CN1957921A - Controlled release injection of carried fluorouracil and synergis - Google Patents
Controlled release injection of carried fluorouracil and synergis Download PDFInfo
- Publication number
- CN1957921A CN1957921A CNA200610200935XA CN200610200935A CN1957921A CN 1957921 A CN1957921 A CN 1957921A CN A200610200935X A CNA200610200935X A CN A200610200935XA CN 200610200935 A CN200610200935 A CN 200610200935A CN 1957921 A CN1957921 A CN 1957921A
- Authority
- CN
- China
- Prior art keywords
- cyclophosphamide
- combination
- slow
- melphalan
- ifosfamide
- 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
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims abstract description 167
- 229960002949 fluorouracil Drugs 0.000 title claims abstract description 167
- 239000007924 injection Substances 0.000 title claims abstract description 123
- 238000002347 injection Methods 0.000 title claims abstract description 123
- 238000013270 controlled release Methods 0.000 title 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims abstract description 135
- 239000004626 polylactic acid Substances 0.000 claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 239000007943 implant Substances 0.000 claims abstract description 39
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 38
- 230000001093 anti-cancer Effects 0.000 claims abstract description 35
- 229960004397 cyclophosphamide Drugs 0.000 claims description 111
- 206010028980 Neoplasm Diseases 0.000 claims description 78
- 238000013268 sustained release Methods 0.000 claims description 55
- 239000012730 sustained-release form Substances 0.000 claims description 55
- 229960001924 melphalan Drugs 0.000 claims description 44
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 44
- 229920001577 copolymer Polymers 0.000 claims description 42
- 229960001101 ifosfamide Drugs 0.000 claims description 42
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 42
- 239000004005 microsphere Substances 0.000 claims description 42
- 229960004630 chlorambucil Drugs 0.000 claims description 37
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 37
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 22
- 239000000375 suspending agent Substances 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 17
- -1 triethylenemelaine Chemical compound 0.000 claims description 14
- 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 claims description 13
- 229920000954 Polyglycolide Polymers 0.000 claims description 13
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 13
- 229940100198 alkylating agent Drugs 0.000 claims description 13
- 239000002168 alkylating agent Substances 0.000 claims description 13
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 13
- 229950004403 polifeprosan Drugs 0.000 claims description 13
- 239000004633 polyglycolic acid Substances 0.000 claims description 13
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 13
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 13
- 239000002689 soil Substances 0.000 claims description 12
- 239000005038 ethylene vinyl acetate Substances 0.000 claims description 11
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 11
- 239000003005 anticarcinogenic agent Substances 0.000 claims description 10
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 claims description 9
- 229960005237 etoglucid Drugs 0.000 claims description 9
- 239000000600 sorbitol Substances 0.000 claims description 9
- PBUUPFTVAPUWDE-UGZDLDLSSA-N 2-[[(2S,4S)-2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2lambda5-oxazaphosphinan-4-yl]sulfanyl]ethanesulfonic acid Chemical compound OS(=O)(=O)CCS[C@H]1CCO[P@](=O)(N(CCCl)CCCl)N1 PBUUPFTVAPUWDE-UGZDLDLSSA-N 0.000 claims description 8
- BYZJBHCTZJGJFV-AOOOYVTPSA-N 2-[[(2s,3r)-2,3-dihydroxy-4-(2-methylsulfonyloxyethylamino)butyl]amino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCNC[C@H](O)[C@H](O)CNCCOS(C)(=O)=O BYZJBHCTZJGJFV-AOOOYVTPSA-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 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 claims description 8
- 229960000952 pipobroman Drugs 0.000 claims description 8
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 claims description 8
- XNWUTCRFGMBUOP-UHFFFAOYSA-N 1,4-bis(oxiran-2-ylmethyl)piperazine Chemical compound C1CN(CC2OC2)CCN1CC1CO1 XNWUTCRFGMBUOP-UHFFFAOYSA-N 0.000 claims description 7
- FQWNGSKQHPNIQG-UHFFFAOYSA-N 3-[[bis(2-chloroethyl)amino-(2-chloroethoxy)phosphoryl]amino]propan-1-ol Chemical compound OCCCNP(=O)(OCCCl)N(CCCl)CCCl FQWNGSKQHPNIQG-UHFFFAOYSA-N 0.000 claims description 7
- KAEVHZSIYLATMK-UHFFFAOYSA-N 6-n-[bis(aziridin-1-yl)phosphoryl]-2-n,2-n,7-trimethylpurine-2,6-diamine Chemical compound C=12N(C)C=NC2=NC(N(C)C)=NC=1NP(=O)(N1CC1)N1CC1 KAEVHZSIYLATMK-UHFFFAOYSA-N 0.000 claims description 7
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 claims description 7
- 229960000473 altretamine Drugs 0.000 claims description 7
- DHZBEENLJMYSHQ-XCVPVQRUSA-N cantharidin Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)OC2=O DHZBEENLJMYSHQ-XCVPVQRUSA-N 0.000 claims description 7
- DHZBEENLJMYSHQ-UHFFFAOYSA-N cantharidine Natural products O1C2CCC1C1(C)C2(C)C(=O)OC1=O DHZBEENLJMYSHQ-UHFFFAOYSA-N 0.000 claims description 7
- 229950004239 defosfamide Drugs 0.000 claims description 7
- 229960004275 glycolic acid Drugs 0.000 claims description 7
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 7
- 229950008097 improsulfan Drugs 0.000 claims description 7
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 claims description 7
- 229950000547 mafosfamide Drugs 0.000 claims description 7
- QTFKTBRIGWJQQL-UHFFFAOYSA-N meturedepa Chemical compound C1C(C)(C)N1P(=O)(NC(=O)OCC)N1CC1(C)C QTFKTBRIGWJQQL-UHFFFAOYSA-N 0.000 claims description 7
- 229950009847 meturedepa Drugs 0.000 claims description 7
- 229950009351 perfosfamide Drugs 0.000 claims description 7
- VPAWVRUHMJVRHU-VGDKGRGNSA-N perfosfamide Chemical compound OO[C@@H]1CCO[P@@](=O)(N(CCCl)CCCl)N1 VPAWVRUHMJVRHU-VGDKGRGNSA-N 0.000 claims description 7
- 229950001100 piposulfan Drugs 0.000 claims description 7
- JAABVEXCGCXWRR-FBXFSONDSA-N rel-norcantharidin Chemical compound C1C[C@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@@H]1O2 JAABVEXCGCXWRR-FBXFSONDSA-N 0.000 claims description 7
- 229950003651 ritrosulfan Drugs 0.000 claims description 7
