CN108434101A - A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application - Google Patents
A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application Download PDFInfo
- Publication number
- CN108434101A CN108434101A CN201810306530.7A CN201810306530A CN108434101A CN 108434101 A CN108434101 A CN 108434101A CN 201810306530 A CN201810306530 A CN 201810306530A CN 108434101 A CN108434101 A CN 108434101A
- Authority
- CN
- China
- Prior art keywords
- tivozanib
- liposomes
- preparation
- novel
- additives
- 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.)
- Pending
Links
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 title claims abstract description 126
- 229960000940 tivozanib Drugs 0.000 title claims abstract description 123
- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- 239000002502 liposome Substances 0.000 title claims abstract description 62
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 28
- 239000000654 additive Substances 0.000 claims abstract description 60
- 239000003814 drug Substances 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 230000000996 additive effect Effects 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 18
- -1 isoflavone glucoside Chemical class 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 244000068988 Glycine max Species 0.000 claims abstract description 8
- 235000010469 Glycine max Nutrition 0.000 claims abstract description 8
- 239000004615 ingredient Substances 0.000 claims abstract description 7
- URRZRRQMNMZIAP-UHFFFAOYSA-N Kudzusapogenol C Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)C(O)CC3(C)CCC21C URRZRRQMNMZIAP-UHFFFAOYSA-N 0.000 claims abstract description 6
- VNGUCOGHCJHFID-FLZFTVBESA-N Soyasapogenol C Chemical compound C([C@@]12C)C[C@H](O)[C@](C)(CO)[C@@H]1CC[C@]1(C)[C@@H]2CC=C2[C@@H]3CC(C)(C)C=C[C@]3(C)CC[C@]21C VNGUCOGHCJHFID-FLZFTVBESA-N 0.000 claims abstract description 6
- 229930182558 Sterol Natural products 0.000 claims abstract description 6
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000008696 isoflavones Nutrition 0.000 claims abstract description 6
- 229930189104 soyasapogenol Natural products 0.000 claims abstract description 6
- 150000003432 sterols Chemical class 0.000 claims abstract description 6
- 235000003702 sterols Nutrition 0.000 claims abstract description 6
- 229930182478 glucoside Natural products 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 35
- 239000007788 liquid Substances 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 22
- 238000002347 injection Methods 0.000 claims description 18
- 239000007924 injection Substances 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 239000012736 aqueous medium Substances 0.000 claims description 14
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000003963 antioxidant agent Substances 0.000 claims description 12
- 230000003078 antioxidant effect Effects 0.000 claims description 12
- 235000006708 antioxidants Nutrition 0.000 claims description 12
- 239000003381 stabilizer Substances 0.000 claims description 12
- 239000004094 surface-active agent Substances 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 8
- 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 7
- 239000002253 acid Substances 0.000 claims description 7
- 235000012000 cholesterol Nutrition 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-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
- 235000021355 Stearic acid Nutrition 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 239000008117 stearic acid Substances 0.000 claims description 6
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 239000008103 glucose Substances 0.000 claims description 5
- 210000003734 kidney Anatomy 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 229940083466 soybean lecithin Drugs 0.000 claims description 5
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 4
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 239000004380 Cholic acid Substances 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 229930003427 Vitamin E Natural products 0.000 claims description 4
- 201000001531 bladder carcinoma Diseases 0.000 claims description 4
- 229940099352 cholate Drugs 0.000 claims description 4
- 235000019416 cholic acid Nutrition 0.000 claims description 4
- 229960002471 cholic acid Drugs 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
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 229940090044 injection Drugs 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- 230000010355 oscillation Effects 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 208000010570 urinary bladder carcinoma Diseases 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
- 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 3
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 3
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 3
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 claims description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 3
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 claims description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 claims description 3
- 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 3
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 claims description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 3
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 claims description 3
- 229930091371 Fructose Natural products 0.000 claims description 3
- 239000005715 Fructose Substances 0.000 claims description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 3
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- 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 3
- 239000005642 Oleic acid Substances 0.000 claims description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 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 3
- 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 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 3
- 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 3
- QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-N 0.000 claims description 3
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 235000009508 confectionery Nutrition 0.000 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229940093181 glucose injection Drugs 0.000 claims description 3
- 125000005456 glyceride group Chemical group 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 3
- 238000006703 hydration reaction Methods 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- 229940064457 osmitrol Drugs 0.000 claims description 3
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 3
- 229940067626 phosphatidylinositols Drugs 0.000 claims description 3
- 239000002504 physiological saline solution Substances 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 229950008882 polysorbate Drugs 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
- 150000003839 salts Chemical class 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- 239000008215 water for injection Substances 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 2
- 229960003964 deoxycholic acid Drugs 0.000 claims description 2
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940079827 sodium hydrogen sulfite Drugs 0.000 claims description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 2
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 claims description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-N disulfuric acid Chemical compound OS(=O)(=O)OS(O)(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-N 0.000 claims 1
