetrexed disodium is in the form of the pemetrexed disodium heptahydrate.
28. A pharmaceutical composition according to any preceding claim wherein the concentration of tromethamine in the composition is from about 10 to about 25 mg/ml, preferably from about 12 to about 20 mg/ml, and preferably from about 1 6 to about 18 mg/ml.
29. A pharmaceutical composition according to any preceding claim wherein the weight ratio of tromethamine to pemetrexed diacid is from about 1 :1 to about 1 :3, preferably from about 1 :1 to about 1 :2, more preferably from about 1 :1 to about 1 :1 .75, and most preferably from about 1 :1 to about 1 :1 .6, or about 1 :1 .5;
or wherein the weight ratio of tromethamine to pemetrexed diacid is from 0.6 to 1 .2, preferably 0.7 to 1 and more preferably 0.8 to 0.9.
30. A pharmaceutical composition according to any preceding claim wherein the weight ratio of citric acid to tromethamine is from about 1 :10 to about 1 :25, preferably from about 1 : 10 to 1 :20, more preferably from about 1 :15 to about 1 :20, and most preferably from about 1 :17 to about 1 :18.
31 . A pharmaceutical composition according to any preceding claim wherein the concentration of the sugar alcohol, preferably wherein the sugar alcohol is mannitol, is from about 10 to about 30 mg/ml, or from about 10 to about 25 mg/ml, preferably from about 12 to about 20 mg/ml, and preferably from about 16 to about 18 mg/ml.
32. A pharmaceutical composition according to any preceding claim, wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% D- pemetrexed.
33. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% De-Glu pemetrexed.
34. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% pemetrexed diethyl ester.
35. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% L-Glu pemetrexed.
36. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.15 wt% D-pemetrexed, less than 0.15 wt% De-Glu pemetrexed, less than 0.15 wt% L-Glu pemetrexed and less than 0.15 wt% L-Glu pemetrexed.
37. A process for preparing a preparing a pharmaceutical composition comprising (a) at least one of the following:
(i) pemetrexed tromethamine salt, or
(ii) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide or tromethamine, preferably tromethamine
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally .
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; or
alternatively wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, citric acid, malonic acid, tartaric acid, or malic acid, or a salt of a mineral acid, such as acetate, citrate, malonate, tartrate, maleate or phosphate; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine, and more preferably wherein the base is tromethamine.
38. A process according to Claim 28 wherein the pH is adjusted to between about 6.0 to about 9.0, preferably about 6.0 to about 8.5, more preferably about 6.5 to about 8.0 and most preferably about 6.6 to about 7.8.
39. A process according to any of Claims 28 and 29 wherein the order of dissolution is (A), (B), (C) and where necessary, (D).
40. A process according to any of Claims 28-30 wherein the pharmaceutical composition is an aqueous concentrate or an aqueous ready-to-use solution, the process further comprising a step of adding water to obtain the final volume.
41 . A process according to Claim 31 wherein the pharmaceutical composition is a powder for reconstitution, the process further comprising a step of removal of the water.
42. A process according to Claim 32 wherein the pharmaceutical composition is a lyophilizate for reconstitution, wherein the process further comprises: optionally adding a cryoprotectant (preferably selected from the group consisting of: sucrose, dextrose, mannitol, glucose, and more preferably mannitol) prior to removal of the water by lyophilization.
43. A process according to any of Claims 37-42, wherein dissolution of the pemetrexed diacid is carried out in an inert atmosphere, preferably excluding oxygen, and more preferably wherein the dissolution is carried out under nitrogen.
44. A process according to any of Claims 37-43, wherein dissolution of the pemetrexed diacid is carried out in the absence of light, preferably in the absence of UV light.
45. A process according to any of Claims 37-44, wherein handling of pemetrexed is carried out in an inert atmosphere, and in the absence of light, preferably wherein the handling is carried out under nitrogen and in the absence of UV light.
46. A process according to any of Claims 37-45, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% D-pemetrexed.
47. A process according to any of Claims 37-46, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% De-Glu pemetrexed.
48. A process according to any of Claims 37-47, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% pemetrexed diethyl ester.
49. A process according to any of Claims 37-48, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% L-Glu pemetrexed.
50. A process according to any of Claims 37-49, wherein the pemetrexed diacid contains less than 0.15 wt% D-pemetrexed, less than 0.15 wt% De-Glu pemetrexed, less than 0.15 wt% L-Glu pemetrexed and less than 0.15 wt% L-Glu pemetrexed.
51 . A process according to any of Claims 37-50, further comprising a step of filling the pharmaceutical composition into a vial or ampoule.
52. A process according to any of Claim 37-51 , wherein the vial or ampoule is formed of clear glass, preferably wherein the vial is a 6R Type I vial.
53. A process according to any of Claim 37-52, wherein the vial or ampoule is sealed with a bromobutyl or chlorobutyl stopper, preferably a bromobutyl stopper.
54. A process according to Claim 37-53, wherein the filling is carried out in an inert atmosphere, preferably under nitrogen.
55. A process according to Claim 37-54, wherein the concentration of oxygen in the headspace of the vial or ampoule is less than 10%, preferably less than 5%, more preferably less than 2.5%, and most preferably 2% or less, or 1 .5% or less, relative to the volume of the headspace in the vial or ampoule.
56. A pharmaceutical composition obtainable by a process according to any of Claims 37-42, or 43-55.
57. A pharmaceutical composition prepared by reconstitution of an aqueous concentrate or powder for reconstitution according to any of Claims 1 -13, or Claim 14, or Claims 15-27, or Claims 28-36.
58. A pharmaceutical composition according to Claim 57 wherein the reconstitution is carried out with saline, preferably 0.9 w/v% saline for injection.
