IL301291A - Pemetrexed formulations - Google Patents
Pemetrexed formulationsInfo
- Publication number
- IL301291A IL301291A IL301291A IL30129123A IL301291A IL 301291 A IL301291 A IL 301291A IL 301291 A IL301291 A IL 301291A IL 30129123 A IL30129123 A IL 30129123A IL 301291 A IL301291 A IL 301291A
- Authority
- IL
- Israel
- Prior art keywords
- pemetrexed
- pharmaceutical composition
- storage
- concentration
- months
- Prior art date
Links
- 229960005079 pemetrexed Drugs 0.000 title claims description 210
- 239000000203 mixture Substances 0.000 title claims description 146
- 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 40
- 238000009472 formulation Methods 0.000 title description 79
- 239000012535 impurity Substances 0.000 claims description 263
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 132
- 239000008194 pharmaceutical composition Substances 0.000 claims description 128
- 239000012895 dilution Substances 0.000 claims description 75
- 238000010790 dilution Methods 0.000 claims description 75
- 239000003125 aqueous solvent Substances 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- 239000003085 diluting agent Substances 0.000 claims description 36
- 239000008156 Ringer's lactate solution Substances 0.000 claims description 19
- 239000003963 antioxidant agent Substances 0.000 claims description 13
- 235000006708 antioxidants Nutrition 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 230000003078 antioxidant effect Effects 0.000 claims description 10
- 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 claims description 10
- 229960003349 pemetrexed disodium Drugs 0.000 claims description 10
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 claims description 9
- 239000008215 water for injection Substances 0.000 claims description 9
- 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 claims description 8
- 239000008121 dextrose Substances 0.000 claims description 8
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) 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-L 0.000 description 172
- 229960004063 propylene glycol Drugs 0.000 description 27
- 235000013772 propylene glycol Nutrition 0.000 description 27
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 16
- 229960000281 trometamol Drugs 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229940110282 alimta Drugs 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000008354 sodium chloride injection Substances 0.000 description 3
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- 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 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- DUORKVZYABUEHW-AHJYMZSGSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol (2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid dihydrate Chemical compound O.O.NC(CO)(CO)CO.NC(CO)(CO)CO.Nc1nc(=O)c2c(CCc3ccc(cc3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)c[nH]c2[nH]1 DUORKVZYABUEHW-AHJYMZSGSA-N 0.000 description 1
- XRCRJFOGPCJKPF-UHFFFAOYSA-N 2-butylbenzene-1,4-diol Chemical compound CCCCC1=CC(O)=CC=C1O XRCRJFOGPCJKPF-UHFFFAOYSA-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
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010035603 Pleural mesothelioma Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N Tetraethylene glycol, Natural products OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 description 1
- 229940045942 acetone sodium bisulfite Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940105990 diglycerin Drugs 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- YQABXEMTTPRASZ-GXKRWWSZSA-L dipotassium;(2s)-2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [K+].[K+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 YQABXEMTTPRASZ-GXKRWWSZSA-L 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000013029 homogenous suspension Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 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 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride 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
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- YNJORDSKPXMABC-UHFFFAOYSA-M sodium;2-hydroxypropane-2-sulfonate Chemical compound [Na+].CC(C)(O)S([O-])(=O)=O YNJORDSKPXMABC-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
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Description
WO 2017/142556 PCT/US2016/018703 PEMETREXED FORMULATIONS BACKGROUND OF THE INVENTION Compounds exhibiting anti-folate activity have a well known role as chemotherapeutic agents. One such compound is pemetrexed, which has the chemical name N-[4-[2-(2-amino-4,7- dihydro-4-oxo-lH-pyrrolo [2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid and the structure of formula (1): Pemetrexed is used in the treatment of pleural mesothelioma and non-small cell lung cancer. ALIMTA, Eli Lilly’s pemetrexed product is presently supplied in 100 mg and 500 mg vials of lyophilized pemetrexed disodium for injection. According to the prescribing information, in order to prepare ALIMTA for infusion the vials are reconstituted in sufficient 0.9% Sodium Chloride Injection (preservative free) to give a solution containing 25 mg/mL of ALIMTA. This concentrated solution is then further diluted into a solution of 0.9% Sodium Chloride Injection (preservative free). The prescribing information cautions that reconstitution and further dilution is only recommended with 0.9% Sodium Chloride Injection (preservative free), and that "ALIMTA is physically incompatible with diluents containing calcium, including Lactated Ringer’s Injection, USP and Ringer’s Injection, USP and therefore these should not be used." Calcium containing diluents, such as Lactated Ringer’s Injection and Ringer’s Injection, are common solutions used in medical settings for the reconstitution and/or dilution of drug products prior to intravenous administration. There is a need for pemetrexed dosage forms that are chemically stable after reconstitution and/or dilution with diluents containing calcium. In addition to being useful with a wider range of available diluents, the use of such a dosage form would minimize both the loss of dosage forms due to improper reconstitution or dilution and the WO 2017/142556 PCT/US2016/018703 risk that a patient would be administered pemetrexed reconstituted or diluted in an incompatible diluent.
In solution, pemetrexed undergoes hydrolysis and degrades rapidly. Due to this rapid degradation, pemetrexed formulations must either be lyophilized for long term stability or comprise stabilizers. However, reconstitution of a lyophilized formulation requires multiple steps, each of which increases the risk of user error. In addition, reconstitution of a lyophilized formulation is clinically inconvenient and can take up to 30 minutes.
While stable, ready to use formulations of pemetrexed are known, they require stabilizers, such as anti-oxidants or amino acids as described in US6,686,365; CN 101081305: and W7O 2012015810, or high levels of non-aqueous solvents, as described in WO2013144814. It would be advantageous to minimize patient exposure to these additional ingredients.
As such, there is a need for a stable, non-lyophilized pemetrexed composition with a minimal amount of additional ingredients. To this end, we have developed a stable pemetrexed formulation.
SUMMARY OF THE INVENTION In certain embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration less than 0.30ml/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 pL/mL propylene glycol, and water, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 24 hours.
In still further embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed at an initial concentration of 10 to 50 mg/mL and a non-aqueous solvent WO 2017/142556 PCT/US2016/018703 present at a concentration less than 0.30ml/mL, wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least months.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 pL/mL propylene glycol, and water, wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 12 months.
