CN1842337B - 稳定的5,10-亚甲基四氢叶酸盐药物组合物 - Google Patents
稳定的5,10-亚甲基四氢叶酸盐药物组合物 Download PDFInfo
- Publication number
- CN1842337B CN1842337B CN2004800177913A CN200480017791A CN1842337B CN 1842337 B CN1842337 B CN 1842337B CN 2004800177913 A CN2004800177913 A CN 2004800177913A CN 200480017791 A CN200480017791 A CN 200480017791A CN 1842337 B CN1842337 B CN 1842337B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- methylene
- tetrahydrofolic acid
- vitamin
- composition
- 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.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 9
- QYNUQALWYRSVHF-OLZOCXBDSA-N (6R)-5,10-methylenetetrahydrofolic acid Chemical compound 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 title description 5
- 239000000203 mixture Substances 0.000 claims abstract description 26
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 8
- MSTNYGQPCMXVAQ-KIYNQFGBSA-N 5,6,7,8-tetrahydrofolic acid Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-KIYNQFGBSA-N 0.000 claims description 31
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 10
- 235000019152 folic acid Nutrition 0.000 claims description 10
- 229960003180 glutathione Drugs 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 159000000007 calcium salts Chemical class 0.000 claims description 7
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 7
- 229940035024 thioglycerol Drugs 0.000 claims description 7
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 claims description 7
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 6
- 229930003268 Vitamin C Natural products 0.000 claims description 6
- 229930003427 Vitamin E Natural products 0.000 claims description 6
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 235000003969 glutathione Nutrition 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 235000019154 vitamin C Nutrition 0.000 claims description 6
- 239000011718 vitamin C Substances 0.000 claims description 6
- 235000019165 vitamin E Nutrition 0.000 claims description 6
- 229940046009 vitamin E Drugs 0.000 claims description 6
- 239000011709 vitamin E Substances 0.000 claims description 6
- 239000002398 materia medica Substances 0.000 claims description 5
- 229940035893 uracil Drugs 0.000 claims description 5
- 229940014144 folate Drugs 0.000 claims description 4
- 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 claims description 4
- 239000011724 folic acid Substances 0.000 claims description 4
- -1 many Xi Taqi Chemical compound 0.000 claims description 4
- 239000005460 tetrahydrofolate Substances 0.000 claims description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- 229930192392 Mitomycin Natural products 0.000 claims description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 3
- 229960004397 cyclophosphamide Drugs 0.000 claims description 3
- 229940088013 hycamtin Drugs 0.000 claims description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- 229960004857 mitomycin Drugs 0.000 claims description 3
- 229960001603 tamoxifen Drugs 0.000 claims description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
- 229960004528 vincristine Drugs 0.000 claims description 3
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 2
- 229930195573 Amycin Natural products 0.000 claims description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 2
