CN1733300A - Anticancer implantation agent - Google Patents
Anticancer implantation agent Download PDFInfo
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- CN1733300A CN1733300A CN 200510044377 CN200510044377A CN1733300A CN 1733300 A CN1733300 A CN 1733300A CN 200510044377 CN200510044377 CN 200510044377 CN 200510044377 A CN200510044377 A CN 200510044377A CN 1733300 A CN1733300 A CN 1733300A
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Abstract
Disclosed is an anti-cancer implant which comprises anti-cancer active constituent and medicinal adjuvant, wherein the active anti-cancer constituents mainly include blood vessel depressant and anti-cancer medicament, the anti-cancer medicament mainly comprises pyrimidine analogue and its derivative, the medicinal subsidiary materials mainly comprise bio-compactable and degradable macromolecular polymers, which can slowly release the anti-cancer medicament onto tumor partially during the degradation and absorption process, thus the whole body toxicity reaction is reduced appreciably, and the effective medicinal concentration can be sustained to the tumor partially. When locally dispensed on the tumor, the implant can lower down the whole body toxicity reaction of the anti-cancer medicament, selectively increase the tumor local medicinal concentration, and the treatment effect of the non-operative treatment methods such as chemotherapy, medicament and radiation can be improved.
Description
(1) technical field
The present invention relates to a kind of anticancer implant, belong to technical field of pharmaceuticals.
(2) background technology
Treatment for cancer mainly comprises methods such as operation, radiotherapy and chemotherapy.Therefore wherein operative treatment not only can not be known the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as Kong Qingzhong, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 69 (2): 76-82).
The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, 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 Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves, 1997 years (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to referring to Chinese patent ZL00111093.4; ZL96115937.5; Chinese patent application 001111264,001111272 and U.S.'s patent of invention 6,376,525B1; 5,651,986; 5,626,862 (patent No.s).
Yet, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf such as carry referring to the Buddhist nun, (Netti PA, Cancer Res.2000,60 (9): 2497-503) in 2000.Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of cancer therapy drug to conventional chemotherapy medicine and insensitive, 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 the growth of its wettability "; referring to beam etc. " increased after the cancer therapy drug pulse screening human lung carcinoma cell Drug tolerance and external invade the profit ability and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (LiangY; et al., Int J Cancer.2004; 111 (4): 484-93).
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer implant is provided, more specifically, is entity-tumor-resistant medicine composition.Decapacitation suppresses outside the tumor growth, can also increase tumor cell to the sensitivity of cancer therapy drug thereby can better treat tumor, reduces recurrence.
Anticancer implant of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is vasoinhibitor and cancer therapy drug, and cancer therapy drug is pyrimidine analogue and derivant thereof.
The formation that blood vessel suppresses to suppress or to destroy the blood vessel of tumor effectively and can suppress the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, also promoted chemotherapeutics around tumor, to reach infiltration and the diffusion in the tumor tissues.
Above-mentioned vasoinhibitor is selected from one of following or combination:
NSC 609974 (carboxyamidotriazole, CAT), thalidomide (thalidomide, Thalidomide), LS-2616 (linomide, inhibitors of integrin), En Jisi peptide booth (angiostatin), En Duosi peptide booth (endostatin), VEGF (VEGF) acceptor inhibitor, imatinib mesylate (Imatinib mesylate, have another name called imatinib mesylate, Glivec), 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate (4-((Methyl-1-piperazinyl) methyl)-N-[4-methyl-3-[[4-(3-pyridinyl) is not-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate, STI 571, CGP-57148B, STI-571A, CGP 57148), 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide (5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic Acid (2-Diethylaminoethyl) amide, Sutent, SU11248, SU011248), 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (3,3-Dichloro-5-(4-methylpiperidinosulfonyl)-2-indolinone, DCM), 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone (3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one, SU9516, SU 95 18), 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-4-methyl (SU6663, SU-5402,1H-Pyrrole-3-propanoic acid, 2-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) methyl]-4-methyl), 2H-indole-2-dihydroindole ketone (2H-Indol-2-one), 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1, (3-((4 for 3-dihydro-[CAS], 5-dimethyl-1H-pyrrol-2-yl) methylene)-1,3-dihydro-[CAS], SU5614, semaxanib, SU-011271, SU-011606, SU-11612), pyrroles's lactone dihydroindole ketone (pyrrolyllactone indolinones, SU6577), lactams dihydroindole ketone (pyrrolyllactam indolinones, SU6597), 3-(4-dimethylamino-naphthal-1-methylene)-1,3-dihydro-indole-2-dihydroindole ketone (3-(4-Dimethylamino-naphthaleh-1-ylmethylene)-1,3-dihydro-indol-2-one, MAZ51), 1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indol-2-indolinone, RPI-1), 3-[5-methyl-2-(2-oxygen-1,2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid (3-[5-methyl-2-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-proprionic acid, SU10944), 5-[(Z)-(5-chloro-2-oxygen-1,2-dihydro-3H-indole-3-methylene) methyl] N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides (5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-N-[2-(diethyllamino) ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, SU11652), 5-[(Z)-(5-fluoro-2-oxygen-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides (5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide), SU11654), 5-[(Z)-(5-chloro-2-oxygen-1,2-dihydro-3H-indole-3-subunit) methyl]-2,4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides ((5-[(Z)-(and 5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide), SU11655), 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl] TGA] hydrazono-]-the 1H-2-dihydroindole ketone (3-[[(3-phenyl-4 (3H)-quinazolinone-2-yl) mercaptoacetyl] hydrazono]-1H-2-indolinones, SU1165), 3-two (4-anisyl) methylene-2-dihydroindole ketone (3-bis (4-methoxyphenyl) methylene-2-indolinone, TAS-301), 3-[4-formyl piperazine-4yl]-benzal]-the 2-dihydroindole ketone (3-[4-(1-formylpiperazin-4yl)-benzylidenyl]-2-indolinone, SU4984), 3-([5-imidazoles] 2,1-methylene thiazole)-and the 2-dihydroindole ketone (3-(5-imidazo) 2,1-blthiazolylmethylene)-2-indolinone, IBMI), 3-1 (2,6-methylimidazole [2,1-Bj-thiazole-5-yl] and methylene-5-methoxyl group-2-dihydroindole ketone (3-1 (2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl] methylenel-5-methoxy-2-indolinone, DMMI, SU9518), imidazoles [2,1-b] methylene thiazole-2-dihydroindole ketone (Imidazo[2,1-b] thiazolylmethylene-2-indolinones, ITI), methylene indole-2-dihydroindole ketone (indolylmethylene-2-indolinones, IMI), (2-chloro-indole) methylene-2-dihydroindole ketone (2-chloroindolyl) methylene-2-indolinone, CMI), arlydene 2-dihydroindole ketone (arylidene 2-indolinone, AI);
1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indol-2-one), Cpd 1), 3-(4-dimethylamino-benzal)-2-dihydroindole ketone (3-(4-dimethylamino-benzylidenyl)-2-indolinone, DMBI), 5-chloro-3-methylene pyridine-2-dihydroindole ketone (5-chloro-3-pyridylmethylene-2-indolinone, CPMI), 3,3-lutidines-1-phenyl-2-dihydroindole ketone (3,3-dipyridylmethyl-1-phenyl-2-indolinone, DPMPI), E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone (E-3-(2-chloro-3-indolyl methylene) 1,3-dihydroindol-2-indolinone, CIDI), gefitinib (Gefitinib, claim 4-quinazoline oxazolone amine again, N-(3-chloro-4-fluoro phenyl)-7-methoxyl group-6-[3-4-morpholine] propoxyl group) [4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin] propoxy], Erlotinib (4-quinazoline oxazolone amine, N-(3-acetenyl)-6, two (the 2-methoxy ethyl)-monohydrochloride [4-Quinazolinamine of 7-, N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)-monohydrochlo ride, Tarceva, OSI-774, erlotinib, CP-358774, OSI-774, R-1415], (phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-yl) (Phenol, 4-(4-(((1R)-1-phenylethyl) amino)-1H-pyrrolo (2,3-d) pyrimidine-6-yl)-, PKI-166, CGP-59326, CGP-59326B, CGP-62706, CGP-74321, CGP-75166, CGP-76627), Lapatinib (4-quinazoline oxazolone amine, N-[3-chloro-4-[(3-fluoro) methoxy ethyl]-the 6-[5-[[2-[sulfidomethyl] ethyl] furan-2-yl]] two (4-tolyl sulfate) single hydrate] [4-Quinazolinamine, N-[3-chloro-4-[(3-fluorobenzyl) methoxyphenyl]-6-[5-[[[2-[methylsulfonyl] ethyl] amino] methyl] furan-2-yl]] bis (4-methylbenzenesulfonate) monohydrate, lapatinibditosylate, GW-2016, GW-572016, GW-572016F], (N-(4-chlorphenyl)-4-(pyridine-4-methyl) faces phenylenedimethylidyne-1-amine (N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl) phtalazin-1-amine to votaranib, vatalanib, PTK-787, PTK/ZK, Schering VEGF-TK1, Schering AG, ZK-222584)), WAY-EKB 569 ((2E)-N-[4-[(3-chloro-4-fluoro phenyl) amine]-3-cyanogen-7-ethoxyquin-6-yl]-4-(dimethylamino) also-the 2-amide ((2E)-N-[4-[(3-chloro-4-fluorophenyl) amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethy lamino) but-2-enamide, EKB-569, pelitinib).
Other vasoinhibitor is referring to relevant international monopoly, application number: WO 97/22596, and WO 97/30035, WO 97/32856and WO 98/13354.
Above vasoinhibitor also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.
Preferred one of the following or combination of above-mentioned vasoinhibitor:
NSC 609974 (CAT); Thalidomide; LS-2616; En Jisi peptide booth; En Duosi peptide booth; imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM); 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; pyrroles's lactone dihydroindole ketone; the lactams dihydroindole ketone; 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indole-2-dihydroindole ketone; 3-[5-methyl-2-(2-oxygen-1; 2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-fluoro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl] TGA] hydrazono-)-1H-2-dihydroindole ketone (SU1165); 3-two (4-anisyl) methylene-2-dihydroindole ketone; 3-[4-formyl piperazine-4yl]-benzal]-the 2-dihydroindole ketone; 3-([5-imidazoles] 2; 1-methylene thiazole)-the 2-dihydroindole ketone; 3-1 (2; 6-methylimidazole [2; 1-Bj-thiazole-5-yl] methylene-5-methoxyl group-2-dihydroindole ketone; imidazoles [2; 1-b] methylene thiazole-2-dihydroindole ketone; methylene indole-2-dihydroindole ketone; (2-chloro-indole) methylene-2-dihydroindole ketone; arlydene 2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone; 3-(4-dimethylamino-benzal)-2-dihydroindole ketone; 5-chloro-3-methylene pyridine-2-dihydroindole ketone; 3; 3-lutidines-1-phenyl-2-dihydroindole ketone; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2; 3-d) pyrimidine-6-base; Lapatinib; ZK-222584; WAY-EKB 569; E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone can singly select or multiselect.But with NSC 609974; thalidomide; LS-2616; En Jisi peptide booth; En Duosi peptide booth; the vascular endothelial growth factor receptor inhibitor; imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM); 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; the 2H-indol-2-one; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; ZK-222584 or WAY-EKB 569.