59. A pharmaceutical product comprising a pharmaceutical composition according to any of Claims 1 -13, or Claim 14 or Clams 15-27 or Claim 56 in a vial or ampoule.
60. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-59, which shows no significant colour change, or no visible colour change, following storage at 2-8eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 2-8eC for 6 months.
61 . A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-60, which shows no significant colour change, or no visible colour change, following storage at 25eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 25eC for 6 months.
62. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-61 , which shows no significant colour change, or no visible colour change, following storage at 40eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 40eC for 6 months.
63. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-62, wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 2-8eC, for 1 -3 weeks, preferably following storage at 2-8eC, for 3 months, and more preferably following storage at 2-8eC for 6 months.
64. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-63, wherein the wt % of pemetrexed diacid is between
97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 25eC, for 1 -3 weeks, preferably following storage at 25eC, for 3 months, and more preferably following storage at 25eC for 6 months.
65. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-64, wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 40eC, for 1 -3 weeks, preferably following storage at 40eC, for 3 months, and more preferably following storage at 40eC for 6 months.
66. A pharmaceutical product according to 59-65, which is in a vial or ampoule.
67. A pharmaceutical composition or product according to any of Claim 66, wherein the vial or ampoule is formed of clear glass, preferably wherein the vial is a 6R Type I vial.
68. A pharmaceutical composition or product according to any of Claims 66 or 67 wherein the vial or ampoule is sealed with a bromobutyl or chlorobutyl stopper, preferably a bromobutyl stopper.
69. A pharmaceutical according to any of Claims 66-68, wherein the concentration of oxygen in the headspace of the vial or ampoule is less than 10%, preferably less than 5%, more preferably less than 2.5%, and most preferably 2% or less, or 1 .5% or less, relative to the volume of the headspace in the vial or ampoule.
70. A pharmaceutical composition or product according to any of Claims 1 -36 and 56-69, wherein the amount of De-Glu pemetrexed relative to pemetrexed diacid is less than 2 wt%, preferably less than 1 .5 wt%, more preferably less than 1 wt% or less than 0.5 wt%, and most preferably less than 0.2 or less than 0.1 wt% relative to the initial amount before storage, following storage at 2-8eC, for 1 -3 weeks, preferably following storage at 2-8eC, for 3 months, and more preferably following storage at 2-8eC for 6 months.
71 . A pharmaceutical composition or product according to any of Claims 1 -36 and 56-70, wherein the amount of De-Glu pemetrexed relative to pemetrexed diacid is less than 2 wt%, preferably less than 1 .5 wt%, more preferably less than 1 wt% or less than 0.5 wt%, and most preferably less than 0.2 or less than 0.1 wt% relative to the initial amount before storage, following storage at 25eC, for 1 -3 weeks, preferably following storage at 25eC, for 3 months, and more preferably following storage at 25eC for 6 months.
72. A pharmaceutical composition or product according to any of Claims 1 -36 and 56-71 , wherein the amount of De-Glu pemetrexed relative to pemetrexed diacid is less than 2 wt%, preferably less than 1 .5 wt%, more preferably less than 1 wt% or less than 0.5 wt%, and most preferably less than 0.2 or less than 0.1 wt% relative to the initial amount before storage, following storage at 40eC, for 1 -3 weeks, preferably following storage at 40eC, for 3 months, and more preferably following storage at 40eC for 6 months.
73. A pharmaceutical composition or product according to any of Claims 1 -36 and 56-72, for use as a medicament.
74. A pharmaceutical composition or product according to Claim 73 for use in the treatment of malignant pleural mesothelioma or non-small cell lung cancer, optionally combination with cisplatin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1418555.7 | 2014-10-16 | ||
| GBGB1418555.7A GB201418555D0 (en) | 2014-10-16 | 2014-10-16 | Pemetrexed formulations |
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| Publication Number | Publication Date |
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| WO2016059238A1 true WO2016059238A1 (en) | 2016-04-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2015/074065 WO2016059238A1 (en) | 2014-10-16 | 2015-10-16 | Pemetrexed formulations |
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| GB (1) | GB201418555D0 (en) |
| WO (1) | WO2016059238A1 (en) |
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| WO2013179248A1 (en) * | 2012-05-30 | 2013-12-05 | Fresenius Kabi Oncology Ltd. | Pharmaceutical compositions of pemetrexed |
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| WO2015008221A1 (en) * | 2013-07-16 | 2015-01-22 | Dr. Reddy’S Laboratories Limited | Novel crystalline forms of pemetrexed tromethamine salts |
-
2014
- 2014-10-16 GB GBGB1418555.7A patent/GB201418555D0/en not_active Ceased
-
2015
- 2015-10-16 WO PCT/EP2015/074065 patent/WO2016059238A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010030598A2 (en) * | 2008-09-11 | 2010-03-18 | Dr. Reddy's Laboratories Limited | Pharmaceutical formulations comprising pemetrexed |
| WO2013179248A1 (en) * | 2012-05-30 | 2013-12-05 | Fresenius Kabi Oncology Ltd. | Pharmaceutical compositions of pemetrexed |
| WO2014084651A1 (en) * | 2012-11-29 | 2014-06-05 | Cj Healthcare Corporation | A stabilized pemetrexed formulation |
| WO2014198337A1 (en) * | 2013-06-14 | 2014-12-18 | Synthon B.V. | Stable and water soluble pharmaceutical compositions comprising pemetrexed |
| WO2015008221A1 (en) * | 2013-07-16 | 2015-01-22 | Dr. Reddy’S Laboratories Limited | Novel crystalline forms of pemetrexed tromethamine salts |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201418555D0 (en) | 2014-12-03 |
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