CN1927170A - Anticancer slow release agent loading both newborn blood vessel and tetrazole violet - Google Patents

Anticancer slow release agent loading both newborn blood vessel and tetrazole violet Download PDF

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CN1927170A
CN1927170A CNA2006102009928A CN200610200992A CN1927170A CN 1927170 A CN1927170 A CN 1927170A CN A2006102009928 A CNA2006102009928 A CN A2006102009928A CN 200610200992 A CN200610200992 A CN 200610200992A CN 1927170 A CN1927170 A CN 1927170A
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acid
violet
slow
tetrazole violet
copolymer
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CN100594886C (en
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孔庆忠
孙娟
俞建江
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Shandong Lanjin Pharmaceuticals Co Ltd
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Jinan Shuaihua Pharmaceutical Technology Co Ltd
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Abstract

Disclosed is an anticancer slow release injection carrying both anti-angiogenesis agent and tetrazole Ionone, which comprises slow release micro-balloons and dissolvent, the slow release micro-balloons include anticancer active constituents, slow release auxiliary materials and specific dissolvent containing suspension agent. The anti-angiogenesis agent is selected from Marimastat, Fumagillin, gefinitib, erlotinib, lapatinib, pelinib, Thalidomide, Ranolazine, endostatin, imatinib, Avastin, sorafenib, sunitinib, the slow release auxiliary materials are selected from Polifeprosan, sebacylic acid copolymer, EVAc, polylactic acid and their mixture of copolymer, the viscosity of the suspension adjuvant is 100-3000cp (at 25-30 deg C), and is selected from sodium carboxymethylcellulose. The agent can also be prepared into implanting agent for injection or placement in or around tumor with the effects of selectively increasing local concentration, lowering general reaction of the drugs, suppressing growth of tumor cells and blood vessel, and improving the treatment effect of the non-operative treatment methods such as chemotherapy.

Description

A kind of anticancer sustained-release agent with carrying angiogenesis inhibitor and tetrazole violet
(1) technical field
The present invention relates to a kind of slow releasing agent its preparation method, belong to technical field of pharmaceuticals with carrying angiogenesis inhibitor and tetrazole violet.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains neovascularization inhibitor and/or tetrazole violet, be mainly slow releasing injection and sustained-release implant.
(2) background technology
It is that entity tumor growth and transfer are necessary that new vessels generates (angiogenesis).When entity tumor diameter during greater than 0.5cm, tumor cell just depends on the vascular system of self.Tumor cell can obtain nutrition and oxygen from the host by tumor vessel, can carry transitional cell to the host continuously by tumor vessel again, and forms at other position continued growths and the induction of vascular of body, causes neoplasm metastasis.And the new metastasis that constantly occurs causes treating the main cause of failure just.Therefore, the vascular system that effectively suppresses tumor has become antineoplaston field brand-new, a target spot likely.
Can destroy or suppress angiogenesis, stop effectively the medicine of growth of tumor and transfer be called as the new vessels formation inhibitor (Angiogenesis Inhibitor, AI).It is generally acknowledged that compare with existing anticarcinogen, the AI treatment has many advantages: when (1) tumor took place, vascularization was activated, so have good specificity; (2) vascular endothelial cell is exposed in the blood flow, and the medicine in the circulation can directly play a role, so required dosage is little, curative effect is high, untoward reaction is light; (3) the endothelial cell gene expression is relatively stable, is difficult for producing drug resistance.
Yet, because entity tumor excessive expansion hypertrophy, therebetween irregular, the tissue elasticity pressure of matter pressure, tumor vessel disorder, fluid pressure and between the viscosity of matter be height all than its normal surrounding tissue, therefore, the conventional route 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 Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).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; et al., Int J Cancer.2004; 111 (4): 484-93).
Pharmaceutical topical application may solve the problem 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, entity tumor is made up of blood vessel and tumor cell, 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).The growth of tumor cell and shift constantly promote new between matter comprise the prosperity of blood vessel, therefore, being convenient to keep high drug level and increase tumor cell at tumor by local just becomes an important subject to the preparation and the method for the sensitivity of medicine.