- 229960003181 treosulfan Drugs 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 229940095758 cantharidin Drugs 0.000 claims description 6
- 229930008397 cantharidin Natural products 0.000 claims description 6
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 claims description 6
- 229950008612 mannomustine Drugs 0.000 claims description 6
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- YADZBEISHVCBSJ-UHFFFAOYSA-N [I].OCC(O)CO Chemical compound [I].OCC(O)CO YADZBEISHVCBSJ-UHFFFAOYSA-N 0.000 claims description 3
- 210000004204 blood vessel Anatomy 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 3
- 238000002513 implantation Methods 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 210000001165 lymph node Anatomy 0.000 claims description 3
- 208000018389 neoplasm of cerebral hemisphere Diseases 0.000 claims description 3
- 229940083037 simethicone Drugs 0.000 claims description 3
- 210000001685 thyroid gland Anatomy 0.000 claims description 3
- 201000000274 Carcinosarcoma Diseases 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 210000003679 cervix uteri Anatomy 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
- 210000004696 endometrium Anatomy 0.000 claims description 2
- 210000003238 esophagus Anatomy 0.000 claims description 2
- 210000001508 eye Anatomy 0.000 claims description 2
- 210000000232 gallbladder Anatomy 0.000 claims description 2
- 210000004907 gland Anatomy 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- 210000005075 mammary gland Anatomy 0.000 claims description 2
- 210000000214 mouth Anatomy 0.000 claims description 2
- 210000004877 mucosa Anatomy 0.000 claims description 2
- 210000001989 nasopharynx Anatomy 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- 210000000496 pancreas Anatomy 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 210000000664 rectum Anatomy 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 210000003932 urinary bladder Anatomy 0.000 claims description 2
- 210000004291 uterus Anatomy 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 87
- 239000011806 microball Substances 0.000 abstract description 2
- 102000029816 Collagenase Human genes 0.000 abstract 1
- 108060005980 Collagenase Proteins 0.000 abstract 1
- 102000003743 Relaxin Human genes 0.000 abstract 1
- 108090000103 Relaxin Proteins 0.000 abstract 1
- 229960002424 collagenase Drugs 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 51
- 238000000034 method Methods 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 24
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 22
- 210000004881 tumor cell Anatomy 0.000 description 22
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 229920000642 polymer Polymers 0.000 description 19
- 239000000546 pharmaceutical excipient Substances 0.000 description 18
- 229920000305 Nylon 6,10 Polymers 0.000 description 16
- 241000196324 Embryophyta Species 0.000 description 15
- 230000004614 tumor growth Effects 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 238000002156 mixing Methods 0.000 description 13
- 238000001694 spray drying Methods 0.000 description 13
- 238000007920 subcutaneous administration Methods 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical compound CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 8
- 239000011859 microparticle Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 230000001629 suppression Effects 0.000 description 8
- 229920002521 macromolecule Polymers 0.000 description 7
- 238000010254 subcutaneous injection Methods 0.000 description 7
- 239000007929 subcutaneous injection Substances 0.000 description 7
- 206010006187 Breast cancer Diseases 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 229920002732 Polyanhydride Polymers 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000007334 copolymerization reaction Methods 0.000 description 6
- 239000000693 micelle Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000011275 oncology therapy Methods 0.000 description 5
- 229920002101 Chitin Polymers 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 229920001400 block copolymer Polymers 0.000 description 4
- 201000008275 breast carcinoma Diseases 0.000 description 4
- 238000011978 dissolution method Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000003349 gelling agent Substances 0.000 description 4
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 4
- 229920001542 oligosaccharide Polymers 0.000 description 4
- 150000002482 oligosaccharides Chemical class 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000000811 xylitol Substances 0.000 description 4
- 235000010447 xylitol Nutrition 0.000 description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 4
- 229960002675 xylitol Drugs 0.000 description 4
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229920005576 aliphatic polyanhydride Polymers 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003205 fragrance Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 208000023958 prostate neoplasm Diseases 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 238000011125 single therapy Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 210000003462 vein Anatomy 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
- QDGAVODICPCDMU-LBPRGKRZSA-N (2s)-2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-LBPRGKRZSA-N 0.000 description 2
- ZSZKJARKHWCBJK-UHFFFAOYSA-N 2-[[3-(2-chloroethyl)-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-yl]amino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCNP1(=O)OCCCN1CCCl ZSZKJARKHWCBJK-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 206010052804 Drug tolerance Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 2
- 229920001273 Polyhydroxy acid Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- LPRCVLBATUMNBP-UHFFFAOYSA-N decanedioic acid;propane Chemical compound CCC.OC(=O)CCCCCCCCC(O)=O LPRCVLBATUMNBP-UHFFFAOYSA-N 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002075 main ingredient Substances 0.000 description 2
- 229950008977 metamelfalan Drugs 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- NKFHKYQGZDAKMX-PPRKPIOESA-N n-[(e)-1-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]ethylideneamino]benzamide;hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 NKFHKYQGZDAKMX-PPRKPIOESA-N 0.000 description 2