Above-mentioned vasoinhibitor with NSC 609974, thalidomide, LS-2616, imatinib mesylate, gefitinib, Erlotinib, Lapatinib, ZK-222584 or WAY-EKB 569 for most preferably.
Pyrimidine analogue and derivant thereof are, but be not limited to, 2,4,5-triamido-6-benzyloxy pyrimidine (2,4,5-triamino-6-benzyloxypyrimidine), 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine (2,4-diamino-6-benzyloxy-5-nitrosopyrimidine), 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine (2,4-diamino-6-benzyloxy-5-nitropyrimidine), 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine (2,4-diamino-6-benzyloxy-5-bromopyrimidine), 2-amino-4-benzyloxy-5-nitro-pyrimidine (2-Amino-4-benzyloxy-5-nitropyrimidine), 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine (2-Amino-4-benzyloxy-6-methyl-5-nitropyrimidine), 2,4-diaminourea-6-benzyloxy-s-triazine (2,4-Diamino-6-benzyloxy-s-triazine), 2-amino-O4-benzyl pteridine (2-amino-O4-benzylpteridine), 2-amino-O4-benzyl-6,7-diformazan pteridine (2-amino-O4-benzyl-6,7-dimethylpteridine), 2-amino-O4-benzyl-6-methylol pteridine (2-amino-O4-benzyl-6-hydroxymethylpteridine), 2-amino-O4-benzyl pteridine-6-carboxylic acid (2-amino-O4-benzylpteridine-6-carboxylic acid), 2-amino-O4-benzyl-6-formyl pteridine (2-amino-O4-benzyl-6-formylpteridine), O4-benzyl folic acid (O4-benzylfolic acid), 5-iodo-2 '-deoxyguanosine (5-Iodo-2 '-deoxyuridine), 5-bromo-2 '-deoxyguanosine (5-bromo-2 '-deoxyuridine), 4-amino-6-benzyl oxygen-5-nitro-pyrimidine (4-amino-6-benzyloxy-5-nitropyrimidine), 2-amino-4-benzyloxy-5-nitro-pyrimidine (2-amino-4-benzyloxy-5-nitropyrimidine), 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine (2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine), 2,4-diaminourea-6-benzyloxy pyrimidine (2,4-diamino-6-benzyloxypyrimidine), N2-2-amino-4-chloro-5-nitro-pyrimidine (2-Amino-4-chloro-5-nitropyrimidine), 2-amino-6-chloro-8-trifluoromethyl pyrimidine (2-Amino-6-chloro-8-trifluoromethylpurine), in the O6-benzyl pyrimidines (O6-benzylpyrimidine) one or more.
Preferred one of the following or combination of pyrimidine analogue and derivant thereof:
2-amino-O4-benzyl-6-formyl pteridine, O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, 2-amino-6-chloro-8-trifluoromethyl pyrimidine, in the O6-benzyl pyrimidines one or more.Preferred O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine or O6-benzyl pyrimidines.
Pyrimidine analogue and derivant thereof shared ratio in implant is decided because of concrete condition, and generally speaking, percentage by weight can be good with 1%-50% from 0.01%-80%, is best with 5%-30%.
The used pharmaceutic adjuvant of anticancer implant of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded.Described pharmaceutic adjuvant comprises one of following or its combination:
(1) biocompatibility polymer, comprise biodegradable or biological nondegradable polymer and composition thereof or copolymer, (2) water-soluble low-molecular chemical compound is or/and (3) are used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.
Above-mentioned biodegradable polymer comprises natural and/or synthetic polymer.Synthetic polymer as, but be not limited to, polyanhydrides, polyhydroxy acid, polyester (polyesters), polyamide (polyamides), polypeptide (polypeptides), polyactide (polylactides) is as polylactic acid (polylactic acid), polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid), poe (polyorthoesters), polyphosphazene (polyphosphazenes), to carboxy phenyl propane (p-CPP), certain herbaceous plants with big flowers diacid (sebacic acid), liposome, Polyethylene Glycol (polyglycolide) (polymer of hydroxyacetic acid and lactic acid), carboxylic acids (carboxylic acids), fatty acid (fatty acids), phospholipid (phospholipids), nucleic acid (nucleic acids), polyamino acid (polyamino acids), aminoacid such as phenylalanine (phenylalanine), tyrosine (tyrosine), different bright (isoleucine), polynucleotide (polynucleotides); Natural polymer as, but be not limited to, protein and polysaccharide (polysaccharides) comprise hyaluronic acid (hyaluronic acid), chondroitin sulfate (chondroitin sulfate), collagen protein, gelatin, albumin etc.Wherein, preferred polymer is polyactide, Polyethylene Glycol or polyactide and glycolide copolymer (as the copolymer (PLGA) of glycolic and lactic acid).