As one of cancer conventional treatments, the neovascularization inhibitor chemotherapy has been widely used in the treatment of multiple malignant tumor, and action effect is comparatively obvious.Yet its tangible general toxicity and chemical sproof generation have greatly limited the application of this medicine.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains neovascularization inhibitor and/or tetrazole violet is provided.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains neovascularization inhibitor and/or tetrazole violet, be mainly slow releasing injection and sustained-release implant.
Neovascularization inhibitor or tetrazole violet have been widely used in the multiple entity tumor of treatment, as the cerebral tumor, pulmonary carcinoma, digestive tract tumor etc.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine, and chemical sproof generation often causes the treatment failure.
Be effectively to improve tumor by local drug level, reduce the drug level of medicine in blood circulation, people have studied the slow-released system that contains cancer therapy drug, 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 neovascularization inhibitor to anticancer medicated bag is relatively poor, and is easy to generate drug resistance in therapeutic process.The present invention finds that through a large amount of experiments tetrazole violet of mentioning among the present invention and neovascularization inhibitor share and can make its antitumaous effect strengthen (the following tetrazole violet that the neovascularization inhibitor antitumaous effect will be increased mutually is referred to as the neovascularization inhibitor synergist) mutually.In addition, with the assembly packaging of neovascularization inhibitor or neovascularization inhibitor 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.Neovascularization inhibitor can suppress or destroy outside the tumor growth effectively, can also increase the sensitivity of tumor cell to cancer therapy drug.The above unexpected main contents of the present invention of finding to constitute.
The newborn neovascularization inhibitor slow releasing injection of the present invention 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 neovascularization inhibitor and/or tetrazole violet; Slow-release auxiliary material is selected from polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA)], one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid or its combination; 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.
Vasoinhibitor is selected from one of following or combination: and gefitinib (Gefitinib claims 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)-monohydrochloride, 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); NSC 609974 (carboxyamidotriazole; CAT); thalidomide (thalidomide, Thalidomide); LS-2616 (linomide, inhibitors of integrin); angiostatin (angiostatin); Endostatin (endostatin); VEGF (VEGF) acceptor inhibitor; blood vessel endothelium chalone (endostar; the grace degree); (Imatinib mesylate has another name called imatinib mesylate, Glivec) to imatinib mesylate; 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)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate; STI 571, CGP-57148B, STI-571A; CGP 57148); 5-[5-fluoro-2-oxygen-1, the 2-indoline-(3Z)-and 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-3carboxylic 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-methyl piperidinosulfonyl)-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 9518); 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 for Sugen 5416; 5-dimethyl-1H-pyrroles-2-yl) methylene)-1,3-dihydro-[CAS] (3-((4,5-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); the lactams dihydroindole ketone (pyrrolyllactam indolinones, SU6597); 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone (3-(4-Dimethylamino-naphthalen-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-(diethylamino) 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)-2-dihydroindole ketone (3-(5-imidazo) 2; 1-blthiazolylmethylene)-2-indolinone, IBMI); 3-1 (2,6-methylimidazole [2; 1-Bj-thiazole-5-yl] methylene-(3-1 (2 for 5-methoxyl group-2-dihydroindole ketone; 6-dimethylimidazo[2,1-bJ-thiazol-5-yl] methylenel-5-methoxy-2-indolinone, DMMI; SU9518]; imidazoles [2; 1-b] and 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 (arylidene2-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, and 3-lutidines-1-phenyl-2-dihydroindole ketone (3,3-dipyridylmethyl-1-phenyl-2-indolinone; DPMPI) and E-3-(2-chloro-3-methylene indole) 1; 3-indoline-2-dihydroindole ketone (E-3-(2-chloro-3-indolylmethylene) 1,3-dihydroindol-2-indolinone, CIDI); BMS 354825 (dasatinib); Avastin (avastin); Cl 1033 (canertinib); Sorafenib (sorafenib); Sutent (sunitinib; sutent; SU11248); TLK286 (Telcyta); ABX-EGF (panitumumab).
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.
