CN1311872C - Anticancer combination of medication - Google Patents
Anticancer combination of medication Download PDFInfo
- Publication number
- CN1311872C CN1311872C CNB2004100758379A CN200410075837A CN1311872C CN 1311872 C CN1311872 C CN 1311872C CN B2004100758379 A CNB2004100758379 A CN B2004100758379A CN 200410075837 A CN200410075837 A CN 200410075837A CN 1311872 C CN1311872 C CN 1311872C
- Authority
- CN
- China
- Prior art keywords
- colchicine
- pharmaceutical composition
- tumor
- anticancer
- nocodazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 56
- 229940079593 drug Drugs 0.000 title abstract description 27
- 239000012635 anticancer drug combination Substances 0.000 title 1
- 229940046044 combinations of antineoplastic agent Drugs 0.000 title 1
- 230000001093 anti-cancer Effects 0.000 claims abstract description 53
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 50
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 239000000463 material Substances 0.000 claims abstract description 8
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 79
- 229960001338 colchicine Drugs 0.000 claims description 56
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 claims description 53
- 239000008194 pharmaceutical composition Substances 0.000 claims description 44
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 claims description 30
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 29
- -1 sulfo--colchicine Chemical compound 0.000 claims description 26
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 claims description 24
- 229920001577 copolymer Polymers 0.000 claims description 24
- 229950006344 nocodazole Drugs 0.000 claims description 24
- TZZNWMJZDWYJAZ-UHFFFAOYSA-N 2-(4-oxo-2-phenylchromen-8-yl)acetic acid Chemical compound OC(=O)CC1=CC=CC(C(C=2)=O)=C1OC=2C1=CC=CC=C1 TZZNWMJZDWYJAZ-UHFFFAOYSA-N 0.000 claims description 21
- CTSPAMFJBXKSOY-UHFFFAOYSA-N ellipticine Chemical compound N1=CC=C2C(C)=C(NC=3C4=CC=CC=3)C4=C(C)C2=C1 CTSPAMFJBXKSOY-UHFFFAOYSA-N 0.000 claims description 20
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 claims description 19
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 claims description 19
- 229960005052 demecolcine Drugs 0.000 claims description 19
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 18
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 claims description 18
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 claims description 18
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 claims description 18
- 229950000163 mitotenamine Drugs 0.000 claims description 16
- SZLHBBCRNVPTRZ-UHFFFAOYSA-N n-[(5-bromo-1-benzothiophen-3-yl)methyl]-2-chloro-n-ethylethanamine Chemical compound C1=C(Br)C=C2C(CN(CCCl)CC)=CSC2=C1 SZLHBBCRNVPTRZ-UHFFFAOYSA-N 0.000 claims description 16
- 229950011260 betanaphthol Drugs 0.000 claims description 15
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical compound CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 claims description 13
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 13
- CVXBEEMKQHEXEN-UHFFFAOYSA-N carbaryl Chemical compound C1=CC=C2C(OC(=O)NC)=CC=CC2=C1 CVXBEEMKQHEXEN-UHFFFAOYSA-N 0.000 claims description 12
- 229950005994 giracodazole Drugs 0.000 claims description 12
- YILCGOCHVFQMTC-WVZVXSGGSA-N girolline Chemical compound NC[C@H](Cl)[C@@H](O)C1=CNC(N)=N1 YILCGOCHVFQMTC-WVZVXSGGSA-N 0.000 claims description 12
- 150000004780 naphthols Chemical class 0.000 claims description 12
- XXVLKDRPHSFIIB-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 XXVLKDRPHSFIIB-UHFFFAOYSA-N 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 claims description 11
- 229950003478 acodazole Drugs 0.000 claims description 11
- 229960005286 carbaryl Drugs 0.000 claims description 11
- JVHIPYJQMFNCEK-UHFFFAOYSA-N cytochalasin Natural products N1C(=O)C2(C(C=CC(C)CC(C)CC=C3)OC(C)=O)C3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 JVHIPYJQMFNCEK-UHFFFAOYSA-N 0.000 claims description 11
- 229950008144 mitoclomine Drugs 0.000 claims description 11
- 229950005710 mitoflaxone Drugs 0.000 claims description 11
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 claims description 11
- 229960003539 mitoguazone Drugs 0.000 claims description 11
- 229950001745 mitonafide Drugs 0.000 claims description 11
- CPTIBDHUFVHUJK-NZYDNVMFSA-N mitopodozide Chemical compound C1([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(=O)NNCC)=CC(OC)=C(OC)C(OC)=C1 CPTIBDHUFVHUJK-NZYDNVMFSA-N 0.000 claims description 11