In certain embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed and a non-aqueous solvent present at a concentration less than 0.30ml/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 pL/mL propylene glycol, and water, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
In still further embodiments, the invention is directed to a pharmaceutical composition comprising pemetrexed at an initial concentration of 10 to 50 mg/mL and a non-aqueous solvent present at a concentration less than 0.30ml/mL, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
In further embodiments, the invention is directed to a pharmaceutical composition comprising 25 mg/mL pemetrexed, 250 pL/mL propylene glycol, and water, the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
Additional embodiments of the invention include: WO 2017/142556 PCT/US2016/018703 1. A pharmaceutical composition comprising:a) pemetrexed andb) a non-aqueous solvent present at less than 0.30 mL/mL;wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a. temperature of 2°C to 8°C for at least hours. 2. The pharmaceutical composition of embodiment 1 wherein the composition retains at least 90% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:a) at least 24 hours, andb) at least 48 hours. 3. The pharmaceutical composition of embodiment 1 wherein the composition retains at least 95% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:a) at least 12 hours,b) at least 24 hours, andc) at least 48 hours. 4. The pharmaceutical composition of embodiment 1 wherein the composition retains at least 98% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:a) at least 12 hours,b) at least 24 hours, andc) at least 48 hours.
. The pharmaceutical composition of embodiment 1 wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer’s Injection, and Lactated Ringer’s Injection.
WO 2017/142556 PCT/US2016/018703 6. The pharmaceutical composition of embodiment 1 comprising 10 to 50 mg/mL pemetrexed. 7. The pharmaceutical composition of embodiment 6 comprising 25 mg/mL pemetrexed. 8. The pharmaceutical formulation of embodiment I wherein the non-aqueous solvent isselected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof. 9. The pharmaceutical formulation of embodiment 8 wherein the non-aqueous solvent is propylene glycol.
. The pharmaceutical formulation of embodiment 9 wherein propylene glycol is present at 250 pL/mL. 11. The pharmaceutical composition of embodiment 1 comprising at least 0.50mL/mL water. 12. The pharmaceutical composition of embodiment 1 wherein the pemetrexed is in the formof pemetrexed diacid. 13. The pharmaceutical composition of embodiment 1 wherein the pemetrexed is in the form of pemetrexed disodium. 14. The pharmaceutical composition of embodiment 1 substantially free of an anti-oxidant.
. A pharmaceutical composition comprisinga) 25 mg/mL pemetrexed, andb) propylene glycol at 250 pL/mLc) waterwherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a. temperature of 2°C to 8°C for at least hours.
WO 2017/142556 PCT/US2016/018703 16. The pharmaceutical composition of embodiment 15 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 48 hours. 17. A pharmaceutical composition comprising:a) pemetrexed at an initial concentration of 10 to 50 mg/mL andb) a non-aqueous solvent present at less than 0.30 mL/mL, wherein the composition comprises at least 90% of the initial pemetrexed concentrati on after storage at a. temperature of 2°C to 8°C for at least 12 months. 18. The pharmaceutical composition of embodiment 17 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage for a period selected from:a) at least 18 months, andb) at least 24 months. 19. The pharmaceutical composition of embodiment 17 wherein the composition comprises at least 95% of the initial pemetrexed concentration after storage for a period selected from:a) at least 12 months,b) at least 18 months, andc) at least 24 months.
. The pharmaceutical composition of embodiment 17 wherein the composition comprises at least 98% of the initial pemetrexed concentration after storage for a period selected from:a) at least 12 months,b) at least 18 months, andc) at least 24 months.
WO 2017/142556 PCT/US2016/018703 21. The pharmaceutical composition of embodiment 17 having an initial pemetrexed concentration of 25 mg/mL. 22. The pharmaceutical formulation of embodiment 17 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof. 23. The pharmaceutical formulation of embodiment 22 wherein the non-aqueous solvent is propylene glycol. 24. The pharmaceutical formulation of embodiment 23 wherein propylene glycol is present at 250 pL/mL.
. The pharmaceutical composition of embodiment 17 comprising at least 0.50mL/mL water. 26. The pharmaceutical composition of embodiment 17 wherein the pemetrexed is in the form of pemetrexed diacid. 27. The pharmaceutical composition of embodiment 17 wherein the pemetrexed is in the form of pemetrexed disodium. 28. The pharmaceutical composition of embodiment 17 substantially free of an anti-oxidant. 29. A pharmaceutical composition comprisinga) an initial pemetrexed concentration of 25 mg/mL,b) propylene glycol at 250 pL/mL, andc) water;wherein the composi tion comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 12 months.
. The pharmaceutical composition of embodiment 29 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 24 months.
WO 2017/142556 PCT/US2016/018703 31. A pharmaceutical composition comprising:a) pemetrexed andb) a non-aqueous solvent present at less than 0.30 mL/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 hours. 32. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 8% w/w total impurities after dilution and storage for a period selected from:a) at least 24 hours, and b) at least 48 hours. 33. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 5% w/w total impurities after dilution and storage for a period selected from:a) at least 12 hours,b) at least 24 hours, andc) at least 48 hours. 34. The pharmaceutical composition of embodiment 31 wherein the composition comprises no more than 2% w/w total impurities after dilution and storage for a period selected from:a) at least 12 hours, b) at least 24 hours, and c) at least 48 hours.
WO 2017/142556 PCT/US2016/018703 . The pharmaceutical composition of embodiment 31 wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer’s Injection, and Lactated Ringer’s Injection. 36. The pharmaceutical composition of embodiment 31 comprising 10 to 50 mg/mL pemetrexed. 37. The pharmaceutical composition of embodiment 36 comprising 25 mg/mL pemetrexed. 38. The pharmaceutical formulation of embodiment 31 wherein the non-aqueous solvent isselected from the group consisting of propylene glycol, alcohol, poly ethylene glycol, or combinations thereof. 39. The pharmaceutical formulation of embodiment 38 wherein the non-aqueous solvent is propylene glycol. 40. The pharmaceutical formulation of embodiment 39 wherein propylene glycol is present at 250 pL/mL. 41. The pharmaceutical composition of embodiment 31 comprising at least 0.50mL/mL water. 42. The pharmaceutical composition of embodiment 31 wherein the pemetrexed is in the form of pemetrexed diacid. 43. The pharmaceutical composition of embodiment 31 wherein the pemetrexed is in the form of pemetrexed disodium. 44. The pharmaceutical composition of embodiment 31 substantially free of an anti-oxidant. 45. A pharmaceutical composition comprisinga) 25 mg/mL pemetrexed,b) propylene glycol at 250 pL/mL, andc) water; WO 2017/142556 PCT/US2016/018703 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours. 46. The pharmaceutical composition of embodiment 45 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 48 hours. 47. A pharmaceutical composition comprising:a) pemetrexed at an initial concentration of 10 to 50 mg/mL andb) a non-aqueous solvent present at less than 0.30 mL/mL, wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months. 48. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 8% w/w total impurities after storage for a period selected from:a) at least 18 months, andb) at least 24 months. 49. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 5% w/w total impurities after storage for a period selected from:a) at least 12 months,b) at least 18 months, andc) at least 24 months. 50. The pharmaceutical composition of embodiment 47 wherein the composition comprises no more than 2% w/w total impurities after storage for a period selected from:a) at least 12 months,b) at least 18 months, andc) at least 24 months.
