CN104812392B - 稳定的培美曲塞制剂 - Google Patents
稳定的培美曲塞制剂 Download PDFInfo
- Publication number
- CN104812392B CN104812392B CN201380062109.1A CN201380062109A CN104812392B CN 104812392 B CN104812392 B CN 104812392B CN 201380062109 A CN201380062109 A CN 201380062109A CN 104812392 B CN104812392 B CN 104812392B
- Authority
- CN
- China
- Prior art keywords
- pemetrexed
- preparation
- acid
- antioxidant
- stability
- 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
- 229960005079 pemetrexed Drugs 0.000 title claims abstract description 73
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 title claims abstract 12
- 239000000203 mixture Substances 0.000 title abstract description 20
- 238000009472 formulation Methods 0.000 title abstract description 15
- 238000002360 preparation method Methods 0.000 claims description 97
- 239000007788 liquid Substances 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 20
- 239000001509 sodium citrate Substances 0.000 claims description 20
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical group O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000007789 sealing Methods 0.000 claims description 3
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 abstract description 38
- 239000003963 antioxidant agent Substances 0.000 abstract description 31
- 230000003078 antioxidant effect Effects 0.000 abstract description 30
- 229960004308 acetylcysteine Drugs 0.000 abstract description 26
- 239000000872 buffer Substances 0.000 abstract description 16
- 150000001860 citric acid derivatives Chemical class 0.000 abstract 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 64
- 235000006708 antioxidants Nutrition 0.000 description 30
- 239000012535 impurity Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 235000011083 sodium citrates Nutrition 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000008215 water for injection Substances 0.000 description 13
- 239000002253 acid Substances 0.000 description 11
- 230000006641 stabilisation Effects 0.000 description 11
- 238000011105 stabilization Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000013112 stability test Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 229940102223 injectable solution Drugs 0.000 description 8
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 7
- 238000002845 discoloration Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 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 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- -1 sulfide compound Chemical class 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000011724 folic acid Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 230000002093 peripheral effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000012549 training Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 230000001133 acceleration Effects 0.000 description 3