- 229950010088 mitopodozide Drugs 0.000 claims description 11
- BFRVNBMAWXNICS-UHFFFAOYSA-N mitoquidone Chemical compound C1=CC=C2C(=O)C3=CN(CC=4C(=CC=CC=4)C4)C4=C3C(=O)C2=C1 BFRVNBMAWXNICS-UHFFFAOYSA-N 0.000 claims description 11
- 229950007466 mitoquidone Drugs 0.000 claims description 11
- 229950005715 mitosper Drugs 0.000 claims description 11
- 229960000350 mitotane Drugs 0.000 claims description 11
- QXYYYPFGTSJXNS-UHFFFAOYSA-N mitozolomide Chemical compound N1=NN(CCCl)C(=O)N2C1=C(C(=O)N)N=C2 QXYYYPFGTSJXNS-UHFFFAOYSA-N 0.000 claims description 11
- 229950005967 mitozolomide Drugs 0.000 claims description 11
- CLZXREZAEIUCGG-UHFFFAOYSA-N n,n-bis(2-chloroethyl)-4-methoxy-3-methylnaphthalen-1-amine Chemical compound C1=CC=C2C(OC)=C(C)C=C(N(CCCl)CCCl)C2=C1 CLZXREZAEIUCGG-UHFFFAOYSA-N 0.000 claims description 11
- JWDFWIZNGSOUGC-INIZCTEOSA-N n-[(7s)-10-amino-1,2,3-trimethoxy-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(N)=CC=C1C1=C2C=C(OC)C(OC)=C1OC JWDFWIZNGSOUGC-INIZCTEOSA-N 0.000 claims description 11
- XYWJNTOURDMTPI-UHFFFAOYSA-N procodazole Chemical compound C1=CC=C2NC(CCC(=O)O)=NC2=C1 XYWJNTOURDMTPI-UHFFFAOYSA-N 0.000 claims description 11
- 229950000989 procodazole Drugs 0.000 claims description 11
- VXRLUFPGDHFNHT-UHFFFAOYSA-O 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium Chemical compound C[N+]1=CC=C2C(C)=C(NC=3C4=CC=CC=3)C4=C(C)C2=C1 VXRLUFPGDHFNHT-UHFFFAOYSA-O 0.000 claims description 10
- UCICRVXYPSKKJK-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-5,11-dimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;chloride Chemical compound [Cl-].C1=C(O)C=C2C3=C(C)C4=C[N+](CCN(CC)CC)=CC=C4C(C)=C3NC2=C1 UCICRVXYPSKKJK-UHFFFAOYSA-N 0.000 claims description 10
- ZIXGXMMUKPLXBB-UHFFFAOYSA-N Guatambuinine Natural products N1C2=CC=CC=C2C2=C1C(C)=C1C=CN=C(C)C1=C2 ZIXGXMMUKPLXBB-UHFFFAOYSA-N 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- SUYXJDLXGFPMCQ-INIZCTEOSA-N SJ000287331 Natural products CC1=c2cnccc2=C(C)C2=Nc3ccccc3[C@H]12 SUYXJDLXGFPMCQ-INIZCTEOSA-N 0.000 claims description 10
- ZMAODHOXRBLOQO-UHFFFAOYSA-N cytochalasin-A Natural products N1C(=O)C23OC(=O)C=CC(=O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 ZMAODHOXRBLOQO-UHFFFAOYSA-N 0.000 claims description 10
- 229950004062 datelliptium chloride Drugs 0.000 claims description 10
- 239000005038 ethylene vinyl acetate Substances 0.000 claims description 10
- 239000007943 implant Substances 0.000 claims description 10
- 239000010452 phosphate Substances 0.000 claims description 10
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 10
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 10
- 229960001860 salicylate Drugs 0.000 claims description 10
- 229920000954 Polyglycolide Polymers 0.000 claims description 7
- 239000004633 polyglycolic acid Substances 0.000 claims description 7
- 229960004275 glycolic acid Drugs 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 241000196324 Embryophyta Species 0.000 claims 2
- 241000189665 Colchicum autumnale Species 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 20
- 238000000034 method Methods 0.000 abstract description 17
- 229920000642 polymer Polymers 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 5
- 238000001959 radiotherapy Methods 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 239000003080 antimitotic agent Substances 0.000 abstract 3
- 230000015556 catabolic process Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 206010020718 hyperplasia Diseases 0.000 abstract 1
- 231100000057 systemic toxicity Toxicity 0.000 abstract 1
- 239000004615 ingredient Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 239000004626 polylactic acid Substances 0.000 description 12
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 229920002732 Polyanhydride Polymers 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 229920000747 poly(lactic acid) Polymers 0.000 description 8
- JVYNJRBSXBYXQB-UHFFFAOYSA-N 4-[3-(4-carboxyphenoxy)propoxy]benzoic acid;decanedioic acid Chemical compound OC(=O)CCCCCCCCC(O)=O.C1=CC(C(=O)O)=CC=C1OCCCOC1=CC=C(C(O)=O)C=C1 JVYNJRBSXBYXQB-UHFFFAOYSA-N 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 238000012856 packing Methods 0.000 description 7
- 229950004403 polifeprosan Drugs 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 239000000654 additive Substances 0.000 description 6
