JP6366685B2 - 安定した高強度のレボロイコボリン医薬組成物 - Google Patents
安定した高強度のレボロイコボリン医薬組成物 Download PDFInfo
- Publication number
- JP6366685B2 JP6366685B2 JP2016510964A JP2016510964A JP6366685B2 JP 6366685 B2 JP6366685 B2 JP 6366685B2 JP 2016510964 A JP2016510964 A JP 2016510964A JP 2016510964 A JP2016510964 A JP 2016510964A JP 6366685 B2 JP6366685 B2 JP 6366685B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- salt
- aqueous pharmaceutical
- calcium
- composition according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 title claims description 45
- 229940008678 levoleucovorin Drugs 0.000 title claims description 41
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000000176 sodium gluconate Substances 0.000 claims description 19
- 235000012207 sodium gluconate Nutrition 0.000 claims description 19
- 229940005574 sodium gluconate Drugs 0.000 claims description 19
- 150000003751 zinc Chemical class 0.000 claims description 19
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 claims description 18
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 claims description 17
- 239000004224 potassium gluconate Substances 0.000 claims description 17
- 235000013926 potassium gluconate Nutrition 0.000 claims description 17
- 229960003189 potassium gluconate Drugs 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 15
- 159000000007 calcium salts Chemical class 0.000 claims description 15
- 239000003963 antioxidant agent Substances 0.000 claims description 13
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 11
- 230000003078 antioxidant effect Effects 0.000 claims description 11
- 239000011777 magnesium Substances 0.000 claims description 11
- 229910052749 magnesium Inorganic materials 0.000 claims description 11
- AVPCPPOOQICIRJ-UHFFFAOYSA-L sodium glycerol 2-phosphate Chemical compound [Na+].[Na+].OCC(CO)OP([O-])([O-])=O AVPCPPOOQICIRJ-UHFFFAOYSA-L 0.000 claims description 11
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 claims description 10
- 239000000872 buffer Substances 0.000 claims description 9
- 229940047417 levoleucovorin calcium Drugs 0.000 claims description 9
- 239000008176 lyophilized powder Substances 0.000 claims description 8
- 159000000003 magnesium salts Chemical class 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 7
- 239000011575 calcium Substances 0.000 claims description 7
- 229910052791 calcium Inorganic materials 0.000 claims description 7
- CHFUHGDBYUITQJ-UHFFFAOYSA-L dipotassium;2,3-dihydroxypropyl phosphate Chemical compound [K+].[K+].OCC(O)COP([O-])([O-])=O CHFUHGDBYUITQJ-UHFFFAOYSA-L 0.000 claims description 6
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 6
- 229940035024 thioglycerol Drugs 0.000 claims description 6
- -1 glycerophosphate dipotassium salt Chemical class 0.000 claims description 5
- 230000003139 buffering effect Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 229960000281 trometamol Drugs 0.000 claims description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 claims description 2
- 239000007995 HEPES buffer Substances 0.000 claims description 2
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 claims 1
- 239000000174 gluconic acid Substances 0.000 claims 1
- 235000012208 gluconic acid Nutrition 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 47
- 239000000243 solution Substances 0.000 description 32
- 238000003860 storage Methods 0.000 description 12
- 239000013618 particulate matter Substances 0.000 description 11
- 235000006708 antioxidants Nutrition 0.000 description 10
- 238000001556 precipitation Methods 0.000 description 10
- 239000008186 active pharmaceutical agent Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000001540 sodium lactate Substances 0.000 description 8
- 235000011088 sodium lactate Nutrition 0.000 description 8
- 229940005581 sodium lactate Drugs 0.000 description 8
- 229940088679 drug related substance Drugs 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- PHZLMBHDXVLRIX-UHFFFAOYSA-M potassium lactate Chemical compound [K+].CC(O)C([O-])=O PHZLMBHDXVLRIX-UHFFFAOYSA-M 0.000 description 7
- 239000001521 potassium lactate Substances 0.000 description 7
- 235000011085 potassium lactate Nutrition 0.000 description 7
- 229960001304 potassium lactate Drugs 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000010525 oxidative degradation reaction Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- QYNUQALWYRSVHF-OLZOCXBDSA-N (6R)-5,10-methylenetetrahydrofolic acid Chemical group C([C@H]1CNC=2N=C(NC(=O)C=2N1C1)N)N1C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QYNUQALWYRSVHF-OLZOCXBDSA-N 0.000 description 2
