CN101336889A - Anticancer sustained-released formulation loaded with blood vessel inhibitor and synergist thereof - Google Patents
Anticancer sustained-released formulation loaded with blood vessel inhibitor and synergist thereof Download PDFInfo
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Abstract
The invention relates to an anticancer slow-release agent (preferably slow-release injection) loading angiogenesis inhibitor and synergist thereof at the same time. The agent is composed of slow-release microspheres and a solvent, wherein the slow-release microsphere contains an anticancer-effective component and a slow-release adjuvant and the solvent is a special solvent containing suspending agent. The viscosity of the suspending agent is in the range from 100 cp to 3000 cp and the suspending agent is preferably sodium carboxymethylcellulose. The anticancer-effective component is the composition of an angiogenesis inhibitor and a synergist thereof selected from an antimitotic agent and an alkylating agent. The slow-release adjuvant is selected from poly-D,L-lactic acid and glycolic acid copolymer thereof, polyethylene glycol and poly(lactic acid) copolymer, carboxyl-terminated poly(lactic acid) copolymer, EVAc, and fatty acid-sebacic acid copolymer. The slow-release microsphere is also formulated as the slow-release implant. After the intratumoral or peritumoral injection or implantation, the slow-release agent can release the drug locally for about 40 days. Accordingly, the slow-release agent can be used alone or in combination with non-operative treatment such as chemotherapy and/or radiotherapy, and can selectively increase the local blood drug concentration in the tumor and significantly enhance the curative effect of the non-operative treatment such as chemotherapy.
Description
(1) technical field
The present invention relates to a kind of compound anti-cancer medicinal slow release agent that contains vasoinhibitor, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains vasoinhibitor and/or its synergist, be mainly slow releasing injection and sustained-release implant.
(2) background technology
Treatment for cancer still mainly comprises methods such as operation, radiotherapy and chemotherapy at present.Therefore wherein operative treatment can not be removed 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 (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).
The local placement of chemotherapeutics 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) (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).
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 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)).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 its infiltrative growth "; referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf (2004) (Liang Y; etal., Int J Cancer.2004; 111 (4): 484-93).
Therefore, develop a kind of effective cancer therapy drug or Therapeutic Method and just become a current important topic.The present invention provides a kind of new anticancer pharmaceutical composition just at the deficiencies in the prior art, can suppress growth of tumour cell effectively, and can strengthen the treatment tumor effect of other medicines, reduces recurrence.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of anticancer medicine slow-release preparation containing that contains vasoinhibitor is provided, particularly, is a kind of anticancer medicine slow-release preparation containing that contains vasoinhibitor and/or its synergist, is mainly slow releasing injection and sustained-release implant.
Vasoinhibitor is mainly used in entity tumors such as treatment gastric cancer, breast carcinoma abroad as a kind of new cancer therapy drug.Yet tangible general toxicity has greatly limited the application of this medicine in application process.
The present invention finds that medicine that has and vasoinhibitor share its antitumaous effect is strengthened mutually, below the vasoinhibitor antitumaous effect will be increased mutually medicine be referred to as the vasoinhibitor synergist; In addition, the compositions of vasoinhibitor or vasoinhibitor and its synergist is made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduces the drug level of medicine in blood circulation, is reduced the toxicity of medicine to normal structure, can also greatly make things convenient for the medicine injection, reduce operation technique complication, reduce patient's expense.The above unexpected main contents of the present invention of finding to constitute.
The vasoinhibitor synergist is the cancer therapy drug that is selected from steroids anti-cancer drugs and/or platinum-like compounds.The cancer therapy drug decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.Vasoinhibitor can suppress or destroy the blood vessel of tumor effectively and can suppress the formation of 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.
Anti-cancer medicine sustained-release 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:
Sustained-release microparticle, the one-tenth following by percentage by weight is grouped into:
Biological effective components 0.5-60%
Slow-release auxiliary material 41-99.9%
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 vasoinhibitor and/or its synergist, and the vasoinhibitor synergist is selected from anti-mitosis medicine and/or alkylating agent;
Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), 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), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), poly-to dioxy cyclohexanone (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue 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)-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; lapatinib ditosylate; 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] benzamidemethanesulfonate; 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-3 carboxylicAcid (2-Diethylaminoethyl) amide, Sutent; SU11248, SUO11248); 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 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 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 (pyrrolyllactoneindolinones, 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-indolyl methylene) 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, with gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; the blood vessel endothelium chalone; imatinib mesylate; Sugen 5416; BMS 354825; Avastin; Cl 1033; Sorafenib; Sutent; TLK286; ABX-EGF is for most preferably.
Above-mentioned vasoinhibitor shared ratio in compositions is decided because of concrete condition, can be 0.1%-50%, is good with 1%-30%, and 5%-20% is best.
Anti-mitosis medicine will make tumor cell stop at the different links of cell cycle.Anti-mitosis medicine mainly is selected from a kind of or its combination in cytochalasin, mitoclomine, mitoflaxone, mitoguazone, mitonafide, mitopodozide, mitoquidone, mitosper, mitotane, mitotenamine, mitozolomide, Flavone acetic acid, colchisal, colchicine, Demecolcine, B cytochalasin B, naphthols, alpha-Naphthol, betanaphthol, alpha-phosphate naphthols, acodazole, procodazole, arsenicum, giracodazole and the nocodazole.Serve as preferred wherein with colchicine, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole and nocodazole.
The percentage by weight of above-mentioned anti-mitosis medicine in slow releasing agent can be 0.01%-80%, is good with 1%-50%, and 5%-30% is best.
Above-mentioned alkylating agent is selected from a kind of or its combination in ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine, the Ah bundle's TEPA.
Above alkylating agent 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.
The percentage by weight of above-mentioned alkylating agent in slow releasing agent is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.
Anticancer effective component is mainly vasoinhibitor and/or its synergist.When the cancer therapy drug in the medicament slow-release microsphere only is vasoinhibitor or vasoinhibitor synergist, slow-releasing anticarcinogen injection is mainly used in the vasoinhibitor of other approach application of increase or the action effect of vasoinhibitor synergist, or is used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was vasoinhibitor or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:
(1) contain the slow releasing injection local injection of vasoinhibitor, other approach of vasoinhibitor synergist are used;
(2) local injection contains the slow releasing injection of vasoinhibitor synergist, and other approach are used vasoinhibitor;
(3) local injection contains the slow releasing injection and the slow releasing injection that contains the vasoinhibitor synergist of vasoinhibitor; Or
(4) local injection contains the slow releasing injection of vasoinhibitor and synergist.
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.
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 vasoinhibitor and vasoinhibitor synergist is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.
Anticancer effective component percentage by weight in the anticancer slow-release microsphere of the present invention is preferably as follows:
(a) 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;
(b) colchicine of 2-40%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole;
(c) ifosfamide of 2-40%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA;
(d) gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the colchicine of TLK286 or ABX-EGF and 2-40%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole;
(e) gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the ifosfamide of TLK286 or ABX-EGF and 2-40%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA; Or
(f) combination of the ifosfamide of the colchicine of 2-40%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole and 2-40%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
Slow-release auxiliary material is selected from poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA)], poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.
Except that above-mentioned adjuvant, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.
For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.
In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.
Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.
The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:
A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or
B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or.
C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.
The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.
Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.
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 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).So viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.
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, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.
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 and the percentage by weight of anti-cancer sustained-released implantation agent of the present invention are preferably as follows:
(a) gefitinib of 2-30%, 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;
(b) colchicine of 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole;
(c) ifosfamide of 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA;
(d) gefitinib of 2-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the colchicine of TLK286 or ABX-EGF and 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole;
(e) gefitinib of 2-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the ifosfamide of TLK286 or ABX-EGF and 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA; Or
(f) combination of the ifosfamide of the colchicine of 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole and 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
Sustained-release micro-spheres also can be used for preparing sustained-release implant, and used slow-release auxiliary material can be any or multiple material in the above-mentioned pharmaceutic adjuvant, is main separation with the high molecular weight water soluble polymer in various high molecular polymers.
Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release implant of the present invention:
(1) PLA of 55-90%;
(2) PLGA of 50-90%;
(3) polifeprosan of 50-85%;
(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;
(5) EVAc of 55-90%;
(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or albumin glue; Or
(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, is mainly slow releasing injection or sustained-release implant.Prepared tumor comprises various entity tumors.Comprise former of originating from brain and central nervous system or shift; And originate from the outer various entity tumors of cranium, as kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, former or cancer or sarcoma or the carcinosarcoma that shifts of rectum are wherein with the cerebral tumor, renal carcinoma, tumor of head and neck, thyroid carcinoma, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, cervical cancer, ovarian cancer, carcinoma of prostate, bladder cancer, colon, former of rectum or metastatic carcinoma are preferred.
Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.Can be in when operation or perioperatively tumor, tumor week injection or place; Can with radiation and systemic chemotherapy simultaneously or front and back separate applications, but sustained-release implant with in the tumor, tumor week inject or be placed as preferably.When the cancer therapy drug in the medicament slow-release microsphere only is vasoinhibitor or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.
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 technology of the present invention is further described:
The local drug concentration that test 1, different modes are used after the vasoinhibitor (gefitinib) 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 gefitinib.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of gefitinib 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 after the vasoinhibitor (Erlotinib) 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 Erlotinib.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 Erlotinib after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.
Test 3, contain tumor-inhibiting action in the body of vasoinhibitor and vasoinhibitor synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and vasoinhibitor is through intratumor injection, and the vasoinhibitor synergist is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.
Table 1
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 60±10 | |
| 2(6) | Vasoinhibitor | 28±3.0 | ＜0.05 |
| 3(6) | Procodazole | 46±5.0 | ＜0.01 |
| 4(6) | Arsenicum | 48±4.0 | ＜0.01 |
| 5(6) | Acodazole | 54±6.6 | ＜0.01 |
| 6(6) | B cytochalasin B | 62±3.0 | ＜0.01 |
| 7(6) | Vasoinhibitor+procodazole | 22±2.4 | ＜0.001 |
| 8(6) | Vasoinhibitor+arsenicum | 20±3.0 | ＜0.001 |
| 9(6) | Vasoinhibitor+acodazole | 12±1.4 | ＜0.001 |
| 10(6) | Vasoinhibitor+B cytochalasin B | 14±2.0 | ＜0.001 |
Above result shows, growth all has the obvious suppression effect to kinds of tumors when this concentration is used separately for vasoinhibitor (gefitinib) and used vasoinhibitor synergist-anti-mitosis medicine (procodazole, arsenicum, acodazole, B cytochalasin B), and is obvious with administering effect in the tumor.When use in conjunction, can show significant potentiation.
The tumor-inhibiting action of test 4, vasoinhibitor and vasoinhibitor synergist (slow releasing injection)
Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Vasoinhibitor and vasoinhibitor synergist 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 | Vasoinhibitor | Giracodazole | Arsenicum | Nocodazole | Vasoinhibitor+giracodazole | Vasoinhibitor+arsenicum | Vasoinhibitor+nocodazole |
| CNS | 38％ | 52％ | 62％ | 62％ | 90％ | 88％ | 88％ |
| C6 | 40％ | 62％ | 64％ | 54％ | 92％ | 90％ | 94％ |
| SA | 24％ | 50％ | 56％ | 62％ | 86％ | 92％ | 90％ |
| BC | 40％ | 52％ | 56％ | 64％ | 92％ | 80％ | 86％ |
| BA | 28％ | 60％ | 62％ | 62％ | 94％ | 96％ | 78％ |
| LH | 30％ | 54％ | 62％ | 58％ | 90％ | 86％ | 84％ |
| PAT | 32％ | 48％ | 60％ | 50％ | 86％ | 82％ | 88％ |
Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used vasoinhibitor (Erlotinib) and vasoinhibitor synergist-anti-mitosis medicine (arsenicum, giracodazole, nocodazole), and is obvious with administering effect in the tumor.When use in conjunction, can show significant potentiation.
The tumor-inhibiting action of test 5, vasoinhibitor and vasoinhibitor synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and vasoinhibitor and vasoinhibitor synergist sustained-release implant are all placed in tumor.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.
Table 3
| Test group (n) | Suffered treatment | Gross tumor volume (cm 3) | The P value |
| 1(6) | Contrast | 70±10 | |
| 2(6) | Ifosfamide | 48±5.0 | ＜0.05 |
| 3(6) | Lapatinib | 46±4.3 | ＜0.01 |
| 4(6) | Ifosfamide+Lapatinib | 24±2.4 | ＜0.001 |
| 5(6) | Urethimine | 46±3.0 | ＜0.01 |
| 6(6) | Urethimine+Lapatinib | 24±2.0 | ＜0.001 |
| 7(6) | Ah bundle's TEPA | 38±3.8 | ＜0.01 |
| 8(6) | Ah bundle's TEPA+Lapatinib | 22±2.6 | ＜0.001 |
| 9(6) | 4H-peroxide cyclophosphamide | 46±4.8 | ＜0.01 |
| 10(6) | 4H-peroxide cyclophosphamide+Lapatinib | 14±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 vasoinhibitor-Lapatinib and vasoinhibitor thing synergist-alkylating agent (ifosfamide, 4H-peroxide cyclophosphamide, urethimine, Ah bundle's TEPA), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 6, vasoinhibitor and vasoinhibitor synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (vasoinhibitor or vasoinhibitor synergist) and therapeutic alliance group (vasoinhibitor and vasoinhibitor synergist).Vasoinhibitor is through intratumor injection, and the vasoinhibitor synergist is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th 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) | Votaranib | 52 | ＜0.05 |
| 3(6) | 4H-peroxide cyclophosphamide | 20 | ＜0.01 |
| 4(6) | Defosfamide | 16 | ＜0.01 |
| 5(6) | Mafosfamide | 14 | ＜0.01 |
| 6(6) | Perfosfamide | 16 | ＜0.01 |
| 7(6) | Votaranib+4H-peroxide cyclophosphamide | 78 | ＜0.001 |
| 8(6) | Votaranib+defosfamide | 82 | ＜0.001 |
| 9(6) | Votaranib+Mafosfamide | 82 | ＜0.001 |
| 10(6) | Votaranib+perfosfamide | 90 | ＜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 vasoinhibitor (votaranib) and vasoinhibitor synergist-alkylating agent (4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 7, vasoinhibitor and vasoinhibitor synergist (slow releasing injection)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Vasoinhibitor is through lumbar injection, and the vasoinhibitor synergist is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th 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) | Vasoinhibitor | 28 | ＜0.05 |
| 3(6) | Hexamethylmelamine | 52 | ＜0.01 |
| 4(6) | Cantharidin | 48 | ＜0.01 |
| 5(6) | Norcantharidin | 66 | ＜0.01 |
| 6(6) | Mannomustine | 68 | ＜0.01 |
| 7(6) | Vasoinhibitor+hexamethylmelamine | 82 | ＜0.001 |
| 8(6) | Vasoinhibitor+cantharidin | 78 | ＜0.01 |
| 9(6) | Vasoinhibitor+norcantharidin | 80 | ＜0.001 |
| 10(6) | Vasoinhibitor+mannomustine | 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 vasoinhibitor (WAY-EKB 569) and vasoinhibitor synergist-alkylating agent (hexamethylmelamine, cantharidin, norcantharidin, mannomustine), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 8, vasoinhibitor and vasoinhibitor synergist (sustained-release implant)
With the rat is subjects, with 2 * 10
5Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is all placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th 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) | Vasoinhibitor | 68 | ＜0.05 |
| 3(6) | Treosulfan | 58 | ＜0.05 |
| 4(6) | Ritrosulfan | 56 | ＜0.05 |
| 5(6) | An improsulfan | 54 | ＜0.05 |
| 6(6) | Etoglucid | 52 | ＜0.01 |
| 7(6) | Vasoinhibitor+treosulfan | 86 | ＜0.01 |
| 8(6) | Vasoinhibitor+ritrosulfan | 88 | ＜0.05 |
| 9(6) | Vasoinhibitor+improsulfan | 78 | ＜0.01 |
| 10(6) | Vasoinhibitor+etoglucid | 90 | ＜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 vasoinhibitor (NSC 609974) and vasoinhibitor synergist-alkylating agent (treosulfan, ritrosulfan, an improsulfan, etoglucid), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 9, vasoinhibitor and vasoinhibitor synergist (sustained-release implant)
By the tumor-inhibiting action of test 8 described methods mensuration vasoinhibitors and vasoinhibitor synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 7.