- 239000003995 emulsifying agent Substances 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 230000035479 physiological effects, processes and functions Effects 0.000 claims 1
- 229920001993 poloxamer 188 Polymers 0.000 claims 1
- 229940044519 poloxamer 188 Drugs 0.000 claims 1
- 235000015424 sodium Nutrition 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 238000005538 encapsulation Methods 0.000 abstract description 5
- 206010067484 Adverse reaction Diseases 0.000 abstract description 3
- 230000006838 adverse reaction Effects 0.000 abstract description 3
- 238000013268 sustained release Methods 0.000 abstract description 2
- 239000012730 sustained-release form Substances 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 229920001983 poloxamer Polymers 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 208000006265 Renal cell carcinoma Diseases 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 208000026935 allergic disease Diseases 0.000 description 4
- 230000007815 allergy Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000012449 Kunming mouse Methods 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 2
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SPFMQWBKVUQXJV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;hydrate Chemical compound O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O SPFMQWBKVUQXJV-BTVCFUMJSA-N 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N 1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylic acid Chemical compound C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 229940124136 Histidine kinase inhibitor Drugs 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 229910017435 S2 In Inorganic materials 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000012550 audit Methods 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- DNVPQKQSNYMLRS-APGDWVJJSA-N ergosterol group Chemical group [C@@H]1(CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)[C@H](C)\C=C\[C@H](C)C(C)C DNVPQKQSNYMLRS-APGDWVJJSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 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 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 231100000567 intoxicating Toxicity 0.000 description 1
- 230000002673 intoxicating effect Effects 0.000 description 1
- 150000002515 isoflavone derivatives Chemical group 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000001095 phosphatidyl group Chemical group 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ZEXKKIXCRDTKBF-UHFFFAOYSA-N quinoline-2-carboxamide Chemical class C1=CC=CC2=NC(C(=O)N)=CC=C21 ZEXKKIXCRDTKBF-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000008470 skin growth Effects 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1277—Preparation processes; Proliposomes
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application, and the ingredient of the Tivozanib liposomes and the mass fraction of various composition include：1 part of Tivozanib, 45 parts of phosphatidase 1,1 20 parts of additives, 1 10 parts of additive；The additive includes but not limited at least one of sterol, soybean isoflavone glucoside and soyasapogenol.The liposome significantly increases the water solubility and stability of drug, increases the combined anti-cancer curative effect and bioavilability of Tivozanib, reduces adverse reaction, slow release drug, has the function that sustained release, targeting, long-acting.The Tivozanib liposomes average grain diameter is in 500nm hereinafter, encapsulation rate is more than 85%.Preparation method technical maturity, it is simple and easy to do, at low cost, be convenient for large-scale production.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of novel Tivozanib liposomes for anticancer, system
Agent and its preparation method and application.
Background technology
Tivozanib also known as AV-951, KRN-951, entitled N- { 2- chloro- 4- [(6, the 7- dimethoxy-4 's-quinoline of chemistry
Base) oxygroup] phenyl }-N'- (5- methyl -3- isoxazolyls) urea, Chinese translation is for Wo Zhani.Yuan Yan companies are AVEO
Pharmaceuticals, Ins..Tivozanib is a novel oral quinoline carbamide derivative, for the intravascular of specificity
VEGFR-1, -2, -3 are all had good inhibitory activity by skin growth factor VEGFR promise histidine kinase inhibitor.Tivozanib
It is a kind of antineoplastic target medicine, is multiple target point anti-angiogenesis inhibitor anti-cancer drugs, is mainly used for treating kidney,
Preferable curative effect is shown in the first-line treatment of advanced renal cell cancer.Mean survival time is 11.8 months after patient takes Tivozanib
And without deteriorating, for the advanced renal cell cancer patient of surgical removal part kidney, curative effect can reach nearly 14.8 months.And most
New information announces that III phase of Aveo Pharmaceuticals Inc. in 2012 analyzes test result clinically by independent audit committee, it was demonstrated that
No matter whether patient received the antineoplaston of system before, for Wo Zhani treatment groups it is average without progression of disease survival period all
It is significantly better than Sorafenib control group.In December, 2015, EUSA pharmacy obtained from AVEO companies hand the drug research and development and
Sale authorization, it is intended to be developed into the first-line drug for the treatment of RCC.On August 28th, 2017, European drugs administration approved
The application for quotation of Tivozanib, for first-line treatment at human renal cell carcinoma (RCC), mainly by inhibiting Agiogenesis inhibition swollen
The growth of tumor.Certain drug also can potential treatment liver cancer, breast cancer, carcinoma of urinary bladder, gastric cancer, colon cancer, oophoroma.Therefore, quilt
EMA regards as the Orphan drug for the treatment of clear-cell carcinoma, it was predicted that will become heavy bomb drugs after medicine listing.The medicine
It will will produce with huge Social benefit and economic benefit after object listing.
For anti-cancer drugs Tivozanib, current research hotspot has focused largely on synthesis or its salt of itself
Synthesis in, such as application No. is 201110322176.5 patents of invention to disclose a kind of Tivozanib ackd salts and its preparation
Method and crystal form；Application No. is 201310631075.5 patents of invention to disclose a kind of antineoplastic target medicine
The synthetic method of Tivozanib.And its Liposomal formulation is a kind of new formulation, it is therefore an objective to the bioavilability of drug is improved,
And the treatment of cancer effect of drug is improved, to reduce adverse reaction or the toxicity of drug.
Invention content
The object of the present invention is to provide a kind of novel Tivozanib liposomes, preparation and its preparation sides for anticancer
Method and application, to overcome the shortcomings of to mention in the prior art.The purpose of the present invention is be achieved through the following technical solutions：
A kind of novel Tivozanib liposomes for anticancer, it is characterised in that：The Tivozanib liposomes
Ingredient and the mass fraction of various composition include：1 part of Tivozanib, -45 parts of phosphatidase 1,1-20 parts of additives, additive 1-
10 parts；Wherein, the additives include antioxidant, surfactant and stabilizer；The additive includes but not limited to solid
At least one of alcohol, soybean isoflavone glucoside and soyasapogenol.