- 230000000996 additive effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000001954 sterilising effect Effects 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 5
- 239000002131 composite material Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002513 implantation Methods 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920005576 aliphatic polyanhydride Polymers 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229920002627 poly(phosphazenes) Polymers 0.000 description 4
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 4
- 229960002066 vinorelbine Drugs 0.000 description 4
- 229920001273 Polyhydroxy acid Polymers 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000011978 dissolution method Methods 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- YBXKKOCGWBHEBM-DGPALRBDSA-N vinmegallate Chemical compound C([C@]([C@@H]12)(C=3)CC)=CCN2CCC(C2=CC=CC=C22)=C1N2C=3COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 YBXKKOCGWBHEBM-DGPALRBDSA-N 0.000 description 3
- 229950001188 vinmegallate Drugs 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- 229920002101 Chitin Polymers 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000011254 conventional chemotherapy Methods 0.000 description 2
- 238000007334 copolymerization reaction Methods 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001827 electrotherapy Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002075 main ingredient Substances 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 229920005615 natural polymer Polymers 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 229920002239 polyacrylonitrile Polymers 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 201000000274 Carcinosarcoma Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- PRGILOMAMBLWNG-HNNXBMFYSA-N Colchiceine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(O)=CC=C1C1=C2C=C(OC)C(OC)=C1OC PRGILOMAMBLWNG-HNNXBMFYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000005422 Foreign-Body reaction Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- PRGILOMAMBLWNG-UHFFFAOYSA-N colchicceine Natural products C1CC(NC(C)=O)C2=CC(=O)C(O)=CC=C2C2=C1C=C(OC)C(OC)=C2OC PRGILOMAMBLWNG-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000000892 gravimetry Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 238000002653 magnetic therapy Methods 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- CMEGANPVAXDBPL-INIZCTEOSA-N n-[(7s)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(SC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC CMEGANPVAXDBPL-INIZCTEOSA-N 0.000 description 1
- XWLUFINGMMDFPD-UHFFFAOYSA-N naphthalen-1-ol Chemical compound C1=CC=C2C(O)=CC=CC2=C1.C1=CC=C2C(O)=CC=CC2=C1 XWLUFINGMMDFPD-UHFFFAOYSA-N 0.000 description 1
- YNXICDMQCQPQEW-UHFFFAOYSA-L naphthalen-1-yl phosphate Chemical compound C1=CC=C2C(OP([O-])(=O)[O-])=CC=CC2=C1 YNXICDMQCQPQEW-UHFFFAOYSA-L 0.000 description 1
- WHQDPSGUFIHZTE-UHFFFAOYSA-N naphthalen-2-ol Chemical compound C1=CC=CC2=CC(O)=CC=C21.C1=CC=CC2=CC(O)=CC=C21 WHQDPSGUFIHZTE-UHFFFAOYSA-N 0.000 description 1
- 210000001989 nasopharynx Anatomy 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229920001558 organosilicon polymer Polymers 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000003361 porogen Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- HJSRRUNWOFLQRG-UHFFFAOYSA-N propanedioic acid Chemical compound OC(=O)CC(O)=O.OC(=O)CC(O)=O HJSRRUNWOFLQRG-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940116353 sebacic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an anticancer medical composition, which belongs to the technical field of drugs. The present invention comprises pharmaceutic supplementary materials and antimitotic drugs, wherein the antimitotic drugs can suppress hyperplasia of tumors; the pharmaceutic supplementary materials are mainly high molecular biologic capacitability polymers which can be degraded and absorbed, and in a degradation and absorption process, the antimitotic drugs can be slowly released locally at the tumors, so the systemic toxicity reactions of human bodies are reduced obviously; simultaneously, the tumors can locally keep effective drug concentration. The composition is put locally at the tumors, the local drug concentration of the tumors can be improved in a selective mode, and the treatment effect of non-operative treatments, such as chemotherapeutics, radiotherapy, etc., can be enhanced.