WO 2017/142556 PCT/US2016/018703 51. The pharmaceutical composition of embodiment 47 comprising 25 mg/mL pemetrexed. 52. The pharmaceutical formulation of embodiment 47 wherein the non-aqueous solvent isselected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof. 53. The pharmaceutical formulation of embodiment 52 wherein the non-aqueous solvent is propylene glycol. 54. The pharmaceutical formulation of embodiment 53 wherein propy lene glycol is present at 250 pL/mL. 55. The pharmaceutical composition of embodiment 47 comprising at least 0.50mL/mL water. 56. The pharmaceutical composition of embodiment 47 wherein the pemetrexed is in the form of pemetrexed diacid. 57. The pharmaceutical composition of embodiment 47 wherein the pemetrexed is in the form of pemetrexed disodium. 58. The pharmaceutical composition of embodiment 47 substantially free of an anti-oxidant. 59. A pharmaceutical composition comprisinga) an initial pemetrexed concentration of 25 mg/mL,b) propylene glycol at 250 uL/mL, andc) water;wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months. 60. The pharmaceutical composition of embodiment 59 wherein the composition comprises no more than 8% w/w total impurities after storage at a. temperature of 2°C to 8°C for at least 24 months.
WO 2017/142556 PCT/US2016/018703 BRIEF DESCRIPTION OF THE FIGURES FIGS 1A-1D: Depicts the effect of propylene glycol (PG) on the stability of certain pemetrexed formulations.
DETAILED DESCRIPTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there is a plurality7 of definitions for a term used herein, those definitions in this section prevail unless stated otherwise.
As used herein "single largest impurity" refers to the impurity with the largest HPLC peak by percentage.
As used herein "initial dosage concentration of pemetrexed" refers the concentration of pemetrexed at the time of dilution, prior to storage.
As used herein "initial pemetrexed concentration" refers to the concentration of pemetrexed at the time of formulation, prior to dilution and/or storage.
As used herein "room temperature" is about 20°C to about 25°C.
Pemetrexed or a pharmaceutically acceptable salt thereof is present in the compositions of the present invention at concentrations of between about 10 mg/mL to about 50 mg/mL when calculated as anhydrous pemetrexed diacid. In certain embodiments of the invention, pemetrexed is present at about 10 mg/mL to about 40 mg/mL, at about 10 mg/mL to about mg/mL, at about 10 mg/mL to about 20 mg/mL, at about 20 mg/mL to about 50 mg/mL, at about mg/mL to about 40 mg/mL, at about 20 mg/mL to about 30 mg/mL, at about 30 mg/mL to about 50 mg/mL, at about 30 mg/mL to about 40 mg/mL, or at about 40 mg/mL to about mg/mL. In further embodiments of the invention, pemetrexed is available at about 10 mg/mL, about 15 mg/mL, 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about mg/mL, about 45 mg/mL, or at about 50 mg/mL.
Pemetrexed is present in the composition as the diacid, monoacid, a pharmaceutically WO 2017/142556 PCT/US2016/018703 acceptable salt, or as combinations thereof. In certain embodiments of the invention, pemetrexed is present as pemetrexed disodium, in further embodiments of the invention, pemetrexed is present as pemetrexed dipotassium. In yet further embodiments of the invention, pemetrexed is present as pemetrexed meglumine. In still further embodiments of the invention, pemetrexed is present as pemetrexed tromethamine.
Non-Aqueous Solvents Suitable non-aqueous solvents include, but are not limited to alcohols, ketones, esters, ethers, aromatic hydrocarbons, nitriles, aprotic polar solvents, acidic solvents, and mixtures of any two or more thereof. Useful alcohols include, for example, methanol, ethanol, denatured spirits, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, polyhydroxy alcohols example glycerin, propylene glycol, polyethylene glycol, diethylene glycol, diglycerin, triethylene glycol, tetraethylene glycol, trimethylolpropane and the like. Useful ketones include propanone, 2- butanone, and the like. Useful esters include, for example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, and the like. Useful ethers include, for example, dimethyl ether, diethyl ether, methyl t-butyl ether, ethyl methyl ether, diisopropyl ether, and the like. Useful aromatic hydrocarbons include, for example, and the like. Useful nitriles include acetonitrile, propionitrile, and the like. Useful aprotic polar solvents include N,N- dimethylformide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like.
In certain embodiments of the invention, the non-aqueous solvent is an alcohol. In further embodiments of the invention, the non-aqueous solvent is a polyhydroxy alcohol . In still further embodiments of the invention, the non-aqueous solvent is propylene glycol. In yet further embodiments of the invention, the non-aqueous solvent is polyethylene glycol. In particular embodiments of the invention, the non-aqueous solvent is low molecular weight polyethylene glycol. In other embodiments of the invention, the non-aqueous solvent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, or combinations thereof. In certain embodiments of the invention, more than one non-aqueous solvent is present, such as, but not limited to polyethylene glycol and propylene glycol WO 2017/142556 PCT/US2016/018703 In certain embodiments of the invention, the non-aqueous solvent is present at a concentration of about 50 mg/mL to 300 mg/mL prior to dilution. In further embodiments of the invention, the non-aqueous solvent is present at about 50 mg/mL to 100 mg/mL, 50 mg/mL to 200 mg/mL, 50 mg/mL to 250 mg/mL, 50 mg/mL to 300 mg/mL, 100 mg/mL to 200 mg/mL, 100 mg/mL to 250 mg/mL, 100 mg/mL to 300 mg/mL, 200 mg/mL to 250 mg/mL, 200 mg/mL to 300 mg/mL, or 250 mg/mL to 300 mg/mL prior to dilution.