- 229940110282 alimta Drugs 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 239000003172 expectorant agent Substances 0.000 description 3
- 235000019152 folic acid Nutrition 0.000 description 3
- 229960000304 folic acid Drugs 0.000 description 3
- 239000007972 injectable composition Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 2
- 101000937647 Drosophila melanogaster Probable malonyl-CoA-acyl carrier protein transacylase, mitochondrial Proteins 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108010093223 Folylpolyglutamate synthetase Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 102000005497 Thymidylate Synthase Human genes 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 102000030722 folylpolyglutamate synthetase Human genes 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000004383 yellowing Methods 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- ZPOROQKDAPEMOL-UHFFFAOYSA-N 1h-pyrrol-3-ol Chemical class OC=1C=CNC=1 ZPOROQKDAPEMOL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 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
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102100035067 Folylpolyglutamate synthase, mitochondrial Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 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
- 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 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000560222 Mibora minima Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- QZDVRJFYQSCEKN-UHFFFAOYSA-N n-(1,1-dioxothiolan-3-yl)formamide Chemical compound O=CNC1CCS(=O)(=O)C1 QZDVRJFYQSCEKN-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940071643 prefilled syringe Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 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 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 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 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000003587 threonine derivatives Chemical class 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical class [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Anti-Oxidant Or Stabilizer Compositions (AREA)
Abstract
本发明涉及稳定的培美曲塞制剂，更具体地涉及包括乙酰半胱氨酸作为抗氧化剂和柠檬酸盐作为缓冲剂的稳定的培美曲塞制剂。
Description
技术领域
本发明涉及稳定的培美曲塞制剂(pemetrexed formulation)，更特别地涉及包括乙酰半胱氨酸作为抗氧化剂和柠檬酸盐作为缓冲剂的稳定的培美曲塞制剂。
背景技术
已知具有抗叶酸活性的特定化合物作为癌症治疗的化学治疗剂而众所周知。美国专利号5,344,932公开了制备某些取代的吡咯并[2,3-d]嘧啶基抗叶酸衍生物——包括培美曲塞——的方法，欧洲专利公开号0434426公开了一系列4-羟基吡咯并[2,3-d]嘧啶-L-谷氨酸衍生物。
培美曲塞，5-取代的吡咯并[2,3-d]嘧啶，是多靶向的抗叶酸剂，其通过抑制参与叶酸代谢的代谢产物的活性显示针对多种癌症——包括非小细胞肺癌——的抗癌作用。