- 238000007500 overflow downdraw method Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 229920001432 poly(L-lactide) Polymers 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
- 239000000843 powder Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- DSNYFFJTZPIKFZ-UHFFFAOYSA-N propoxybenzene Chemical compound CCCOC1=CC=CC=C1 DSNYFFJTZPIKFZ-UHFFFAOYSA-N 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229950008275 sufosfamide Drugs 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 229960000875 trofosfamide Drugs 0.000 description 2
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- NTKNUVXCGJPJQP-HNNXBMFYSA-N (2S)-2-[[4-[(2,4-diamino-5-methylquinazolin-6-yl)methylamino]benzoyl]amino]butanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C(C)=C1CNC1=CC=C(C(=O)N[C@@H](CC(O)=O)C(O)=O)C=C1 NTKNUVXCGJPJQP-HNNXBMFYSA-N 0.000 description 1
- WUQNOBSCYAIJIH-FIPCFZRWSA-N (3as,4r,7s,7ar)-2,3a,7a-trimethyl-4,5,6,7-tetrahydro-octahydro-1h-4,7-epoxyisoindole-1,3-dione Chemical compound C([C@@H]1O2)C[C@@H]2[C@]2(C)[C@@]1(C)C(=O)N(C)C2=O WUQNOBSCYAIJIH-FIPCFZRWSA-N 0.000 description 1
- NUNCOHUMTCDISK-AWEZNQCLSA-N (7s)-7-amino-1,2,3-trimethoxy-10-methylsulfanyl-6,7-dihydro-5h-benzo[a]heptalen-9-one Chemical compound C1([C@@H](N)CC2)=CC(=O)C(SC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC NUNCOHUMTCDISK-AWEZNQCLSA-N 0.000 description 1
- FFGSXKJJVBXWCY-UHFFFAOYSA-N 1,4-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO FFGSXKJJVBXWCY-UHFFFAOYSA-N 0.000 description 1
- JGQGCJKPBAYEHO-UHFFFAOYSA-N 1-(morpholin-4-ylmethyl)-4-[2-[4-(morpholin-4-ylmethyl)-3,5-dioxopiperazin-1-yl]ethyl]piperazine-2,6-dione Chemical compound C1C(=O)N(CN2CCOCC2)C(=O)CN1CCN(CC1=O)CC(=O)N1CN1CCOCC1 JGQGCJKPBAYEHO-UHFFFAOYSA-N 0.000 description 1
- SNYUHPPZINRDSG-UHFFFAOYSA-N 1-(oxiran-2-ylmethyl)-4-[1-(oxiran-2-ylmethyl)piperidin-4-yl]piperidine Chemical compound C1CC(C2CCN(CC3OC3)CC2)CCN1CC1CO1 SNYUHPPZINRDSG-UHFFFAOYSA-N 0.000 description 1
- CURYRIVJTBNEGU-UHFFFAOYSA-L 3-bromo-1-[12-(3-bromopropanoyl)-3,12-diaza-6,9-diazoniadispiro[5.2.5^{9}.2^{6}]hexadecan-3-yl]propan-1-one;dichloride Chemical compound [Cl-].[Cl-].C1CN(C(=O)CCBr)CC[N+]21CC[N+]1(CCN(CC1)C(=O)CCBr)CC2 CURYRIVJTBNEGU-UHFFFAOYSA-L 0.000 description 1
- GBLIGNUYGOFIKS-UHFFFAOYSA-N 4-[2-(3,5-dioxopiperazin-1-yl)ethyl]piperazine-2,6-dione Chemical compound C1C(=O)NC(=O)CN1CCN1CC(=O)NC(=O)C1 GBLIGNUYGOFIKS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- NBEALWAVEGMZQY-UHFFFAOYSA-N Enpromate Chemical compound C=1C=CC=CC=1C(C#C)(C=1C=CC=CC=1)OC(=O)NC1CCCCC1 NBEALWAVEGMZQY-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- BIAKLJFRJUFBQE-AWEZNQCLSA-N FC1=C2C[C@H](N(C2=CC=C1)C(C)C)C1=CN=CN1 Chemical compound FC1=C2C[C@H](N(C2=CC=C1)C(C)C)C1=CN=CN1 BIAKLJFRJUFBQE-AWEZNQCLSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SGDBTWWWUNNDEQ-UHFFFAOYSA-N Merphalan Chemical compound OC(=O)C(N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FNNZMRSRVYUVQT-AZUAARDMSA-N Taxodione Chemical compound CC1(C)CCC[C@]2(C)C3=C(O)C(=O)C(C(C)C)=CC3=CC(=O)[C@H]21 FNNZMRSRVYUVQT-AZUAARDMSA-N 0.000 description 1
- 102400000160 Thymopentin Human genes 0.000 description 1
- 101800001703 Thymopentin Proteins 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- USDJGQLNFPZEON-UHFFFAOYSA-N [[4,6-bis(hydroxymethylamino)-1,3,5-triazin-2-yl]amino]methanol Chemical compound OCNC1=NC(NCO)=NC(NCO)=N1 USDJGQLNFPZEON-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 229950011363 ametantrone Drugs 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
- 239000007864 aqueous solution Substances 0.000 description 1
- QLULGSLAHXLKSR-UHFFFAOYSA-N azane;phosphane Chemical compound N.P QLULGSLAHXLKSR-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl n-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000006243 chemical reaction 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
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 229960003608 clomifene Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229950001022 enpromate Drugs 0.000 description 1
- 229950004926 epipropidine Drugs 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- PKWIYNIDEDLDCJ-UHFFFAOYSA-N guanazole Chemical compound NC1=NNC(N)=N1 PKWIYNIDEDLDCJ-UHFFFAOYSA-N 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000012155 injection solvent Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960000733 mannosulfan Drugs 0.000 description 1
- UUVIQYKKKBJYJT-ZYUZMQFOSA-N mannosulfan Chemical compound CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H](OS(C)(=O)=O)COS(C)(=O)=O UUVIQYKKKBJYJT-ZYUZMQFOSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003716 mesoderm Anatomy 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000011645 metastatic carcinoma Diseases 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229950008885 polyglycolic acid Drugs 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000003361 porogen Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 229950007401 pumitepa Drugs 0.000 description 1
- OZAXUJFBBVPKOJ-UHFFFAOYSA-N pyrazole-1-carbothioamide Chemical compound NC(=S)N1C=CC=N1 OZAXUJFBBVPKOJ-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- NOMPUOUIIHWRJU-UHFFFAOYSA-M sodium;4-cyclohexyloxy-4-oxobutanoate Chemical compound [Na+].[O-]C(=O)CCC(=O)OC1CCCCC1 NOMPUOUIIHWRJU-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- ABFQREMAZQPJLS-UHFFFAOYSA-N taxodione Natural products CC(C)C1=CC2=CC(=O)C3C(C)(C)CCCC3(C)C2=CC1=O ABFQREMAZQPJLS-UHFFFAOYSA-N 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- PSWFFKRAVBDQEG-YGQNSOCVSA-N thymopentin Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-YGQNSOCVSA-N 0.000 description 1
- 229960004517 thymopentin Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A slowly-release anticancer medicine in the form of injection or implant is disclosed. Said slowly-release injection is composed of a special solvent containing suspending aid and the slowly-release microballs consisting anticance medicine, iterstitial hydrolyte and slowly-releasing auxiliary. Said anticancer medicine is chosen from 5-FU, genoxal, etc. Said interstitial hydrolyte is chosen from collagenase, relaxin, etc. Said slowly-releasing auxiliary is chosen from polylactic acid, FAD, polyethanediol, etc.