In particular embodiments, the non-aqueous solvent is present at a concentration of no more than 30 weight percent (wt.%) of the formulation prior to dilution. In further embodiments, the non-aqueous solvent is present at a concentration of at least 5 weight percent (wt.%) of the formulation prior to dilution. In certain embodiments of the invention the non-aqueous solvent is present at 5-30 weight percent (wt.%) of the formulation prior to dilution. In particular embodiments of the invention the non-aqueous solvent is present at about 10-30 wt.%, 15-wt.%, 20-30 wt.%, 25-30 wt.%, 5-28%, 10-28 wt.%, 15-28 wt.%, 20-28 wt.%, 25-28 wt.%, 5- 25%, 1025־ wt.%, 15-25 wt.%, 20-25 wt.%, 25-28 wt.%, 5-20%, 10-20 wt.%, 15-20 wt.%, 5- 15%, 10-15 wt.%, or 5-10 wt% prior to dilution.
In particular embodiments, the non-aqueous solvent is present at a concentration of no more than 300 pL/mL prior to dilution. In further embodiments, the non-aqueous solvent is present at a. concentration of at least 50 pL/mL prior to dilution. In certain embodiments of the invention, the non-aqueous solvent is present at a concentration of about 50 pL/mL to 3pL/mL. In further embodiments of the invention, the non-aqueous solvent is present at about pL/mL to 100 pL/mL, 50 pL/mL to 200 pL/mL, 50 pL/mL to 250 pL/mL, 50 pL/mL to 2pL/mL, 50 pL/mL to 300 pL/mL, 100 pL/mL to 200 pL/mL, 100 pL/mL to 250 pL/mL, 1pL/mL to 275 pL/mL, 100 pL/mL to 300 pL/mL, 200 pL/mL to 250 pL/mL, 200 pL/mL to 3pL/mL, or 250 pL/mL to 300 pL/mL prior to dilution.
In certain embodiments, water is present at a concentration of at least about 500 pL/mL prior to dilution. In other embodiments of the invention, water is present at a concentration of at least about 600 pL/mL, 750 pL/mL, or 950 pL/mL prior to dilution. In further embodiments of the invention, water is present at a concentration of about 500 pL/mL to 950 pL/mL prior to dilution. In still further embodiments of the invention, water is present at about 500 pL/mL to WO 2017/142556 PCT/US2016/018703 800 pL/mL, 500 pL/mL to 700 pL/mL, 500 pL/mL to 600 pL/mL, 600 pL/mL to 750 pL/mL, 600 pL/mL to 800 pL/mL, 600 pL/mL to 950 pL/mL, 700 pL/mL to 800 pL/mL, 700 pL/mL to 950 pL/mL, or 750 pL/mL to 950 pL/mL prior to dilution.
In particular embodiments, water is present at a concentration of at least about 50 wt.% of the formulation prior to dilution. In further embodiments, water is present at a concentration of at least about 60 wt.%, 75 w t%, or 95 wt.% prior to dilution. In certain embodiments of the invention water is present at a concentration of at least about 50-95 wt.% prior to dilution, of the invention water is present at a concentration of at least about 50-60 wt.%, 50-70 wt.%, 50-wt.%, 60-70 wt.%, 60-80 wt.%, 60-95 wt.%, 70-80 wt.%, or 70-95 wt.% prior to dilution In certain embodiments of the invention the formulation is substantially free of anti- oxidants and/or amino acids. In particular embodiments of the invention, the formulation is substantially free of anti-oxidants. In further embodiments of the invention, the formulation is substantially free of chelating agents. As used herein, substantially free of anti-oxidants, amino acids, and/or chelating agents means the formulation does not comprise one or more anti- oxidants, amino acids, and/or chelating agents, at a concentration sufficient to have a stabilizing effect.
In particular embodiments, the formulation is substantially free of additives selected from the group consisting of ascorbic acid and derivatives, tocopherols and derivatives, propyl gallate, thioglycerol, lactobionic acid, methionine, tertiary' butylhydroquinone (TBHQ), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium formaldehyde sulfoxylate, sodium hydrogen sulfite, Eethylenediaminetetraacetic acid (EDTA) and derivatives, monoethanol amine gentisate, glutathione, propionic acid, acetone sodium bisulfite, sodium dithionite, citric acid and derivatives, tribasic (tri sodium citrate dihydrate), or suitable mixtures thereof. As used herein, substantially free means the formulation does not comprise one or more additives listed above at a concentration sufficient to have a stabilizing effect.
In particular embodiments of the invention, the formulation comprises tromethamine. In certain embodiments of the invention, the formulation comprises about 12 to 24 mg/mL tromethamine. In further embodiments of the invention, the formulation comprises about 12 to WO 2017/142556 PCT/US2016/018703 14 mg/mL tromethamine, about 12 to 16 mg/mL tromethamine, about 14 to 16 mg/mL tromethamine, about 14 to 18 mg/mL tromethamine, about 16 to 18 mg/mL tromethamine, about to 20 mg/mL tromethamine, about 17 to 19 mg/mL tromethamine, about 17 to 21 mg/mL tromethamine, about 18 to 20 mg/mL tromethamine, about 18 to 22 mg/mL tromethamine, about 20 to 22 mg/mL tromethamine, about 20 to 24 mg/mL tromethamine, or about 22 to mg/mL tromethamine. In yet further embodiments of the invention, the formulation comprises about 18 mg/mL tromethamine.
In certain embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 6 months. In particular embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 1 year. In further embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 18 months. In still further embodiments of the invention, the formulation is not substantially degraded after storage at room temperature for at least about 2 years.
In further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 6 months. In certain embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 1 year. In further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 18 months. In still further embodiments of the invention, the formulation is not substantially degraded after storage at 2-8°C for at least about 2 years.
In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.
WO 2017/142556 PCT/US2016/018703 In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after storage at 2-8°C for at least about 6 months, about 12 months, about 18, months, or about months.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after storage at room temperature for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In yet further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after storage at 2-8°C for at least WO 2017/142556 PCT/US2016/018703 about 6 months, about 12 months, about 18, months, or about 24 months.
In particular embodiments of the invention, the formulation retains at least about 85% of its initial pemetrexed concentration, at least about 90% of its initial pemetrexed concentration, the formulation retains at least about 92% of its initial pemetrexed concentration, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration, after storage at room temperature for at least about 6 months, about months, about 18, months, or about 24 months.
In further embodiments of the invention, the formulation retains at least about 85% of its initial pemetrexed concentration, at least about 90% of its initial pemetrexed concentration, the formulation retains at least about 92% of its initial pemetrexed concentration, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration, after storage at 2-8°C for at least about 6 months, about 12 months, about 18, months, or about 24 months.