Above-mentioned vasoinhibitor is with gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; the blood vessel endothelium chalone; imatinib mesylate; 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline 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; 2H-indole-2-dihydroindole ketone; Sugen 5416; 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-]-the 1H-2-dihydroindole ketone; 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 or E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone; BMS 354825; Avastin; Cl 1033; Sorafenib; Sutent; TLK286; ABX-EGF is preferred.
Above-mentioned vasoinhibitor can singly select or multiselect, with gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF for most preferably.
In addition, up-to-date preclinical test finds that existing at present tens of kinds of TA inhibitor have certain inhibitory action to tumor-blood-vessel growth.As matrix metalloproteinase (matrix metalloproteinases, MMP) inhibitor (inhibitor), angiogenesis factor activation inhibitor, endotheliocyte inhibitor etc.
(MMP inhibitor MMPi) brings into play the effect that it suppresses tumor growth and transfer by suppressing basement membrane degradation to matrix metallo-proteinase inhibitor.It represents medicine is that (marimastat MP-4), optionally suppresses matrix metalloproteinases such as MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9 to Marimastat.Growth and transfer to ovarian cancer, breast carcinoma, cancer of pancreas, carcinoma of prostate, nonsmall-cell lung cancer, small cell lung cancer, colon cancer have the obvious suppression effect.
The angiogenesis factor activation inhibitor can suppress the activation of angiogenesis factor, thereby makes the angiogenesis factor inactivation.It represents medicine is indole ketone micromolecular compounds such as SU5416 and SU6668.SU5416 is the micromolecular inhibitor that a specificity suppresses vegf receptor 2.It suppresses effect and its minimizing tumor-blood-vessel growth of tumor growth, thereby suppresses tumor cell proliferation, the promotion apoptosis of tumor cells is relevant.Clinical trial shows that SU5416 can be used for treating entity tumors such as malignant melanoma, transitivity colon cancer.SU6668[(Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-and 1H-pyrrol-3-yl] propionic acid] be a kind of antiangiogenic agent with many target spots, be VEGF, FGF, the micromolecular inhibitor of pdgf receptor, and can reach antitumor action by the apoptosis of inducing endothelial cell and tumor cell.Multiple advanced solid tumor there is better therapeutic effect.
The endotheliocyte inhibitor can directly suppress the growth of endotheliocyte.It represents medicine is Amebacilin (fumagillin) and derivant such as TNP-470.As a kind of blood vessel endothelium chalone, TNP-470 can block the dna replication dna of new vessels endotheliocyte, suppresses microvascular hypertrophy.Human breast carcinoma, carcinoma of prostate and nerve sheath tumor cell all there is the effect that suppresses growth.Clinical trial finds that old advanced solid tumor and lymphoma, acute leukemia etc. are had certain therapeutical effect.
Therefore, newborn neovascularization inhibitor of the present invention also is selected from one of following or combination:
(1) (MMP inhibitor MMPi), is selected from Marimastat to matrix metallo-proteinase inhibitor;
(2) angiogenesis factor activation inhibitor is selected from indole ketone micromolecular compounds such as SU5416 and SU6668;
(3) endotheliocyte inhibitor is selected from Amebacilin (fumagillin) and derivant such as TNP-470.
Above newborn neovascularization inhibitor 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.Above-mentioned neovascularization inhibitor shared ratio in slow releasing agent is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 5%-30% is best.
The percentage by weight of tetrazole violet in slow releasing agent is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.
When the anticancer effective component in the medicament slow-release microsphere only is neovascularization inhibitor or tetrazole violet, slow-releasing anticarcinogen injection is mainly used in the neovascularization inhibitor of other approach application of increase or the action effect of tetrazole violet, or is used for the potentiation to radiotherapy or other therapies.When the anticancer effective component in the medicament slow-release microsphere only was neovascularization inhibitor or its synergist (tetrazole violet), the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of neovascularization inhibitor, and tetrazole violet is used through other approach;
(2) local injection contains the slow releasing injection of tetrazole violet, and other approach are used neovascularization inhibitor;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains tetrazole violet of neovascularization inhibitor; Or
(4) local injection contains the slow releasing injection of neovascularization inhibitor and tetrazole violet.
The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.
Anticancer effective component neovascularization inhibitor and/or the tetrazole violet percentage by weight in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of neovascularization inhibitor and tetrazole violet is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.
Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:
(a) combination of the tetrazole violet of the Marimastat of 2-40%, SU5416, SU6668, Amebacilin or TNP-470 and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet;
(b) combination of the tetrazole violet of the gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer (PFAD-SA) of preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid in multiple slow-release auxiliary material], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], gather one of (fumaric acid-decanedioic acid) [P (FA-SA)] 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 be for arbitrarily, but preferably 1-99% and 99-1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-200, and 000, but 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, but 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, 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 10000 to 100000 polylactic acid with molecular weight is that 20000 to 150000 polylactic acid mixes, molecular weight is 10000 to 100000 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 slow-release auxiliary material, 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.; 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.
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 slow-release auxiliary material 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 the usefulness of injection.Be convenient injection, the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).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 mutually deserved 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 ways 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 decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably 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, the 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 are first-selection, mixture and copolymer can be selected from, but be not limited to PLA, PLGA, the mixture of PLA and PLGA, the mixture or the copolymer of certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride, bis-fatty acid and decanedioic acid copolymer [P (FAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)].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.
Another 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 that the slow releasing agent that biocompatibility, degradable absorb is implanted, 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.
The anticancer effective component of sustained-release implant is preferably as follows, and all is weight percentage:
(a) combination of the tetrazole violet of the Marimastat of 2-40%, SU5416, SU6668, Amebacilin or TNP-470 and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet;
(b) combination of the tetrazole violet of the gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, bis-fatty acid and the decanedioic acid copolymer (PFAD-SA) of preferred polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid in multiple slow-release auxiliary material], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], gather one of (fumaric acid-decanedioic acid) [P (FA-SA)] or its combination.
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.When the cancer therapy drug in the medicament slow-release microsphere only is neovascularization inhibitor or its synergist (cytotoxic drug), the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates 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.The tumor of above-mentioned internal organs can be different histological type, and why the tumor of the lymph node of lymph node divides outstanding golden lymphoma and non_hodgkin lymphoma, and pulmonary carcinoma comprises small cell lung cancer and nonsmall-cell lung cancer etc., and the cerebral tumor comprises glioma etc.Yet common tumor comprises entity tumors such as the retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis of the cerebral tumor, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, eyes.
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 neovascularization inhibitor (Marimastat) compares
With the rat is subjects, with 2 * 10 5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 1 cm diameter its grouping.Every group of dosage is the 5mg/kg Marimastat.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of Marimastat 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 neovascularization inhibitor (Amebacilin) compares
With the rat is subjects, with 2 * 10 5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is the 5mg/kg Amebacilin.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.The result shows, the tumor-inhibiting action significant difference of Amebacilin 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.
Tumor-inhibiting action in the body of test 3, neovascularization inhibitor and tetrazole violet (slow releasing injection)
(Fisher344) is subjects with rat, 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 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 20th day.
Table 1
Test group (n) Suffered treatment Gross tumor volume (cm3) The P value
1(6) Contrast 60±10
2(6) Tetrazole violet 44±5.2 ＜0.05
3(6) Marimastat 40±2.0 ＜0.01
4(6) Amebacilin 48±4.4 ＜0.01
5(6) SU5416 46±4.2 ＜0.01
6(6) SU6668 48±3.6 ＜0.01
7(6) Tetrazole violet+Marimastat 16±2.0 ＜0.001
8(6) Tetrazole violet+Amebacilin 24±3.0 ＜0.001
9(6) Tetrazole violet+SU5416 16±2.2 ＜0.001
10(6) Tetrazole violet+SU6668 20±2.0 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for neovascularization inhibitor (Marimastat, Amebacilin, SU5416, SU6668) and tetrazole violet, can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 4, neovascularization inhibitor and tetrazole violet (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.Neovascularization inhibitor and tetrazole violet are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 2.