Further, the Tivozanib liposomes further include polyethylene glycol, and parts by weight are 1-15 parts.
Further, the phosphatide includes but not limited at least one of following component：Lecithin, hydrolecithin,
Soybean lecithin, hydrogenated soya phosphatide, phosphatidic acid, cephalin, cuorin, phosphatidylinositols, phosphatidyl serine, phosphatidyl are sweet
Oil, phosphatidyl-ethanolamine, dipalmitoylphosphatidylglycerol, dipalmitophosphatidic acid, dipalmitoylphosphatidylethanolamine.
Further, the average molecular weight of the polyethylene glycol is 5000-20000.
Further, the additive is sterol, soybean isoflavone glucoside or soyasapogenol.
Further, the mass ratio between the antioxidant, surfactant and stabilizer is：1:(1-5):(1-5).
Further, the sterol includes at least one of cholesterol, beta-cholestanol and ergosterol.
Further, the antioxidant includes but not limited to any one in following component：Sodium sulfite, sulfurous acid
Hydrogen sodium, sodium pyrosulfate, sodium thiosulfate, vitamin E, vitamin-e ester, propylgallate, butylated hydroxyarisol and
Cysteine.
Further, the surfactant includes but not limited to any one in following component：Polyoxyethylene caster
Oil, PLURONICS F87, fatty glyceride, sapn, polysorbate, cholate, cholic acid, dexycholate, deoxycholic acid, ox
Sulphur cholate, Tween 80.
Further, the stabilizer includes but not limited to any one in following component：Stearic acid, phosphatidic acid, ten
Tetracid, oleic acid and glycerine.
A kind of preparation method of the novel Tivozanib liposomes for anticancer, the preparation method include following step
Suddenly：S1：Various recipe ingredients are weighed by formula rate；S2：Ivozanib, phosphatide, additive are dissolved in organic solvent, fully
Dissolving, then vacuum distillation removes organic solvent at 20~60 DEG C；S3：Organic solvent is removed in step S2 adds water phase later
Medium is hydrated, and then ultrasound or high-pressure homogeneous rear up to Tivozanib liposomes of the present invention, is liquid
Tivozanib liposomes.
If additives are fat-soluble additives, by fat-soluble additives in step s 2 with Tivozanib, phosphatide and add
Agent is added to be added in organic solvent together；If additives are water soluble agents, it is dissolved in aqueous media being situated between with water phase
Matter is added together, i.e., will be added in step S2 in the substance after removing organic solvent dissolved with the aqueous media of water soluble agents；
If the additives include fat-soluble additives and water soluble agents, fat-soluble additives are added in step s 2, water-soluble
Property additives are added in step s3.
Further, if the Tivozanib liposomes further include polyethylene glycol, by its in step s 2 with
Ivozanib, phosphatide and additive are added in organic solvent together.
Further, the aqueous media be pure water, physiological saline, Osmitrol and glucose solution in extremely
Few one kind；The organic solvent in ethyl alcohol, methanol, acetic acid, acetone, ethyl acetate, chloroform and dichloromethane at least one
Kind.
A kind of novel Tivozanib Liposomal formulations for anticancer, the formula of the preparation are as shown above；The system
Agent includes Tivozanib lipidosome orals preparation and Tivozanib lipidosome injections；
The Tivozanib lipidosome orals preparation includes liquid oral medicine and solid orally ingestible：(1) liquid
Oral preparation is consistent with the above-mentioned method for preparing Tivozanib liposomes；(2) solid orally ingestible is in liquid port system of mourning
Caffolding agent is added in agent or caffolding agent is added with aqueous media when preparing liquid preparation, then to the Tivozanib fat of gained
Plastid liquid preparation is freeze-dried or is sprayed Atmosphere and is drying to obtain.
The preparation method of the Tivozanib lipidosome injections is：By the liquid oral medicine and water for injection, life
Brine or glucose injection oscillation hydration are managed, Tivozanib lipidosome injections are formed.
Further, the caffolding agent includes but not limited to any one in following component：Glycine, serine, sugarcane
The dosage of sugar, lactose, mannitol, glucose, trehalose, xylitol, sorbierite, fructose, dextran, the caffolding agent is：
It is calculated as 1 part of phosphatide by phosphatide weight ratio and adds 1~500 part of caffolding agent.
Further, the liposome in the Tivozanib lipidosome orals preparation and Tivozanib lipidosome injections
Average grain diameter be 10-500nm, preferably 20-150nm.
Further, the Tivozanib lipidosome injections are the injection that can be used in intravenous administration.
A kind of application of novel Tivozanib liposomes in the drug for preparing treating cancer, the cancer include but
It is not limited to kidney, liver cancer, breast cancer, carcinoma of urinary bladder, gastric cancer, colon cancer and oophoroma.
Beneficial effects of the present invention are：
The present invention provides a kind of novel Tivozanib liposomes for anticancer, preparation and preparation method thereof and answer
With the liposome significantly increases the water solubility and stability of drug, increases the combined anti-cancer curative effect and biology profit of Tivozanib
Expenditure, reduces adverse reaction, slow release drug, has the function that sustained release, targeting, long-acting.The Tivozanib liposomes are flat
Equal grain size is in 500nm hereinafter, encapsulation rate is more than 85%.Preparation method technical maturity, it is simple and easy to do, at low cost, be convenient for scale
Metaplasia is produced.