Description
(1) technical field
The present invention relates to a kind of slow releasing injection that contains fluorouracil (5-FU) and synergist thereof and preparation method thereof, belong to medicine
Technical field.
(2) background technology
As a kind of chemotherapeutics commonly used, 5-fluorouracil (5-FU) has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its beat all neurotoxicity has greatly limited the application of this medicine.Blood vessel in the mesenchyma stroma of tumors, connective tissue, stromatin, fibrin and collagen protein etc. not only provide support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Because 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, be difficult to tumor by local and form 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) (Kong Q et al., J SurgOncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82), improve the restriction that dosage is subjected to general reaction again merely.Pharmaceutical topical application may solve the problem (Chinese patent) of drug level to a certain extent, yet operation techniques such as medicine implantation are complicated, traumatic big, the various complication such as, infection hemorrhage, immunity reduction, also can cause or quicken the diffusion and the transfer of tumor except that easily causing.In addition, the preparation of perioperatively itself and expensive expense usually influence its effective enforcement.
In addition, the DNA repair function in many tumor cells obviously increases after chemotherapy.The latter often causes the enhancing of tumor cell to the toleration of cancer therapy drug, consequently treatment failure.
In addition, the cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth " (referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93)).
Therefore, be convenient to keep high drug level and increase tumor cell the preparation and the method for the sensitivity of medicine just become an important subject at tumor by local.
(3) summary of the invention
5-fluorouracil has been widely used in the treatment kinds of tumors as a kind of cancer therapy drug commonly used, as straight colon cancer etc.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.
Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the drug sustained release system that contains 5-fluorouracil, comprise that sustained-release micro-spheres (capsule) (sees: (China Patent No. ZL00809160.9; Application number 91109723.6), Ciftci K etc. " with the polylactic acid microsphere treatment entity tumor that contains fluorouracil and the research of drug release " " drug development technology " (Pharm Dev Technol.) 2 (2): 151-60,1997), sustained-release implant (sees: China Patent No. ZL96115937.5; ZL97107076.8) etc.Yet, solid sustained-release implant (China Patent No. ZL96115937.5; ZL97107076.8) and existing as be used for the treatment of the cerebral tumor (ZL00809160.9) sustained-release micro-spheres or United States Patent (USP) (US5,651,986) and all have problem such as be not easy more than operation, weak curative effect, the complication.In addition, the sensitivity that many entity tumors are drawn together 5-fluorouracil to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.The present invention finds that medicine of mentioning among the present invention and 5-FU share and can make its antitumaous effect strengthen (the following medicine that the 5-FU antitumaous effect will be increased mutually is referred to as the 5-FU synergist) mutually.
In addition, with the assembly packaging of 5-FU and its synergist in specific slow-release auxiliary material and be equipped with special solvent and make drug level that anti-cancer medicine sustained-release injection not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, reduce the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The decapacitation of 5-FU synergist suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.
The present invention finds, is not that all adjuvants can both effectively discharge 5-FU.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected 5-FU among the present invention slowly can be discharged in the regular hour in human body or animal body must could obtain through a large amount of creationary experiments, specific slow-release auxiliary material and can need be passed through a large amount of creative works by the selection of the combination of slow releasing pharmaceutical and could determine.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.
Topical remedy's slow release in the stable lastingly and drug level, has obviously reduced systemic drug concentration in having guaranteed local application's scope, alleviated toxic and side effects.
The present invention is directed to the deficiencies in the prior art, invented the anticancer slow release agent that contains 5-FU and synergist thereof.The slow releasing agent of this treatment entity tumor comprises anticancer effective component and medicinal slow-release auxiliary material.
Wherein anticancer effective component is the combination of 5-FU and 5-FU synergist, and the 5-FU synergist comprises the alkylating agent that is selected from.
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains fluorouracil and 5-fluorouracil synergist is provided.
A kind of form of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is 5-FU and 5-FU synergist, and the 5-FU synergist is selected from alkylating agent; Slow-release auxiliary material comprises one of following or its combination: poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.
In various high molecular polymers, with polylactic acid, decanedioic acid, 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 PLA, 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 polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 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, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 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 decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
Except that above-mentioned slow-release auxiliary material, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.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 blocker etc.
For regulating drug releasing rate or changing other characteristic 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 or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.; Also can add other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
Above-mentioned alkylating agent is selected from one of following or combination: cyclophosphamide (CTX), melphalan (Melphalan), Chlorambucil (chlorambucil), 4H-peroxide cyclophosphamide (4H-CTX), ifosfamide (Ifosfamide, Isophosphamide), three mustard cyclophosphamide, sufosfamide (Sufosfamide), defosfamide (Defosfamide), Mafosfamide (Mafosfamide), perfosfamide (Perfosfamide), trofosfamide (Trofosfamide), thiocarzolamide, metamelfalan (Metamelfalan), formylmerphalan (Formylmerphalan), hexamethylmelamine (hexamethylmelamine), Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin (cantharidine), sodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, norcantharidin (Norcantharidin), thiocolciran, sarcolysine, methasquin, NSC-1895, mannomustine (Mannosulfan), treosulfan (Treosulfan), ritrosulfan (Ritrosulfan), an improsulfan (Improsulfan), Z 7557, Spirobromin, d-mannitobusulphan, cis-diamminetetrachloroplatinum, enpromate, epipropidine, ethoxene, bimolane, second hydroxyl urea, ethyliminum, etoglucid (etoglucid, Ethoglucid, Etoglucid), benefit hair phosphorus ammonium, E39, pipobroman (pipobroman, Pipobroman), piposulfan (A-20968, Piposulfan), Li Chuikexin, Dup 942, NSC 122402, radioplex, rofecoxib, taxodione, trimethylolmelamine, urethane, Zorubicin Hydrochloride, RP-22050, triethylenemelaine (triethylenemelamine), epoxypiperazine (epoxypiperazine), benzene assistant TEPA (Benzodepa), Phopurine (Pumitepa), meturedepa (Meturedepa), Ah bundle's TEPA (Aza-TEPA), the salt of urethimine (Uredepa) or said medicine.
Above-mentioned alkylating agent serves as preferred with cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
The salt of above-mentioned alkylating agent comprises: sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.