Above-mentioned polyanhydrides can be selected for use, but is not limited to, fragrant polyanhydride, aliphatic polyanhydride; Wherein fragrant polyanhydride will be separated slower, the fusing point height, and dissolubility is low in the organic solvent, however the copolymer of fragrant polyanhydride and aliphatic polyanhydride is comparatively desirable (United States Patent (USP) 4757128) but.Representative wherein is polifeprosan (to the copolymer of carboxy phenyl propane (p-CPP) and certain herbaceous plants with big flowers diacid (SA)), and is fragrant polyanhydride to carboxy phenyl propane, and the certain herbaceous plants with big flowers diacid then is the copolymer of an aromatic diacid and a fat diacid.The copolymer of available other fragrance or aliphatic polyanhydride has a detailed description (US4857311 in other United States Patent (USP); 4888176; 4789724).
Above-mentioned polyhydroxy acid can be selected for use, but is not limited to, the copolymer (PLGA) of mixture, glycolic and the lactic acid of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and polyglycolic acid.Above polyhydroxy acid can singly select or multiselect, and when singly selecting, the molecular weight of polylactic acid (PLA) can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-30000 is for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 10,000-50000 is preferred, with 10,000-20000 is for most preferably; The molecular weight of the copolymer of glycolic and lactic acid (PLGA) can be, but is not limited to, 1000-100, and 000, but with 10,000-50000 is preferred; With 10,000-20000 is for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or certain herbaceous plants with big flowers diacid or copolymer for most preferably, as, but be not limited to, molecular weight is 5000 to 10000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 20000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 5000 to 10000 polylactic acid mixes with the certain herbaceous plants with big flowers diacid, molecular weight is that 30000 to 80000 PLGA mixes with the certain herbaceous plants with big flowers diacid.When PLA and PGA mixing, its content percentage by weight is respectively 0.1-99.9% and 99.9-0.1%.Compositions can discharge effective ingredient by the mode of direct diffusion and/or degraded.Above molecular weight peak value scope is that GPC records.
The nondegradable polymer of above-mentioned biology comprises, but be not limited to: polyethylene propylene (polyvinyl propylene), polyvinylpyrrolidone (polyvinylpyrrolidone, PVP), organosilicon polymer, ethylene vinyl acetate copolymer (Ethelene-vinyl acetate copolymer, EVAc), polyacrylonitrile (polyacrylonitriles), polyurethanes (polyurethanes), silicone (silicone) and polyphosphazene (polyphosphazenes) etc.Compositions can discharge effective ingredient by the mode of direct diffusion.
For regulating other characteristic of drug releasing rate or change entity-tumor-resistant medicine composition of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar and salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide and chitin etc., and wherein salt can be but is not limited to, potassium salt and sodium salt etc.
The used pharmaceutic adjuvant of anticancer implant of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.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.
Pharmaceutic adjuvant has a detailed description in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor).In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvants.Comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or inhibitor.Above pharmaceutic adjuvant has has multiple action, and therefore the material of the same race that has is listed in different classifications.The available holder of anticancer implant of the present invention can be any or multiple material in the above-mentioned pharmaceutic adjuvant, and not exclusively comes the technical characterictic of limit combination according to its classification or definition.
The effective ingredient of anticancer 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.In addition, the effective ingredient of anticancer implant also can be packaged in the liposome equably, or makes microsphere with art methods.
The characteristics of anticancer implant of the present invention are that used pharmaceutic adjuvant removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other pharmaceutic adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, inhibitor, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.
Pharmaceutic adjuvant also can be liquid, as, but be not limited to Oleum sesami, suspension, distilled water, physiology towards liquid and semisolid, as (but being not limited to) fruit jelly, paste, ointment etc., above-mentioned pharmaceutic adjuvant is applicable to the compositions that contains or do not contain additive.
The Main Ingredients and Appearance that the present invention resists can be made into multiple dosage form.As, but be not limited to injection, muddy suspension, ointment, capsule, slow releasing agent, controlled release agent, slowbreak agent, implant, sustained-release implant, controlled release implant, slowbreak implant; Be multiple shape, as, but be not limited to granular, lamellar, sphere, bulk, needle-like, bar-shaped and membranaceous.In various dosage forms, based on the sustained release profile in vivo test implant.Above-mentioned dosage form and shape are applicable to the compositions that contains or do not contain additive.
The most preferred dosage form of anticancer implant of the present invention is the implantation slow release agent that bio-capacitivity, degradable absorb, and can make different shape because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, the universe is dry, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.Wherein dissolution method can be in order to the manufacturing of microsphere, and its method is arbitrarily, and anticancer pharmaceutical composition also can be packed in the liposome.
Because anticancer implant of the present invention can make the action effect of methods such as conventional chemotherapy, immunization therapy, high thermal therapeutical, photochemical therapy, electrotherapy, Biotherapeutics, hormone therapy, magnetic therapy, ultrasonic therapeutic, radiotherapy and gene therapy strengthen.Therefore when local slow discharges, can share, thereby its anticancer effect is further strengthened with above-mentioned non-operative treatment.
Route of administration
The main component of anticancer implant of the present invention can be through various administrations, as in passages through which vital energy circulates, tremulous pulse, subcutaneous, muscle, Intradermal, intracavity, the tumor, tumor week etc.Route of administration depends on multiple factor, for obtaining valid density in position, tumor place, medicine can give through other number of ways, as arterial perfusion optionally, administration in the intra-bladder instillation (intracavitary), abdominal cavity (intraperitoneal) or thoracic cavity (intrapleural) and canalis spinalis.In number of ways, with topical, as with in selective arterial, the tumor, tumor week injection or be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, can plant slow-releasing pump, slow releasing capsule, slow releasing agent, implant or sustained-release implant as selecting for use.With the tremulous pulse approach is good, directly is placed as the best in the tumor body.