已知培美曲塞通过还原型叶酸载体(RFC)——其是主要的叶酸转运系统——进入细胞，然后由叶酰聚谷氨酸合酶(folylpolyglutamate synthetase)(FPGS)激活，形成聚谷氨酸衍生物，其靶向胸苷酸合酶(TS)和二氢叶酸还原酶(DHFR)。
当前，培美曲塞以商品名Alimta被推向市场并用作治疗恶性胸膜间皮瘤和非小细胞肺癌的剂(参见Physicians'Desk Reference,60th ed.,pp.1722-1728(2006))。Alimta以冻干制剂销售，其必须在施用之前重构(reconstituted)。具体地，Alimta以冻干的粉末制剂(100mg或500mg)销售，其需要在施用给患者之前用0.9％氯化钠溶液重构，并最终用0.9％氯化钠溶液稀释到0.25mg/ml的最终浓度。
冻干的粉末制剂制备麻烦，并且制备这些制剂的工艺非常昂贵。此外，冻干制剂具有在重构之后被微生物污染的危险，并且参与包括这些制剂在内的药物准备的药剂师、医师、护士等非常可能暴露于细胞破坏物质。因此，在细胞毒性抗癌剂如培美曲塞的情况中，需要开发可长时期储存的即用型(ready-to-use)液体制剂，而不是开发冻干制剂。
在许多情况中，液体制剂的问题是储存期间的不稳定性。由于该不稳定性，大量可注射制剂以在注射之前立即溶解的冻干制剂的形式使用。即使在培美曲塞或其药学上可接受的盐——其最近已以冻干制剂的形式提供——的情况中，作为水溶液制剂的制备引起当在室温长时期储存时未知的杂质增加的问题。即，该水溶液制剂遭受稳定性问题。由于该稳定性问题，培美曲塞或其药学上可接受的盐目前在临床应用中以冻干制剂的形式使用。
为了克服上面描述的缺点，已提出了一些制剂。例如，美国专利号6,686,365(对应于韩国专利公开号2002-0081293)公开了稳定性培美曲塞液体制剂，其包括治疗有效量的培美曲塞、有效量的抗氧化剂和药学上可接受的赋形剂，其中抗氧化剂选自一硫代甘油、L-半胱氨酸和巯基乙酸。
然而，关于以上专利中公开的制剂的问题，据报道，当制剂在25℃长期储存时，发生沉淀，这提示持续期望时期的制剂的长期稳定性不能保证(PCT国际专利公开号WO2012/015810)。到目前为止没有长期储存稳定的液体培美曲塞制剂已在实验上或商业上实现。实际上，本发明人利用上面描述的抗氧化剂L-半胱氨酸制备了含有培美曲塞的液体制剂并对制备的制剂进行了稳定性试验，在应激(stress)测试条件下2周之后只观察到了几个问题，包括外观的改变，如变色、杂质的增加和pH的降低。此外，本发明人利用约60种稳定剂制备了含有培美曲塞的液体制剂，该稳定剂包括抗坏血酸、硫代硫酸钠、丁羟茴醚、没食子酸丙酯、EDTA、L-甲硫氨酸和乙酰半胱氨酸，但是这些制剂都具有不足的稳定性。
发明内容
技术问题
针对该背景，本发明人已进行了广范的研究以克服液体培美曲塞制剂的稳定性问题，结果，已发现当乙酰半胱氨酸作为抗氧化剂和柠檬酸作为缓冲剂一起使用时，储存期间稳定的培美曲塞制剂具有高稳定性并保持透明溶液的状态，而没有沉淀，其中培美曲塞异构体杂质和未知杂质的形成被有效控制或抑制，从而完成本发明。
问题的解决方案
本发明的目的是提供稳定的培美曲塞制剂。
发明的有益效果
本发明可提供培美曲塞制剂，其容易以商业方式制备，可防止冻干和重构期间可能发生的微生物污染，并具有提高的便利和稳定性。此外，本发明可提供稳定的培美曲塞制剂，其含有乙酰半胱氨酸作为抗氧化剂以及柠檬酸钠作为缓冲剂，从而显示外观无异常，如变色或沉淀，并满足接受标准，而不像常规的含有培美曲塞的可注射液体制剂。
附图说明
图1显示4周的应激稳定性试验(60℃和80％)之后常规的含有培美曲塞的可注射液体制剂(比较实施例1、12和14)和根据本发明的含有培美曲塞的可注射液体制剂(实施例11)之间外观的比较。为了比较，WFI(注射用水)的外观也显示在图1中。
具体实施方式
一方面，本发明提供培美曲塞制剂，其包括：培美曲塞或其药学上可接受的盐作为活性成分；N-乙酰-L-半胱氨酸；和柠檬酸盐。
在本发明中，培美曲塞或其药学上可接受的盐、N-乙酰-L-半胱氨酸和柠檬酸盐可以以1-30:0.15-2.0:1.0-15.0的浓度比存在。
优选，培美曲塞或其药学上可接受的盐、N-乙酰-L-半胱氨酸和柠檬酸盐可以以1-30:1.5:1.0-15.0的浓度比存在。
在本发明中，制剂可以是以溶液状态可储存的液体制剂。
在本发明中，制剂可以是密封容器中含有的可注射液体制剂以便随时使用(beready to use)。
然而，本发明的范围不必限于可注射液体制剂并包括其它液体制剂和非液体制剂，其可根据本领域技术人员的常识或根据相关技术领域中通常使用的方法来制备。
以下，本发明将被详细描述。
通常，许多种抗氧化剂用于稳定制剂的目的，其具体实例包括对羟基苯甲酸酯衍生物、醇、苯酚衍生物、硫柳汞、醋酸酐、羧酸钠、月桂基硫酸盐、抗氧化剂、硫化物化合物、亚硫酸盐、胱氨酸、半胱氨酸(cystein)、半胱胺、氨基酸、有机酸如抗坏血酸、视黄醇、生育酚、丁羟茴醚等。
此外，韩国专利登记号10-0774366公开了作为紫杉醇的抗氧化剂的N-乙酰氨基酸，以及韩国专利公开号10-2007-0028331公开了作为双氯芬酸组合物的抗氧化剂的一硫代甘油和乙二胺四乙酸。
本发明人在可注射培美曲塞制剂中用上面描述的抗氧化剂测试，但是当用作赋形剂(抗氧化剂)，不是用作API时，特别是在可注射制剂中，这些通常使用的物质的日剂量受限制。此外，单独的抗氧化剂不提高制剂稳定性。进一步，当使用常规的可注射制剂中经常使用的抗坏血酸、乳酸等时，这些可注射制剂部分变色和/或产生沉淀，这指示这些制剂是酸不稳定的(实验实施例1和2)。
然而，本发明人已令人惊讶地发现，当包括培美曲塞或其药学上可接受的盐作为活性成分的组合物与乙酰半胱氨酸和柠檬酸钠一起使用时，活性成分在应激试验条件(60℃和80％)下在4周稳定性试验期期间基本上没有改变，并且没有变色或沉淀发生，这指示组合物具有稳定性，其满足要求的接受标准(实验实施例1和2)。乙酰半胱氨酸和柠檬酸钠均是通常使用的并且由于它们的低价而在商业方面还是有利的物质。
本发明的培美曲塞制剂包括培美曲塞或其药学上可接受的盐作为活性成分。所述根据本发明的培美曲塞包括药学上有活性的药物或通过体内化学或酶过程变得药学上有活性的药物。具体地，用于本发明的培美曲塞可以是培美曲塞药物自身或其药学上可接受的盐。