In certain embodiments of the invention, the formulation is further diluted in a pharmaceutically acceptable diluent. Suitable diluents include, but are not limited to saline, dextrose, water, Ringer’s Injection, and Lactated Ringer’s Injection. In certain embodiments of the invention, the formulation can be diluted in a calcium containing diluent, such as Ringer’s Injection or Lactated Ringer’s Injection.
In particular embodiments of the invention, the formulation is diluted in a pharmaceutically acceptable diluent to a suitable initial dosage concentration of pemetrexed. In certain embodiments of the invention the initial dosage concentration of pemetrexed is based on various factors, such as, but not limited to the patient’s weight, age, and condition as well as the volume of diluent and can be determined by a practitioner or one of skill in the art. In further embodiments, pemetrexed is diluted to an initial dosage concentration and can be further diluted WO 2017/142556 PCT/US2016/018703 prior to administration.
In other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2°C to about 8°C for at least about 12 hours.
In still other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2°C to about 8°C for at least about24 hours.
In yet other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial dosage concentration of pemetrexed, at least about 97% of its initial dosage concentration of pemetrexed, at least about 98% of its initial dosage concentration of pemetrexed, at least about 99% of its initial dosage concentration of pemetrexed, at least about 99.5% of its initial dosage concentration of pemetrexed, after dilution and storage at about 2°C to about 8°C for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no WO 2017/142556 PCT/US2016/018703 more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at about 2°C to about 8°C for at least about 12 hours.
In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at about 2°C to about 8°C for at least about 24 hours.
In yet other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at about 2°C to about 8°C for at least about 48 hours.
In still other embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity׳, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% WO 2017/142556 PCT/US2016/018703 w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2°C to about 8°C for at least about 12 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2°C to about 8°C for at least about 24 hours.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at about 2°C to about 8°C for at least about 48 hours.
In other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its dosage concentration of pemetrexed, at least about 97% of its dosage WO 2017/142556 PCT/US2016/018703 concentration of pemetrexed, at least about 98% of its dosage concentration of pemetrexed, at least about 99% of its dosage concentration of pemetrexed, at least about 99.5% of its dosage concentration of pemetrexed, after dilution and storage at room temperature for at least about hours.
In still other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its dosage concentration of pemetrexed, at least about 97% of its dosage concentration of pemetrexed, at least about 98% of its dosage concentration of pemetrexed, at least about 99% of its dosage concentration of pemetrexed, at least about 99.5% of its dosage concentration of pemetrexed, after dilution and storage at room temperature for at least about 24 hours.
In yet other embodiments of the invention, the formulation retains at least about 85% of its initial dosage concentration of pemetrexed, at least about 90% of its initial dosage concentration of pemetrexed, at least about 92% of its initial dosage concentration of pemetrexed, at least about 95% of its initial pemetrexed concentration, the formulation retains at least about 97% of its initial pemetrexed concentration, at least about 98% of its initial pemetrexed concentration, at least about 99% of its initial pemetrexed concentration, at least about 99.5% of its initial pemetrexed concentration, after dilution and storage at about room temperature for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% w/w impurities, no more than about 2% w/w impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at room temperature for at least about 12 hours.
WO 2017/142556 PCT/US2016/018703 In other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% w/w impurities, no more than about 2.5% wAv impurities, no more than about 2% wAv impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at room temperature for at least about 24 hours.
In yet other embodiments of the invention, the formulation comprises no more than about 10% w/w impurities, no more than about 8% w/w impurities, no more than about 6% w/w impurities, no more than about 5% w/w impurities, no more than about 4% w/w impurities, no more than about 3.5% w/w impurities, no more than about 3% wAv impurities, no more than about 2.5% wAv impurities, no more than about 2% wAv impurities, no more than about 1.5% w/w impurities, no more than about 1% w/w impurities, no more than about 0.5% w/w impurities, no more than about 0.2% w/w impurities, no more than about 0.1% w/w impurities, after dilution and storage at room temperature for at least about 48 hours.
In further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% wAv of the single largest impurity', no more than about 6% w/w of the single largest impurity', no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity', no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at room temperature for at least about 12 hours.
In yet further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest WO 2017/142556 PCT/US2016/018703 impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at room temperature for at least about 24 hours.
In still further embodiments of the invention, the formulation comprises no more than about 10% w/w of the single largest impurity, no more than about 8% w/w of the single largest impurity, no more than about 6% w/w of the single largest impurity, no more than about 5% w/w of the single largest impurity, no more than about 4% w/w of the single largest impurity, no more than about 3.5% w/w of the single largest impurity, no more than about 3% w/w of the single largest impurity, no more than about 2.5% w/w of the single largest impurity, no more than about 2% w/w of the single largest impurity, no more than about 1.5% w/w of the single largest impurity, no more than about 1% w/w of the single largest impurity, no more than about 0.5% w/w of the single largest impurity, no more than about 0.2% w/w of the single largest impurity, no more than about 0.1% w/w of the single largest impurity, after dilution and storage at a. room temperature for at least about 48 hours.
In particular embodiments of the invention the formulation is in a vial with a headspace oxygen concentration of less than about 20 v/v%, 18 v/v%, 16 v/v%, 14 v/v%, 12 v/v%, v/v%, 8 v/v%, 6 v/v%, 5 v/v%, 4 v/v%, 3 v/v%, 2 v/v%, or 1 v/v% oxygen.
In certain embodiments of the invention, the formulation is in a single-dose vial. In further embodiments of the invention, the formulation is in a. multi-dose vial. In yet further embodiments of the invention, the formulation is in a multi-dose vial intended for use by the same patient. In still further embodiments of the invention, the formulation is in a multi-dose vial intended for use by different patients.
WO 2017/142556 PCT/US2016/018703 In another embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation as described herein. In a further embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation comprising pemetrexed and a non-aqueous solvent present at less than 30 wt%. In a further embodiment, the invention relates to a method of administering pemetrexed to a patient in need thereof comprising administering an effective amount of a formulation comprising pemetrexed and propylene glycol wherein the propylene glycol is present at 5-30 wt%.