- 239000012752 auxiliary agent Substances 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims description 2
- 229950005454 doxifluridine Drugs 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 2
- 229960005420 etoposide Drugs 0.000 claims description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 2
- 229960001101 ifosfamide Drugs 0.000 claims description 2
- 229960004768 irinotecan Drugs 0.000 claims description 2
- 229960001756 oxaliplatin Drugs 0.000 claims description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 claims description 2
- 229960001674 tegafur Drugs 0.000 claims description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims 5
- 229960004308 acetylcysteine Drugs 0.000 claims 5
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound 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 claims 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 3
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims 1
- 229930012538 Paclitaxel Natural products 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 229960004117 capecitabine Drugs 0.000 claims 1
- 239000002131 composite material Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 229960005277 gemcitabine Drugs 0.000 claims 1
- 229960001592 paclitaxel Drugs 0.000 claims 1
- 229960005079 pemetrexed Drugs 0.000 claims 1
- 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 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 35
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 abstract description 30
- 230000006641 stabilisation Effects 0.000 abstract description 9
- 239000007864 aqueous solution Substances 0.000 abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003638 chemical reducing agent Substances 0.000 abstract description 5
- 238000004108 freeze drying Methods 0.000 abstract description 5
- 239000007924 injection Substances 0.000 abstract description 5
- 238000002347 injection Methods 0.000 abstract description 5
- 239000000843 powder Substances 0.000 abstract description 4
- MSTNYGQPCMXVAQ-NEPJUHHUSA-N 6R-Tetrahydrofolic acid Chemical compound 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 abstract 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract 1
- 229910052791 calcium Inorganic materials 0.000 abstract 1
- 239000011575 calcium Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 16
- 150000002148 esters Chemical class 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 150000002224 folic acids Chemical class 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 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 5
- 239000000126 substance Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 108010022394 Threonine synthase Proteins 0.000 description 4
- 102000005497 Thymidylate Synthase Human genes 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CIWBSHSKHKDKBQ-SZSCBOSDSA-N 2-[(1s)-1,2-dihydroxyethyl]-3,4-dihydroxy-2h-furan-5-one Chemical compound OC[C@H](O)C1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-SZSCBOSDSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002211 L-ascorbic acid Substances 0.000 description 2
- 235000000069 L-ascorbic acid Nutrition 0.000 description 2
- 239000004201 L-cysteine Substances 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 125000003047 N-acetyl group Chemical group 0.000 description 2