如本文所用，术语"培美曲塞"指命名为5-取代的吡咯并[2,3-d]嘧啶的化合物。具体地，该术语指多靶向的抗叶酸剂，其由下面的式1表示并显示针对多种癌症——包括非小细胞肺癌和恶性胸膜间皮瘤——的抗癌作用：
式1
培美曲塞通过抑制参与叶酸代谢的代谢产物的活性而显示针对多种癌症——包括非小细胞肺癌和恶性胸膜间皮瘤——的抗癌作用。
如本文所用，术语"药学上可接受的盐"指根据本领域已知的常规方法制备的盐。该制备方法为本领域技术人员所知。药学上可接受的盐的具体实例包括，但不限于，源自如下所述的药理学上或生理学上可接受的无机酸、有机酸和碱的盐。合适的酸的实例包括盐酸、溴酸、氢溴化物、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、羟乙酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、蚁酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸等。源自合适的碱的盐的实例包括，但不限于，碱金属如钠和钾的盐，和碱土金属如镁的盐。
如本文所用，术语"乙酰半胱氨酸"指命名为N-乙酰-L-半胱氨酸(NAC、C5H9NO3S，CAS号616-91-1)的化合物，其在本发明的培美曲塞制剂中用作抗氧化剂。在本发明中，"乙酰半胱氨酸"和"N-乙酰-L-半胱氨酸"彼此可互换地使用。
乙酰半胱氨酸作为抗氧化剂在美国药典中被描述(参见美国药典35-国家处方集10，p 2069)。乙酰半胱氨酸是食物中含有的氨基酸L-半胱氨酸的前体。半胱氨酸通过氧化容易变成不溶物质，而乙酰半胱氨酸是稳定的并且不容易改变，以便口服或静脉内施用。
如本文所用，术语"柠檬酸盐"指柠檬酸的盐和指用作本发明的培美曲塞制剂中缓冲剂的化合物。柠檬酸盐可以是柠檬酸钠。
根据本发明，能够使培美曲塞以稳定的方式在1至30℃的温度在药学上储存长时期的培美曲塞制剂可通过利用乙酰半胱氨酸作为抗氧化剂和柠檬酸钠作为缓冲剂而被提供。
在本发明的培美曲塞制剂中，培美曲塞或其药学上可接受的盐:N-乙酰-L-半胱氨酸:柠檬酸盐的浓度比优选是1-30:0.15-2.0:1.0-15.0，更优选1-30:1.5:1.0-15.0。这里，浓度中的每种可以以mg/mL的单位给出。可见在具有以上浓度比范围之外的浓度比的培美曲塞制剂的情况中，杂质的产生增加超过一段储存时间的接受标准(实验实施例1)。
在本发明中，培美曲塞制剂可包括药学上可接受的载体和pH-调节剂。
在本发明中，培美曲塞制剂优选可以是在溶液状态可储存的液体制剂，更优选密封容器中含有的可注射液体制剂以便随时使用。
本发明的培美曲塞制剂是可注射液体制剂时，药学上可接受的载体是WFI(注射用水)。
在本发明中，培美曲塞的可注射液体制剂的pH优选可以是约6.0-8.0，更优选约7.2-7.8。液体制剂的pH可利用酸如盐酸，或碱如氢氧化钠来调节。
虽然可能的是本发明的培美曲塞制剂除了乙酰半胱氨酸和柠檬酸盐可不包括其它添加剂，但是它可进一步包括药学上可接受的赋形剂。药学上可接受的赋形剂的实例包括已知的添加剂，如乳糖、葡萄糖、环糊精和它的衍生物、蔗糖、甘油、碳酸钠。优选的赋形剂可以是氯化钠和甘露醇。
在制备本发明的制剂的过程中，进行用惰性气体如氮气或氩气的换气(purging)以保持低氧条件，之后是灭菌和过滤。
此外，本发明的稳定的培美曲塞制剂可包装在本领域已知的适当容器中。例如，容器可以是玻璃小瓶、玻璃瓶、筒、预装注射器等。优选，容器是玻璃小瓶。
根据本发明的培美曲塞的可注射液体制剂分散在先前洗过的和灭菌的容器中，并将容器用聚四氟乙烯(Teflon)塞子——其表面不与液体制剂反应——密封。需要时，使可注射液体制剂和塞子之间的空间充满惰性气体。塞子利用卷曲机附加，然后需要时，将充满可注射液体制剂的小瓶加热和灭菌。
发明的方式
以下，本发明将参考实施例被进一步详细地描述。然而，应当理解，这些实施例仅用于说明的目的，并不意欲限制本发明的范围。
实施例1至14：含有不同量的乙酰半胱氨酸作为抗氧化剂和柠檬酸钠作为缓冲剂
的含有培美曲塞的可注射溶液的制备
将2.5g D-甘露醇溶解于100ml WFI(注射用水)，然后将乙酰半胱氨酸和柠檬酸钠以下面的表1所示的浓度连续地加入其中并完全溶解在其中。将2.5g培美曲塞缓慢地加入到溶液中(在实施例14中将3.0g培美曲塞缓慢地加入)，并搅拌溶液直到它们变得澄清。然后，利用盐酸或氢氧化钠的水溶液将溶液调到表1所示的pH。将溶液在洁净室中通过灭菌的0.22-μm膜滤器无菌过滤。将获得的溶液灌入先前用氮气换气的洗过/灭菌的可密封容器。
获得的含有培美曲塞的可注射溶液的组分和pH显示在下面的表1中。
表1
实施例15和16：具有不同pH的含有培美曲塞的可注射溶液的制备
将2.5g D-甘露醇溶解于100ml WFI(注射用水)，然后将乙酰半胱氨酸和柠檬酸钠以下面的表2所示的浓度连续地加入其中并完全溶解在其中。将2.5g培美曲塞缓慢地加入到溶液中，并搅拌溶液直到它们变得澄清。然后，利用盐酸或氢氧化钠的水溶液将溶液调到表2所示的pH。将溶液在洁净室中通过灭菌的0.22-μm膜滤器无菌过滤。将获得的溶液灌入先前用氮气换气的洗过/灭菌的可密封容器。
获得的含有培美曲塞的可注射溶液的组分和pH显示在下面的表2中。
表2
比较实施例1至8：利用不同种类的抗氧化剂的含有培美曲塞的可注射溶液的制备
根据下面的表3中显示的组分和含量，以与实施例1中描述的相同方式制备含有培美曲塞的溶液。在比较实施例1中，制备没有抗氧化剂和含有仅WFI(注射用水)作为载体的的溶液。
表3
比较实施例9至14：含有不同种类抗氧化剂和含有或不含有缓冲剂的含有培美曲
塞的可注射溶液的制备
根据下面的表4中显示的组分和含量，以与实施例1中描述的相同方式制备含有培美曲塞的溶液。
表4
比较实施例15与17：含有不同种类缓冲剂的含有培美曲塞的可注射溶液的制备
根据下面的表5中显示的组分和含量，以与实施例1中描述的相同方式制备含有培美曲塞的溶液。
表5
实验实施例：稳定性试验
测试实施例1至16和比较实施例1至17中制备的组合物在应激试验条件(60℃和80％)下4周它们的稳定性。这些组合物之中，还测试实施例11和比较实施例1、12和14的组合物在加速(accelerated)条件(40℃和70％)下4个月它们的稳定性。稳定性评价通过在下面的表6所示的条件下利用高效液相色谱测量水溶液中培美曲塞和杂质的含量而进行。
表6