Description
(1) technical field
The present invention relates to a kind of anticancer pharmaceutical composition, belong to technical field of pharmaceuticals.
(2) background technology
The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.In used various chemotherapeutics, the action effect of anti-mitosis medicine is comparatively obvious, has been widely used in multiple malignant tumor.Yet, further discover, entity tumor excessive expansion hypertrophy, the viscosity of matter was high than its normal surrounding tissue all between matter pressure, tissue elasticity pressure, fluid pressure reached therebetween, therefore, conventional chemotherapy is difficult to tumor by local and forms effective drug level (referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (KongQ et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer pharmaceutical composition is provided.
Anticancer pharmaceutical composition comprises anticancer effective component and pharmaceutic adjuvant, and wherein, anticancer effective component is an anti-mitosis medicine.Anti-mitosis medicine is selected from one of following or its combination:
Cytochalasin (podophyllotoxin), Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine (Mitoclomine), mitoflaxone [Mitoflaxone], mitoguazone [Mitoguazone], mitonafide [Mitonafide], mitopodozide [Mitopodozide], mitoquidone [Mitoquidone], mitosper [Mitosper], mitotane [Mitotane], mitotenamine [Mitotenamine], mitozolomide [Mitozolomide], Flavone acetic acid, colchicine, Salicylate (colchisal), colchiceinamide [Colchiceinamide], colchicine [Colchicine], 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a (colchiceine), sulfo--colchicine (thio-colchicine), Demecolcine [Demecolcine], Colchiceinamidum, Colchicine, B cytochalasin B (cytochalasins) is (as A-E, H, J), carbaryl (sevin, carbaryl), naphthols (naphthol), alpha-Naphthol (1-naphthol), betanaphthol (2-naphthol), alpha-phosphate naphthols (1-naphthylphosphate), acodazole (Acodazole), procodazole [Procodazole], giracodazole [Giracodazole], nocodazole (nocodazole), malonic acid (malonate) or malonate.
Anti-mitosis medicine will make tumor cell stop at the different links of cell cycle.Anti-mitosis medicine shared percentage by weight in compositions is also decided because of concrete condition, can be 0.01%-80%, is good with 1%-50%, is best with 2%-30%.
Anti-mitosis medicine in the anticancer pharmaceutical composition of the present invention is preferably as follows, and all is weight percentage:
(a) cytochalasin of 0.01%-10%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, the mitoclomine mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt); Perhaps
(b) 5%-20% cytochalasin, Datelliptium Chloride, ellipticine, 2-Methylellipticine, the mitoclomine mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt); Perhaps
(c) 15%-30% cytochalasin, Datelliptium Chloride, ellipticine, 2-Methylellipticine, the mitoclomine mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt)
Pharmaceutic adjuvant comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (poiyamides), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacicacid), polifeprosan (to the copolymer of carboxy phenyl propane and certain herbaceous plants with big flowers diacid) etc.; Natural polymer as, but be not limited to, protein and polysaccharide comprise hyaluronic acid, collagen protein, gelatin, albumin etc.
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description in other United States Patent (USP) that (US 4857311; 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the hydroxy carboxylic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid; When PLA and PLGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.The molecular weight of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 1000-100,000, but with 10,000-50000 is preferred; With 10,000-20000 is for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or certain herbaceous plants with big flowers diacid or copolymer for most preferably, as, but be not limited to, molecular weight is 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change anticancer pharmaceutical composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
The used pharmaceutic adjuvant of anticancer pharmaceutical composition of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of composition for treating solid tumor of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of anticancer pharmaceutical composition can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion or through mode or dual mode like this that polymer is degraded.In addition, the effective ingredient of anticancer pharmaceutical composition also can be packaged in the liposome equably, or makes microsphere with art methods.
Characteristics of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
Anticancer pharmaceutical composition of the present invention can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc.; Be different shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and mould shape.In various dosage forms, serve as preferred with implant, slow releasing agent and implantation slow release agent.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
Because anticancer pharmaceutical composition of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
Route of administration
Anticancer pharmaceutical composition of the present invention can be used through various approach, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as based in selective arterial, the tumor, tumor week injection, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump and slow releasing capsule as selecting for use, body is implanted into agent, sustained-release implant.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.But effective dose commonly used is 0.01-80 milligram/kg body weight, is ideal with 1-50 milligram/kg body weight, with 2-10 milligram/kg body weight for the most desirable.Percentage by weight shared in compositions is decided because of concrete condition, can be good with 1%-50% from 0.01%-80%, is best with 2%-30%.Below all be weight percentage.