Dosage
The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.Generally speaking, vasoinhibitor can be 0.01-200 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, cancer therapy drug can be 0.01-100 milligram/kg body weight, with 1-180 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.
The present invention can be used to prepare the medicine of the various entity tumors for the treatment of people, house pet and animal, comprises former or cancer or sarcoma or the carcinosarcoma that shifts originating from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.
Also can add other medicinal ingredient in the anticancer implant of the present invention, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.
Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application.Said composition can be through various administrations, with topical, as selective arterial injection and directly injection or be placed as goodly in the tumor body, wherein are released to the best with local slow again.When used the part, anticancer implant of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place former or all or part of excision of entity tumor shifted formed intracavity afterwards.
Main Ingredients and Appearance of the present invention is a holder with the bio-capacitivity material, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out, because of at tumor by local release contained drug, thereby optionally improve and prolong local drug concentration, the while can be reduced the general toxic reaction that is caused by the conventional route administration.
The characteristics of technology of preparing of the present invention are vasoinhibitor and/or cancer therapy drug are packaged in the pharmaceutic adjuvant, proportionally with active ingredient and pharmaceutic adjuvant dissolving, treat that abundant mixing is dry afterwards.Be shaped immediately after to be dried and sterilize packing.
Above vasoinhibitor and/or cancer therapy drug are local to be placed, not only can overcome the toxic reaction that the whole body administration brings, and has solved the tumor by local drug level and cross the low and cell sensitive question to medicine.
Tumor-inhibiting action in the body of test one, vasoinhibitor and/or cancer therapy drug
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of vasoinhibitor is 50mg/kg, and the dosage of cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.
Table 1
| Test group (n) | Used medicine | Gross tumor volume (cm3) | The P value |
| 1(6) | Contrast | 64±12cm 3 | |
| 2(6) | Thalidomide | 48±11cm 3 | ＜0.05 |
| 3(6) | (A) | 48±8cm 3 | ＜0.01 |
| 4(6) | (B) | 36±8cm 3 | ＜0.01 |
| 5(6) | (C) | 32±6cm 3 | ＜0.01 |
| 6(6) | (D) | 34±6cm 3 | ＜0.01 |
| 7(6) | Thalidomide+(A) | 22±6cm 3 | ＜0.001 |
| 8(6) | Thalidomide+(B) | 18±2.6cm 3 | ＜0.001 |
| 9(6) | Thalidomide+(C) | 16±3.6cm 3 | ＜0.001 |
| 10(6) | Thalidomide+(D) | 14±2.4cm 3 | ＜0.001 |
Above vasoinhibitor all has notable synergistic effect (P＜0.001) to the examination cancer therapy drug.Wherein, the vasoinhibitor representative that Thalidomide is, and (A), (B), (C) and (D) be respectively O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine and 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine is the representative of pyrimidine derivatives.
Tumor-inhibiting action in the body of test two, vasoinhibitor and/or cancer therapy drug
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of vasoinhibitor is 50mg/kg, and the dosage of cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.
Table 2
| Test group (n) | Used medicine | Gross tumor volume (cm3) | The P value |
| 1(6) | Contrast | 48±22cm 3 | |
| 2(6) | Imatinib | 24±14cm 3 | ＜0.05 |
| 3(6) | (A) | 24±18.cm 3 | ＜0.01 |
| 4(6) | (B) | 36±16cm 3 | ＜0.01 |
| 5(6) | (C) | 26±8.2cm 3 | ＜0.01 |
| 6(6) | (D) | 24±6cm 3 | ＜0.01 |
| 7(6) | Imatinib+(A) | 14±8cm 3 | ＜0.001 |
| 8(6) | Imatinib+(B) | 12±8cm 3 | ＜0.001 |
| 9(6) | Imatinib+(C) | 8±4cm 3 | ＜0.001 |
| 10(6) | Imatinib+(D) | 6±4cm 3 | ＜0.001 |
Above vasoinhibitor all has notable synergistic effect (P＜0.001) to the examination cancer therapy drug.Wherein, the vasoinhibitor representative that imatinib is, and (A), (B), (C) and (D) be respectively 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine and 2-amino-O4-benzyl pteridine is the representative of pyrimidine derivatives.
Tumor-inhibiting action in the body of test three, vasoinhibitor and cancer therapy drug
With the rat is subjects, with 2 * 10
5Individual 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.The dosage of vasoinhibitor is 50mg/kg, and the dosage of cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 30th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 68±13cm 3 | |
| 2(6) | Gefitinib | 42±8cm 3 | ＜0.05 |
| 3(6) | (A) | 45±8cm 3 | ＜0.01 |
| 4(6) | (B) | 38±6cm 3 | ＜0.01 |
| 5(6) | (C) | 42±6.4cm 3 | ＜0.01 |
| 6(6) | (D) | 40±6.8cm 3 | ＜0.01 |
| 7(6) | Gefitinib+(A) | 26±4.6cm 3 | ＜0.001 |
| 8(6) | Gefitinib+(B) | 20±3.6cm 3 | ＜0.001 |
| 9(6) | Gefitinib+(C) | 18±4.6cm 3 | ＜0.001 |
| 10(6) | Gefitinib+(D) | 20±2.6cm 3 | ＜0.001 |
Above vasoinhibitor all has notable synergistic effect (P＜0.001) to the examination cancer therapy drug.Wherein, the vasoinhibitor representative that gefitinib is, and (A), (B), (C) and (D) be respectively O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine and O6-benzyl pyrimidines chlormethine are the representative of pyrimidine derivatives.