The percentage by weight of alkylating agent in slow releasing agent is good from 0.1%-60% with 1%-50%, is best with 5%-30%.
Anticancer effective component is the combination of 5-FU and its synergist.When the cancer therapy drug in the medicament slow-release microsphere only was the 5-FU synergist, slow-releasing anticarcinogen injection was mainly used in the action effect that increases the 5-FU that other approach use or is used for potentiation to radiotherapy or other therapies.When being used to increase the action effect of the 5-FU that other approach use, 5-FU can be through tremulous pulse, vein or local injection, placement administration.
The percentage by weight of medicine in sustained-release micro-spheres is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of 5-FU and 5-FU synergist is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.
Anticancer effective component percentage by weight in the anticancer slow-release microsphere of the present invention is preferably as follows:
The combination of the 5-FU of 5-30% and the cyclophosphamide of 5-30%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
Anticancer effective component percentage by weight in the anticancer slow-release microsphere is most preferably as follows:
(a) cyclophosphamide of the 5-FU of 5-30% and 5-30%;
(b) melphalan of the 5-FU of 5-30% and 5-30%;
(c) Chlorambucil of the 5-FU of 5-30% and 5-30%;
(d) ifosfamide of the 5-FU of 5-30% and 5-30%;
(e) the 4H-peroxide cyclophosphamide of the 5-FU of 5-30% and 5-30%.
The copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), FAD: one of SA copolymer and polifeprosan or its combination.
When selecting the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content percentage by weight are respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-200, and 000, with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-200, and 000, with 20,000-60,000 is preferred, with 30,000-50,000 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, 5000-200,000, with 20,000-60,000 be preferably, with 30,000-50,000 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 decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.
In various high molecular polymers, with polylactic acid, decanedioic acid, 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 PLA, 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 polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
Except that above-mentioned adjuvant, also can select for use other materials to see United States Patent (USP) (4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.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 blocker etc.).
For regulating drug releasing rate or changing other characteristic 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 or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
(a) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
(b) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
(c) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or Tween 80 (0.1%) are dissolved in the normal saline corresponding solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).
The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).
The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in methods such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection because of specifically deciding, can be, but is not limited to, 10-400mg/ml is preferred with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant 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 PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic 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.
The another kind of form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant 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 and/or the mode of degrading through polymer.
The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.
The most preferred dosage form of sustained-release implant is the sustained-release implant that biocompatibility, degradable absorb, and can make different shape and various dosage form 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, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.
Anticancer effective component percentage by weight in the sustained-release implant is as follows, the combination of the 5-FU of 5-30% and the cyclophosphamide of 5-30%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
Anticancer effective component percentage by weight in the sustained-release implant is most preferably as follows:
(a) cyclophosphamide of the 5-FU of 5-30% and 5-30%;
(b) melphalan of the 5-FU of 5-30% and 5-30%;
(c) Chlorambucil of the 5-FU of 5-30% and 5-30%;
(d) ifosfamide of the 5-FU of 5-30% and 5-30%;
(e) the 4H-peroxide cyclophosphamide of the 5-FU of 5-30% and 5-30%.
The copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), FAD: one of SA copolymer and polifeprosan or its combination.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, is mainly slow releasing injection or sustained-release implant.Prepared tumor comprises various entity tumors.Comprise former of originating from brain and central nervous system or shift, and originate from the outer various entity tumors of cranium, as kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, former or cancer or sarcoma or the carcinosarcoma that shifts of rectum are wherein with the cerebral tumor, renal carcinoma, tumor of head and neck, thyroid carcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, cervical cancer, ovarian cancer, carcinoma of prostate, bladder cancer, colorectal former or metastatic carcinoma are preferred.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.Can in when operation or perioperatively in tumor, tumor week injection or place; Can with radiation and systemic chemotherapy simultaneously or front and back separate applications, but sustained-release implant with in the tumor, tumor week inject or be placed as preferably.
Also can add other medicinal ingredient in slow releasing injection that the present invention is made or the sustained-release implant, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.
By following test and embodiment technical method of the present invention is further described:
The local drug concentration that test 1, different modes are used behind the 5-FU compares
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is treated behind tumor growth to 1 cm diameter it to be divided into following 8 groups (seeing Table 1) in its hypochondrium.Every group of dosage is 5mg/kg.Measure medicament contg (%) in the different time tumor.
Table 1
| Test group (n) | Administering mode | Medication amount in first day tumor | Medicament contg in the third-largest tumor | Medicament contg in the 7th day tumor |
| 1(3) | The agent of tail vein injection normal injection | 0.60 | 0.32 | 0.12 |
| 2(3) | The agent of lumbar injection normal injection | 0.56 | 0.3 | 0.08 |
| 3(3) | The agent of tumor week injection normal injection | 2.6 | 1.2 | 0.3 |
| 4(3) | Tumor week injection slow releasing injection | 10 | 18 | 20 |
| 5(3) | Tumor week is placed sustained-release implant | 18 | 30 | 32 |
| 6(3) | The agent of intratumor injection normal injection | 4 | 2 | 1 |
| 7(3) | The intratumor injection slow releasing injection | 92 | 80 | 60 |
| 8(3) | Place sustained-release implant in the tumor | 94 | 92 | 86 |
Above result shows, the local drug concentration significant difference of 5-FU after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.
The interior tumor-inhibiting action of body that test 2, different modes are used behind the 5-FU compares
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is treated behind tumor growth to 0.5 cm diameter it to be divided into following 9 groups (seeing Table 2) in its hypochondrium.Every group of dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 20th day.
Table 2
| Test group (n) | Administering mode | Gross tumor volume (cm 3) | The P value |
| 1(6) | - | 70 | |
| 2(6) | The agent of tail vein injection normal injection | 68 | 0.05 |
| 3(6) | The agent of lumbar injection normal injection | 64 | 0.05 |
| 4(6) | The agent of tumor week injection normal injection | 56 | 0.04 |
| 5(6) | Tumor week injection slow releasing injection | 34 | ＜0.01 |
| 6(6) | Tumor week is placed sustained-release implant | 22 | ＜0.01 |
| 7(6) | The agent of intratumor injection normal injection | 52 | 0.03 |
| 8(6) | The intratumor injection slow releasing injection | 20 | ＜0.001 |
| 9(6) | Place sustained-release implant in the tumor | 18 | ＜0.001 |
Above result shows, the tumor-inhibiting action significant difference of 5-FU after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of 5-FU and 5-FU synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Dosage sees Table.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 20th day.
Table 3
| Test group (n) | Suffered treatment (mg/kg) | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 50±12 | |
| 2(6) | 5-FU(1) | 34±8.4 | ＜0.05 |
| 3(6) | 5-FU(2) | 24±6.0 | ＜0.01 |
| 4(6) | 5-FU(4) | 22±4.2 | ＜0.01 |
| 5(6) | 5-FU(8) | 18±3.2 | ＜0.01 |
| 6(6) | Cyclophosphamide (4) | 34±3.0 | ＜0.01 |
| 7(6) | 5-FU (1)+cyclophosphamide | 30±6.2 | ＜0.001 |
| 8(6) | 5-FU (2)+cyclophosphamide | 24±4.8 | ＜0.001 |
| 9(6) | 5-FU (4)+cyclophosphamide | 16±3.6 | ＜0.001 |
| 10(6) | 5-FU (8)+cyclophosphamide | 10±2.0 | ＜0.001 |
Above result shows that 5-FU and used 5-FU synergist (cyclophosphamide) all have the obvious suppression effect to tumor growth when this concentration is used separately, can show significant potentiation when use in conjunction.Wherein, 5-FU is relevant with dosage to the inhibitory action of tumor growth.
The tumor-inhibiting action of test 4,5-FU and 5-FU synergist (slow releasing injection)
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.5-FU and 5-FU synergist are added in 24 hours the various tumor cells of In vitro culture by 10 μ g/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 4.
Table 4
| Oncocyte | 5-FU | Melphalan | Chlorambucil | Ifosfamide | The 5-FU+ melphalan | The 5-FU+ Chlorambucil | The 5-FU+ ifosfamide |
| CNS | 56％ | 50％ | 60％ | 40％ | 92％ | 86％ | 92％ |
| C6 | 54％ | 64％ | 64％ | 44％ | 94％ | 84％ | 90％ |
| SA | 48％ | 62％ | 56％ | 42％ | 88％ | 90％ | 92％ |
| BC | 44％ | 64％ | 54％ | 34％ | 94％ | 84％ | 82％ |
| BA | 48％ | 60％ | 62％ | 50％ | 90％ | 90％ | 90％ |
| LH | 50％ | 58％ | 62％ | 48％ | 90％ | 88％ | 84％ |
| PAT | 60％ | 58％ | 50％ | 32％ | 92％ | 84％ | 90％ |
Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used 5-FU and 5-FU synergist (melphalan, Chlorambucil, ifosfamide), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5,5-FU and 5-FU synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 5).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.The equal 5mg/kg of 5-FU dosage, the dosage of synergist is 2.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 20th day.
Table 5
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 50±10 | |
| 2(6) | Cyclophosphamide | 42±8.4 | ＜0.05 |
| 3(6) | 5-FU | 36±6.8 | ＜0.01 |
| 4(6) | Cyclophosphamide+5-FU | 30±6.4 | ＜0.001 |
| 5(6) | Melphalan | 46±6.0 | ＜0.01 |
| 6(6) | Melphalan+5-FU | 30±6.0 | ＜0.001 |
| 7(6) | Chlorambucil | 36±6.8 | ＜0.01 |
| 8(6) | Chlorambucil+5-FU | 22±4.6 | ＜0.001 |
| 9(6) | Ifosfamide | 40±4.6 | ＜0.01 |
| 10(6) | Ifosfamide+5-FU | 18±2.2 | ＜0.001 |
Above result shows, used 5-FU and 5-FU thing synergist-alkylating agent (cyclophosphamide, melphalan, Chlorambucil, ifosfamide) all have the obvious suppression effect to growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6,5-FU and 5-FU synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (5-FU or 5-FU synergist) and therapeutic alliance group (5-FU and 5-FU synergist).Medicine is through intratumor injection.The equal 2.5mg/kg of 5-FU dosage, the dosage of synergist is 5mg/kg.The treatment back was measured the gross tumor volume size on the 30th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.
Table 6
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU | 48 | ＜0.05 |
| 3(6) | 4H-peroxide cyclophosphamide | 40 | ＜0.01 |
| 4(6) | Cyclophosphamide | 36 | ＜0.01 |
| 5(6) | Ifosfamide | 38 | ＜0.01 |
| 6(6) | Melphalan | 44 | ＜0.01 |
| 7(6) | 5-FU+4H-peroxide cyclophosphamide | 80 | ＜0.001 |
| 8(6) | The 5-FU+ cyclophosphamide | 82 | ＜0.001 |
| 9(6) | The 5-FU+ ifosfamide | 86 | ＜0.001 |
| 10(6) | The 5-FU+ melphalan | 90 | ＜0.001 |
Above result shows, used 5-FU and 5-FU synergist-alkylating agent (4H-peroxide cyclophosphamide, cyclophosphamide, ifosfamide, melphalan) all have the obvious suppression effect to growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7,5-FU and 5-FU synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Medicine is through intratumor injection.5-FU dosage is 7.5mg/kg, and the dosage of synergist is 2.5mg/kg.The treatment back was measured the gross tumor volume size on the 30th day, made relatively therapeutic effect (seeing Table 7) of index with inhibition rate of tumor growth.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | ||
| 2(6) | 5-FU | 58 | ＜0.05 |
| 3(6) | 4H-peroxide cyclophosphamide | 50 | ＜0.01 |
| 4(6) | Cyclophosphamide | 56 | ＜0.01 |
| 5(6) | Ifosfamide | 48 | ＜0.01 |
| 6(6) | Melphalan | 54 | ＜0.01 |
| 7(6) | 5-FU+4H-peroxide cyclophosphamide | 88 | ＜0.001 |
| 8(6) | The 5-FU+ cyclophosphamide | 88 | ＜0.001 |
| 9(6) | The 5-FU+ ifosfamide | 86 | ＜0.001 |
| 10(6) | The 5-FU+ melphalan | 92 | ＜0.001 |
Above result shows, used 5-FU and 5-FU synergist-alkylating agent (4H-peroxide cyclophosphamide, cyclophosphamide, ifosfamide, melphalan) all have the obvious suppression effect to growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8,5-FU and 5-FU synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 8) of index with inhibition rate of tumor growth.
Table 8
| Test group (n) | Suffered treatment (mg/kg) | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU(5) | 56 | ＜0.05 |
| 3(6) | Cyclophosphamide (2) | 32 | ＜0.05 |
| 4(6) | Cyclophosphamide (4) | 40 | ＜0.05 |
| 5(6) | Cyclophosphamide (8) | 52 | ＜0.05 |
| 6(6) | Cyclophosphamide (16) | 62 | ＜0.01 |
| 7(6) | 5-FU+ cyclophosphamide (2) | 76 | ＜0.01 |
| 8(6) | 5-FU+ cyclophosphamide (4) | 82 | ＜0.01 |
| 9(6) | 5-FU+ cyclophosphamide (8) | 88 | ＜0.01 |
| 10(6) | 5-FU+ cyclophosphamide (16) | 94 | ＜0.001 |
Above result shows that used 5-FU and 5-FU synergist-alkylating agent (cyclophosphamide) all have the obvious suppression effect to growth of tumour cell when this concentration is used separately, can show significant potentiation when use in conjunction, and be dose-effect relationship.
The tumor-inhibiting action of test 9,5-FU and 5-FU synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration 5-FU and 5-FU synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 9.
Table 9
| Test group (n) | Suffered treatment (mg/kg) | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | 5-FU(5) | 56 | ＜0.05 |
| 3(6) | 4H-peroxide cyclophosphamide (2) | 32 | ＜0.05 |
| 4(6) | 4H-peroxide cyclophosphamide (4) | 40 | ＜0.05 |
| 5(6) | 4H-peroxide cyclophosphamide (8) | 52 | ＜0.05 |
| 6(6) | 4H-peroxide cyclophosphamide (16) | 62 | ＜0.01 |
| 7(6) | 5-FU+4H-peroxide cyclophosphamide (2) | 76 | ＜0.01 |
| 8(6) | 5-FU+4H-peroxide cyclophosphamide (4) | 82 | ＜0.01 |
| 9(6) | 5-FU+4H-peroxide cyclophosphamide (8) | 88 | ＜0.01 |
| 10(6) | 5-FU+4H-peroxide cyclophosphamide (16) | 94 | ＜0.001 |
Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used 5-FU and 5-FU synergist-alkylating agent (4H-peroxide cyclophosphamide), can show significant potentiation when use in conjunction.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used 5-FU and various 5-FU synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of 5-FU and any one 5-FU synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container respectively, add 100 milliliters of dichloromethane then, add 10mg5-FU and 10mg cyclophosphamide behind the dissolving mixing, shake up the back contains 10%5-FU and 10% cyclophosphamide with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 360cp-480cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 2.
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 50: 50) copolymer is put into container respectively, add 100 milliliters of dichloromethane then, add 5mg5-FU and 15mg cyclophosphamide behind the dissolving mixing, shake up the back contains 5%5-FU and 15% cyclophosphamide with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection, viscosity is 380cp-460cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 14-20 days, is about 25-35 days at the subcutaneous drug release time of mice.
Embodiment 3
The method step that is processed into slow releasing injection is identical with embodiment 2, but different is that contained anticancer effective component and percentage by weight thereof are: 15% 5-FU and 5% cyclophosphamide, the viscosity of suspension type slow releasing injection are 420cp-520cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-22 days, is about 25-35 days at the subcutaneous drug release time of mice.
Embodiment 4.
With 80mg molecular weight peak value is that PLGA (50: the 50) copolymer of 25000-50000 is put into container respectively, add 100 milliliters of dichloromethane then, add 10mg5-FU and 10mg cyclophosphamide behind the dissolving mixing, shake up the back contains 10%5-FU and 10% cyclophosphamide with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection, viscosity is 340cp-420cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 14-20 days, is about 20-25 days at the subcutaneous drug release time of mice.
Embodiment 5.
With 70mg molecular weight peak value is that the PLGA (75: 25) of 40000-60000 puts into container respectively, add 100 milliliters of dichloromethane then, add 10mg5-FU and 20mg4H-peroxide cyclophosphamide behind the dissolving mixing, shake up the back contains 10%5-FU and 20%4H-peroxide cyclophosphamide with spray drying method for preparation injectable microsphere again.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 6
With 80mg molecular weight peak value is that the PLGA (50: 50) of 20000-40000 puts into container respectively, add 100 milliliters of dichloromethane then, add 15mg5-FU and 5mg4H-peroxide cyclophosphamide behind the dissolving mixing, shake up the back contains 15%5-FU and 5%mg4H-peroxide cyclophosphamide with spray drying method for preparation injectable microsphere again.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 14-20 days, is about 20-25 days at the subcutaneous drug release time of mice.
Embodiment 7
The method step that is processed into slow releasing injection is identical with embodiment 6, but different is that contained anticancer effective component and percentage by weight thereof are: the combination of the 5-FU of 5-30% and the cyclophosphamide of 5-30%, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
Embodiment 8.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of 5-FU and 10 milligrams of melphalans, shake up the back contains 20%5-FU and 10% melphalan with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 9.
The method step that is processed into slow releasing injection is identical with embodiment 8, but different is that contained anticancer effective component is:
The combination of the 5-FU of 10-20% and the cyclophosphamide of 10-20%, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
Embodiment 10.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 50: 50) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and 20mg melphalan, shake up the back contains 10%5-FU and 20% melphalan with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 11.
The method step that is processed into slow releasing injection is identical with embodiment 10, but different is that contained anticancer effective component is:
The combination of 10% 5-FU and 20% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
Embodiment 12.
70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg5-FU and 15mg4H-peroxide cyclophosphamide, shake up the back contains 15%5-FU and 15% with spray drying method for preparation 4H-peroxide cyclophosphamide injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 13.
The method step that is processed into slow releasing injection is identical with embodiment 12, but different is that contained anticancer effective component is:
The combination of 15% 5-FU and 15% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
Embodiment 14
80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 7.5mg Chlorambucil and 12.5mg5-FU, shake up the back contains 7.5% Chlorambucil and 12.5%5-FU with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.
Embodiment 15
The method step that is processed into sustained-release implant is identical with embodiment 14, but different is that contained anticancer effective component is:
The combination of 12.5% 5-FU and 7.5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
Embodiment 16
With 70mg molecular weight peak value is that the PLGA (50: 50) of 20000-40000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and 20mg4H-peroxide cyclophosphamide, shake up the back contains 10%5-FU and 20%4H-peroxide cyclophosphamide with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 15-25 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 17
The method step of processing sustained-release implant is identical with embodiment 16, but different is that contained anticancer effective component is:
The combination of (1) 15% 5-FU and 5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (2) 10% 5-FU and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (3) 5% 5-FU and 15% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (4) 5% 5-FU and 25% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (5) 25% 5-FU and 5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
Embodiment 18
The method step that is processed into slow releasing agent is identical with embodiment 1-17, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 10000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) FAD and certain herbaceous plants with big flowers diacid (SA) copolymer;
F) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 19.
The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20.
Above embodiment only is used for explanation, and is not limitation application of the present invention.
The present invention disclosed and the protection the content see claim.
Claims (10)
1. the slow releasing injection with year fluorouracil and synergist thereof is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component 0.5-60%
Slow-release auxiliary material 40-99%
Suspending agent 0.0-30%
More than be weight percentage
With
(B) solvent is for common solvent or contain the special solvent of suspending agent.
Wherein,
Anticancer effective component is 5-FU and the 5-FU synergist that is selected from alkylating agent;
Suspending agent is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination,
The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time).
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that alkylating agent is selected from one of cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine, Ah bundle's TEPA or its combination.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is: the 5-FU of 5-30% and the cyclophosphamide of 5-30%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.
Below all be weight percentage.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection is:
The combination of (1) 15% 5-FU and 5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (2) 10% 5-FU and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (3) 5% 5-FU and 15% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (4) 5% 5-FU and 25% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (5) 25% 5-FU and 5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) FAD and certain herbaceous plants with big flowers diacid copolymer.
6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% carboxymethyl cellulose (sodium);
B) 5-15% mannitol;
C) 5-15% sorbitol;
D) 0.1-1.5% surfactant;
E) 0.1-0.5% polysorbas20, or
F) (iodine) glycerol, simethicone, propylene glycol or carbomer.
7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is one of following:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
8. be used to prepare the sustained-release implant that treatment originates from people and the outer entity tumor of animal cranium or the cerebral tumor according to the described anticancer slow-release microsphere of claim 1.
9. described according to Claim 8 anti-cancer sustained-released implantation agent is characterized in that:
Anticancer effective component is:
The combination of (1) 15% 5-FU and 5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (2) 10% 5-FU and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (3) 5% 5-FU and 15% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (4) 5% 5-FU and 25% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide; Or
The combination of (5) 25% 5-FU and 5% cyclophosphamide, melphalan, Chlorambucil, ifosfamide or 4H-peroxide cyclophosphamide.
Slow-release auxiliary material is selected from one of following or its combination:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) FAD and certain herbaceous plants with big flowers diacid copolymer.
10. described according to Claim 8 described anti-cancer sustained-released implantation agent is characterized in that the outer entity tumor of cranium is to originate from people and animal origin in former or cancer, sarcoma or the carcinosarcoma of secondary of people and animal 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 or rectum.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610200935XA CN1957921A (en) | 2006-09-28 | 2006-09-28 | Controlled release injection of carried fluorouracil and synergis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610200935XA CN1957921A (en) | 2006-09-28 | 2006-09-28 | Controlled release injection of carried fluorouracil and synergis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1957921A true CN1957921A (en) | 2007-05-09 |
Family
ID=38069875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200610200935XA Pending CN1957921A (en) | 2006-09-28 | 2006-09-28 | Controlled release injection of carried fluorouracil and synergis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1957921A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1957920B (en) * | 2006-09-28 | 2010-05-19 | 山东蓝金生物工程有限公司 | Anti cancer slow release agent carrying fluorouracil and synergist |
-
2006
- 2006-09-28 CN CNA200610200935XA patent/CN1957921A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1957920B (en) * | 2006-09-28 | 2010-05-19 | 山东蓝金生物工程有限公司 | Anti cancer slow release agent carrying fluorouracil and synergist |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1857221A (en) | Slow released anticancer medicien containing both platinum compound and its synergist | |
| CN1868453A (en) | Slow-release injection contg. platinum compounds and cellulotoxic medicines | |
| CN1861052A (en) | Slow-releasing injection contg. platinum compound and cytotoxin type anticarcinogen | |
| CN1861053A (en) | Slow-releasing injection contg. platinum compounds and cytotoxin type anticarcinogen | |
| CN1957921A (en) | Controlled release injection of carried fluorouracil and synergis | |
| CN1957923A (en) | A kind of controlled release injection of carried fluorouracil and synergis | |
| CN1861051A (en) | Slow-releasing injection contg. platinum compounds and its potentiator type anticarcinogen | |
| CN1861054A (en) | Composite slow-releasing anticarcinogen contg. platinum compounds such as sunpla | |
| CN1857210A (en) | Slow released anticancer medicine with both antimetabolite and its synergist | |
| CN1957919A (en) | Controlled release agent of containing fluorouracil and synergist | |
| CN1875935A (en) | A sustained release anticancer agent containing clorfarabine and cytotoxic drug | |
| CN101028244A (en) | Anti-cancer composition containing neoformative vascular inhibitor and antimetabolite | |
| CN1957920A (en) | Anti cancer controlled release agent of carried fluorouracil and synergist | |
| CN101040865A (en) | Sustained-released injection including antimetabolite medicine and alkylate agent | |
| CN1857214A (en) | Slow released anticancer injection with both antimetabolite and cellular poison medicine | |
| CN101040852A (en) | Sustained-released injection including platinum compound and the alkylate agent | |
| CN1857212A (en) | Slow released anticancer injection containing antimetabolite and cellular poison medicine | |
| CN1846687A (en) | A sustained-release agent containing taxane and its synergist | |
| CN101040840A (en) | Anticancer compound including taxanes and phosphatidylinostitol 3-kinase inhibitor | |
| CN1927176A (en) | Anticancer slow release comprising tetrazole violet and cytotoxic drug | |
| CN1927178A (en) | Slow release injection loading both tetrazole violet and cytotoxic drug | |
| CN1846680A (en) | Methotrexate Sustained Release Injection | |
| CN1887268A (en) | A New Anticancer Sustained Release Injection | |
| CN1875937A (en) | A sustained release injection carrying clorfarabine and cytotoxic drug | |
| CN1857202A (en) | Slow released anticancer injection with blood vessel inhibitor and cellular poison medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20070509 |