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000008207 calcium folinate Nutrition 0.000 description 2
- 239000011687 calcium folinate Substances 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 229960002293 leucovorin calcium Drugs 0.000 description 2
- 229940075961 levoleucovorin calcium pentahydrate Drugs 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- VVIAGPKUTFNRDU-OLZOCXBDSA-N (2s)-2-[[4-[[(6r)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioic acid Chemical compound C([C@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-OLZOCXBDSA-N 0.000 description 1
- ZNOVTXRBGFNYRX-OLZOCXBDSA-N (2s)-2-[[4-[[(6r)-2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioic acid Chemical compound C([C@H]1N(C=2C(=O)NC(N)=NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-OLZOCXBDSA-N 0.000 description 1
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical class C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- MSTNYGQPCMXVAQ-NEPJUHHUSA-N 6R-Tetrahydrofolic acid Chemical class C([C@@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-NEPJUHHUSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 239000013011 aqueous formulation 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
- 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
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- ARRNBPCNZJXHRJ-UHFFFAOYSA-M hydron;tetrabutylazanium;phosphate Chemical compound OP(O)([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC ARRNBPCNZJXHRJ-UHFFFAOYSA-M 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- YZYKBQUWMPUVEN-UHFFFAOYSA-N zafuleptine Chemical compound OC(=O)CCCCCC(C(C)C)NCC1=CC=C(F)C=C1 YZYKBQUWMPUVEN-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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
Claims (13)
- レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩、任意に、薬学的に許容される緩衝化合物、任意に、薬学的に許容される抗酸化化合物、および、グルコン酸ナトリウム、グルコン酸カリウム、グリセロリン酸ジナトリウム塩またはグリセロリン酸ジカリウム塩のうちの1つ又は複数を含有することを特徴とする、レボロイコボリンを含有する水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、前記緩衝化合物がトロメタモールおよびHEPESからなる群から選択されることを特徴とする、前記水性医薬組成物。
- 請求項2に記載された水性医薬組成物において、前記緩衝化合物の濃度が5乃至50mMであることを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、前記抗酸化化合物は、チオグリセロール、ジチオトレイドールおよびシステインの群から選択され、前記抗酸化化合物の量は、0.1%乃至1.0%(w/v)であることを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩1モルに対して、グルコン酸ナトリウムまたはグルコン酸カリウムを0.8乃至6.0モル含有することを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩1モルに対して、グリセロリン酸ジナトリウム塩またはグリセロリン酸ジカリウム塩を0.4乃至4.0モル含有することを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、(遊離酸として計算して)水1ml中に、レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩を7乃至300mg含有することを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、(遊離酸として計算して)水1ml中に、レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩を7乃至100mg含有し、且つ、0.8乃至6.0モルのグルコン酸ナトリウムまたはグルコン酸カリウムを含有することを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、(遊離酸として計算して)水1ml中に、レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩を7乃至100mg含有し、且つ、0.4乃至4.0モルのグリセロリン酸ジナトリウム塩またはグリセロリン酸ジカリウム塩を含有することを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、レボロイコボリンのカルシウム塩(レボロイコボリンカルシウム、遊離酸として計算)を7乃至100mg含有し、且つ、1.5乃至3.0モルのグルコン酸ナトリウムまたはグルコン酸カリウムを含有することを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、(遊離酸として計算して)水1ml中に、レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩を50乃至300mg含有し、且つ、1.5乃至3.0モルのグルコン酸ナトリウムまたはグルコン酸カリウムを含有することを特徴とする、前記水性医薬組成物。
- 請求項1に記載された水性医薬組成物において、(遊離酸として計算して)水1ml中に、レボロイコボリンのカルシウム塩、マグネシウム塩または亜鉛塩を50乃至300mg含有し、且つ、0.4乃至4.0モルのグリセロリン酸ジナトリウム塩またはグリセロリン酸ジカリウム塩を含有することを特徴とする、前記水性医薬組成物。
- 凍結乾燥粉末製造における、請求項1乃至12のうちのいずれか一項に記載された水性医薬組成物の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13002298.1A EP2799060A1 (en) | 2013-04-30 | 2013-04-30 | Stable high dose pharmaceutical composition comprising levoleucovorin |
EP13002298.1 | 2013-04-30 | ||
PCT/EP2014/001152 WO2014177273A1 (en) | 2013-04-30 | 2014-04-30 | Stable high strength pharmaceutical composition of levoleucovorin |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016519122A JP2016519122A (ja) | 2016-06-30 |
JP6366685B2 true JP6366685B2 (ja) | 2018-08-01 |
Family
ID=48226927
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016510964A Active JP6366685B2 (ja) | 2013-04-30 | 2014-04-30 | 安定した高強度のレボロイコボリン医薬組成物 |
Country Status (7)
Country | Link |
---|---|
US (1) | US9301922B1 (ja) |
EP (2) | EP2799060A1 (ja) |
JP (1) | JP6366685B2 (ja) |
AU (1) | AU2014261790B2 (ja) |
ES (1) | ES2719348T3 (ja) |
PL (1) | PL2991618T3 (ja) |