Tumor-inhibiting action in the body of test four, vasoinhibitor and/or cancer therapy drug
With the rat is subjects, with 2 * 10
5Individual tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).First group is contrast, and the 2nd to 10 group is the treatment group.The dosage of vasoinhibitor is 50mg/kg, and the dosage of cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 30th day.
Table 4
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 68±14cm 3 | |
| 2(6) | Erlotinib | 48±11cm 3 | ＜0.05 |
| 3(6) | (A) | 48±10cm 3 | ＜0.01 |
| 4(6) | (B) | 44±8cm 3 | ＜0.01 |
| 5(6) | (C) | 44±6cm 3 | ＜0.01 |
| 6(6) | (D) | 42±6cm 3 | ＜0.01 |
| 7(6) | Erlotinib+(A) | 32±3.2cm 3 | ＜0.001 |
| 8(6) | Erlotinib+(B) | 28±3.8cm 3 | ＜0.001 |
| 9(6) | Erlotinib+(C) | 28±4.2cm 3 | ＜0.001 |
| 10(6) | Erlotinib+(D) | 20±2cm 3 | ＜0.001 |
Above vasoinhibitor all has notable synergistic effect (P＜0.001) to the examination cancer therapy drug.Wherein, the vasoinhibitor representative that Erlotinib is, and and (A), (B), (C) and (D) be respectively O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine and O6-benzyl pyrimidines chlormethine are the representative of pyrimidine derivatives.
Tumor-inhibiting action in the body of test five, vasoinhibitor and cancer therapy drug
With the rat is subjects, with 2 * 10
5Individual tumor cell 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.The dosage of vasoinhibitor is 50mg/kg, and the dosage of cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 30th day.
Table 5
| Test group (n) | Suffered treatment | Gross tumor volume (cm3) | The P value |
| 1(6) | Contrast | 64±12cm 3 | |
| 2(6) | Lapatinib | 42±10cm 3 | ＜0.05 |
| 3(6) | (A) | 40±8cm 3 | ＜0.01 |
| 4(6) | (B) | 38±6cm 3 | ＜0.01 |
| 5(6) | (C) | 36±6.4cm 3 | ＜0.01 |
| 6(6) | (D) | 34±6.8cm 3 | ＜0.01 |
| 7(6) | Lapatinib+(A) | 24±4.6cm 3 | ＜0.001 |
| 8(6) | Lapatinib+(B) | 18±3.4cm 3 | ＜0.001 |
| 9(6) | Lapatinib+(C) | 18±4.2cm 3 | ＜0.001 |
| 10(6) | Lapatinib+(D) | 16±2.2cm 3 | ＜0.001 |
Above vasoinhibitor all has notable synergistic effect (P＜0.001) to the examination cancer therapy drug.Wherein, the vasoinhibitor representative that Lapatinib is, and and (A), (B), (C) and (D) be respectively 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine and 2-amino-O4-benzyl pteridine is the representative of pyrimidine derivatives.
In a word, the vasoinhibitor among the present invention all has the notable synergistic effect to the examination cancer therapy drug.Therefore, the effective ingredient of anticancer implant of the present invention is the associating of above-mentioned any one or multiple vasoinhibitor and any one or multiple cancer therapy drug or packing separately.The anticancer implant that contains above effective ingredient can be made into any dosage form or shape, but with agent for slow releasing or to implant dosage form serve as preferred.
The preparation method of anticancer implant of the present invention is as follows:
1. the pharmaceutic adjuvant of weighing is put into container, add the certain amount of organic solvent dissolving evenly, the not strict qualification of the amount of organic solvent, suitable fully to be dissolved as.
2. adding the anticancer active ingredient of weighing shakes up again.The usage ratio of anticancer active ingredient and pharmaceutic adjuvant is decided because of specific requirement.
3. removal organic solvent.Vacuum drying, spraying or cold drying all can.
4. dried solid composite is made different shape as required.Also can be with straight forming behind adjuvant and the anticancer active ingredient mixing.
5. ray sterilizing (roentgendosis is different because of volume) is standby after the packing.Also available other method sterilization.
(4) specific embodiment
Embodiment 1.
With 80mg molecular weight peak value is that the polylactic acid (PLGA) of 15000-25000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mgO4-benzyl folic acid (pyrimidine derivatives) and 10mg thalidomide (vasoinhibitor), shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer implant of 10% O4-benzyl folic acid and 10% thalidomide.All be weight percentage.The drug release time of this anticancer implant in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 2.
The method step that is processed into anticancer implant is identical with embodiment 1, but different is that contained anticancer effective component is:
(A) vasoinhibitor of 1-50%, be selected from NSC 609974, thalidomide, LS-2616, En Jisi peptide booth, En Duosi peptide booth, the vascular endothelial growth factor receptor inhibitor, imatinib mesylate, 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide, 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM), 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone, 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl, the 2H-indol-2-one, 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS], gefitinib, Erlotinib, phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base, Lapatinib, ZK-222584 or WAY-EKB 569; With
(B) 2-of 1-50% amino-O4-benzyl-6-formyl pteridine, O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, 2-amino-6-chloro-8-trifluoromethyl pyrimidine or O6-benzyl pyrimidines.
Below all be weight percentage.
Embodiment 3.
With 80mg molecular weight peak value is that the polyglycolic acid of 20000-40000 and the copolymer of hydroxyacetic acid (PLGA) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg imatinib (vasoinhibitor) and 10mg2-amino-O4-benzyl-6-formyl pteridine (pyrimidine derivatives), shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing makes the anticancer implant that contains 10% imatinib and 10%2-amino-O4-benzyl-6-formyl pteridine.All be weight percentage.The drug release time of this anticancer implant in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 4.