Table 2
Oncocyte Tetrazole violet Marimastat Amebacilin TNP-470 Tetrazole violet+Marimastat Tetrazole violet+Amebacilin Tetrazole violet+TNP-470
CNS 50％ 40％ 38％ 36％ 78％ 78％ 88％
C6 60％ 50％ 38％ 24％ 84％ 86％ 82％
SA 60％ 40％ 22％ 22％ 88％ 86％ 80％
BC 58％ 44％ 26％ 28％ 80％ 86％ 72％
BA 54％ 42％ 22％ 26％ 88％ 76％ 76％
LH 58％ 50％ 22％ 28％ 80％ 86％ 80％
PAT 54％ 46％ 48％ 38％ 82％ 84％ 84％
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used tetrazole violet and neovascularization inhibitor (Marimastat, Amebacilin, TNP-470), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 5, neovascularization inhibitor and tetrazole violet (slow releasing injection)
(Fisher344) is subjects with rat, 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 3).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Dosage is 5mg/kg.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 Gross tumor volume (cm 3) The P value
1(6) Contrast 60±12
2(6) Tetrazole violet 40±4.0 ＜0.05
3(6) Gefitinib 44±2.0 ＜0.01
4(6) Tetrazole violet+gefitinib 20±2.2 ＜0.001
5(6) Erlotinib 36±3.2 ＜0.01
6(6) Tetrazole violet+Erlotinib 18±1.8 ＜0.001
7(6) Lapatinib 30±2.8 ＜0.01
8(6) Tetrazole violet+Lapatinib 18±2.4 ＜0.001
9(6) Votaranib 42±4.0 ＜0.01
10(6) Tetrazole violet+votaranib 22±2.0 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (gefitinib, Erlotinib, Lapatinib, votaranib) and tetrazole violet, can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 6, neovascularization inhibitor and tetrazole violet (slow releasing injection)
(Fisher344) is subjects with rat, 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 (neovascularization inhibitor or tetrazole violet) and therapeutic alliance group (neovascularization inhibitor and tetrazole violet).Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.
Table 4
Test group (n) Suffered treatment Tumor control rate (%) The P value
1(6) Contrast -
2(6) Tetrazole violet 46 ＜0.05
3(6) WAY-EKB 569 36 ＜0.01
4(6) Thalidomide 46 ＜0.01
5(6) LS-2616 52 ＜0.01
6(6) Angiostatin 42 ＜0.01
7(6) Tetrazole violet+WAY-EKB 569 80 ＜0.001
8(6) Tetrazole violet+thalidomide 76 ＜0.001
9(6) Tetrazole violet+LS-2616 82 ＜0.001
10(6) Tetrazole violet+angiostatin 88 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (WAY-EKB 569, thalidomide, LS-2616, angiostatin) and tetrazole violet, can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, neovascularization inhibitor and tetrazole violet (slow releasing injection)
(Fisher344) is subjects with rat, 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.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 5) of index with inhibition rate of tumor growth.
Table 5
Test group (n) Suffered treatment Tumor control rate (%) The P value
1(6) Contrast -
2(6) Marimastat 44 ＜0.05
3(6) Endostatin 36 ＜0.01
4(6) The blood vessel endothelium chalone 36 ＜0.01
5(6) Imatinib mesylate 38 ＜0.01
6(6) Sugen 5416 44 ＜0.01
7(6) Marimastat+Endostatin 80 ＜0.001
8(6) Marimastat+blood vessel endothelium chalone 72 ＜0.001
9(6) Marimastat+imatinib mesylate 82 ＜0.001
10(6) Marimastat+Sugen 5416 86 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416) and tetrazole violet, can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 8, neovascularization inhibitor and tetrazole violet (slow releasing injection)
(Fisher344) is subjects with rat, 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.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th 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) Tetrazole violet 48 ＜0.05
3(6) BMS 354825 40 ＜0.01
4(6) Avastin 36 ＜0.01
5(6) Cl 1033 32 ＜0.01
6(6) Sorafenib 36 ＜0.01
7(6) Tetrazole violet+BMS 354825 80 ＜0.001
8(6) Tetrazole violet+Avastin 84 ＜0.001
9(6) Tetrazole violet+Cl 1033 78 ＜0.001
10(6) Tetrazole violet+Sorafenib 82 ＜0.001
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used neovascularization inhibitor (BMS 354825, Avastin, Cl 1033, Sorafenib) and tetrazole violet, can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.
The tumor-inhibiting action of test 9, neovascularization inhibitor and tetrazole violet (slow releasing injection)
Measure the tumor-inhibiting action of tetrazole violet (slow releasing injection) by test 7 described methods, the result shows that tetrazole violet can significantly strengthen the tumor killing effect of Marimastat, SU5416, SU6668, Amebacilin, TNP-470, Sorafenib, Sutent, TLK286, ABX-EGF, and potentiation is in 50-60% (P＜0.01).
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used neovascularization inhibitor and/or tetrazole violet were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention be any one neovascularization inhibitor or tetrazole violet or with the combination of any one neovascularization inhibitor and tetrazole violet.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, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg tetrazole violet and 10mg Marimastat, shake up the back contains 10% tetrazole violet and 10% Marimastat 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 220cp-460cp (20 ℃-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.
The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component and percentage by weight thereof are:
(a) combination of the tetrazole violet of the Marimastat of 2-40%, SU5416, SU6668, Amebacilin or TNP-470 and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet;
(b) combination of the tetrazole violet of the gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 3.
With 70mg molecular weight peak value is that 65000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg Amebacilin and 15mg p-iodonitrotetrazolium violet, shakes up final vacuum again in dry removal organic solvent.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% Amebacilin and 15%p-iodonitrotetrazolium violet, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 300cp-400cp (20 ℃-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 4
The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are:
(1) combination of the tetrazole violet of the Marimastat of 2-40%, SU5416, SU6668, Amebacilin or TNP-470 and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
(2) combination of the tetrazole violet of the gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 5.
(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of nitro tetrazole violets and 10 milligrams of Marimastats, shake up the back contains 20% nitro tetrazole violet and 10% Marimastat 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, viscosity is 100cp-200cp (20 ℃-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 6.
The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is:
The combination of (1) 20% Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and 10% tetrazole violet, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
The combination of the tetrazole violet of (2) 20% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 10%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 7.
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 10mg Marimastat and 20mg tetrazole violet, shake up the back contains 10% Marimastat and 20% tetrazole violet 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, viscosity is 80cp-150cp (20 ℃-25 ℃ 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 8.
The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is:
The combination of (1) 10% Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and 20% tetrazole violet, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
The combination of the tetrazole violet of (2) 10% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 20%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 9
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 15mg Marimastat and 15mg tetrazole violet, shake up the back contains 15% Marimastat and 15% with spray drying method for preparation tetrazole violet 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, viscosity is 560cp-640cp (20 ℃-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 10
The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is:
The combination of (1) 15% Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and 15% tetrazole violet, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
The combination of the tetrazole violet of (2) 15% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 15%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 11
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 10mg gefitinib and 10mg tetrazole violet, shake up the back contains 10% gefitinib and 10% tetrazole violet 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 12
The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is:
The combination of (1) 10% Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and 10% tetrazole violet, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
The combination of the tetrazole violet of (2) 10% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 10%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 13
With 60mg molecular weight peak value 35000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Erlotinib and 20mg tetrazole violet, shake up the back contains 20% Erlotinib and 20% tetrazole violet 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 35-50 days at the subcutaneous drug release time of mice.
Embodiment 14
The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is:
The combination of (1) 20% Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and 20% tetrazole violet, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
The combination of the tetrazole violet of (2) 20% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 20%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 15.
With 70mg molecular weight peak value is that 35000 polylactic acid (PLA) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg tetrazole violet and 20mg Amebacilin, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 10% tetrazole violet and 20% Amebacilin, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-260cp (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 16
The method step that is processed into slow releasing injection is identical with embodiment 15, but different is that contained anticancer effective component and percentage by weight thereof are:
The combination of Marimastat, SU5416, SU6668, Amebacilin or the TNP-470 of (1) 10% tetrazole violet, p-iodonitrotetrazolium violet or nitro tetrazole violet and 15%;
The combination of the tetrazole violet of (2) 10% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 20%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 17.
With 70mg molecular weight peak value is that 30000 bis-fatty acid and certain herbaceous plants with big flowers diacid (SA) copolymer (bis-fatty acid: the certain herbaceous plants with big flowers diacid is 20: 80) are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg imatinib mesylate and 15mg nitro tetrazole violet, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% imatinib mesylate and 15% nitro tetrazole violet, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make 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 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 18.