EXAMPLES Example 1: Effect of Non-Aqueous Solvents on Pemetrexed Stability Formulations as described in Table 1 were prepared as follows: Water for Injection, a suitable base solution (0.1 ---1 N NaOH or KOH), and citric acid, if present, were combined and mixed to yield a visually uniform mixture. Pemetrexed diacid was incrementally added to the mixture under continuous agitation, and the resulting homogenous suspension was agitated until all solids were completely dissolved. The pH of the solution was adjusted to about 7.4-7.6. Propylene glycol, if present, was then added to the pemetrexed solution, and the mixture was agitated until a visually uniform mixture was obtained. The pH of the solution was adjusted to 7.4-7.6. b C F IPemetrexeddiacid) (m»/mL)25 25 25 Citric Acid * H:O(mg/mL)13.2 13.2 - PropyleneGb col(pL/m I.)250 - - 250 1111■qs to pH 7.5qs to pH 7.5qstopH 7.5qs to pH 7.5Hydrochloric Acid qs to pH 7.5qs to pH 7.5qs to pH 7.5qs to pH 7.5WFI qsqs qsqs The stability of Formulations B, C, F, and I was tested under accelerated conditions at WO 2017/142556 PCT/US2016/018703 60°C and 40°C/75% RH over the course of several days. Samples were taken at various time points and diluted with HPLC diluents (60:40 (v/v, Water:ACN)) prior to testing. Impurities were measured by HPLC.
The results are shown in Tables 2A-2D and Figures 1A-1D.
Table 2A: Single Largest Impurity (% w/w) after storage at 60°C B C F IInitial 0.09 0.15 0.10 0.07day 0.61 1.26 1.00 0.56day1.16 2.56 1.97 1.04day1.68 4.01 2.91 1.50 Table 2B: Total Impurities (% w/w) after storage at 60°C TotalImpurityB C F IInitial 0.69 0.92 0.74 0.70day 1.50 2.35 2.02 1.39day 2.20 3.93 3.31 2.04day2.86 5.63 4.54 2.65 Table 2C: Single Largest Impurity (% w/w) after storage at 40°C/75% RH RRT 0.87 B C F IInitial 0.09 0.15 0.10 0.07days 1.70 6.36 3.36 1.33days 3.29 13.44 9.24 2.35 Table 2D: Total Impurities after (% w/w) storage at 40°C/75% RH Total ImpurityB C F IInitial 0.69 0.92 0.74 0.70days 3.63 11.75 7.28 2.75days 6.05 20.94• 16.71 4.31 The long term stability, real-time, and projected, of formulations B, I, and K (See Table4, prepared as described above) were also measured. Results are shown in Table 3 WO 2017/142556 PCT/US2016/018703 Table 3: Long Term Stability' of Pemetrexed Formulations B, I, and K Storage at 2-8C (Month s) Single Largest Impurity (% w/w) Total Impurities (% w/w) Projected Projected fl in SLI in 24M M (%(% u/w) w/w) Assay(%LC)pHHead space oxygen Formulation B 15 0.57 4.70 7.52 0.91 93.6 7.59 18.1Formulation I 15 0.31 1.70 2.72 0.50 97.8 7.50 20.9Formulation K 14 0.42 2.96 5.07 i 0.72 95.2 7.47 19.6 Table 4: Pemetrexed Formulation K Ingredient pml.Pemetrexed diacid 25.0 mgPropylene Glycol 250 pLTromethamine qs to pH 7.4-7.6Hydrochloric Acid qs to pH 7.4-7.6Water for Injection | qs to 1 mL Example 2: Stability ofPemetrexed Formulation K after dilution.
The stability of pemetrexed for up to 48 hours after dilution of Formulation K was evaluated. . Normal saline, water for injection and 5% dextrose in water, Ringer’s Injection, and Lactated Ringer’s Injection were purchased directly and used as is. The pH of each diluent was tested and recorded in Table 6.
Table 6: pH of diluents Normal Saline (NS) 6.8Water for Injection (WFI) 7.01Ringer’s Injection (LR) I 6.6Lactated Ringer’s Injection (LRS) 6.55% Dextrose in Water (D5W) 7.5 WO 2017/142556 PCT/US2016/018703 Formulation K (25 mg/mL) was diluted to 0.15, 1.5, and 15 mg/mL in the diluents listed above. The mixtures were stored at 2-8° C and tested at 12, 24, and 48 hours for appearance, assay, impurities, and pH. A sample was taken immediately after dilution for the time zero sample. The 0.15 mg/mL samples were analyzed as is without further dilution, while the 1.mg/mL and 15 mg/mL samples were diluted with HPLC diluents (60:40 (v/v. Water: ACN)) prior to testing. Results are in Tables 6 & 7 (each Table represents separate studies).
Table 6: Stability of Formulation K after dilution in Normal Saline or Water for Injection Diluents Time (hrs)Theoretical Pemetrexed cone (mg/mL)Assay(mg/g)*Percentage of Theoretical Pemetrexed %PHTotal Impurity (% w/w)Bulk Solution- 25.0 24.80 99.2 7.50 0.16 NS nI 0J.5 100.00 7.45 0.08|||||^llllll،-7.43 50^^1.51.52 HH .54 iiiiii 0.127.52 o. 1 71.50 100.20 11111111 0.161514.55 98.84 7.47 0.0814.61 99.25 7.54 0.1914.71 99.93 7.58 0.17 WFI ןןן|ן^0J.5 (00.000.07-mITBiBlii ........7,5.3.dII:VAvSSASsj-Zt•:•:•:•:•:•:•:•:•:•:•:•: 4<> 0d5 100.00 7.50 0.07«)1.50 100.20 7.30 0.141111^^ 7.47 DJ 71.51 7 50 0.16 1514.60 99.18 7.52 0.1414.40 97.82 7.58 0.1614.70 99.86 7.59 0.11 Table 7: Stability of Formulation K after dilution in Ringer's Injection, Lactated Ringer’sInjection, or 5% Dextrose DiluentsTime (hrs)Theoretical Pemetrexed cone (mg/mL)Assay (% LC)*Percentage ofTheoretical Pemetrexed %pHT otalImpurity WO 2017/142556 PCT/US2016/018703 Bulk solution- 25.0 97.6 NA 7.37 0.35 RS iiiiilii !■■oiןןןן، ،iiiiUE95.8............97,8............11111■.... 7.23..... 7,^2.......0.41........■iBSii■ 4895395,4 97.8 iiiiiii■1.595.8 ■■■■■ 7.45 0.319999>’6.2198.697.47.537.469990.3695.4 97.7 7.53 0.341597.8 100.2 7.47 0.3598.3 100.7 7.55 0.3597.4 99.7 7.39 0.3695.6 98.0 7.53 0.33 LRS 0—ms98,5 100,9 7.54 0.47ii■■®98.9 I7.iiiiilii0.55•0m11iiiiilii 12 NN98.498.14■98.2 9999999:06.5־ 9999999 ■iiiiii7.59749737.58 iii،iii،320.330.34999991597.8 100.2 7.41 0.332498.398.2100.7100.67.587.360.320.3498.7 101.1 7.46 0.33 D5W mOn IIIIII■ 7,50 lllll■■iiiiiiiiiiii،||||||،100J—ysy iiiiilii0.58------ "IlOI ille■! 0,521297.096. G99S999I7.397.G29.310.3348597.299.999.6307.530.409.391597.7 100.1 7.47 0.3198.0 100.3 7.61 0.3497.9 100.3 7.40 0.3298.0 100.4 7.59 0.34 The foregoing detailed description has been given for clearness of understanding only and no unnecessary' limitations should be understood there from as modifications will be obvious to those skilled in the art.