Anticancer pharmaceutical composition of the present invention can be used to prepare the various entity tumors for the treatment of the people, comprises former or the cancer of transfer or the medicine of sarcoma or carcinosarcoma originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Anticancer pharmaceutical composition of the present invention also can be used for the treatment of the various entity tumors of house pet and animal, and when being used for the treatment of the various entity tumor of house pet and animal, the material of species specificity is preferably selected in the active ingredient of anticancer pharmaceutical composition of the present invention for use.
Also can add other medicinal ingredient in the anticancer pharmaceutical composition of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Anticancer pharmaceutical composition of the present invention can be used in the following manner.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can be through various administrations, with topical, as selective arterial injection and directly injection or be placed as goodly in the tumor body, wherein implant with the part again and slowly are released to the best.When used the part, anticancer pharmaceutical composition of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Anticancer pharmaceutical composition Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out.Cause discharges contained drug at tumor by local, thereby optionally improves and prolong local drug concentration, can reduce the general toxic reaction that is caused by the conventional route administration simultaneously.
Anticancer pharmaceutical composition can be made into different shape, and wherein the content of active ingredient is decided because of different needs.Can be good with 1%-50% from 0.1%-80%, be best with 2%-30%.This anticancer pharmaceutical composition can be made into various dosage forms, as, but be not limited to injection, muddy suspension, ointment, capsule, implant, slow releasing agent and implantation slow release agent etc.; Be different shape, as, but be not limited to graininess, lamellar, sphere, bulk, needle-like, bar-shaped or mould shape; Can be good with the tremulous pulse approach through various administrations, directly be placed as the best in the tumor body.Most preferred dosage form of the present invention is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and composition for treating solid tumor also can be packed in the liposome.
The characteristics of anticancer pharmaceutical composition technology of preparing of the present invention are one or more anti-mitosis medicines are packaged in the pharmaceutic adjuvant, and proportionally with active ingredient and pharmaceutic adjuvant dissolving, the universe is dry afterwards to wait to fill part mixing.Treat that the universe is shaped immediately after dry and sterilizes packing.The local placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
The present invention be processed into anticancer pharmaceutical composition preparation method as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.Active ingredient percentage by weight 0.01%-80%.
3. removal organic solvent.Vacuum drying, cold drying or cold drying all can.
4. dried solid composite is made different shape as required.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
In a word, the anticancer pharmaceutical composition that contains above effective ingredient can be made into any dosage form or shape, the effective ingredient of anticancer compound is any one (or multiple) anti-mitosis medicine, but serving as preferred with implant, agent for slow releasing and implantation agent for slow releasing.
(4) specific embodiment
The present invention is processed into anticancer pharmaceutical composition and further is illustrated by following examples, but is not limited thereto.
Embodiment 1.
It with the 90mg molecular weight 10000 the PLGA (copolymer of hydroxyacetic acid and glycolic, hydroxyacetic acid and glycolic weight ratio 25: 75) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add the 10mg nocodazole, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% nocodazole.
Embodiment 2.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 1, and different is that contained effective ingredient is:
The cytochalasin of 0.01%-10%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole or malonic acid (salt).More than be weight percentage.
Embodiment 3.
80mg pharmaceutic adjuvant ethylene vinyl acetate copolymer (EVAc) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 20mg betanaphthol, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 20% betanaphthol.The drug release time of this anticancer pharmaceutical composition in external normal saline is 14-24 days, is 20-35 days at the subcutaneous drug release time of mice.
Embodiment 4.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 3, and different is that contained effective ingredient is the cytochalasin of 5%-20%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt).More than be weight percentage.
Embodiment 5.
70mg polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid copolymer, weight ratio 40: 60) is put into container, add 100 milliliters of dichloromethane dissolving mixings after, add the 30mg B cytochalasin B, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 30% B cytochalasin B.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-25 days, is 25-40 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 5, and the effective ingredient that different is wherein is respectively the 15%-30% cytochalasin, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchicine, Salicylate, colchiceinamide, colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, nocodazole or malonic acid (salt).More than be weight percentage.
Embodiment 7.
The method step that is processed into anticancer pharmaceutical composition is identical with embodiment 1,3 or 5, but used pharmaceutic adjuvant be following one of a)-e) or its combination:
A) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,25000-35000 or 30000-50000;
B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc);
D) to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan), to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.All be weight percentage;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or albumin.
Embodiment 8.