Specific implementation mode
Illustrate specific implementation mode by taking specific experiment case as an example below, it should be understood that specific reality described herein
It applies example to be only used to explain the present invention, be not intended to limit the present invention.
Embodiment 1
The ingredient of the preparation and the mass fraction of various composition can as it is following 1.~5. shown in.
A kind of novel Tivozanib liposomes for anticancer, it is characterised in that：The Tivozanib liposomes
Ingredient and the mass fraction of various composition can as it is following 1.~5. in any one shown in：1. 1 part of Tivozanib, phosphatide
45 parts, 1 part of polyethylene glycol, 20 parts of additives, 1 part of additive.
Wherein, additives include antioxidant, surfactant and stabilizer, and the weight ratio of three is 1:1:1, it is described to add
It is cholesterol to add agent；The average molecular weight of the polyethylene glycol is 5000.
2. 1 part of Tivozanib, phosphatidase 1 part, 15 parts of polyethylene glycol, 1 part of additives, 10 parts of additive；Wherein, additives
Including antioxidant, surfactant and stabilizer, the weight ratio of three is 1:5:1, the additive is isoflavones sugar
Glycosides；The average molecular weight of the polyethylene glycol is 20000.
3. 1 part of Tivozanib, 5 parts of phosphatidase 1,7 parts of additives, 7 parts of additive；Wherein, additives include antioxidant,
The weight ratio of surfactant and stabilizer, three is 1:1:5, the additive is soyasapogenol.
4. 1 part of Tivozanib, 0 part of phosphatidase 3,13 parts of additives, 3 parts of additive；Wherein, additives include anti-oxidant
The weight ratio of agent, surfactant and stabilizer, three is 1:2:4, the additive is beta-cholestanol.
5. 1 part of Tivozanib, 2 parts of phosphatidase 2,8 parts of polyethylene glycol, 10 parts of additives, 5 parts of additive.Wherein, additives
Including antioxidant, surfactant and stabilizer, the weight ratio of three is 1:3:2, the additive is ergosterol；It is described
The average molecular weight of polyethylene glycol is 12000.
It is above-mentioned 1.~5. in, the phosphatide be lecithin, hydrolecithin, soybean lecithin, hydrogenated soya phosphatide, phosphatide
Acid, cephalin, cuorin, phosphatidylinositols, phosphatidyl serine, phosphatidyl glycerol, phosphatidyl-ethanolamine, two palmityl phosphatide
At least one of acyl glycerine, dipalmitophosphatidic acid and dipalmitoylphosphatidylethanolamine.
The antioxidant is sodium sulfite, sodium hydrogensulfite, sodium pyrosulfate, sodium thiosulfate, vitamin E, vitamin E
At least one of ester, propylgallate, butylated hydroxyarisol and cysteine；The surfactant is polyoxy
Ethylene castor oil, PLURONICS F87, fatty glyceride, sapn, polysorbate, cholate, cholic acid, dexycholate, deoxidation
At least one of cholic acid, taurocholate and Tween 80；The stabilizer is stearic acid, phosphatidic acid, tetradecylic acid, oleic acid and sweet
At least one of oil.
Embodiment 2
A kind of preparation method of the novel Tivozanib liposomes for anticancer, it is shown that steps are as follows：S1：By formula
Ratio weighs various recipe ingredients；
S2：Ivozanib, phosphatide, additive are dissolved in organic solvent, fully dissolved, then depressurizes and steams at 20~60 DEG C
Organic solvent is removed in distillation；
S3：Aqueous media is added in step S2 after removing organic solvent to be hydrated, then ultrasound or high-pressure homogeneous
It is the Tivozanib liposomes of liquid afterwards up to Tivozanib liposomes of the present invention.
If additives are fat-soluble additives, by fat-soluble additives in step s 2 with ivozanib, phosphatide and add
Agent is added to be added in organic solvent together；If additives are water soluble agents, it is dissolved in aqueous media being situated between with water phase
Matter is added together, i.e., will be added in step S2 in the substance after removing organic solvent dissolved with the aqueous media of water soluble agents；
If the additives include fat-soluble additives and water soluble agents, fat-soluble additives are added in step s 2, water-soluble
Property additives are added in step s3.
As preferred embodiment, if the Tivozanib liposomes further include polyethylene glycol, by it in step S2
In be added in organic solvent together with ivozanib, phosphatide and additive.
As preferred embodiment, the aqueous media is pure water, physiological saline, Osmitrol and glucose water
At least one of solution；The organic solvent is selected from ethyl alcohol, methanol, acetic acid, acetone, ethyl acetate, chloroform and dichloromethane
At least one of.
In the present embodiment, restriction is not repeated herein referring to embodiment 1 in the mass ratio of various components.
Embodiment 3
A kind of novel Tivozanib Liposomal formulations for anticancer, described in the formulation Example 1 of said preparation
Tivozanib liposomes are consistent.The preparation includes Tivozanib lipidosome orals preparation and Tivozanib liposome injections
Agent；
The Tivozanib lipidosome orals preparation includes liquid oral medicine and solid orally ingestible：(1) liquid
Oral preparation is 2 obtained Tivozanib liposomes of embodiment；(2) solid orally ingestible is in liquid oral medicine
Caffolding agent is added with aqueous media when preparing liquid preparation in middle addition caffolding agent, then to the Tivozanib lipids of gained
Body fluid body preparation is freeze-dried or is sprayed Atmosphere and is drying to obtain.The caffolding agent includes but not limited to any one in following component
Kind：Glycine, serine, sucrose, lactose, mannitol, glucose, trehalose, xylitol, sorbierite, fructose, dextran,
The dosage of the caffolding agent is：Be calculated as 1 part of phosphatide by phosphatide weight ratio and add 1~500 part of caffolding agent, such as 10 parts, 100 parts, 300
Part etc..