While the invention has been described in connection with specific embodiments thereof,
Claims (60)
1. A pharmaceutical composition comprising:a) pemetrexed andb) a non-aqueous solvent present at less than 0.30 mL/mL;wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least hours.
2. The pharmaceutical composition of claim 1 wherein the composition retains at least 90% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:a) at least 24 hours, andb) at least 48 hours.
3. The pharmaceutical composition of claim 1 wherein the composition retains at least 95% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:a) at least 12 hours,b) at least 24 hours, andc) at least 48 hours.
4. The pharmaceutical composition of claim 1 wherein the composition retains at least 98% of the initial dosage concentration of pemetrexed upon dilution and storage for a period selected from:a) at least 12 hours,b) at least 24 hours, andc) at least 48 hours. WO 2017/142556 PCT/US2016/018703
5. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer’s Injection, and Lactated Ringer’s Injection.
6. The pharmaceutical composition of claim 1 comprising 10 to 50 mg/mL pemetrexed.
7. The pharmaceutical composition of claim 6 comprising 25 mg/mL pemetrexed.
8. The pharmaceutical formulation of claim I wherein the non-aqueous solvent is selectedfrom the group consisting of propylene glycol, alcohol, polyethy lene glycol, or combinations thereof.
9. The pharmaceutical formulation of claim 8 wherein the non-aqueous solvent is propylene glycol.
10. The pharmaceutical formulation of claim 9 wherein propylene glycol is present at 2pL/mL.
11. The pharmaceutical composition of claim 1 comprising at least 0.50mL/mL water.
12. The pharmaceutical composition of claim 1 wherein the pemetrexed is in the form ofpemetrexed diacid.
13. The pharmaceutical composition of claim 1 wherein the pemetrexed is in the form of pemetrexed disodium.
14. The pharmaceutical composition of claim 1 substantially free of an anti-oxidant.
15. A pharmaceutical composition comprisinga) 25 mg/mL pemetrexed, andb) propylene glycol at 250 pL/mLc) waterwherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage WO 2017/142556 PCT/US2016/018703 concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least hours.
16. The pharmaceutical composition of claim 15 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed, the composition comprises at least 90% of the initial dosage concentration of pemetrexed after storage at a temperature of 2°C to 8°C for at least 48 hours.
17. A pharmaceutical composition comprising:a) pemetrexed at an initial concentration of 10 to 50 mg/mL andb) a non-aqueous solvent present at less than 0.30 mL/mL, wherein the composition comprises at least 903-0 of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 12 months.
18. The pharmaceutical composition of claim 17 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage for a period selected from:a) at least 18 months, andb) at least 24 months.
19. The pharmaceutical composition of claim 17 wherein the composition comprises at least 95% of the initial pemetrexed concentration after storage for a period selected from:a) at least 12 months,b) at least 18 months, and c) at least 24 months.
20. The pharmaceutical composition of claim 17 wherein the composition comprises at least 98% of the initial pemetrexed concentration after storage for a period selected from:a) at least 12 months,b) at least 18 months, andc) at least 24 months. WO 2017/142556 PCT/US2016/018703
21. The pharmaceutical composition of claim 17 having an initial pemetrexed concentration of 25 mg/mL.
22. The pharmaceutical formulation of claim 17 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
23. The pharmaceutical formulation of claim 22 wherein the non-aqueous solvent is propylene glycol.
24. The pharmaceutical formulation of claim 23 wherein propylene glycol is present at 2pL/mL.
25. The pharmaceutical composition of claim 17 comprising at least 0.50mL/mL water.
26. The pharmaceutical composition of claim 17 wherein the pemetrexed is in the form ofpemetrexed diacid.
27. The pharmaceutical composition of claim 17 wherein the pemetrexed is in the form of pemetrexed disodium.
28. The pharmaceutical composition of claim 17 substantially free of an anti-oxidant.
29. A pharmaceutical composition comprisinga) an initial pemetrexed concentration of 25 mg/mL,b) propylene glycol at 250 uL/mL, andc) water,wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a. temperature of 2°C to 8°C for at least 12 months.
30. The pharmaceutical composition of claim 29 wherein the composition comprises at least 90% of the initial pemetrexed concentration after storage at a temperature of 2°C to 8°C for at least 24 months. WO 2017/142556 PCT/US2016/018703
31. A pharmaceutical composition comprising:a) pemetrexed andb) a non-aqueous solvent present at less than 0.30 mL/mL, wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a. temperature of 2°C to 8°C for at least 12 hours.
32. The pharmaceutical composition of claim 1 wherein the composition comprises no more than 8% w/w total impurities after dilution and storage for a period selected from:a) at least 24 hours, andb) at least 48 hours.
33. The pharmaceutical composition of claim 1 wherein the composition comprises no more than 5% w/w total impurities after dilution and storage for a period selected from:a) at least 12 hours,b) at least 24 hours, andc) at least 48 hours.
34. The pharmaceutical composition of claim 1 wherein the composition comprises no more than 2% w/w total impurities after dilution and storage for a period selected from:a) at least 12 hours,b) at least 24 hours, andc) at least 48 hours.
35. The pharmaceutical composition of claim 31 wherein the pharmaceutically acceptable diluent is selected from the group consisting of normal saline, water for injection, 5% dextrose in water, Ringer’s Injection, and Lactated Ringer’s Injection.