With the 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (sA) copolymer) put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 10mg B cytochalasin B and 10mg alpha-Naphthol, shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer pharmaceutical composition of percentage by weight 10% B cytochalasin B and 10% alpha-Naphthol.The drug release time of this anticancer pharmaceutical composition in external normal saline is 15-25 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 9.
Method step is identical with embodiment 8, and the effective ingredient that different is wherein is respectively:
(a) cytochalasin of 1%-50%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide or mitoquidone, mitosper, mitotane, mitotenamine, the colchicine of mitozolomide or Flavone acetic acid and 1%-50%, Salicylate, colchiceinamide, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, the combination of nocodazole or malonic acid (salt);
(b) colchicine of 1%-50%, Salicylate, colchiceinamide, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, sulfo--colchicine, Demecolcine, Colchiceinamidum, Colchicine, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide or mitoquidone, mitosper, mitotane, mitotenamine, the cytochalasin of mitozolomide or Flavone acetic acid and 1%-50%, Datelliptium Chloride, ellipticine, 2-Methylellipticine, B cytochalasin B, carbaryl, naphthols, alpha-Naphthol, betanaphthol, the alpha-phosphate naphthols, acodazole, procodazole, giracodazole, the combination of nocodazole or malonic acid (salt).
Below all be weight percentage.
Tumor-inhibiting action in the body of embodiment 10. anti-mitosis medicines.
With the white mice is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 7 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is colchicine, and the 5th to 7 group is nocodazole, and the 8th to 10 group is alpha-Naphthol.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.Local colchicine, nocodazole and the alpha-Naphthol of placing is selected from embodiment 4,2 and 6 respectively, and the percentage by weight of medicine in implant is respectively 10%, 20% and 30%.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6) | Contrast colchicin (ip) colchicin (it) colchicin (itp) nocodazole (ip) nocodazole (it) nocodazole (itp) alpha-Naphthol (ip) alpha-Naphthol (it) alpha-Naphthol (itp) | 60.5±10.5 24±5.0 14±3.5 10±1.8 22±4.3 16±4.6 10±1.6 20±2.6 14±1.6 5±0.6 | ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
Tumor-inhibiting action in the body of embodiment 11. anti-mitosis medicines.
EXPERIMENTAL DESIGN is with embodiment 10, and local nocodazole, betanaphthol and the B cytochalasin B of placing is selected from embodiment 1,3 and 5 respectively, and the percentage by weight of medicine in implant is respectively 10%, 20% and 30%, (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is nocodazole, and the 5th to 7 group is betanaphthol, and the 8th to 10 group is B cytochalasin B.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 10th day.
Table 2
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6) | Contrast nocodazole (ip) nocodazole (it) nocodazole (itp) betanaphthol (ip) betanaphthol (it) betanaphthol (itp) B cytochalasin B (ip) B cytochalasin B (it) B cytochalasin B (itp) | 76±13 45±6.2 38±4.0 28±2.6 54±6.0 32±3.2 18±2.2 53±5.8 22±3.0 10±1.6 | ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
Tumor-inhibiting action in the body of embodiment 12. anti-mitosis medicines.
EXPERIMENTAL DESIGN is with embodiment 10, and the local medicine of placing is that 10% naphthols, 20% giracodazole and 30% mitotenamine are respectively from embodiment 2,4 and 6.First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd to 4 group is vinorelbine, and the 5th to 7 group is naphthols, and the 8th to 10 group is mitotenamine.Medicine is placed (itp) respectively in lumbar injection (ip), intratumor injection (it) and tumor.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) 2(6) 3(6) 4(6) 5(6) 6(6) 7(6) 8(6) 9(6) 10(6) | Contrast vinorelbine (ip) vinorelbine (ip) vinorelbine (ip) Vinmegallate (ip) Vinmegallate (ip) Vinmegallate (ip) Mitotenamine (ip) Mitotenamine (it) Mitotenamine (itp) | 74±10 48±6.6 39±4.1 28±2.2 54±7.0 36±3.0 17±2.2 42±6.6 20±2.6 12±1.6 | ＜0.05 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
The result of embodiment 10 to 12 shows that used various anti-mitosis medicines all have the obvious suppression effect to growth of tumour cell when this concentration, but comparatively obvious with local application's effect, wherein locally places that to be that tumor is implanted into the most effective.Local placement not only can suppress tumor growth effectively, and can significantly reduce the general toxic reaction of medicine, and selected anti-mitosis medicine is of universal significance.