实验实施例1：应激稳定性试验(60℃/80％，4周评价)
应激稳定性试验如上所述进行，试验结果显示在下面的表7至11中。
还有，图1显示在应激试验条件(60℃和80％)下在4周稳定性试验期期间根据本发明的含有培美曲塞的可注射液体制剂(实施例11)和本领域中含有培美曲塞的可注射的液体制剂(比较实施例1、12和14)之间外观的比较。为了比较，WFI(注射用水)的外观也显示在图1中。
表7
从表7中的结果可见，含有1.5mg/mL乙酰半胱氨酸作为抗氧化剂和1-15mg/mL柠檬酸钠作为缓冲剂的制剂在4周应激试验条件期间显示0.2％或更少的单个(individual)杂质含量和1.0％或更少的总杂质含量，这指示这些制剂具有优异的稳定性(实施例9至12)。
此外，含有1.0-1.5mg/mL乙酰半胱氨酸和2.0mg/mL柠檬酸钠作为缓冲剂的制剂显示0.2％或更少的单个杂质含量和1.0％或更少的总杂质含量，这指示这些制剂具有优异的稳定性(实施例8和10)。然而，观察到当乙酰半胱氨酸的浓度低于1.0-1.5mg/mL时，外观改变(变色)发生，尽管杂质含量满足接受标准(实施例1至2)。
此外，当乙酰半胱氨酸浓度是2.0mg/mL和柠檬酸钠浓度是5.0mg/mL时，杂质含量满足接受标准，但是外观改变(变色)发生(实施例13)。
而且，当乙酰半胱氨酸浓度是0.5mg/mL和柠檬酸钠浓度是1.0-5.0mg/mL时，杂质含量满足接受标准，但是外观改变(变色)发生(实施例3至7)。
表8
从上面的表8中的结果可见，尽管pH改变，含有乙酰半胱氨酸作为抗氧化剂和柠檬酸钠作为缓冲剂的制剂在应激条件下在4周稳定性试验期期间显示0.2％或更少的单个杂质含量和1.0％或更少的总杂质含量，这指示这些制剂具有优异的稳定性。
表9
从上面的表9中的结果可见，在含有本领域中通常使用的抗氧化剂的制剂中，在应激条件下在稳定性试验期期间外观的改变(沉淀或变色)发生，或单个杂质含量增加到高于0.2％和总杂质含量增加到高于1.0％。这显示含有本领域中通常使用的抗氧化剂的含有培美曲塞的可注射溶液在杂质或外观改变方面没有提供足够的稳定性。
表10
从上面的表10中的结果可见，当制剂含有乙酰半胱氨酸作为抗氧化剂和柠檬酸钠作为缓冲剂时，优选当乙酰半胱氨酸浓度是1.5mg/mL和柠檬酸钠浓度是5.0mg/mL时，在应激条件下在4周稳定性试验期期间制剂显示0.2％或更少的单个杂质含量和1.0％或更少的总杂质含量，这指示该制剂具有优异的稳定性(实施例11)。
然而，在制剂溶液只含有柠檬酸钠作为缓冲剂的情况中，清楚地观察到在应激条件下在2周之后溶液颜色开始变成深黄色(比较实施例9和10)。此外，在制剂含有L-半胱氨酸或乙酰半胱氨酸作为抗氧化剂的情况中，清楚地观察到在应激条件下在2周之后溶液颜色开始变成浅黄色，并且在应激条件下在4周试验期期间pH显著降低(比较实施例11和12至14)。换言之，看到乙酰半胱氨酸和柠檬酸钠的组合使用显著提高杂质的稳定性，而不像单独使用乙酰半胱氨酸或柠檬酸钠那样。
此外，显示在只含有L-半胱氨酸的比较实施例13和14的制剂溶液中，在严格条件下在2周之后像坏鸡蛋一样的异臭开始发生，但是在本发明的制剂中，异臭没有发生。
表11
从上面的表11中的结果可见，比较了含有乙酰半胱氨酸作为抗氧化剂和通常使用的多种缓冲剂的制剂的稳定性，发现当使用除外柠檬酸钠以外的缓冲剂时，外观改变(变色)在最初阶段发生，或单个杂质含量增加到高于0.2％和总杂质含量增加到高于1.0％。
因此，证实只有含有乙酰半胱氨酸作为抗氧化剂和柠檬酸钠作为缓冲剂的含有培美曲塞的可注射溶液显示最佳稳定性。
实验实施例2：加速稳定性试验(40℃/70％，4个月评价)
加速稳定性试验如上所述进行，试验结果显示在下面的表12中。
表12
从上面的表12中的结果可见，在只利用WFI(注射用水)作为载体而没有加入抗氧化剂制备的比较实施例1的制剂中，在加速条件下在2个月之后溶液外观变成黄色，并且在4个月溶液显示0.2％或更多的单个杂质含量和1％的总杂质含量，这指示该制剂具有不足的稳定性。同时，在含有乙酰半胱氨酸作为抗氧化剂和柠檬酸钠作为缓冲剂的实施例11的制剂中，在加速条件下在6个月试验期期间显示0.2％或更少的单个杂质含量和1.0％或更少的总杂质含量，这指示该制剂具有优异的稳定性。
通过比较，发现在只含有乙酰半胱氨酸作为抗氧化剂的制剂中，在加速条件下在4个月之后溶液颜色变成黄色，并且单个杂质含量超过0.2％，这指示制剂具有不足的稳定性(比较实施例12)。
此外，在只含有L-半胱氨酸的比较实施例14的制剂中，杂质含量满足接受标准，并且像坏鸡蛋一样的异臭发生，如在应激稳定性试验的结果中那样。然而，该异臭没有发生在本发明的制剂中，即，实施例11的制剂中。
Claims (6)
1.培美曲塞液体制剂，其包括：培美曲塞或其药学上可接受的盐作为活性成分；N-乙酰-L-半胱氨酸；和柠檬酸盐。
2.权利要求1所述的培美曲塞液体制剂，其中培美曲塞或其药学上可接受的盐:N-乙酰-L-半胱氨酸:柠檬酸盐的浓度比是1-30:0.15-2.0:1.0-15.0。
3.权利要求2所述的培美曲塞液体制剂，其中培美曲塞或其药学上可接受的盐:N-乙酰-L-半胱氨酸:柠檬酸盐的浓度比是1-30:1.5:1.0-15.0。
4.权利要求1所述的培美曲塞液体制剂，其中所述柠檬酸盐是柠檬酸钠。
5.权利要求1所述的培美曲塞液体制剂，其中所述制剂是以溶液状态可储存的液体制剂。
6.权利要求1所述的培美曲塞液体制剂，其中所述制剂是密封容器中包含的可注射液体制剂以便随时使用。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2012-0137375 | 2012-11-29 | ||
| KR1020120137375A KR101260636B1 (ko) | 2012-11-29 | 2012-11-29 | 안정화된 페메트렉시드 제제 |
| PCT/KR2013/010967 WO2014084651A1 (en) | 2012-11-29 | 2013-11-29 | A stabilized pemetrexed formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104812392A CN104812392A (zh) | 2015-07-29 |