The method step that is processed into anticancer implant is identical with embodiment 3, but different is that contained anticancer effective component is:
(A) vasoinhibitor of 1-50%, be selected from NSC 609974, thalidomide, LS-2616, En Jisi peptide booth, En Duosi peptide booth, the vascular endothelial growth factor receptor inhibitor, imatinib mesylate, 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide, 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM), 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone, 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl, the 2H-indol-2-one, 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS], gefitinib, Erlotinib, phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base, Lapatinib, ZK-222584 or WAY-EKB 569; With
(A) 2-of 1-50% amino-O4-benzyl-6-formyl pteridine, O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, 2-amino-6-chloro-8-trifluoromethyl pyrimidine or O6-benzyl pyrimidines.
Below all be weight percentage.
Embodiment 5.
With 80mg molecular weight peak value is that 30000-50000 polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg gefitinib (vasoinhibitor) and 10mg2,4-diaminourea-6-benzyloxy-s-triazine (pyrimidine derivatives) shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain 10% gefitinib and 10%2, the anticancer implant of 4-diaminourea-6-benzyloxy-s-triazine.All be weight percentage.The drug release time of this anticancer implant in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 6.
The method step that is processed into anticancer implant is identical with embodiment 5, and different is that contained anticancer effective component is:
(A) vasoinhibitor of 1-50%, be selected from NSC 609974, thalidomide, LS-2616, En Jisi peptide booth, En Duosi peptide booth, the vascular endothelial growth factor receptor inhibitor, imatinib mesylate, 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene] 2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide, 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM), 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone, 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl, the 2H-indol-2-one, 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS], gefitinib, Erlotinib, phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base, Lapatinib, ZK-222584 or WAY-EKB 569; With
(B) 2-of 1-50% amino-O4-benzyl-6-formyl pteridine, O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, 2-amino-6-chloro-8-trifluoromethyl pyrimidine or O6-benzyl pyrimidines.
Below all be weight percentage.
Embodiment 7.
(EVAc) puts into container with the 80mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 10 milligrams of Erlotinib (vasoinhibitor) and 10mgO6-benzyl pyrimidines (pyrimidine derivatives), shake up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer implant of 10% Erlotinib and 10%O6-benzyl pyrimidines.All be weight percentage.The drug release time of this anticancer implant in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 8.
The method step that is processed into anticancer implant is identical with embodiment 5, and different is that contained anticancer effective component is:
(A) vasoinhibitor of the 1-50% of 1-50%, be selected from NSC 609974, thalidomide, LS-2616, En Jisi peptide booth, En Duosi peptide booth, the vascular endothelial growth factor receptor inhibitor, imatinib mesylate, 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-methylene] 2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide, 3,3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM), 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone, 1H-pyrroles-3-propanoic acid, 2-[(1,2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl, the 2H-indol-2-one, 3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS], gefitinib, Erlotinib, phenol, 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base, Lapatinib, ZK-222584 or WAY-EKB 569; With
(B) 2-of 1-50% amino-O4-benzyl-6-formyl pteridine, O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, 2-amino-6-chloro-8-trifluoromethyl pyrimidine or O6-benzyl pyrimidines.
Below all be weight percentage.
Embodiment 9.
With 80mg molecular weight peak value is that 20000-40000 polifeprosan (to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg Lapatinib (vasoinhibitor) and 10mg 2,4-diaminourea-6-benzyloxy pyrimidine (pyrimidine derivatives) shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain 2 of 10% Lapatinib and 10, the anticancer implant of 4-diaminourea-6-benzyloxy pyrimidine.All be weight percentage.The drug release time of this anticancer implant in external normal saline is 15-20 days, is 30-40 days at the subcutaneous drug release time of mice.
Embodiment 10.
The method step that is processed into anticancer implant is identical with embodiment 9, different is that contained anticancer effective component is: the NSC 609974 of 5-30%, thalidomide, LS-2616, imatinib mesylate, gefitinib, Erlotinib, Lapatinib, the O4-benzyl folic acid of ZK-222584 or WAY-EKB 569 and 5-30%, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, the combination of 2-amino-6-chloro-8-trifluoromethyl pyrimidine or O6-benzyl pyrimidines.
Below all be weight percentage.
Embodiment 11.
The method step that is processed into anticancer implant is identical with embodiment such as embodiment 1,3,5,7 or 9, used pharmaceutic adjuvant is respectively one of following or its combination that different is:
A) molecular weight is 5000-15000,10000-20000,20000-30000, the polylactic acid of 30000-40000 or 40000-80000 (PLA);
B) molecular weight is 5000-15000,10000-20000,20000-30000,30000-40000, the polyglycolic acid of 40000-50000 or 50000-80000 and the copolymer of hydroxyacetic acid (PLGA);
C) ethylene vinyl acetate copolymer (EVAc); Or
D) to the copolymer (polifeprosan) of carboxy phenyl propane and certain herbaceous plants with big flowers diacid, to carboxy phenyl propane: certain herbaceous plants with big flowers diacid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, chondroitin sulfate, collagen protein, gelatin or albumin.
Embodiment 12.
The method step that is processed into anticancer implant is identical with embodiment such as embodiment 1,3,5,7,9,11, and anticancer effective component that different is is one of following:
(a) combination of 10% thalidomide, LS-2616, imatinib mesylate, gefitinib, Erlotinib, Lapatinib, ZK-222584 or WAY-EKB 569 and 10%O4-benzyl folic acid; Or
(b) combination of 10% thalidomide, LS-2616, imatinib mesylate, gefitinib, Erlotinib, Lapatinib, ZK-222584 or WAY-EKB 569 and 10%O6-benzyl pyrimidines
More than be weight percentage.