The result of embodiment 10 to 12 shows that tumor by local placement anti-mitosis medicine has obvious superiority, be further clear and definite slow release effect of the present invention, selected the copolymer (PLGA of polyglycolic acid and hydroxyacetic acid respectively for use, molecular weight is 10000), ethylene vinyl acetate copolymer (EVAc) and polifeprosan (to carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA) copolymer) be that pharmaceutic adjuvant, gravimetry percentage ratio are the release conditions of 20% anti-mitosis medicine.The result shows that the drug release time of this anticancer pharmaceutical composition in external normal saline is 15-20 days, is about 30-40 days at the subcutaneous drug release time of mice.Therefore the obvious tumor-inhibiting action that this anticancer pharmaceutical composition is described is mainly from its medicament slow release characteristic, and the latter is apparent at the superiority of keeping aspect the local drug concentration, and to selected anti-mitosis medicine tool universal meaning.Wherein PLGA is excellent than EVAc or polifeprosan.
As mentioned above, the preparation method of anticancer pharmaceutical composition of the present invention can be selected as the case may be.Anticancer pharmaceutical composition can be made various dosage forms with existing method, and therefore, above embodiment only is used for explanation, and is not limitation application of the present invention.Said composition except that independent application, also can with many treatment measure use in conjunction: as with use in conjunction such as radiotherapy, high thermal therapeutical, immunization therapy, phototherapy, electrotherapy.The local placement used said composition has uniqueness as synergist advantage and very high clinical value.When said composition and other treatment measure use in conjunction, said composition can be simultaneously or prior to other treatment measure.
Claims (3)
1, a kind of anticancer pharmaceutical composition, comprise anticancer effective component and pharmaceutic adjuvant, it is characterized in that this pharmaceutical composition is a sustained-release implant, described anticancer effective component is an anti-mitosis medicine, the percentage by weight of anti-mitosis medicine in compositions is 0.01-30%, and anti-mitosis medicine is selected from one of following or its combination:
The alpha-phosphate naphthols, alpha-Naphthol, betanaphthol, acodazole, procodazole, giracodazole, carbaryl, 2-Methylellipticine, sulfo--colchicine, Datelliptium Chloride, mitoguazone, mitopodozide, mitoquidone, the mitoclomine mitoflaxone, mitotenamine, mitonafide, Flavone acetic acid, mitosper, mitotane, mitozolomide, naphthols, nocodazole, the nocodazole malonic acid, the nocodazole malonate, colchiceinamide, Demecolcine, colchicine, Colchicine, Colchicum autumnale phthalein amine, 7-acetamido-10-hydroxy-1,2,3-trimethoxy-6,7-dihydrobenzo[a, Salicylate, cytochalasin, ellipticine, B cytochalasin B;
Described pharmaceutic adjuvant is a slow-release auxiliary material, selects for use one of following:
(1) molecular weight is 5000-15000,10000-20000, the polyglycolic acid of 25000-35000 or 30000-50000 and the copolymer of hydroxyacetic acid;
(2) ethylene vinyl acetate copolymer;
(3) to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid copolymer, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40; Be weight ratio.
2, the anticancer pharmaceutical composition according to claim 1 is characterized in that in this anti-cancer composition tumor or all placements of tumor.
3, the anticancer pharmaceutical composition according to claim 1 is characterized in that this entity-tumor-resistant medicine composition is graininess, lamellar, sphere, bulk, needle-like, bar-shaped or membranaceous.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100758379A CN1311872C (en) | 2004-12-29 | 2004-12-29 | Anticancer combination of medication |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100758379A CN1311872C (en) | 2004-12-29 | 2004-12-29 | Anticancer combination of medication |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1660436A CN1660436A (en) | 2005-08-31 |
| CN1311872C true CN1311872C (en) | 2007-04-25 |
Family
ID=35010170
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100758379A Expired - Fee Related CN1311872C (en) | 2004-12-29 | 2004-12-29 | Anticancer combination of medication |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1311872C (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250563A (en) * | 1991-09-25 | 1993-10-05 | Merck & Co., Inc. | Inhibitors of HIV protease |
| CN1192142A (en) * | 1995-08-03 | 1998-09-02 | 普罗克特和甘保尔公司 | Use of 1H-1,2,4-triazole derivatives for inhibiting cancer growth |
| CN1275377A (en) * | 2000-04-29 | 2000-12-06 | 孔庆忠 | Anticancer medicine composition |