| CN104812392B true CN104812392B (zh) | 2017-05-17 |
Family
ID=48665454
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380062109.1A Active CN104812392B (zh) | 2012-11-29 | 2013-11-29 | 稳定的培美曲塞制剂 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US9265832B2 (zh) |
| EP (1) | EP2925325B1 (zh) |
| JP (1) | JP5934448B2 (zh) |
| KR (1) | KR101260636B1 (zh) |
| CN (1) | CN104812392B (zh) |
| AR (1) | AR093645A1 (zh) |
| BR (1) | BR112015012460B1 (zh) |
| CL (1) | CL2015001461A1 (zh) |
| ES (1) | ES2656901T3 (zh) |
| HK (1) | HK1212224A1 (zh) |
| JO (1) | JOP20130342B1 (zh) |
| MX (1) | MX355461B (zh) |
| PH (1) | PH12015500900B1 (zh) |
| RU (1) | RU2620341C2 (zh) |
| TW (1) | TWI498128B (zh) |
| WO (1) | WO2014084651A1 (zh) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102012010774A1 (de) | 2012-05-31 | 2013-12-05 | Stada Arzneimittel Ag | Pharmazeutische Pemetrexed-Lösung |
| KR101485243B1 (ko) * | 2013-05-08 | 2015-01-21 | 씨제이헬스케어 주식회사 | 안정화된 페메트렉시드 제제 |
| JP6094388B2 (ja) * | 2013-06-07 | 2017-03-15 | ニプロ株式会社 | ペメトレキセドを含む注射用組成物 |
| CN105611932B (zh) * | 2013-10-03 | 2019-02-12 | 富士胶片株式会社 | 注射液制剂及其制造方法 |
| JP6120766B2 (ja) * | 2013-12-27 | 2017-04-26 | 富士フイルム株式会社 | 注射液製剤及びその製造方法 |
| KR101703980B1 (ko) | 2013-12-30 | 2017-02-08 | 주식회사 삼양바이오팜 | 항산화제를 함유하지 않는 약학 조성물 및 그의 제조방법 |
| DK3124026T3 (en) * | 2014-03-28 | 2018-10-01 | Fujifilm Corp | INJECTION PREPARATION AND METHOD OF PREPARING IT |
| GB201418555D0 (en) * | 2014-10-16 | 2014-12-03 | Teva Gmbh | Pemetrexed formulations |
| KR101770605B1 (ko) | 2014-11-17 | 2017-08-23 | 동아에스티 주식회사 | 페메트렉시드 또는 그것의 약제학적으로 허용가능 한 염을 함유하는 안정한 약제학적 조성물 |
| KR101919436B1 (ko) | 2015-05-28 | 2018-11-16 | 주식회사 삼양바이오팜 | 안정화된 약학 조성물 및 그의 제조방법 |
| KR101693675B1 (ko) | 2015-12-14 | 2017-01-06 | 주식회사 종근당 | 페메트렉시드 또는 그의 약제학적으로 허용가능한 염을 함유하는 안정화된 약학조성물 |
| JP6837895B2 (ja) * | 2017-04-04 | 2021-03-03 | 日本化薬株式会社 | 医薬品溶液製剤の製造方法 |
| WO2019043569A1 (en) * | 2017-08-29 | 2019-03-07 | Fresenius Kabi Oncology Limited | STREAMABLE LIQUID COMPOSITIONS OF PEMETREXED |
| KR102040034B1 (ko) | 2017-12-13 | 2019-11-05 | 주식회사 아이큐어비앤피 | 페메트렉시드를 포함하는 경구용 약학 조성물 및 이의 제조방법 |
| US10966982B2 (en) | 2018-11-20 | 2021-04-06 | Cipla Limited | Stable pharmaceutical formulations of pemetrexed |
| US20230201203A1 (en) * | 2020-04-09 | 2023-06-29 | Emphascience, Inc. | Methods of treatment using antifolates and pharmaceutical formulations comprising antifolates |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396828A (zh) * | 2000-02-04 | 2003-02-12 | 伊莱利利公司 | 含有培美西德以及一硫代甘油l－半胱氨酸或巯乙酸的药物组合物 |
| US20090181990A1 (en) * | 2007-12-23 | 2009-07-16 | Patel Nileshkumar S | Stable amorphous form of pemetrexed disodium |
| WO2012015810A2 (en) * | 2010-07-28 | 2012-02-02 | Eagle Pharmaceuticals, Inc. | Pharmaceutical compositions containing pemetrexed having extended storage stability |
| WO2012121523A2 (en) * | 2011-03-10 | 2012-09-13 | Kuhnil Pharm. Co., Ltd. | Process for preparing pharmaceutical formulation in form of antioxidant-free solution for injection containing pemetrexed or its salt |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0162654B1 (ko) | 1989-12-11 | 1998-11-16 | 알렌 제이. 시니스갤리 | N-(피롤로[2,3-d]피리미딘-3-일아크릴)-글루타민산 유도체 |
| CA2032695A1 (en) | 1989-12-20 | 1991-06-21 | Hiroshi Akimoto | Condensed heterocyclic compounds, their production and use |
| US6686365B2 (en) * | 2000-02-04 | 2004-02-03 | Eli Lilly And Company | Pharmaceutical composition |
| KR100774366B1 (ko) | 2001-09-10 | 2007-11-08 | 주식회사 중외제약 | 파클리탁셀 주사제 조성물 |
| CH697021A5 (de) * | 2003-06-26 | 2008-03-31 | Merck Eprova Ag | Stabile pharmazeutische Zusammensetzungen von 5, 10-Methylentetrahydrofolat. |
| US20050238674A1 (en) | 2004-03-10 | 2005-10-27 | Shimoda Biotech (Pty) Ltd. | Stable injectable compositions |
| US8629152B2 (en) * | 2006-08-14 | 2014-01-14 | Sicor, Inc. | Processes for the preparation of lyophilized pharmaceutically acceptable salts of pemetrexed diacid |
| DE102012010774A1 (de) * | 2012-05-31 | 2013-12-05 | Stada Arzneimittel Ag | Pharmazeutische Pemetrexed-Lösung |
| KR101485243B1 (ko) * | 2013-05-08 | 2015-01-21 | 씨제이헬스케어 주식회사 | 안정화된 페메트렉시드 제제 |
-
2012
- 2012-11-29 KR KR1020120137375A patent/KR101260636B1/ko active IP Right Grant
-
2013
- 2013-11-27 JO JOP/2013/0342A patent/JOP20130342B1/ar active
- 2013-11-28 TW TW102143402A patent/TWI498128B/zh active
- 2013-11-28 AR ARP130104389A patent/AR093645A1/es not_active Application Discontinuation
- 2013-11-29 RU RU2015122023A patent/RU2620341C2/ru active
- 2013-11-29 MX MX2015006325A patent/MX355461B/es active IP Right Grant
- 2013-11-29 BR BR112015012460-7A patent/BR112015012460B1/pt active IP Right Grant
- 2013-11-29 ES ES13858153.3T patent/ES2656901T3/es active Active
- 2013-11-29 WO PCT/KR2013/010967 patent/WO2014084651A1/en active Application Filing
- 2013-11-29 EP EP13858153.3A patent/EP2925325B1/en active Active
- 2013-11-29 JP JP2015544000A patent/JP5934448B2/ja active Active
- 2013-11-29 US US14/646,615 patent/US9265832B2/en active Active
- 2013-11-29 CN CN201380062109.1A patent/CN104812392B/zh active Active
-
2015
- 2015-04-22 PH PH12015500900A patent/PH12015500900B1/en unknown
- 2015-05-29 CL CL2015001461A patent/CL2015001461A1/es unknown
-
2016
- 2016-01-08 HK HK16100181.1A patent/HK1212224A1/zh unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1396828A (zh) * | 2000-02-04 | 2003-02-12 | 伊莱利利公司 | 含有培美西德以及一硫代甘油l－半胱氨酸或巯乙酸的药物组合物 |
| US20090181990A1 (en) * | 2007-12-23 | 2009-07-16 | Patel Nileshkumar S | Stable amorphous form of pemetrexed disodium |
| WO2012015810A2 (en) * | 2010-07-28 | 2012-02-02 | Eagle Pharmaceuticals, Inc. | Pharmaceutical compositions containing pemetrexed having extended storage stability |
| WO2012121523A2 (en) * | 2011-03-10 | 2012-09-13 | Kuhnil Pharm. Co., Ltd. | Process for preparing pharmaceutical formulation in form of antioxidant-free solution for injection containing pemetrexed or its salt |
Also Published As
| Publication number | Publication date |
|---|---|
| US20150297724A1 (en) | 2015-10-22 |
| JOP20130342B1 (ar) | 2021-08-17 |
| HK1212224A1 (zh) | 2016-06-10 |
| BR112015012460B1 (pt) | 2022-04-05 |
| JP2016500099A (ja) | 2016-01-07 |
| ES2656901T3 (es) | 2018-02-28 |
| MX2015006325A (es) | 2016-02-25 |
| TWI498128B (zh) | 2015-09-01 |
| PH12015500900A1 (en) | 2015-07-06 |
| CL2015001461A1 (es) | 2015-10-23 |
| BR112015012460A2 (zh) | 2017-08-22 |
| EP2925325A1 (en) | 2015-10-07 |
| WO2014084651A1 (en) | 2014-06-05 |
| US9265832B2 (en) | 2016-02-23 |
| KR101260636B1 (ko) | 2013-05-13 |
| TW201434493A (zh) | 2014-09-16 |
| JP5934448B2 (ja) | 2016-06-15 |
| RU2015122023A (ru) | 2017-01-10 |
| EP2925325A4 (en) | 2016-07-13 |
| MX355461B (es) | 2018-04-19 |
| PH12015500900B1 (en) | 2015-07-06 |
| CN104812392A (zh) | 2015-07-29 |
| AR093645A1 (es) | 2015-06-17 |
| RU2620341C2 (ru) | 2017-05-24 |
| EP2925325B1 (en) | 2017-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104812392B (zh) | 稳定的培美曲塞制剂 | |
| CN105451717B (zh) | 稳定的培美曲塞制剂 | |
| JP2013540104A (ja) | 延長された保存安定性を有するペメトレキセドを含有する医薬組成物 | |
| CN106456654A (zh) | 环磷酰胺液体浓缩制剂 | |
| JP2020125359A (ja) | ペメトレキセドまたはその薬剤学的に許容可能な塩を含有する安定化された薬学組成物 | |
| JP2011530540A (ja) | テトラヒドロビオプテリンを含有する医薬剤形 | |
| CN103110640B (zh) | 一种注射用头孢唑肟钠和复方氨基酸注射液的药物组合物 | |
| WO2016024369A1 (ja) | がん治療用医薬組成物 | |
| US11433115B2 (en) | Glycopeptide antibiotics liquid formulations and methods and uses thereof | |
| CN101697973B (zh) | 一种注射用头孢硫脒制剂及其制备方法 | |
| CN110314132B (zh) | 一种门冬氨酸鸟氨酸注射液及其制备方法 | |
| CN102641272B (zh) | 甲硫氨酸维生素b1的药物组合物及其制备方法 | |
| CN103393689B (zh) | 一种注射用盐酸头孢替安和复方氨基酸注射液的药物组合物 | |
| CN103446158B (zh) | 盐酸头孢甲肟和小儿复方氨基酸注射液的药物组合物 | |
| CN103446056B (zh) | 一种含头孢唑肟钠和小儿复方氨基酸注射液(19aa-i）的药物组合物 | |
| CN104825431A (zh) | 注射用复方二氯醋酸二异丙胺冷冻干燥粉针剂药物组合物 | |
| CN103446159B (zh) | 一种包含小儿复方氨基酸注射液和盐酸头孢替安的药物组合物 | |
| CN102018664A (zh) | 一种化合物/氯化钠制剂 | |
| JP2016041684A (ja) | がん治療用医薬組成物 | |
| CN104922133A (zh) | 一种注射用头孢匹胺(钠)和复方氨基酸注射液(18aa-v)的药物组合物 | |
| EP3222271A1 (en) | Stable pharmaceutical composition comprising pemetrexed or pharmaceutically acceptable salt thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1212224 Country of ref document: HK |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1212224 Country of ref document: HK |