Embodiment 13. is anticancer implant inside and outside release characteristics relatively
Get the anticancer implant among the embodiment 12, be placed in the room temperature normal saline and soak, survey the different time release amount of medicine, calculate external accumulative total and discharge percent (%).It is subcutaneous to be put in white mice, regularly takes out and surveys medicament contg, according to the residual drug amount, calculates the interior accumulative total of body and discharges percent (%).The result shows, the different pharmaceutical release in vitro no significant difference that tries discharged the about 20%, the 14th day and discharges 88-94% in first day.Try to discharge in the different pharmaceutical body also no significant difference, discharged the about 10%, 28th day and discharge more than 98% in first day.But the inside and outside discharges notable difference is arranged, release in vitro is fast than being released in the body.Can keep one month in vivo.
Claims (9)
1. an anticancer implant comprises anticancer effective component and pharmaceutic adjuvant, it is characterized in that anticancer effective component is vasoinhibitor and cancer therapy drug, and cancer therapy drug is pyrimidine analogue and derivant thereof.
2. the anticancer implant according to claim 1; it is characterized in that described vasoinhibitor is a NSC 609974; thalidomide; LS-2616; En Jisi peptide booth; En Duosi peptide booth; the vascular endothelial growth factor receptor inhibitor; imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; the 2H-indol-2-one; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; a kind of or its combination in ZK-222584 or the WAY-EKB 569.
3. the anticancer implant according to claim 1, it is characterized in that described pyrimidine analogue and derivant thereof are selected from 2-amino-O4-benzyl-6-formyl pteridine, O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, in 2-amino-6-chloro-8-trifluoromethyl pyrimidine one or more.
4. the anticancer implant according to claim 1 is characterized in that the effective ingredient of this implant is:
NSC 609974; thalidomide; LS-2616; En Jisi peptide booth; En Duosi peptide booth; the vascular endothelial growth factor receptor inhibitor; imatinib mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (DCM); 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; the 2H-indol-2-one; 3-((4; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1; 3-dihydro-[CAS]; gefitinib; Erlotinib; phenol; 4-(4-(((1R)-1-phenethyl) amino)-1H-pyrrolo-(2,3-d) pyrimidine-6-base; Lapatinib; ZK-222584 or WAY-EKB 569 and
2-amino-O4-benzyl-6-formyl pteridine, O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, the combination of 2-amino-6-chloro-8-trifluoromethyl pyrimidine or O6-benzyl pyrimidines.
5. the anticancer implant according to claim 1 is characterized in that the effective ingredient of this implant is:
The NSC 609974 of percentage by weight 5-30%, thalidomide, LS-2616, imatinib mesylate, gefitinib, Erlotinib, Lapatinib, the O4-benzyl folic acid of ZK-222584 or WAY-EKB 569 and percentage by weight 5-30%, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitro-pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine, 2-amino-O4-benzyl-6,7-diformazan pteridine, 2-amino-O4-benzyl-6-methylol pteridine, 5-iodo-2 '-deoxidation bird (pyrimidine nuclear) glycosides, 5-bromo-2 '-deoxyguanosine, 4-amino-6-benzyl oxygen-5-nitro-pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy pyrimidine, N2-2-amino-4-chloro-5-nitro-pyrimidine, 2-amino-O4-benzyl pteridine-6-carboxylic acid, the combination of 2-amino-6-chloro-8-trifluoromethyl pyrimidine or O6-benzyl pyrimidines.
6. the anticancer implant according to claim 1 is characterized in that the effective ingredient of this implant is:
(A) combination of 10% thalidomide, LS-2616, imatinib mesylate, gefitinib, Erlotinib, Lapatinib, ZK-222584 or WAY-EKB 569 and 10%O4-benzyl folic acid; Or
(B) combination of 10% thalidomide, LS-2616, imatinib mesylate, gefitinib, Erlotinib, Lapatinib, ZK-222584 or WAY-EKB 569 and 10%O6-benzyl pyrimidines;
More than be weight percentage.
7. the anticancer implant according to claim 1 is characterized in that pharmaceutic adjuvant is selected from one of following or its combination:
(a) molecular weight is 5000-15000,10000-20000,20000-30000, the polylactic acid of 30000-40000 or 40000-80000;
(b) molecular weight is 5000-15000,10000-20000,20000-30000,30000-40000, the polyglycolic acid of 40000-50000 or 50000-80000 and the copolymer of hydroxyacetic acid;
(c) ethylene vinyl acetate copolymer; Or
(d) polifeprosan, wherein the weight ratio to carboxy phenyl propane and certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40; Or
(e) xylitol, oligosaccharide, chitin, potassium salt, sodium salt, hyaluronic acid, chondroitin sulfate, collagen protein, gelatin or albumin.
8. the anticancer implant according to claim 1 is characterized in that this anticancer implant is suspension, slow releasing agent, implant or sustained-release implant.
9. the application of the described anticancer implant of claim 1 is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum former or secondary.
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| CN104011224A (en) * | 2011-12-22 | 2014-08-27 | 霍夫曼-拉罗奇有限公司 | Methods and reagents for reducing non-specific amplification |
| CN104011224B (en) * | 2011-12-22 | 2016-05-25 | 霍夫曼-拉罗奇有限公司 | For reducing method and the reagent of non-specific amplification |
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