The preparation method of the Tivozanib lipidosome injections is：By the liquid oral medicine and water for injection, life
Brine or glucose injection oscillation hydration are managed, Tivozanib lipidosome injections are formed.The Tivozanib liposome injections
Agent is that can be used in the injection of intravenous administration.
Pass through the Tivozanib lipidosome orals preparation and Tivozanib obtained by above-mentioned component and method
The average grain diameter of liposome in lipidosome injection is 10-500nm, generally between 20-150nm.
Embodiment 4
A kind of novel Tivozanib Liposomal formulations for anticancer and preparation method thereof are as follows.
The group of Tivozanib Liposomal formulations becomes：Tivozanib 10mg, hydrolecithin 200mg, cholesterol
20mg, PLURONICS F87 20mg, stearic acid 10mg, butylated hydroxyarisol 20mg.
Preparation method is：Take Tivozanib, hydrolecithin, cholesterol PLURONICS F87, tertiary butyl to hydroxyl fennel
In fragrant ether and stearic acid input eggplant-shape bottle, 20m1 ethyl alcohol is added：Acetone volume ratio=2:1 mixed solvent fully dissolves；By eggplant
Shape bottle, which is placed in be evaporated under reduced pressure in 40 DEG C of waters bath with thermostatic control, flings to ethyl alcohol and acetone mixed solvent, removes after the organic solvent in bottle inner wall
One layer of lipid membrane of upper formation；15m1 phosphate buffers (pH7.4) are slowly added to, are hydrated, vortex oscillation makes on eggplant-shape bottle
Lipid membrane is completely dissolved；Mixed liquor ultrasonic disperse 30min obtains Tivozanib liposome liquid body preparations.
After testing, the average grain diameter of liposome is 225nm in the liquid preparation, and narrow particle size distribution shows liposome point
It dissipates uniform.The liposome liquid body preparation can be stablized storage a couple of days at room temperature, can stablize storage at least three moon, storage period at 4 DEG C
Between do not observe precipitation or lamination.
Embodiment 5
A kind of novel Tivozanib lipidosome solid preparations for anticancer and preparation method thereof are as follows.
The group of Tivozanib lipidosome solid preparations becomes：Tivozanib 20mg, soybean lecithin 600mg, two palmityls
It is phosphatidyl glycerol 50mg, cholesterol 30mg, polyethylene glycol (average molecular weight 10000) 100mg, PLURONICS F87 20mg, hard
Resin acid 20mg, butylated hydroxyarisol 25mg.
Preparation method is：Take Tivozanib, soybean lecithin, dipalmitoylphosphatidylglycerol, cholesterol, tertiary butyl pair
In hydroxyl polyethylene glycol, stearic acid, butylated hydroxyarisol and PLURONICS F87 input eggplant-shape bottle, add 20m1 acetic acid second
Liposoluble solution, then removes organic solvent in 40 DEG C of vacuum rotary steams, and vacuum drying obtains constant weight film in 1~2 day.20m1 is added and contains 10%
The tris-HCl buffer solutions (20mol/L, pH7.0 contain 0.15mo1/LNaC1) of sucrose, 10% mannitol, pear shape bottle is shaken in rotation
Make film dispersion wherein, then high-pressure homogeneous processing (homogenization pressure 12000psi) 5 times, obtain Tivozanib liposome liquids
Body preparation.
Gained liquid preparation is placed in pre-freeze 24 hours at 40 DEG C, (program, which is lyophilized, is for freeze-drying in freeze drier：40
DEG C, 6 hours；30 DEG C, 6 hours；20 DEG C, 6 hours；10 DEG C, 4 hours；0 DEG C, 4 hours), obtain Tivozanib lipidosome solids
Preparation, average grain diameter is 126 ± 30nm after gained Tivozanib lipidosome solid preparations add water to redissolve.
Embodiment 6：The measurement of encapsulation rate
The Tivozanib not wrapped up in Tivozanib liposome liquid body preparations is isolated using dialysis, uses RP-HPLC
Measure Tivozanib contents of dissociating.Encapsulation rate is calculated according to the following formula.
Encapsulation rate (%)=(the free Tivozanib amounts of Tivozanib total amounts-in liposome)/Tivozanib total amounts
Chromatographic condition：Chromatographic column：Welch Ultimate XB-C18(5μm,250*4.6mm)；Detection wavelength：254nm；
Detect mobile phase：Methanol：Water (80：20)；Sample size：20μl；Flow velocity：1ml/min.
According to the above assay method, the entrapment efficiency for measuring embodiment 4 and embodiment 5 is respectively 87.63% He
88.12%.
Embodiment 7：Toxotest
Using the Tivozanib liposomes in embodiment 4 and 5 as experimental group 1 and experimental group 2, with common pure water
Group as a comparison.
Experimental subjects：Healthy kunming mice 9, every group 3,22 ± 2g of average weight, animal subject is through medical fitness.
One, by the equal shaving of the abdomen of experiment mice, every mouse is containing there are two about 1cm2Skin exposed section, respectively will be right
It is applied to rat skin exposed section than the Tivozanib liposomes in group, experimental group 1 and experimental group 2, is smeared 7 times, 3 days daily
Afterwards without finding any allergy or intoxicating phenomenon, skin color is essentially unchanged, and the vigor of rat does not become, referring specifically to table 1.