WO (1) | WO2014177273A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102014004512A1 (de) * | 2014-03-28 | 2015-10-01 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts Bereich Universitätsmedizin | Anorganisch-organische Hybridverbindung |
KR101683635B1 (ko) | 2014-12-29 | 2016-12-09 | 가천대학교 산학협력단 | 락테이트 금속염을 포함하는 암 치료용 약학 조성물 |
EP3461826A1 (en) | 2017-09-29 | 2019-04-03 | Aprofol AG | Multifunctional folate salts |
CN111587110A (zh) | 2018-01-12 | 2020-08-25 | 麦提麦迪制药有限公司 | 治疗慢性炎症性疾病的方法 |
EP3586849A1 (en) * | 2018-06-29 | 2020-01-01 | Aprofol AG | Folate preparations |
EP3646873A1 (en) | 2018-10-31 | 2020-05-06 | Aprofol AG | Folate salts |
US20210393636A1 (en) * | 2019-02-28 | 2021-12-23 | Clark Gerald Sullivan | Treatment of cns and developmental disorders using high dose 5-formyl-(6s)-tetrahydrofolate |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4931441A (en) | 1988-11-09 | 1990-06-05 | Luitpold Pharmaceuticals, Inc. | Stabilized aqueous leucovorin calcium compositions |
DK0416232T3 (da) * | 1989-08-21 | 1995-09-18 | American Cyanamid Co | Stabil injicerbar farmaceutisk formulering med folsyre- og leukovorinsalte og fremgangsmåde |
CA2410885C (en) | 2000-06-02 | 2010-07-13 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Composition for the treatment and/or the prevention of osteoporosis and/or inflammatory joint diseases |
CH697021A5 (de) * | 2003-06-26 | 2008-03-31 | Merck Eprova Ag | Stabile pharmazeutische Zusammensetzungen von 5, 10-Methylentetrahydrofolat. |
ATE498401T1 (de) | 2004-09-15 | 2011-03-15 | Nipro Corp | Wässrige, stabile (6s)-folinsäurelösung zur injektion |
JP4956942B2 (ja) * | 2004-09-15 | 2012-06-20 | ニプロ株式会社 | 安定化された注射用水溶液製剤 |
ES2704986T3 (es) * | 2008-10-16 | 2019-03-21 | Celator Pharmaceuticals Inc | Combinaciones de una camptotecina liposomal soluble en agua con cetuximab o bevacizumab |
-
2013
- 2013-04-30 EP EP13002298.1A patent/EP2799060A1/en not_active Withdrawn
-
2014
- 2014-04-30 AU AU2014261790A patent/AU2014261790B2/en active Active
- 2014-04-30 ES ES14721211T patent/ES2719348T3/es active Active
- 2014-04-30 PL PL14721211T patent/PL2991618T3/pl unknown
- 2014-04-30 WO PCT/EP2014/001152 patent/WO2014177273A1/en active Application Filing
- 2014-04-30 US US14/787,984 patent/US9301922B1/en active Active
- 2014-04-30 JP JP2016510964A patent/JP6366685B2/ja active Active
- 2014-04-30 EP EP14721211.2A patent/EP2991618B8/en active Active
Also Published As
Publication number | Publication date |
---|---|
US20160081926A1 (en) | 2016-03-24 |
EP2799060A1 (en) | 2014-11-05 |
AU2014261790B2 (en) | 2018-11-29 |
AU2014261790A1 (en) | 2015-11-12 |
PL2991618T3 (pl) | 2019-08-30 |
EP2991618A1 (en) | 2016-03-09 |
US9301922B1 (en) | 2016-04-05 |
ES2719348T3 (es) | 2019-07-09 |
EP2991618B1 (en) | 2019-01-09 |
WO2014177273A1 (en) | 2014-11-06 |
EP2991618B8 (en) | 2019-05-15 |
JP2016519122A (ja) | 2016-06-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6366685B2 (ja) | 安定した高強度のレボロイコボリン医薬組成物 | |
US9642853B2 (en) | Stable pharmaceutical composition containing folates | |
JP3357376B2 (ja) | 安定な凍結乾燥医薬処方 | |
RU2620341C2 (ru) | Стабилизированная композиция пеметрекседа | |
AU2014227660B2 (en) | Ceftolozane antibiotic compositions | |
CA2948148C (en) | Formulations of cyclophosphamide liquid concentrate | |
JP6879582B2 (ja) | ビオプテリン誘導体を含む固体薬学的組成物およびそのような組成物の使用 | |
JP6182262B2 (ja) | 抗がん剤を含む安定な水溶性医薬組成物 | |
US9061016B2 (en) | Aqueous solution comprising 3-quinuclidinones for the treatment hyperproliferative, autoimmune and heart disease | |
JP6942182B2 (ja) | カルグルミン酸を含有する非経口的薬剤配合物 | |
JP2014237607A (ja) | ペメトレキセドを含む注射用組成物 | |
CZ2002788A3 (cs) | Farmaceutické roztoky levosimendanu | |
UA59376C2 (uk) | Стабілізована фармацевтична композиція на основі хінупристину та дальфопристину та спосіб її одержання | |
US10945947B2 (en) | Formulations for intravenous administration | |
JP2014037377A (ja) | 医薬製剤およびその製造方法 | |
JP2014037379A (ja) | 医薬製剤およびその製造方法 | |
CN109674744B (zh) | 稳定的盐酸替罗非班液体组合物及其制备方法 | |
WO2012093404A2 (en) | Parenteral formulations of levosimendan | |
JP2012188421A (ja) | シベレスタットナトリウム塩又はその水和物を含有する注射用製剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170428 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180115 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180414 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180427 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20180607 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180703 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6366685 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |