CN105982892A - Antioxidant-containing temozolomide medicinal composition and preparation method thereof - Google Patents
Antioxidant-containing temozolomide medicinal composition and preparation method thereof Download PDFInfo
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- CN105982892A CN105982892A CN201510079367.1A CN201510079367A CN105982892A CN 105982892 A CN105982892 A CN 105982892A CN 201510079367 A CN201510079367 A CN 201510079367A CN 105982892 A CN105982892 A CN 105982892A
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- CN
- China
- Prior art keywords
- temozolomide
- agent
- pharmaceutical composition
- antioxidant
- dissolving
- Prior art date
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Links
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229960004964 temozolomide Drugs 0.000 title claims abstract description 73
- 239000003963 antioxidant agent Substances 0.000 title claims abstract description 24
- 230000003078 antioxidant effect Effects 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 32
- 239000008215 water for injection Substances 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 235000006708 antioxidants Nutrition 0.000 claims description 21
- 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 claims description 18
- 229930195725 Mannitol Natural products 0.000 claims description 18
- 239000000594 mannitol Substances 0.000 claims description 18
- 235000010355 mannitol Nutrition 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 14
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 239000003002 pH adjusting agent Substances 0.000 claims description 12
- 239000000872 buffer Substances 0.000 claims description 10
- 239000008176 lyophilized powder Substances 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000000080 wetting agent Substances 0.000 claims description 10
- 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 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 235000010265 sodium sulphite Nutrition 0.000 claims description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- -1 azoles amine Chemical class 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 229930003427 Vitamin E Natural products 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 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 claims description 4
- 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 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 235000019165 vitamin E Nutrition 0.000 claims description 4
- 229940046009 vitamin E Drugs 0.000 claims description 4
- 239000011709 vitamin E Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 235000017471 coenzyme Q10 Nutrition 0.000 claims description 3
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 3
- 229940110767 coenzyme Q10 Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 claims description 3
- 239000000473 propyl gallate Substances 0.000 claims description 3
- 235000010388 propyl gallate Nutrition 0.000 claims description 3
- 229940075579 propyl gallate Drugs 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 229940035024 thioglycerol Drugs 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 2
- 102000009027 Albumins Human genes 0.000 claims description 2
- 108010088751 Albumins Proteins 0.000 claims 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 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 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 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000003833 bile salt Substances 0.000 claims description 2
- 229940093761 bile salts Drugs 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940027278 hetastarch Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000787 lecithin Substances 0.000 claims description 2
- 235000010445 lecithin Nutrition 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229950008882 polysorbate Drugs 0.000 claims description 2
- 229940068977 polysorbate 20 Drugs 0.000 claims 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 claims description 2
- 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 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 235000002710 Ilex cornuta Nutrition 0.000 claims 2
- 241001310146 Ilex cornuta Species 0.000 claims 2
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 claims 2
- 241000220324 Pyrus Species 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- 235000009508 confectionery Nutrition 0.000 claims 1
- 230000008014 freezing Effects 0.000 claims 1
- 238000007710 freezing Methods 0.000 claims 1
- 235000021017 pears Nutrition 0.000 claims 1
- 235000011007 phosphoric acid Nutrition 0.000 claims 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims 1
- 229940113124 polysorbate 60 Drugs 0.000 claims 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims 1
- 229910052939 potassium sulfate Inorganic materials 0.000 claims 1
- 229940093914 potassium sulfate Drugs 0.000 claims 1
- 235000011151 potassium sulphates Nutrition 0.000 claims 1
- 229940001482 sodium sulfite Drugs 0.000 claims 1
- 229940001474 sodium thiosulfate Drugs 0.000 claims 1
- 235000011044 succinic acid Nutrition 0.000 claims 1
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract 1
- 238000004108 freeze drying Methods 0.000 description 19
- 239000000843 powder Substances 0.000 description 18
- 239000007788 liquid Substances 0.000 description 15
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 14
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 14
- 230000003750 conditioning effect Effects 0.000 description 13
- 239000012982 microporous membrane Substances 0.000 description 8
- 239000012528 membrane Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical group [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940090044 injection Drugs 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 2
- 229940043349 potassium metabisulfite Drugs 0.000 description 2
- 235000010263 potassium metabisulphite Nutrition 0.000 description 2
- LYHRBIAPWZFXBG-UHFFFAOYSA-N 7h-imidazo[4,5-e]tetrazine Chemical class N1=NNC2=NC=NC2=N1 LYHRBIAPWZFXBG-UHFFFAOYSA-N 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- SNDJGKIVHKOEHY-UHFFFAOYSA-M S(=S)(=O)(O)O.S[Na] Chemical compound S(=S)(=O)(O)O.S[Na] SNDJGKIVHKOEHY-UHFFFAOYSA-M 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- OURRXQUGYQRVML-AREMUKBSSA-N [4-[(2s)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate Chemical compound CC1=CC(C)=CC=C1C(=O)OCC1=CC=C([C@@H](CN)C(=O)NC=2C=C3C=CN=CC3=CC=2)C=C1 OURRXQUGYQRVML-AREMUKBSSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940011406 temozolomide injection Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of medicinal preparations, and concretely relates to a stable temozolomide medicinal composition. The composition comprises an active component temozolomide or a pharmaceutically acceptable salt thereof, and at least one antioxidant. The antioxidant is added to reduce the temozolomide degradation rate in order to make a temozolomide preparation be stable, so the medicinal composition being able to guarantee the stability of temozolomide is obtained, and the production, the storage and the clinic use of the temozolomide are facilitated. The invention also provides a preparation method of the medicinal composition.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of stable pharmaceutical composition of temozolomide, it comprises activity one-tenth
Divide temozolomide or its officinal salt and at least one antioxidant.
Background technology
Temozolomide (temozolomide) chemical name: 3,4-dihydro-3-methyl-4-oxomidazos also [5, l-d]-l, 2,3,
5-tetrazine-8-amide, has the protective embankment agent of anti-tumor activity for imidazo tetrazine class, and chemical structural formula is as follows:
This product is treatment cerebral glioma and the medicine of malignant melanoma of first Ling-Bao Ya (Schering-Plough) company production
Thing.It is hard capsule that domestic temozolomide lists preparation, and oral formulations is easy to use, can be completely absorbed after being administered orally, biological profit
Expenditure is up to 98%, and main side effect is Nausea and vomiting, weak, constipation and slight bone marrow depression, wherein severe
The side reactions such as Nausea and vomiting are common.This often results in the fluctuation of drug absorption, thus affects bioavailability.Some patients
Nausea and vomiting reaction is excessively serious and is difficult to be administered orally, and has a lot of patient's dysphagia clinically, it is impossible to
Being administered orally, urgent clinical needs can temozolomide's preparation of intravenously administrable.But temozolomide is stable at pH < 7 time,
Easily decomposing during pH > 7, temozolomide is as prodrug, the most degradable for activated product, and preparation becomes conventional
Intravenous fluid it cannot be guaranteed that long-time stability, therefore consider to be solidified by lyophilization and prepare and become aseptic freeze-dried
Powder, uses the aqueous diluent of front injection to rebuild, obtains temozolomide's injection, it will be the one of temozolomide's preparation
Individual good breakthrough.
Chinese patent CN 1923197 discloses a kind of freeze-dried temzolomide powder, and it is by adding in water for injection
Lyophilizing proppant, temozolomide, then regulate pH to 1.2-7.0 by pH adjusting agent, filters lyophilizing and obtains.In product only
Containing lyophilizing proppant and pH adjusting agent, products obtained therefrom stability is bad.
Chinese patent CN 101172104 discloses a kind of temozolomide freeze-dried powder pin, containing lyophilizing proppant, profit in prescription
Humectant, pH adjusting agent, solubilizing agent.Except regulation product pH value, control, outside preparation moisture, prescription not to strengthen product
The adjuvant of product stability, product stability is not the best enough.
To sum up, a kind of more stable freeze-dried temzolomide powder it is badly in need of clinically.
Summary of the invention
For the problem that freeze-dried temzolomide powder stability present in prior art is relatively poor, the present inventor is by big
The prescription screening of amount and Study on Preparation, it is provided that a kind of stable pharmaceutical composition of temozolomide and preparation method thereof.Invention
By research, people finds that adding antioxidant in the formulation can improve the stability of temozolomide.
The present invention provides a kind of pharmaceutical composition, comprises active component temozolomide or its pharmaceutically acceptable salt, Yi Jizhi
Few a kind of antioxidant, wherein said antioxidant is selected from Inorganic antioxidant, organic oxidation-resistant agent or a combination thereof.Described
Inorganic antioxidant is selected from: sodium sulfite, Potassium acid sulfite, sodium pyrosulfite, potassium metabisulfite, sodium sulfite, sulfur
Sodium thiosulfate or its combination in any, described organic oxidation-resistant agent is selected from: vitamin E, coenzyme Q10, the tert-butyl group are to hydroxyl fennel
Fragrant ether, thioglycerol, dibenzylatiooluene, propylgallate or its combination in any.
The pharmaceutical composition of the present invention, wherein said temozolomide or its pharmaceutically acceptable salt are in terms of temozolomide, described
Antioxidant and weight ratio≤1 of temozolomide；Preferred anti-oxidant and weight ratio≤0.5 of temozolomide.
The pharmaceutical composition of the present invention, also comprises at least one aqueous diluent, described aqueous diluent selected from water for injection,
Normal saline, one of the dextrose solution of 5% or its mixture, preferably water for injection.
The pharmaceutical composition of the present invention, for injectable parenteral medicinal, described pharmaceutical preparation preferred lyophilized powder form.
The pharmaceutical composition of the present invention, it is also possible to comprise the one in excipient, wetting agent, pH adjusting agent or buffer agent or
Multiple.
The pharmaceutical composition of the present invention, wherein said excipient selected from sodium chloride, glucose, lactose, mannitol, trehalose,
One of xylitol, sucrose, sorbitol, dextrose, albumin, hetastarch, cyclodextrin, glycine or its any group
Close；Wherein said wetting agent selected from polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, bile salts,
One of lecithin, Polyethylene Glycol or its combination in any, be preferably selected from polysorbate-20, polysorbate-40, poly-Pyrusussuriensis
One of alcohol ester-60, Polyoxyethylene Sorbitan Monooleate or its combination in any；Wherein said buffer agent is selected from citrate, lactate, vinegar
One of hydrochlorate, tartrate, succinate, phosphate or its combination in any, be preferably selected from citrate, acetate, phosphorus
One of hydrochlorate or its combination in any；Wherein said pH adjusting agent selected from hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid,
One of tartaric acid, succinic acid or its combination in any.
For excipient, wetting agent, buffer agent, pH adjusting agent, those skilled in the art prepare requirement according to lyophilized formulations
May be made that selection and adjust.
Preferably, the pharmaceutical composition of the present invention, wherein said excipient is selected from mannitol, and described wetting agent is selected from poly-Pyrusussuriensis
Alcohol ester-80, described buffer agent is selected from sodium citrate, and described pH adjusting agent is selected from hydrochloric acid.
The present invention, by adding antioxidant, reduces the degradation rate of temozolomide, it is ensured that gained temozolomide's preparation
Stability, thus obtained ensure that the pharmaceutical composition that temozolomide is stable, is conducive to it to prepare, stores and clinic makes
With.It was discovered by researchers that for the pharmaceutical composition of temozolomide with lyophilized powder as representative, the addition of antioxidant is further
Improve the stability of temozolomide, this stability shows that the related substance amplification that has that ensure that injection temozolomide becomes
Slowly.
The present invention also provides for a kind of method preparing aforementioned pharmaceutical compositions, including by temozolomide or its officinal salt with at least
A kind of mixed uniformly step of antioxidant.
The preparation method of the present invention, specifically includes following steps:
1) by one or more and at least one the antioxidant stirring and dissolving in excipient, wetting agent, buffer agent in aqueous
In diluent, solution temperature 0-60 DEG C；
2) use pH adjusting agent that pH value of solution is adjusted to 2.0-6.0, preferably 2.5-5.5, more preferably 3.0-5.0；
3) by temozolomide or its officinal salt, stirring and dissolving is in above-mentioned solution；
4) addition aqueous diluent is to final volume, stirs.
The preparation method of the present invention, also includes step 4) mixed solution that obtains carries out filtering, lyophilization, to obtain
A kind of lyophilized powder.
In this preparation method, the process for preparation of medicinal liquid suitably controls temperature, it is therefore an objective to reduce the degraded of temozolomide.
Detailed description of the invention
In order to preferably illustrate the present invention, compare explanation using the dosage form of lyophilized powder as embodiment below, but do not limit
In this.The pharmaceutical composition of the present invention is generally prepared by below step:
Weighing excipient, wetting agent, buffer agent, antioxidant stirring and dissolving in water for injection, water is dispensing cumulative volume
About 90%.
Add pH adjusting agent to regulate the pH value of above-mentioned solution to 3.0-5.0.
Weighing temozolomide, stirring and dissolving, in above-mentioned solution, measures the pH value of solution after being completely dissolved, as required,
Regulation solution ph is to 3.0-5.0 again.
Solution, to final volume, is continued stirring to mix homogeneously by addition water for injection.
Above-mentioned solution is filtered, lyophilization.
Embodiment 1
Weigh 15.00g mannitol, 0.075g sodium sulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 2
Weigh 15.00g mannitol, 2.5g Potassium acid sulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.0, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 3
Weigh 15.00g mannitol, 1.25g sodium pyrosulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 5.0, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 4
Weigh 15.00g mannitol, 0.075g potassium metabisulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.0, adds 2.50g
Temozolomide's stirring and dissolving, adds water to 1000mL after dissolving, feed liquid stir after by 0.22 μm microporous filter membrane mistake
Filter, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 5
Weigh 15.00g mannitol, 0.25g sodium sulfite, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 5.0, adds 2.50g
Temozolomide, stirring and dissolving, add water to 1000mL after dissolving, feed liquid stir after with 0.22 μm microporous filter membrane
Filtering, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 6
Weigh 15.00g mannitol, 0.75g sodium thiosulfate, 3.0g polyoxyethylene sorbitan monoleate, 5.88g sodium citrate dihydrate,
Adding 900mL and be cooled to the water for injection of room temperature, stirring and dissolving, using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g
Temozolomide, stirring and dissolving, add water to 1000mL after dissolving, feed liquid stir after with 0.22 μm microporous filter membrane
Filtering, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 7
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 1.0g vitamin E, after mixing with 3.0g polyoxyethylene sorbitan monoleate, adds stirring and dissolving in above-mentioned solution,
Using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g temozolomide's stirring and dissolving, adds water to 1000mL after dissolving,
Feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 8
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 0.20g coenzyme Q10, after mixing with 3.0g polyoxyethylene sorbitan monoleate, adds stirring and dissolving in above-mentioned solution,
Using hydrochloric acid conditioning solution pH is 4.0, adds 2.50g temozolomide, stirring and dissolving, adds water to 1000mL after dissolving,
Feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 9
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 0.25g butylated hydroxyarisol, after the stirring mixing of 3.0g polyoxyethylene sorbitan monoleate, adds above-mentioned molten
Stirring and dissolving in liquid, using hydrochloric acid conditioning solution pH is 4.5, adds 2.50g temozolomide, stirring and dissolving, dissolves complete
After add water to 1000mL, feed liquid obtains temozolomide freeze with 0.22 μm filtering with microporous membrane, lyophilization after stirring
Dry powder.
Embodiment 10
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weigh 0.45g thioglycerol and 3.0g polyoxyethylene sorbitan monoleate stirring mixing after, add above-mentioned solution stirs molten
Solving, using hydrochloric acid conditioning solution pH is 3.5, adds 2.50g temozolomide's stirring and dissolving, adds water to after dissolving
1000mL, feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 11
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weigh 0.8g dibenzylatiooluene and 3.0g polyoxyethylene sorbitan monoleate mixing after, add above-mentioned solution stirs molten
Solving, using hydrochloric acid conditioning solution pH is 3.8, adds 2.50g temozolomide's stirring and dissolving, adds water to after dissolving
1000mL, feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 12
Weigh 15.00g mannitol, 5.88g sodium citrate dihydrate, add 900mL and be cooled to the water for injection of room temperature,
Stirring and dissolving, weighs 0.6g propylgallate, after mixing with 3.0g polyoxyethylene sorbitan monoleate, add above-mentioned solution stirs molten
Solving, using hydrochloric acid conditioning solution pH is 5.0, adds 2.50g temozolomide, stirring and dissolving, adds water to after dissolving
1000mL, feed liquid obtains temozolomide freeze-dried powder with 0.22 μm filtering with microporous membrane, lyophilization after stirring.
Embodiment 13
Weigh 15.00g mannitol, 0.25g sodium sulfite, 5.88g sodium citrate dihydrate, add 900mL the coldest
To the water for injection of room temperature, stirring and dissolving, after weighing 0.2g vitamin E and the mixing of 3.0g polyoxyethylene sorbitan monoleate, in addition
Stating stirring and dissolving in solution, using hydrochloric acid conditioning solution pH is 3.7, adds 2.50g temozolomide's stirring and dissolving, has dissolved
Add water to 1000mL after Biing, feed liquid stir after with 0.22 μm filtering with microporous membrane, lyophilization obtains temozolomide
Lyophilized powder.
Reference examples 1 (with reference to Chinese patent CN 1923197)
Weighing 20g sodium chloride, add in water for injection, under room temperature, stirring makes to be completely dissolved, addition 1g temozolomide, and 40
DEG C stirring in water bath makes temozolomide be completely dissolved and mix homogeneously, adds water for injection to 400ml, uses salt acid for adjusting pH value
To 3.0, with 0.22 μm microporous filter membrane aseptic filtration, fill 40ml/ bottle in 100ml lyophilizing bottle, lyophilization.
Reference examples 2 (Chinese patent CN 101172104 embodiment 2)
Weigh 4.00gL-threonine, 3.00g Tween-80,15.00g mannitol, 5.88g sodium citrate dihydrate,
1.48g hydrochloric acid is sequentially added in 800mL water for injection, stirring and dissolving, adds 2.5g temozolomide, and stirring and dissolving is complete
Quan Hou, adds water to 1000mL, with 0.22 μm filtering with microporous membrane, lyophilization, obtains temozolomide freeze-dried powder.
Stability comparative experiments
Preparing corresponding temozolomide's solution according to embodiment 1-13 prescription and reference examples 1,2 prescription, lyophilization is prepared into
To lyophilized powder.The lyophilized powder of preparation is kept sample under the conditions of 60 DEG C investigate 10 days have related substance situation, have related substance to make
Measure by high performance liquid chromatography (HPLC), the method being referred to 2010 editions second annex V D of Chinese Pharmacopoeia, knot
Fruit is shown in Table 1.
Table 1 embodiment contrasts with reference examples product stability
Note: " ND " expression is not detected by
Result shows, in the present invention embodiment 1-13 group lyophilized powder place at 60 DEG C 10 days stability be superior to matched group 1,
2, illustrate that the addition of antioxidant can significantly improve preparation stability.
Claims (10)
1. a pharmaceutical composition, it is characterised in that comprise active component temozolomide or its pharmaceutically acceptable salt,
And at least one antioxidant, described antioxidant is selected from sodium sulfite, Potassium acid sulfite, sodium pyrosulfite, Jiao Ya
Potassium sulfate, sodium sulfite, sodium thiosulfate, vitamin E, coenzyme Q10, butylated hydroxyarisol, thioglycerol,
One of dibenzylatiooluene, propylgallate or its combination in any.
Pharmaceutical composition the most according to claim 1, it is characterised in that wherein said temozolomide or its pharmaceutically
Acceptable salt in terms of temozolomide, weight ratio≤1 of described antioxidant and temozolomide；Preferred anti-oxidant with for not
Weight ratio≤0.5 of azoles amine.
Pharmaceutical composition the most according to claim 1, also comprises at least one aqueous diluent, and described aqueous dilutes
Agent is selected from water for injection, normal saline, one of the dextrose solution of 5% or its mixture, preferably water for injection.
Pharmaceutical composition the most according to claim 1, for injectable parenteral medicinal, described medicine system
Agent preferred lyophilized powder form.
5., according to the pharmaceutical composition according to any one of claim 1-4, also comprise excipient, wetting agent, pH regulator
One or more in agent or buffer agent.
Pharmaceutical composition the most according to claim 5, wherein said excipient selected from sodium chloride, glucose, lactose,
Mannitol, trehalose, xylitol, sucrose, sorbitol, dextrose, albumin, hetastarch, cyclodextrin, sweet ammonia
One of acid or its combination in any；Wherein said wetting agent is selected from polysorbate, polyoxyethylene castor oil, polyethylene glycol hydrogenated
One of Oleum Ricini, bile salts, lecithin, Polyethylene Glycol or its combination in any, be preferably selected from polysorbate-20, poly-mountain
One of pears alcohol ester-40, polysorbate-60, Polyoxyethylene Sorbitan Monooleate or its combination in any；Wherein said buffer agent is selected from Chinese holly
One of same regimen acid salt, lactate, acetate, tartrate, succinate, phosphate or its combination in any, be preferably selected from Chinese holly
One of same regimen acid salt, acetate, phosphate or its combination in any；Wherein said pH adjusting agent selected from hydrochloric acid, sodium hydroxide,
One of citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or its combination in any.
Pharmaceutical composition the most according to claim 6, wherein said excipient is selected from mannitol, and described wetting agent selects
From Polyoxyethylene Sorbitan Monooleate, described buffer agent is selected from sodium citrate, and described pH adjusting agent is selected from hydrochloric acid.
8. the method preparing pharmaceutical composition as claimed in claim 6, including by temozolomide or its officinal salt
Step mixed uniformly with at least one antioxidant.
Method the most according to claim 8, comprises the following steps:
1) by one or more and at least one the antioxidant stirring and dissolving in excipient, wetting agent, buffer agent in aqueous
In diluent, solution temperature 0-60 DEG C；
2) use pH adjusting agent that pH value of solution is adjusted to 2.0-6.0, preferably 2.5-5.5, more preferably 3.0-5.0；
3) by temozolomide or its officinal salt, stirring and dissolving is in above-mentioned solution；
4) addition aqueous diluent is to final volume, stirs.
Method the most according to claim 9, also includes step 4) mixed solution that obtains carries out filtering, freezing
It is dried, to obtain a kind of lyophilized powder.
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| US20140275195A1 (en) * | 2013-03-14 | 2014-09-18 | Mahmoud S. AlSwisi | Stabilized pharmaceutical formulations comprising antineoplastic compounds |
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| US20140275195A1 (en) * | 2013-03-14 | 2014-09-18 | Mahmoud S. AlSwisi | Stabilized pharmaceutical formulations comprising antineoplastic compounds |
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Application publication date: 20161005 |