Table 1 smears the situation after anticancer preparation
| Skin of abdomen | Mouse vigor | |
| Experimental group 1 | Without allergy, color is unchanged | It is unchanged |
| Experimental group 2 | Without allergy, color is unchanged | It is unchanged |
| Contrast groups | Without allergy, color is unchanged | It is unchanged |
Two, contrast groups are gavaged into pure water, respectively by the Tivozanib liposomes in experimental group 1 and experimental group 2 by each
3mL gavages mouse 3 times a day, is observed continuously 10 days, claims its weight, observation vigor situation, as a result, it has been found that, weight and vigor base
This is unchanged, referring specifically to table 2.
Table 2 gavages the situation after anticancer preparation
| Changes of weight | Rat vigor | |
| Experimental group 1 | Substantially unchanged | It is unchanged |
| Experimental group 2 | Substantially unchanged | It is unchanged |
| Contrast groups | Substantially unchanged | It is unchanged |
Wherein, weight is substantially unchanged refers in normal growth disparity range.
Embodiment 8
Experimental subjects：Healthy kunming mice 12, half male and half female, 22 ± 3g of average weight, animal subject is through medical fitness.
Experimental drug：Tested group：Tivozanib liposome liquid body preparations (Tivozanib10mg/ prepared by the present invention
mL)；Control group：Tivozanib Common liquid formulations (Tivozanib 10mg/mL).
Experimental design：Animal subject is stayed overnight in experiment fasted for one day prior, is administered on an empty stomach when testing day early morning 7.Randomly select 6
Only tested group of animal, qf oral administration dosage 0.5mL, another 6 control animals, qf oral administration dosage 0.5mL.Respectively to
10min, 30min, 45min, 1h, 1.5h, 1.75h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h and quiet from foreleg respectively for 24 hours after medicine
Arteries and veins blood sampling 2mL, is placed in the processed dry test tube of heparin, and 6000rpm centrifuges l0min, and upper plasma is taken to set in cryopreservation tube ,-
70 DEG C of preservations, it is to be measured.
Assay method：The concentration of Tivozanib in blood plasma is measured using high performance liquid chromatography (HPLC).Chromatographic condition：
Chromatographic column：Welch Ultimate XB-C18(5μm,250*4.6mm)；Detection wavelength：254nm；Detect mobile phase：Methanol：Water
(80：20)；Sample size：20μl；Flow velocity：1ml/min.
The measurement of Tivozanib concentration in blood plasma：100 μ L of plasma sample are taken, acetic acid ethyl ester is separately added into：Dichloromethane
(3:2) Extraction solvent 3mL, vortex mixing 1min, shake 10min, and 3000rpm centrifuges 10min, pipettes under 40 DEG C of water-baths of supernatant
Nitrogen dries up, and 20010min is added in residue, and 3000rpm centrifuges l0min, pipettes nitrogen under 40 DEG C of water-baths of supernatant and dries up, residual
Stay object that 200 μ L flowing phased solns are added, vortex mixing takes 20 μ L to carry out HPLC analyses.
The AUCo-t of Tivozanib in two groups of drugs that experimental result medication is calculated for dynamics software
Tivozanib measurement results in 3 blood plasma of table
| Project | Tested group | Control group |
| Tmax(h) | 4.1±0.3 | 1.6+0.72 |
| Cmax(μg/mL) | 3.12+0.38 | 1.38+0.41 |
| AUCo-t.(μg/h/mL) | 16.25+1.56 | 7.33±1.73 |
The relative bioavailability of Tivozanib in tested group of drug relative comparison group drug is calculated with AUCo-t, as a result
It is 133.7% ± 21.2%.
According to the above results it can be found that Tivozanib liposome liquids body preparation can to significantly improve Tivozanib common
The bioavilability of liquid preparation.
Embodiment 9
Take healthy kunming mice, 22 ± 3g of average weight that it is small containing tumour to build tumor model formation in every mouse
Mouse, the mouse for going tumor size consistent is as subjects.
Experimental group：The Tivozanib liposomes of 5 gained of the embodiment of the present invention
Contrast groups 1：Tivozanib Common liquid formulations
Contrast groups 2：Etc. quality pure water
Experimental group and each 5 mice with tumor of contrast groups gavage for mice with tumor in above-mentioned experimental group and contrast groups respectively
Preparation, after 20 days, the tumor tissues in mouse in each group are stripped down, then weigh tumor tissues weight.As a result
It was found that weight is as shown in table 4.
The weight for the tumor tissues removed in 4 experiment mice of table
From the foregoing, it will be observed that the tumor tissues in experimental group are obviously reduced compared with the weight in contrast groups 1, therefore the liposome of the present invention
Anti-cancer effectiveness can also be dramatically increased.
In the present invention, the cancer that can be treated includes but not limited to kidney, liver cancer, breast cancer, carcinoma of urinary bladder, gastric cancer, knot
Intestinal cancer and oophoroma.
The present invention is not limited to above-mentioned preferred forms, anyone can show that other are various under the inspiration of the present invention
The product of form, however, make any variation in its shape or structure, it is every that there is skill identical or similar to the present application
Art scheme, is within the scope of the present invention.