- 108010020346 Polyglutamic Acid Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229920002643 polyglutamic acid Polymers 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- OQJVXNHMUWQQEW-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazine Chemical compound C1CNC=CN1 OQJVXNHMUWQQEW-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- QYNUQALWYRSVHF-ABLWVSNPSA-N 5,10-methylenetetrahydrofolic acid Chemical compound C1N2C=3C(=O)NC(N)=NC=3NCC2CN1C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QYNUQALWYRSVHF-ABLWVSNPSA-N 0.000 description 1
- UEJQGOKMPMUMTO-UHFFFAOYSA-N C(C#C)OC1=NC=C(C(=N1)OCC#C)F Chemical compound C(C#C)OC1=NC=C(C(=N1)OCC#C)F UEJQGOKMPMUMTO-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 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 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101100166829 Mus musculus Cenpk gene Proteins 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- GKJSPWCDMPVQHB-KZCZEQIWSA-N OS(O)(=O)=O.Nc1nc2NC[C@@H]3CN(CN3c2c(=O)[nH]1)c1ccc(cc1)C(=O)N[C@@H](CCC(O)=O)C(O)=O Chemical compound OS(O)(=O)=O.Nc1nc2NC[C@@H]3CN(CN3c2c(=O)[nH]1)c1ccc(cc1)C(=O)N[C@@H](CCC(O)=O)C(O)=O GKJSPWCDMPVQHB-KZCZEQIWSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- JSRLJPSBLDHEIO-SHYZEUOFSA-N dUMP Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 JSRLJPSBLDHEIO-SHYZEUOFSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940087477 ellence Drugs 0.000 description 1
- 229940120655 eloxatin Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940090411 ifex Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nutrition Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及通过将pH值调节到碱性范围并同时使用柠檬酸盐而得到的稳定的5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸盐或酯类药物组合物。该稳定化本身在不存在还原剂的情况下实现。由于稳定的MTHF溶液可以在高浓度下装入相应的容器例如管形瓶、安瓿瓶等中，本发明特别适合用来制备冻干溶液和冻干物或者干燥粉和干混物。所述冻干物的储存性出乎意料的好且稳定。通过添加水或含水溶液可以顺利地重新构建，其中形成的清澈的注射液重新获得优越的稳定性。此外，本发明也可以将MTHF的本身难溶的钙盐或酸式盐以高浓度且作为生理兼容的等渗溶液制备。
Description
本发明涉及稳定的5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸盐或酯类药物组合物。
在本文中，术语5，10-亚甲基四氢叶酸盐或酯类(缩写为MTHF)指以游离酸、药物学兼容的盐、特别是酸式盐以及碱金属或碱土金属盐形式的5，10-亚甲基四氢叶酸及其聚谷氨酸酯。5，10-亚甲基四氢叶酸及其聚谷氨酸酯既包括各种旋光异构体的混合物，特别是1∶1的非对映异构体混合物，而且也包括纯的非对映异构体。特别是旋光纯的天然5，10-亚甲基-(6R)-四氢叶酸。
药物学兼容的盐可以是酸式盐，例如是硫酸盐或磺酸盐，优选硫酸盐，也可以是碱金属盐或碱土金属盐，例如钠、钾、镁或钙盐。
MTHF是一种与氟化的嘧啶如5-氟化尿嘧啶(5-FU)(一种宽范围的治疗实体肿瘤的细胞生长抑制剂(Zytostatikum))联合使用的优选胃肠外应用的活性物质[CoFactor Biokeys Pharmaceuticals.Seley，K.L.IDrugs 4(1)，99-101(2001)]。MTHF是一种经还原的叶酸盐，与碱性类似物5-FdUMP一起通过抑制胸苷酸合酶(TS)来实现化学治疗作用，后者对脱氧尿苷酸(dUMP)转化成为脱氧胸苷酸(dTMP)的反应起催化作用，脱氧胸苷酸是DNS合成的核心要素。由于该步骤是细胞内脱氧胸苷酸的唯一从头的(de novo)来源，通过使用氟化的嘧啶碱如5-FU或5-FU前药卡培他滨(Xeloda)来抑制该关键的酶是肿瘤治疗的主要切入点。TS的失活通过在TS、碱性类似物5-FdUMP与MTHF之间形成一种共价的抑制性三元复合物来实现，其中5-FdUMP是5-FU的一种代谢产物。5-FU细胞毒作用的加强可以通过细胞内MTHF浓度的提高来实现，其中三元复合物的稳定性同时提高。这引起了对DNS合成和修复的直接抑制，最终导致细胞死亡和肿瘤生长的延缓。
MTHF的药学应用由于其对于空气氧化具有特别高的敏感性而受到限制[Chemical Stability and Human Plasma Pharmacokinetics of Reduced Folates.Odin，E.et al，Cancer Investigation 16(7)，447-455(1998)，The Structureof“Active Formaldehyde”(N5，N10-Methylene Tetrahydrofolic Acid)Osborn，M.J.et al.J.Am.Chem.Soc.82，4921-4927(1960)，Folates in foods：Reactivity，stability during processing，and nutritional implications.Hawkes，J.and Villota，R.Food Sci.Nutr.28，439-538(1989)]。MTHF是四氢叶酸(THF)和甲醛的加合物[5，10-Methylene-5，6，7，8-tetrahydrofolate.Conformation of the Tetrahydropyrazine andImidazolidine Rings.Poe，M.et al.Biochemistry 18(24)，5527-5530(1979)，Tetrahydrofolic Acid and Formaldehyde.Kallen，R.G.Methods inEnzymology 18B，705-716(1971)]。MTHF一方面与THF和甲醛另一方面在含水溶液中保持平衡。为了稳定MTHF溶液，迄今为止采取了以下措施：
通过使用特殊的工业设备来严格排除空气氧，以便重新构建固体配制剂，并在没有空气的环境下注射MTHF[Chemical Stability and Human PlasmaPharmacokinetics of Reduced Folates.Odin，E.et al.Cancer Investigation16(7)，447-455(1998)，Fluid Transfer Systems US 4564054]。
添加一种还原剂如L(+)-抗坏血酸及其盐类、还原的γ-谷胱甘肽、β-氢硫基乙醇、硫代甘油、N-乙酰基-L-半胱氨酸等作为敏感的MTHF和特别是THF的氧化保护。
借助于EP0579996(Eprova)的环糊精嵌入化合物实现稳定化。使用高浓度的活性物质。
为了稳定其它四氢叶酸衍生物，还公开了以下方法：
如EP0755396(Pharmachemie)所述，通过添加柠檬酸钠、醋酸钠或氯化钠来稳定含有5-甲酰基四氢叶酸的溶液。
如EP0677159(SAPEC)所述，在pH值为7.5-8.5之间来稳定含有5-甲酰基四氢叶酸的钠盐或钾盐的注射液。
如US4931441(Luitpold Pharmaceutical)所述，通过添加柠檬酸钠来稳定含有5-甲酰基四氢叶酸的钙盐的溶液。
然而，5-甲酰基四氢叶酸特别是英溶液的稳定化并不能与5，10-亚甲基四氢叶酸溶液的稳定化相提并论。在5，10-亚甲基四氢叶酸中的五元环中结合的亚甲基，与5-甲酰基四氢叶酸相比，它具有显然不同的物质特性。其表现为例如明显另一种稳定行为和另一种降解途径。与5-甲酰基四氢叶酸相反，5，10-亚甲基四氢叶酸在溶液中总是与甲醛和四氢叶酸(THF)保持平衡，这表现为极高的氧化敏感性。与此相反，5-甲酰基四氢叶酸不具有这种离解行为，且作为一种药物学兼容的含水溶液通常非常稳定，即使不添加柠檬酸钠和氢氧化钠也行。
因此，迄今还没有公开过任何稳定的MTHF药物组合物。
现发明人出人意料地发现，通过调节pH值到一个碱性范围并同时使用柠檬酸盐，可以显著提高在含水溶液、悬浮液和固体形式例如粉末或冻干物(Lyophilisaten)中的MTHF的稳定性。出乎意料的是，该稳定化是在不存在还原剂的情况下实现的。
因此，不用添加还原剂(抗氧化剂)且不用排除空气氧即可使MTHF溶液稳定数小时。更加出乎意料的是，在用醋酸盐、草酸盐、马来酸盐和其它酸类代替柠檬酸盐的情况下根本得不到MTHF的稳定组合物。相反，在5-甲酰基四氢叶酸的情况下，使用醋酸盐可以得到与柠檬酸盐相类似的效果(EP0755396)。柠檬酸盐在5-甲酰基四氢叶酸溶液中降低骨架的水解和氧化分解，由此减少产物如邻氨基苯酰基谷氨酸、蝶呤和四氢蝶呤衍生物的形成。与此相反，在MTHF的碱性范围内，柠檬酸盐抑制甲醛从分子中裂解(水解)。这在这两种同属于叶酸盐物质类别的化合物的行为中是一个显著的、惊人的区别。
本发明经此使得MTHF的难溶性钙盐或酸式盐[Eprova的5，10-亚甲基四氢叶酸稳定盐专利EP0537492]在高浓度生理兼容的等渗溶液中的制备成为可能。
由柠檬酸盐在碱性pH范围引起的无法预期的MTHF的稳定化基于柠檬酸盐缓冲液在该pH范围出乎意料的协同作用。一方面在柠檬酸盐与MTHF之间、另一方面在柠檬酸盐与MTHF的抗衡离子(盐)之间的复合物形成，通过抑制甲醛由MTHF分子裂解(水解)，对亚甲基的稳定化作出了决定性的贡献。由此阻止了氧化极敏感的THF的产生和MTHF的分解。
在本发明的组合物中，pH值范围调节到7.5-10.5，优选8.5-9.5。这借助于氢氧化钠溶液、盐酸在MTHF溶液中实现，该溶液含有柠檬酸、二氢柠檬酸钠或柠檬酸三钠二水合物作为稳定化物质和缓冲物质。同样也可以添加还原剂例如L(+)-抗坏血酸或其盐类、还原的γ-谷胱甘肽、β-氢硫基乙醇、硫代甘油、N-乙酰基-L-半胱氨酸等作为氧化保护。
本发明的配制剂也特别适合于制备冻干溶液和冻干物或干燥粉和干混物，因为可以将稳定的MTHF溶液以高浓度装入到相应的容器例如管形瓶、安瓿瓶等中。所术冻干物具有出乎意料的良好储存性和稳定性。通过添加水或含水溶液，可以顺利地重新构建，并使得所形成的清澈的注射液重新具有优越的稳定性质。
要求保护的配制剂优选胃肠外施用。当然，由冻干物和配制剂也可以制备成肠内给药(例如口服、舌下或直肠给药)或者局部施用(例如透皮)的剂型。
这些配制剂优选直接作为水基的溶液或油基的悬浮液或者作为冻干物施用。胃肠外施用的制剂含有活性化合物的无菌含水和不含水的注射溶液和悬浮液，它们优选为等渗组合物。
所述配制剂也可以与载体一起服用。可以使用与活性物质不发生反应的有机或无机物质作为载体，例如水、油、苄基醇、聚乙二醇、甘油三醋酸酯或者其它的脂肪酸甘油酯、明胶、卵磷脂、环糊精、碳水化合物如乳二糖或淀粉、硬脂酸镁、滑石粉或纤维素。口服施用优选片剂、糖衣药丸、胶囊、粉剂、糖浆、浓缩物或滴剂，直肠施用优选栓剂。
同样可以使用悬浮液、乳液或植入体，局部施用可用膏剂或霜剂。
所述制剂可以含有稳定剂、控制药物活性化合物释放的添加剂、抗氧化剂、缓冲剂、抑菌剂和用于调节等渗溶液用的助剂。含水和不含水的无菌悬浮液可以含有悬浮液添加物和增稠剂。所述制剂可以放在单一剂量或多次剂量容器中，例如放在带栓塞和密封盖的熔封安瓿瓶或管形瓶中，可以作为冷冻干燥(冻干的)的产物存放，在需要时用无菌液体例如水或生理盐溶液提供使用。以此方式也可以使用无菌粉末、颗粒或片剂。
所有制剂还可以含有一或多种单独或有协同作用的活性化合物。它们是氟化的嘧啶碱，例如5-氟化尿嘧啶(5-FU)、卡培他滨(Xeloda)、替加氟、UFT、去氧氟尿苷、2’-脱氧-5-氟代尿苷，各种细胞生长抑制剂，例如吉西他滨(Gemzar)、多西他奇(Taxotere)、紫杉醇(Taxol)、托泊替康(Hycamtin)、依立替康(CPT-11)、阿霉素(Rubex)、丝裂霉素(MTC)、顺铂(CDDP)、环磷酰胺(CPM)、甲氨蝶呤(氨甲蝶呤)、培美曲塞(Alimta)、长春新碱(VCR)、阿糖胞苷(Ara-C)、表柔比星(Ellence)、奥沙利铂(Eloxatin)、它莫昔芬(三苯氧胺)、卡铂(CBDCA)、依托泊甙(Etopophos)、异环磷酰胺(Ifex)，或者抗氧化剂，例如维生素C、维生素E、谷胱甘肽、硫代甘油、酰基半胱氨酸，以及两种MTHF的离解产物甲醛和四氢叶酸。
每剂量的制剂含有0.001mg-10000mg MTHF。治疗时使用每剂量含有1mg-1000mg MTHF的制剂。
剂量取决于治疗方式、制剂的施用方式、病人的年龄、体重、营养和状态。治疗可以由在最佳剂量以下的低剂量开始，逐步提高剂量以达到最佳的治疗效果。优选的治疗剂量在每天1mg和1000mg之间变化，特别是每天100mg和500mg之间。可以一次性服用，也可以多次服用。
该制剂可以用于所有叶酸盐或酯类的应用领域。
基于上述描述，本领域的技术人员可以直接采用本发明的决定性要素，而不偏离本发明的基本思路和范围，即可作出各种改进和补充，由此使得本发明适合于各种不同的需求和条件。
本文引用的所有申请、专利及出版物公开的所有内容，都通过参考而包括在内。
下面的实施例通过更换常见或特殊描述的产物和/或本发明下述实施例所采用的工艺条件，可以得到类似的效果。同样，以下具体描述的实施方式纯粹是举例性的，根本不应当视为限制本发明公开的范围。
用于详细解释本发明的实施例
实施例1
含有5，10-亚甲基-(6R，S)-四氢叶酸的冻干物
用氩气饱和9900毫升水。在搅拌条件下向其完全溶入421.9g柠檬酸。添加232.0g 5，10-亚甲基-(6R，S)-四氢叶酸的钙盐。用氢氧化钠溶液将pH值调节到8.0，其中5，10-亚甲基-(6R，S)-四氢叶酸缓慢地溶解。此后用氢氧化钠溶液将pH值调节到8.5。将溶液在无菌条件下过滤，在10ml的玻璃管形瓶中每瓶装入5.0ml。此后使溶液冻结并冷冻干燥。
得到若干含有5，10-亚甲基-(6R，S)-四氢叶酸的管形瓶。
实施例2
5，10-亚甲基-(6R，S)-四氢叶酸(冻干物)的稳定化
按实施例1制备的管形瓶显示了以下的稳定值(Am 1466-A)：
在+4℃存放(相对稳定性％)
在-15℃存放(相对稳定性％)
与此相比，未经处理的5，10-亚甲基-(6R)-四氢叶酸的钙盐的对照样品显示了以下稳定值(Co 751)：
在+25℃存放(相对稳定性％)
实施例3
5，10-亚甲基-(6R，S)-四氢叶酸(溶液)的稳定化
按实施例1制备的组合物作为生理食盐溶液中的稀释溶液显示了以下的稳定值(AC 0448)：
在+25℃存放(相对稳定性％)，未排除空气
按实施例1制备的细合物作为稀释的含水溶液显示了以下的稳定值(AC0447)：
在+25℃存放(相对稳定性％)，未排除空气
按实施例1制备的组合物作为浓缩的水溶液显示了以下的稳定值(AC0447)：
在+25℃存放(相对稳定性％)，未排除空气
在现有技术中可以找到5，10-亚甲基-(6R，S)-四氢叶酸的钙盐在生理食盐溶液中的数据作为对比，其稳定性数值如下[参见Chemical Stability andHuman Plasma Pharmacokinetics of Reduced Folates.Odin，E.et al.CancerInvestigation 16(7)，447-455(1998)]：
在+25℃存放(相对稳定性％)
实施例4
含有5，10-亚甲基-(6R)-四氢叶酸的片剂
用氩气饱和990升水。在搅拌条件下向其完全溶入42.2kg柠檬酸。添加21.4kg 5，10-亚甲基-(6R)-四氢叶酸的游离酸。用氢氧化钠溶液将pH值调节到8.0，其中5，10-亚甲基-(6R)-四氢叶酸缓慢地溶解。此后用氢氧化钠溶液将pH值调节到8.5。将溶液在无菌条件下过滤并冷冻干燥。将含有1000g 5，10-亚甲基-(6R)-四氢叶酸的冻干物与4kg乳糖、1.2kg淀粉、0.2kg滑石粉和0.1kg硬脂酸镁一起压片，使得每片含有100mg 5，10-亚甲基-(6R)-四氢叶酸。
该片剂也可以涂层成为包膜片剂。
实施例5
含有5-亚甲基-(6R，S)-四氢叶酸的栓剂
用50g羟丙基纤维素和2kg半合成的甘油酯将按照实施例1制备的含有500g 5，10-亚甲基-(6R，S)-四氢叶酸的冻干物熔化成栓剂，使得每个栓剂含有500mg 5，10-亚甲基-(6R，S)-四氢叶酸。
实施例6
含有尤其是5，10-亚甲基-(6R，S)-四氢叶酸和5-氟化尿嘧啶的联合制剂
类似于实施例1、4、5和7制备一种联合制剂，除了含有对于相应地应用常规量的5，10-亚甲基-(6R，S)-四氢叶酸以外，还含有对于该应用是常规量的5-氟化尿嘧啶。
实施例7
含有5，10-亚甲基-(6R)-四氢叶酸的冻干物
用氩气饱和9900ml水。在搅拌条件下向其完全溶入316.5g柠檬酸。添加212.5g 5，10-亚甲基-(6R)-四氢叶酸的硫酸盐。用氢氧化钠溶液将pH值调节到8.0，其中5，10-亚甲基-(6R)-四氢叶酸硫酸盐缓慢地溶解。此后用氢氧化钠溶液将pH值调节到8.5。将溶液在无菌条件下过滤，在10ml的玻璃管形瓶中每瓶装入5.0ml。此后使溶液冻结并冷冻干燥。
得到若干含有5，10-亚甲基-(6R)-四氢叶酸的管形瓶。
实施例8
5，10-亚甲基-(6R)-四氢叶酸(溶液)的稳定化
按实施例7制备的组合物作为浓缩的含水溶液显示了以下的稳定值(Am1758-2/a)：
在+25℃存放(相对稳定性％)，未排除空气
在现有技术中可以找到5，10-亚甲基-(6R，S)-四氢叶酸的钙盐在生理食盐溶液中的数据作为对比，其稳定性数值如下[参见Chemical Stability andHuman Plasma Pharmacokinetics of Reduced Folates.Odin，E.et al.CancerInvestigation 16(7)，447-455(1998)]：
在+25℃存放(相对稳定性％)
Claims (19)
1.稳定的5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸盐药物组合物，其特征在于，该组合物含有
(i)5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸或5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸的药物学兼容的盐，
(ii)柠檬酸盐或柠檬酸，
且pH值为7.5-10.5之间。
2.权利要求1所述的稳定的药物组合物，其特征在于，所述组合物pH值为8.5-9.5之间。
3.权利要求1所述的药物组合物，其特征在于，所述组合物进一步含有甲醛作为助剂。
4.权利要求2所述的药物组合物，其特征在于，所述组合物含有另一种叶酸盐作为其它的活性成分。
5.权利要求4所述的药物组合物，其特征在于，所述组合物含有四氢叶酸及其盐作为其它的叶酸盐。
6.权利要求1所述的药物组合物，其特征在于，使用钙盐或酸式盐作为5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸的药物学兼容的盐。
7.权利要求1所述的药物组合物，其特征在于，所述组合物包含吉西他滨、多西他奇、紫杉醇、托泊替康、依立替康、阿霉素、丝裂霉素、顺铂、环磷酰胺、甲氨蝶呤、培美曲塞、长春新碱、阿糖胞苷、表柔比星、奥沙利铂、它莫昔芬、卡铂、依托泊甙或异环磷酰胺作为其它活性成分。
8.权利要求1所述的药物组合物，其特征在于，所述组合物包含5-氟化尿嘧啶、卡培他滨、替加氟、UFT、去氧氟尿苷或2′-脱氧-5-氟代尿苷作为其它活性成分。
9.权利要求1所述的药物组合物，其还包含维生素C、维生素E、还原的谷胱甘肽、β-巯基乙醇、硫代甘油或乙酰半胱氨酸。
10.权利要求3所述的药物组合物，其还包含维生素C、维生素E、还原的谷胱甘肽、β-巯基乙醇、硫状甘油或乙酰半胱氨酸。
11.权利要求4所述的药物组合物，其还包含维生素C、维生素E、还原的谷胱甘肽、β-巯基乙醇、硫代甘油或乙酰半胱氨酸。
12.权利要求7所述的药物组合物，其还包含维生素C、维生素E、还原的谷胱甘肽、β-巯基乙醇、硫代甘油或乙酰半胱氨酸。
13.权利要求8所述的药物组合物，其还包含维生素C、维生素E、还原的谷胱甘肽、β-巯基乙醇、硫代甘油或乙酰半胱氨酸。
14.权利要求1-13任一项的药物组合物，其特征在于，该细合物以冻干物形式存在。
15.权利要求1-13任一项的药物组合物，其特征在于，该组合物以干燥粉形式存在。
16.权利要求1-13任一项的药物组合物，其特征在于，该组合物以干燥混合物形式存在。
17.权利要求1-13任一项的药物组合物，其特征在于，该组合物以冻干物溶液的形式存在。
18.使含有5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸盐的组合物稳定化的方法，其特征在于，将柠檬酸盐与5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸混合，并将pH值调节到7.5-10.5。
19.使含有5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸盐的组合物稳定化的方法，其特征在于，将柠檬酸盐与5，10-亚甲基-(6R)-、-(6S)-或-(6R，S)-四氢叶酸混合，并将pH值调节到8.5-9.5。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH01123/03A CH697021A5 (de) | 2003-06-26 | 2003-06-26 | Stabile pharmazeutische Zusammensetzungen von 5, 10-Methylentetrahydrofolat. |
| CH20031123/03 | 2003-06-26 | ||
| PCT/EP2004/006944 WO2004112761A2 (de) | 2003-06-26 | 2004-06-28 | Stabile pharmazeutische zusammensetzungen von 5,10-methylentetrahydrofolat |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1842337A CN1842337A (zh) | 2006-10-04 |
| CN1842337B true CN1842337B (zh) | 2010-05-26 |
Family
ID=33520351
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2004800177913A Expired - Lifetime CN1842337B (zh) | 2003-06-26 | 2004-06-28 | 稳定的5,10-亚甲基四氢叶酸盐药物组合物 |
Country Status (16)
| Country | Link |
|---|---|
| US (2) | US9180128B2 (zh) |
| EP (1) | EP1641460B1 (zh) |
| JP (1) | JP4755980B2 (zh) |
| KR (1) | KR101156074B1 (zh) |
| CN (1) | CN1842337B (zh) |
| AT (1) | ATE439842T1 (zh) |
| AU (1) | AU2004248923B2 (zh) |
| CA (1) | CA2529531C (zh) |
| CH (2) | CH697021A5 (zh) |
| DE (1) | DE502004009927D1 (zh) |
| ES (1) | ES2334030T3 (zh) |
| MX (1) | MXPA05014232A (zh) |
| PT (1) | PT1641460E (zh) |
| RU (1) | RU2343923C2 (zh) |
| WO (1) | WO2004112761A2 (zh) |
| ZA (1) | ZA200510349B (zh) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH697021A5 (de) * | 2003-06-26 | 2008-03-31 | Merck Eprova Ag | Stabile pharmazeutische Zusammensetzungen von 5, 10-Methylentetrahydrofolat. |
| EP1968551A2 (en) * | 2005-12-02 | 2008-09-17 | Adventrx Pharmaceuticals, Inc. | Stable pharmaceutical compositions of 5,10 methylenetetrahydrofolate |
| WO2012015810A2 (en) * | 2010-07-28 | 2012-02-02 | Eagle Pharmaceuticals, Inc. | Pharmaceutical compositions containing pemetrexed having extended storage stability |
| CN102827272B (zh) * | 2010-11-08 | 2014-04-02 | 上海汉升生物科技有限公司 | 一种叶酸偶联抗体药物及其制备方法与应用 |
| EP2617421A1 (en) | 2012-01-20 | 2013-07-24 | Isofol Medical AB | Tetrahydrofolates in combination with EGFR-inhibitors in the use of treating cancer |
| EP2617422A1 (en) | 2012-01-20 | 2013-07-24 | Isofol Medical AB | Anti-tumor activity of reduced folates like methylene-tetrahydrofolate, tetrahydrofolate or methyl-tetrahydrofolate |
| KR101260636B1 (ko) * | 2012-11-29 | 2013-05-13 | 씨제이제일제당 (주) | 안정화된 페메트렉시드 제제 |
| EP2799061A1 (en) * | 2013-04-30 | 2014-11-05 | Aprofol AG | Stable high dose pharmaceutical composition containing folates |
| EP2799060A1 (en) * | 2013-04-30 | 2014-11-05 | Aprofol AG | Stable high dose pharmaceutical composition comprising levoleucovorin |
| EP2837631A1 (en) | 2013-08-14 | 2015-02-18 | Merck & Cie | New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid |
| US10059710B2 (en) | 2016-02-17 | 2018-08-28 | Merck & Cie | Stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid |
| US20170239250A1 (en) | 2016-02-19 | 2017-08-24 | Eagle Pharmaceuticals, Inc. | Pemetrexed formulations |
| EP3668516B1 (en) * | 2017-08-16 | 2021-09-22 | Merck Patent GmbH | Stable lyophilisates comprising 5,10-methylene-(6r)-tetrahydrofolic acid and a dicarboxylic acid |
| WO2023237484A1 (en) * | 2022-06-08 | 2023-12-14 | Merck Patent Gmbh | Compositions comprising disodium 5,10-methylene-(6r)-tetrahydrofolate |
| WO2023237480A1 (en) | 2022-06-08 | 2023-12-14 | Merck Patent Gmbh | Stable pharmaceutical compositions comprising 5,10-methylene-(6r)-tetrahydrofolic acid and nacl |
| WO2023237482A1 (en) | 2022-06-08 | 2023-12-14 | Merck Patent Gmbh | Concentrated solutions comprising sodium 5,10-methylene-(6r)- tetrahydrofolate |
| WO2023237485A1 (en) | 2022-06-08 | 2023-12-14 | Merck Patent Gmbh | Stable lyophilisates comprising 5,10-methylene-(6r)-tetrahydrofolic acid |
| WO2023237483A1 (en) | 2022-06-08 | 2023-12-14 | Merck Patent Gmbh | Concentrated solutions comprising 5,10-methylene-(6r)-tetrahydrofolic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4931441A (en) * | 1988-11-09 | 1990-06-05 | Luitpold Pharmaceuticals, Inc. | Stabilized aqueous leucovorin calcium compositions |
| US5434087A (en) * | 1993-02-24 | 1995-07-18 | Abbott Laboratories | Folate immunoassay utilizing folate binding protein in a multiclonal antibody format |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL9400530A (nl) | 1994-04-05 | 1995-11-01 | Pharmachemie Bv | Stabiele waterige folinaatoplossing. |
| EP0750907B1 (en) * | 1995-06-30 | 2002-03-20 | American Cyanamid Company | Stable macrolide and macrolide vaccine compositions |
| US5997915A (en) * | 1996-01-31 | 1999-12-07 | South Alabama Medical Science Foundation | Compositions for human and animal consumption containing reduced folates and methods for making and using same |
| US6544994B2 (en) * | 2000-06-07 | 2003-04-08 | Eprov Ag | Pharmaceutical preparation for treating or preventing cardiovascular or neurological disorders by modulating of the activity of nitric oxide synthase |
| US20020183277A1 (en) * | 2001-05-15 | 2002-12-05 | Lise Binderup | Combination of vitamin D analogue and pyrimidine nucleoside analogue |
| CH697021A5 (de) * | 2003-06-26 | 2008-03-31 | Merck Eprova Ag | Stabile pharmazeutische Zusammensetzungen von 5, 10-Methylentetrahydrofolat. |
-
2003
- 2003-06-26 CH CH01123/03A patent/CH697021A5/de not_active IP Right Cessation
-
2004
- 2004-06-28 CA CA2529531A patent/CA2529531C/en not_active Expired - Lifetime
- 2004-06-28 KR KR1020057024793A patent/KR101156074B1/ko active IP Right Grant
- 2004-06-28 EP EP04763030A patent/EP1641460B1/de not_active Expired - Lifetime
- 2004-06-28 PT PT04763030T patent/PT1641460E/pt unknown
- 2004-06-28 CH CH00311/05A patent/CH698204B1/de not_active IP Right Cessation
- 2004-06-28 US US10/562,200 patent/US9180128B2/en active Active
- 2004-06-28 JP JP2006516067A patent/JP4755980B2/ja not_active Expired - Lifetime
- 2004-06-28 ES ES04763030T patent/ES2334030T3/es not_active Expired - Lifetime
- 2004-06-28 AT AT04763030T patent/ATE439842T1/de active
- 2004-06-28 WO PCT/EP2004/006944 patent/WO2004112761A2/de active Application Filing
- 2004-06-28 RU RU2006102028/15A patent/RU2343923C2/ru active
- 2004-06-28 CN CN2004800177913A patent/CN1842337B/zh not_active Expired - Lifetime
- 2004-06-28 MX MXPA05014232A patent/MXPA05014232A/es active IP Right Grant
- 2004-06-28 DE DE502004009927T patent/DE502004009927D1/de not_active Expired - Lifetime
- 2004-06-28 AU AU2004248923A patent/AU2004248923B2/en not_active Expired
-
2005
- 2005-12-20 ZA ZA200510349A patent/ZA200510349B/en unknown
-
2015
- 2015-10-15 US US14/883,797 patent/US20160030573A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4931441A (en) * | 1988-11-09 | 1990-06-05 | Luitpold Pharmaceuticals, Inc. | Stabilized aqueous leucovorin calcium compositions |