The method step that is processed into slow releasing injection is identical with embodiment 17, but different is that contained anticancer effective component and percentage by weight thereof are:
The combination of Marimastat, SU5416, SU6668, Amebacilin or the TNP-470 of (1) 15% tetrazole violet, p-iodonitrotetrazolium violet or nitro tetrazole violet and 15%;
The combination of the tetrazole violet of (2) 15% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 15%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
Embodiment 19
The method step that is processed into slow releasing agent is identical with embodiment 1-18, but different is used slow-release auxiliary material is one of following or its combination:
A) polylactic acid (PLA), the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) ethylene vinyl acetate copolymer (EVAc);
D) polifeprosan, to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;
E) bis-fatty acid and decanedioic acid copolymer [P (FAD-SA)];
F) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];
G) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];
H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.
Embodiment 20
The method step that is processed into slow releasing injection is identical with embodiment 1-19, 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.
Embodiment 21
The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is that contained anticancer effective component is:
(1) combination of the tetrazole violet of the Marimastat of 5-30%, SU5416, SU6668, Amebacilin or TNP-470 and 5-30%, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
(2) combination of the tetrazole violet of the gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 5-30%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
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 anticarcinogen injection with carrying angiogenesis inhibitor and tetrazole violet is become to be grouped into by following:
(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 neovascularization inhibitor and/or tetrazole violet;
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) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer.
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 suspending agent is 100cp-3000cp (20 ℃-30 ℃ time).
2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that neovascularization inhibitor is selected from one of Marimastat, SU5416, SU6668, Amebacilin, TNP-470, gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF or its combination.
3. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that tetrazole violet and the neovascularization inhibitor percentage by weight in slow releasing agent is 1-9: 1 to 1: 1-9.
4. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection and percentage by weight are:
(1) combination of the tetrazole violet of the Marimastat of 2-40%, SU5416, SU6668, Amebacilin or TNP-470 and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
(2) combination of the tetrazole violet of the gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 2-40%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
5. according to claim 1 and 6 described slow-releasing anticarcinogen injections, it is characterized in that in the slow-release auxiliary material,
A) polylactic acid molecule amount peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
B) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;
C) in the polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40.
6. according to claim 1 and 6 described slow-releasing anticarcinogen injections, it 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;
F) (iodine) glycerol, simethicone, propylene glycol or carbomer;
G) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80;
H) 5-20% mannitol+0.1-0.5% soil temperature 80; Or
I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
7. according to claim 1 and 6 described slow-releasing anticarcinogen injections, it is characterized in that sustained-release micro-spheres in the slow-releasing anticarcinogen injection also is used for the preparation treatment and originates from people and animal brain, the central nervous system, 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, former or the cancer of secondary of colon or rectum, the sustained-release implant of sarcoma or carcinosarcoma is in tumor or tumor week injection or place administration.
8. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that the constituent of sustained-release implant is:
Anticancer effective component is:
(1) combination of the tetrazole violet of the Marimastat of 5-30%, SU5416, SU6668, Amebacilin or TNP-470 and 5-30%, p-iodonitrotetrazolium violet or nitro tetrazole violet; Or
(2) combination of the tetrazole violet of the gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 5-30%, p-iodonitrotetrazolium violet or nitro tetrazole violet.
9. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that slow-release auxiliary material is selected from:
A) polylactic acid;
B) copolymer of polyglycolic acid and hydroxyacetic acid;
C) polifeprosan;
D) ethylene vinyl acetate copolymer;
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer; Or
G) poly-(fumaric acid-decanedioic acid) copolymer.
10. the anti-cancer sustained-released implantation agent according to claim 7 is characterized in that suspending agent is selected from:
A) 0.0-3.0% carboxymethyl cellulose (sodium);
B) 0.0-15% mannitol;
C) 0.0-15% sorbitol;
D) 0.0-1.5% surfactant; And/or
E) 0.0-0.5% polysorbas20.
CN200610200992A 2006-10-16 2006-10-16 Anticancer slow release agent loading both newborn blood vessel and tetrazole violet Expired - Fee Related CN100594886C (en)

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