36. The pharmaceutical composition of claim 31 comprising 10 to 50 mg/mL pemetrexed.
37. The pharmaceutical composition of claim 36 comprising 25 mg/mL pemetrexed. WO 2017/142556 PCT/US2016/018703
38. The pharmaceutical formulation of claim 31 wherein the non-aqueous solvent is selected from the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
39. The pharmaceutical formulation of claim 38 wherein the non-aqueous solvent is propylene glycol.
40. The pharmaceutical formulation of claim 39 wherein propylene glycol is present at 2pL/mL.
41. The pharmaceutical composition of claim 31 comprising at least 0.50mL/mL water.
42. The pharmaceutical composition of claim 31 wherein the pemetrexed is in the form ofpemetrexed diacid.
43. The pharmaceutical composition of claim 31 wherein the pemetrexed is in the form of pemetrexed disodium.
44. The pharmaceutical composition of claim 31 substantially free of an anti-oxidant.
45. A pharmaceutical composition comprisinga) 25 mg/mL pemetrexed,b) propylene glycol at 250 uL/mL, andc) water;wherein upon dilution with a. pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 24 hours.
46. The pharmaceutical composition of claim 45 wherein upon dilution with a pharmaceutically acceptable diluent to an initial dosage concentration of pemetrexed the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 48 hours. WO 2017/142556 PCT/US2016/018703
47. A pharmaceutical composition comprising:a) pemetrexed at an initial concentration of 10 to 50 mg/mL andb) a non-aqueous solvent present at less than 0.30 mL/mL, wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
48. The pharmaceutical composition of claim 47 wherein the composition comprises no more than 8% w/w total impurities after storage for a period selected from:a) at least 18 months, andb) at least 24 months.
49. The pharmaceutical composition of claim 47 wherein the composition comprises no more than 5% w/w total impurities after storage for a. period selected from:a) at least 12 months,b) at least 18 months, andc) at least 24 months.
50. The pharmaceutical composition of claim 47 wherein the composition comprises no more than 2% w/w total impurities after storage for a period selected from:a) at least 12 months,b) at least 18 months, andc) at least 24 months.
51. The pharmaceutical composition of claim 47 comprising 25 mg/mL- pemetrexed.
52. The pharmaceutical formulation of claim 47 wherein the non-aqueous solvent is selectedfrom the group consisting of propylene glycol, alcohol, polyethylene glycol, or combinations thereof.
53. The pharmaceutical formulation of claim 52 wherein the non-aqueous solvent is propylene glycol. WO 2017/142556 PCT/US2016/018703
54. The pharmaceutical formulation of claim 53 wherein propylene glycol is present at 2uL/mL.
55. The pharmaceutical composition of claim 47 comprising at least 0.50mL/mL water.
56. The pharmaceutical composition of claim 47 wherein the pemetrexed is in the form ofpemetrexed diacid.
57. The pharmaceutical composition of claim 47 wherein the pemetrexed is in the form of pemetrexed disodium.
58. The pharmaceutical composition of claim 47 substantially free of an anti-oxidant.
59. A pharmaceutical composition comprisinga) an initial pemetrexed concentration of 25 mg/mL,b) propylene glycol at 250 pL/mL, andc) water;wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least 12 months.
60. The pharmaceutical composition of claim 59 wherein the composition comprises no more than 8% w/w total impurities after storage at a temperature of 2°C to 8°C for at least months.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2016/018703 WO2017142556A1 (en) | 2016-02-19 | 2016-02-19 | Pemetrexed formulations |
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| IL301291A IL301291A (en) | 2016-02-19 | 2016-02-19 | Pemetrexed formulations |
| IL261179A IL261179B (en) | 2016-02-19 | 2018-08-15 | Pemetrexed formulations |
| IL290647A IL290647B2 (en) | 2016-02-19 | 2022-02-15 | Pemetrexed formulations |
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| IL290647A IL290647B2 (en) | 2016-02-19 | 2022-02-15 | Pemetrexed formulations |
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| CN (1) | CN109152778B (en) |
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| MX (2) | MX2018010037A (en) |
| WO (1) | WO2017142556A1 (en) |
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| US6686365B2 (en) * | 2000-02-04 | 2004-02-03 | Eli Lilly And Company | Pharmaceutical composition |
| US8629152B2 (en) * | 2006-08-14 | 2014-01-14 | Sicor, Inc. | Processes for the preparation of lyophilized pharmaceutically acceptable salts of pemetrexed diacid |
| WO2012015810A2 (en) * | 2010-07-28 | 2012-02-02 | Eagle Pharmaceuticals, Inc. | Pharmaceutical compositions containing pemetrexed having extended storage stability |
| 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 |
| WO2013179310A1 (en) * | 2012-05-31 | 2013-12-05 | Mylan Laboratories Limited | Stable aqueous compositions of pemetrexed |
| JP6099557B2 (en) * | 2013-12-27 | 2017-03-22 | 富士フイルム株式会社 | Injection solution preparation and method for producing the same |
| KR101703980B1 (en) * | 2013-12-30 | 2017-02-08 | 주식회사 삼양바이오팜 | Antioxidant-free pharmaceutical composition and preparation method thereof |
| US20180235969A1 (en) * | 2014-10-16 | 2018-08-23 | Synthon B.V. | Liquid pharmaceutical composition comprising pemetrexed |
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- 2016-02-19 MX MX2018010037A patent/MX2018010037A/en unknown
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- 2016-02-19 EP EP16890851.5A patent/EP3416646A4/en active Pending
- 2016-02-19 CN CN201680084554.1A patent/CN109152778B/en active Active
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| IL290647B2 (en) | 2023-08-01 |
| EP3416646A1 (en) | 2018-12-26 |
| EP3416646A4 (en) | 2019-09-04 |
| MX2018010037A (en) | 2019-07-04 |
| JP2019505561A (en) | 2019-02-28 |
| CA3014755A1 (en) | 2017-08-24 |
| CN109152778A (en) | 2019-01-04 |
| IL261179B (en) | 2022-03-01 |
| CA3014755C (en) | 2023-11-14 |
| MX2022009547A (en) | 2022-09-09 |
| KR20180132643A (en) | 2018-12-12 |
| IL261179A (en) | 2018-10-31 |
| IL290647B1 (en) | 2023-04-01 |
| AU2016393213B2 (en) | 2022-03-31 |
| AU2023202089A1 (en) | 2023-06-01 |
| AU2016393213A1 (en) | 2018-10-04 |
| IL312427A (en) | 2024-06-01 |
| WO2017142556A1 (en) | 2017-08-24 |
| KR20240049356A (en) | 2024-04-16 |
| CN109152778B (en) | 2021-08-10 |
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