Claims (10)
1. a kind of novel Tivozanib liposomes for anticancer, it is characterised in that：The Tivozanib liposomes at
Divide and the mass fraction of various composition includes：1 part of Tivozanib, -45 parts of phosphatidase 1,1-20 parts of additives, additive 1-10
Part；
The additives include antioxidant, surfactant and stabilizer；
The additive includes but not limited at least one of sterol, soybean isoflavone glucoside and soyasapogenol.
2. the novel Tivozanib liposomes for anticancer according to claim 1, it is characterised in that：It is described
Tivozanib liposomes further include polyethylene glycol, and parts by weight are 1-15 parts.
3. the novel Tivozanib liposomes for anticancer according to claim 2, it is characterised in that：The phosphatide
Including but not limited at least one of following component：Lecithin, hydrolecithin, soybean lecithin, hydrogenated soya phosphatide, phosphatide
Acid, cephalin, cuorin, phosphatidylinositols, phosphatidyl serine, phosphatidyl glycerol, phosphatidyl-ethanolamine, two palmityl phosphatide
Acyl glycerine, dipalmitophosphatidic acid, dipalmitoylphosphatidylethanolamine；
The average molecular weight of the polyethylene glycol is 5000-20000.
4. the novel Tivozanib liposomes for anticancer according to claim 3, it is characterised in that：The addition
Agent is sterol, soybean isoflavone glucoside or soyasapogenol；
Mass ratio between the antioxidant, surfactant and stabilizer is：1:(1-5):(1-5).
5. the novel Tivozanib liposomes for anticancer according to claim 4, it is characterised in that：The sterol
Including at least one of cholesterol, beta-cholestanol and ergosterol；
The antioxidant includes but not limited to any one in following component：Sodium sulfite, sodium hydrogensulfite, pyrosulfuric acid
Sodium, sodium thiosulfate, vitamin E, vitamin-e ester, propylgallate, butylated hydroxyarisol and cysteine；
The surfactant includes but not limited to any one in following component：Emulsifier EL-60, poloxamer
188, fatty glyceride, sapn, cholate, cholic acid, dexycholate, deoxycholic acid, taurocholate, are spat polysorbate
Temperature 80；
The stabilizer includes but not limited to any one in following component：Stearic acid, phosphatidic acid, tetradecylic acid, oleic acid and sweet
Oil.
6. a kind of preparation of the novel Tivozanib liposomes for anticancer according to any one of claims 1-5
Method, which is characterized in that the preparation method includes the following steps：
S1：Various recipe ingredients are weighed by formula rate；
S2：Ivozanib, phosphatide, additive are dissolved in organic solvent, fully dissolved, then be evaporated under reduced pressure and remove at 20~60 DEG C
Remove organic solvent；
S3：Removed in step S2 and add aqueous media and be hydrated after organic solvent, then ultrasound or it is high-pressure homogeneous after i.e.
Tivozanib liposomes of the present invention are obtained, are the Tivozanib liposomes of liquid.
If additives be fat-soluble additives, by fat-soluble additives in step s 2 with Tivozanib, phosphatide and additive
It is added in organic solvent together；If additives are water soluble agents, it is dissolved in aqueous media with aqueous media one
It rises and is added；If the additives include fat-soluble additives and water soluble agents, fat-soluble additives add in step s 2
Enter, water soluble agents are added in step s3.
7. the preparation method of the novel Tivozanib liposomes for anticancer according to claim 6, feature exist
In：If the Tivozanib liposomes further include polyethylene glycol, by its in step s 2 with ivozanib, phosphatide and addition
Agent is added in organic solvent together；
The aqueous media is at least one of pure water, physiological saline, Osmitrol and glucose solution；
The organic solvent is selected from least one of ethyl alcohol, methanol, acetic acid, acetone, ethyl acetate, chloroform and dichloromethane.
8. a kind of novel Tivozanib Liposomal formulations for anticancer, which is characterized in that the preparation includes
Tivozanib lipidosome orals preparation and Tivozanib lipidosome injections；
The Tivozanib lipidosome orals preparation includes liquid oral medicine and solid orally ingestible：(1) liquid oral
Preparation is the obtained Tivozanib liposomes of claim 7；(2) solid orally ingestible is in liquid oral medicine
Caffolding agent is added or caffolding agent is added with aqueous media when preparing liquid preparation, then to the Tivozanib liposomes of gained
Liquid preparation is freeze-dried or is sprayed Atmosphere and is drying to obtain.
The preparation method of the Tivozanib lipidosome injections is：By the liquid oral medicine and water for injection, physiology salt
Water or glucose injection oscillation hydration, form Tivozanib lipidosome injections.
9. the novel Tivozanib Liposomal formulations for anticancer according to claim 8, it is characterised in that：It is described
Caffolding agent includes but not limited to any one in following component：Glycine, serine, sucrose, lactose, mannitol, glucose,
The dosage of trehalose, xylitol, sorbierite, fructose, dextran, the caffolding agent is：It is calculated as 1 part of phosphorus by phosphatide weight ratio
Fat adds 1~500 part of caffolding agent；
The average grain diameter of the Tivozanib lipidosome orals preparation and the liposome in Tivozanib lipidosome injections is
10-500nm, preferably 20-150nm；
The Tivozanib lipidosome injections are the injection that can be used in intravenous administration.