| US6326402B1 (en) * | 1998-08-12 | 2001-12-04 | Octamer, Inc. | Methods for treating viral infections using a compound capable of inhibiting microtubules |
| CN1533765A (en) * | 2003-03-31 | 2004-10-06 | 清华大学 | Preparation method of anticancer drug colchicine microsphere freeze-dried agent |
-
2004
- 2004-12-29 CN CNB2004100758379A patent/CN1311872C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5250563A (en) * | 1991-09-25 | 1993-10-05 | Merck & Co., Inc. | Inhibitors of HIV protease |
| CN1192142A (en) * | 1995-08-03 | 1998-09-02 | 普罗克特和甘保尔公司 | Use of 1H-1,2,4-triazole derivatives for inhibiting cancer growth |
| US6326402B1 (en) * | 1998-08-12 | 2001-12-04 | Octamer, Inc. | Methods for treating viral infections using a compound capable of inhibiting microtubules |
| CN1275377A (en) * | 2000-04-29 | 2000-12-06 | 孔庆忠 | Anticancer medicine composition |
| CN1533765A (en) * | 2003-03-31 | 2004-10-06 | 清华大学 | Preparation method of anticancer drug colchicine microsphere freeze-dried agent |
Non-Patent Citations (1)
| Title |
|---|
| 抗癌活性物质鬼臼类木脂素的研究进展 刘长军，侯嵩生，天然产物研究与开发，第9卷第3期 1997 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1660436A (en) | 2005-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101204365A (en) | Implant agent treating for solid tumor | |
| CN101181230A (en) | Estramustine sustained-release implantation agent for curing entity tumour | |
| CN1311872C (en) | Anticancer combination of medication | |
| CN1311818C (en) | Pharmaceutical composition for solid tumour | |
| CN101185629A (en) | Decitabine sustained-release preparation for treating solid tumor | |
| CN1304054C (en) | Combination of slow released anticancer medication | |
| CN101219101A (en) | Fludarabine sustained-release implantation agent for treating solid tumors | |
| CN1299774C (en) | Slow released anticancer combination of medication embedded the interior of the body | |
| CN1748671A (en) | Slow releasing injection containing anti-mitosis medicine | |
| CN100464783C (en) | Anti-cancer medicine composition containing antineoplastic antibiotics | |
| CN100500220C (en) | Anti entity tumour medicinal composition containing blood vessel inhibitor | |
| CN101176710A (en) | Mitoxantrone sustained-release implantation agent for curing entity tumour | |
| CN1330299C (en) | Medicament composition for treating extracranial noumenal tumour | |
| CN100431607C (en) | Medicinal composition for tumor body | |
| CN101204369A (en) | Sorafenib sustained-release implant treating for solid tumor | |
| CN1676165A (en) | In vivo slow-releasing anticancer medicinal composition | |
| CN1311817C (en) | Solid tumor treating medicine composition | |
| CN101176709A (en) | Beisalutin sustained-release implantation agent for curing entity tumour | |
| CN100431605C (en) | Anticarcinogen composition | |
| CN1299674C (en) | Slow released combination of anticancer drugs embedded in vivo | |
| CN101234084A (en) | Fluorouracil containing anti-cancer sustained-release injection | |
| CN101336898A (en) | Anticancer sustained-released formulation loaded with platinum compound and synergist thereof | |
| CN100369632C (en) | Anti-cancer medicine composition | |
| CN100386115C (en) | Anti-cancer medicine composition | |
| CN101181235B (en) | Tantudinun sustained-release implantation agent for curing entity tumour |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Free format text: FORMER OWNER: KONG QINGZHONG Owner name: SHANDONG ENDUO BIO-PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: SHANDONG LANJIN BIOENGINEERING CO., LTD. Effective date: 20110506 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 250100 -802, BUILDING 7, OVERSEAS STUDENTS VENTURE PARK, NO. 69, HUAYANG ROAD, HIGH-TECH. DEVELOPMENT ZONE, JI'NAN CITY, SHANDONG PROVINCE TO: 250101 NO. 1750, TIANCHEN ROAD, HIGH-TECH. ZONE, JI'NAN CITY, SHANDONG PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20110506 Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 Patentee after: Shandong many biological pharmaceutical Co., Ltd. Address before: 250100 No. 69, building 7, Pioneer Park, Huayang Road, Ji'nan hi tech Development Zone, Shandong, -802 Co-patentee before: Kong Qingzhong Patentee before: Shandong Lanjin Pharmaceuticals Co., Ltd. |
|
| C56 | Change in the name or address of the patentee |
Owner name: DASEN BIOPHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: SHANDONG ENDUO BIOLOGICAL PHARMACEUTICAL CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 Patentee after: DASEN BIOLOGICAL PHARMACEUTICAL CO., LTD. Address before: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 1750 Patentee before: Shandong many biological pharmaceutical Co., Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070425 Termination date: 20161229 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