| US5434087A (en) * | 1993-02-24 | 1995-07-18 | Abbott Laboratories | Folate immunoassay utilizing folate binding protein in a multiclonal antibody format |
Non-Patent Citations (4)
| Title |
|---|
| M. J. Osborn,et al.The Structure of "Active Formaldehyde"(N5, N10 -MethyleneTetrahydrofolic Acid).Journal of the American Chemical Society82 18.1960,82(18),4921-4927. |
| M.J.Osborn,et al.The Structure of "Active Formaldehyde"(N5, N10-MethyleneTetrahydrofolic Acid).Journal of the American Chemical Society82 18.1960,82(18),4921-4927. * |
| odin elisabeth,et al.chemical stability and human plasmapharmacokinetics ofreduced folates.Cancer Investigation16 7.1998,16(7),447-455. |
| odin elisabeth,et al.chemical stability and human plasmapharmacokinetics ofreduced folates.Cancer Investigation16 7.1998,16(7),447-455. * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1641460A2 (de) | 2006-04-05 |
| ZA200510349B (en) | 2007-12-27 |
| EP1641460B1 (de) | 2009-08-19 |
| PT1641460E (pt) | 2009-12-28 |
| US20070099866A1 (en) | 2007-05-03 |
| ES2334030T3 (es) | 2010-03-04 |
| KR20060082035A (ko) | 2006-07-14 |
| JP4755980B2 (ja) | 2011-08-24 |
| KR101156074B1 (ko) | 2012-06-20 |
| RU2006102028A (ru) | 2007-08-10 |
| WO2004112761A3 (de) | 2005-03-03 |
| CH697021A5 (de) | 2008-03-31 |
| DE502004009927D1 (de) | 2009-10-01 |
| AU2004248923B2 (en) | 2010-12-02 |
| RU2343923C2 (ru) | 2009-01-20 |
| CA2529531C (en) | 2012-02-21 |
| US20160030573A1 (en) | 2016-02-04 |
| CA2529531A1 (en) | 2004-12-29 |
| WO2004112761A2 (de) | 2004-12-29 |
| CH698204B1 (de) | 2009-06-15 |
| ATE439842T1 (de) | 2009-09-15 |
| CN1842337A (zh) | 2006-10-04 |
| MXPA05014232A (es) | 2006-02-24 |
| JP2009514776A (ja) | 2009-04-09 |
| US9180128B2 (en) | 2015-11-10 |
| AU2004248923A1 (en) | 2004-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1842337B (zh) | 稳定的5,10-亚甲基四氢叶酸盐药物组合物 | |
| CA2468916C (en) | A stable oxaliplatin solution formulation | |
| RU2620341C2 (ru) | Стабилизированная композиция пеметрекседа | |
| CN101970439B (zh) | 叶酸盐、其组合物和用途 | |
| AU2006320388A1 (en) | Stable pharmaceutical compositions of 5,10 methylenetetrahydrofolate | |
| CN102429864B (zh) | 一种脂溶性维生素注射液（ii）和注射用水溶性维生素的药物组合物及其制法 | |
| TWI415631B (zh) | 室溫下安定之半合成的長春花生物鹼衍生物經冷凍乾燥之可注射的藥學組成物 | |
| US8778405B2 (en) | Kit of pharmaceutical formulations characterized by the presence of molecular oxygen | |
| JP2005281324A (ja) | アミノ糖含有製剤 | |
| JP2003300888A (ja) | 抗腫瘍効果増強剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: MERCK + CIE PARTNERSHIP CORPORATION Free format text: FORMER OWNER: MERCK EPROVA AG Effective date: 20110512 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee |
Owner name: MERCK + CIE CORPORATION Free format text: FORMER NAME: MERCK + CIE PARTNERSHIP CORPORATION |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Schaffhausen Patentee after: Eprova AG Address before: Schaffhausen Patentee before: Merck and Seay partnership |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20110512 Address after: Schaffhausen Patentee after: Merck and Seay partnership Address before: Schaffhausen Patentee before: Merck Eprova AG |
|
| CX01 | Expiry of patent term |
Granted publication date: 20100526 |
|
| CX01 | Expiry of patent term |