10. a kind of application of novel Tivozanib liposomes in the drug for preparing treating cancer, which is characterized in that described
Cancer includes but not limited to kidney, liver cancer, breast cancer, carcinoma of urinary bladder, gastric cancer, colon cancer and oophoroma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810306530.7A CN108434101A (en) | 2018-04-08 | 2018-04-08 | A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810306530.7A CN108434101A (en) | 2018-04-08 | 2018-04-08 | A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108434101A true CN108434101A (en) | 2018-08-24 |
Family
ID=63198699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810306530.7A Pending CN108434101A (en) | 2018-04-08 | 2018-04-08 | A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108434101A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021234548A1 (en) * | 2020-05-18 | 2021-11-25 | Max Biology Co. Ltd. | Lipid-polymer compositions and methods of use |
| CN114652681A (en) * | 2022-02-28 | 2022-06-24 | 东南大学 | Preparation and application of a kind of bisartesunate glyceride phosphorylcholine liposome preparation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101579312A (en) * | 2008-05-16 | 2009-11-18 | 中国科学院上海药物研究所 | Teniposide liposome and preparation method thereof |
| CN104000783A (en) * | 2014-05-14 | 2014-08-27 | 河南牧翔动物药业有限公司 | Cefquinome liposome |
| CN103179952B (en) * | 2010-09-02 | 2015-06-03 | 斯克里普斯研究学院 | Nanoparticle-based tumor-targeted drug delivery |
| CN105457038A (en) * | 2015-11-09 | 2016-04-06 | 东南大学 | Quick release type medicine phosphatide compound and medicine composition thereof |
-
2018
- 2018-04-08 CN CN201810306530.7A patent/CN108434101A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101579312A (en) * | 2008-05-16 | 2009-11-18 | 中国科学院上海药物研究所 | Teniposide liposome and preparation method thereof |
| CN103179952B (en) * | 2010-09-02 | 2015-06-03 | 斯克里普斯研究学院 | Nanoparticle-based tumor-targeted drug delivery |
| CN104000783A (en) * | 2014-05-14 | 2014-08-27 | 河南牧翔动物药业有限公司 | Cefquinome liposome |
| CN105457038A (en) * | 2015-11-09 | 2016-04-06 | 东南大学 | Quick release type medicine phosphatide compound and medicine composition thereof |
Non-Patent Citations (1)
| Title |
|---|
| TANYA B DORFF ETAL: "Tivozanib in the treatment of renal cell carcinoma", 《BIOLOGICS:TARGETS AND THERAPY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021234548A1 (en) * | 2020-05-18 | 2021-11-25 | Max Biology Co. Ltd. | Lipid-polymer compositions and methods of use |
| CN115968278A (en) * | 2020-05-18 | 2023-04-14 | 麦氏生物科技有限公司 | Lipid-polymer compositions and methods of use |
| CN114652681A (en) * | 2022-02-28 | 2022-06-24 | 东南大学 | Preparation and application of a kind of bisartesunate glyceride phosphorylcholine liposome preparation |
| CN114652681B (en) * | 2022-02-28 | 2023-09-12 | 东南大学 | Preparation and application of double artesunate glyceride phosphorylcholine liposome preparation |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101579310A (en) | Decataxel self-microemulsifying composition and preparation method thereof | |
| Zhang et al. | Therapeutic efficacy of lipid emulsions of docetaxel-linoleic acid conjugate in breast cancer | |
| CN104000783B (en) | Cefquinome liposome | |
| CN106256345A (en) | Vitamin C delivery system and liposome composition thereof | |
| CA2982162A1 (en) | Self-emulsifying formulations of dim-related indoles | |
| JP2022530752A (en) | Self-emulsifying compositions of flavonoid polyphenols, their preparation methods, pharmaceutical compositions and uses | |
| CN114796110A (en) | Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution | |
| CN101780037B (en) | Dipyridamole self-emulsifying medicament administration system and preparation method thereof | |
| CN101524329B (en) | Bicyclo-ethanol submicron emulsion and preparation method thereof | |
| Shailendrakumar et al. | Improved oral pharmacokinetics of pentoxifylline with palm oil and capmul® mcm containing self-nano-emulsifying drug delivery system | |
| CN104826122A (en) | Lipid-modified substance of chlorogenic acid and derivative thereof, preparation method and purification method of the lipid-modified substance | |
| CN101524459A (en) | Oil-in-water type garlicin-garlic oil sub-microemulsion as well as method for preparing same | |
| CN108434101A (en) | A kind of novel Tivozanib liposomes for anticancer, preparation and its preparation method and application | |
| CN104826118A (en) | Application of lipid-modified substance of chlorogenic acid and derivative thereof | |
| CN112206206B (en) | Preparation method and application of curcumin microemulsion gel for vaginal administration | |
| CN109453123A (en) | A kind of Combretastatin analog derivative freeze-dried powder and preparation method thereof | |
| CN108853056A (en) | A kind of modification of folate-targeted carries doxorubicin hydrochloride and gambogicacid nano structured lipid carrier preparation and preparation method thereof altogether | |
| JP2010529175A (en) | Terpenes with antifungal activity against Malassezia yeast | |
| CN104710433A (en) | Chlorambucil derivative, and preparation method and application thereof | |
| CN103859395B (en) | A kind of ubiquinone of high-absorbility 10self-emulsifying drug delivery system and preparation method thereof and application | |
| CN102133184A (en) | Icaritin liposome and preparation method thereof | |
| CN108310390B (en) | Docetaxel linoleate and fat emulsion and application thereof | |
| CN1706371B (en) | Efficient sword-like iris seed preparation and its preparation process | |
| Higashino et al. | Control of oral absorption of nutritional supplement using lipid-based formulations (LBFs): Application to the poorly water-soluble ingredient | |
| CN106137957A (en) | A kind of oleanolic acid type saponin fat microemulsion and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180824 |