Table 7
| Test group (n) | Suffered treatment | Tumor control rate (%) | The P value |
| 1(6) | Contrast | - | |
| 2(6) | Vasoinhibitor | 42 | ＜0.05 |
| 3(6) | Triethylenemelaine | 40 | ＜0.01 |
| 4(6) | Epoxypiperazine | 48 | ＜0.01 |
| 5(6) | Urethimine | 44 | ＜0.01 |
| 6(6) | Ah bundle's TEPA | 42 | ＜0.01 |
| 7(6) | Vasoinhibitor+triethylenemelaine | 78 | ＜0.001 |
| 8(6) | Vasoinhibitor+epoxypiperazine | 80 | ＜0.001 |
| 9(6) | Vasoinhibitor+urethimine | 82 | ＜0.001 |
| 10(6) | Vasoinhibitor+Ah bundle's TEPA | 78 | ＜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 vasoinhibitor (imatinib mesylate) and vasoinhibitor synergist-alkylating agent (triethylenemelaine, epoxypiperazine, urethimine, Ah bundle's TEPA), can show significant potentiation when use in conjunction.
The tumor-inhibiting action of test 10, vasoinhibitor and vasoinhibitor synergist (slow releasing injection)
Measure the tumor-inhibiting action of vasoinhibitor synergist (slow releasing injection) by test 7 described methods, the result shows and is selected from gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the vasoinhibitor of TLK286 or ABX-EGF can significantly strengthen ifosfamide, 4H-peroxide cyclophosphamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine, the tumor killing effect of Ah bundle's TEPA, potentiation is in 38-68% (P＜0.01).
The tumor-inhibiting action of test 11, vasoinhibitor synergist (slow releasing injection)
Measure the tumor-inhibiting action of vasoinhibitor synergist (slow releasing injection) by test 7 described methods, the result shows and is selected from the tumor killing effect that colchicine, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole can significantly strengthen ifosfamide, 4H-peroxide cyclophosphamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine, Ah bundle's TEPA that potentiation is in 58-80% (P＜0.05).
Release ratio in the body of the gefitinib sustained-release implantation agent that test 12, different molecular weight polylactic acid are made
With the rat is subjects, grouping (3/group) and the equivalent gefitinib sustained-release implantation agent that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Then respectively at 1,3,7,14,21,28
With the surplus of 35 days survey medicines in implant, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90), 28 (94) and 35 (98%).Discharge in the body of the gefitinib sustained-release implantation agent that comparison different molecular weight polylactic acid is made and find, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, the bacteriostatic rate increases with the polylactic acid molecule amount and improves, and is followed successively by 68% (MW:5000), 66% (MW:15000), 54% (MW:25000), 50% (MW:40000) and 48 (MW:60000).
It is 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 the ABX-EGF slow releasing agent that adjuvant is made that same result also sees with polylactic acid.
That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.
Different drug packages is to want characteristic different with different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin, one of albumin glue or its combination; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.
In a word, growth all had the obvious suppression effect to kinds of tumor cells when used vasoinhibitor and various vasoinhibitor synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of vasoinhibitor and any one vasoinhibitor synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.
Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.
(4) specific embodiment
Embodiment 1.
With 90,90 and 80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, add 10m Sutent, 10mg colchicine, 10mg Sutent and 10mg colchicine respectively, shake up the back contains 10% Sutent, 10% colchicine and 10% Sutent and 10% colchicine 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.The viscosity of injection is 300cp-600cp (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) 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;
(b) colchicine of 2-40%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole; Or
(c) gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the colchicine of TLK286 or ABX-EGF and 2-40%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole.
Used adjuvant is: poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer; The viscosity of slow releasing injection is 10cp-650cp (20 ℃-30 ℃ time).
Embodiment 3.
With 70mg molecular weight peak value 65000 polylactic acid (PLGA, 75: 25) put into (first), (second) and (the third) three container respectively, add 100 milliliters of dichloromethane then in each, behind the dissolving mixing, in three containers, add 30mg Erlotinib, 30mg ifosfamide, 15mg Erlotinib and 15mg ifosfamide respectively, shake up the back contains 30% Erlotinib, 30% ifosfamide, 15% Erlotinib and 15% ifosfamide with spray drying method for preparation injectable microsphere again.Dried microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose, makes corresponding suspension type slow releasing injection.The viscosity of injection is 300cp-600cp (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) ifosfamide of 2-40%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or
(2) gefitinib of 2-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the ifosfamide of TLK286 or ABX-EGF and 2-40%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.
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 4H-peroxide cyclophosphamide and 10 milligrams of acodazoles, shake up the back contains 20%4H-peroxide cyclophosphamide and 10% acodazole with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 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 colchicine, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or the nocodazole of the ifosfamide of 10-20%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA and 10-20%.
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 20mg Lapatinib and 10mg etoglucid, shake up the back contains 20% Lapatinib and 10% etoglucid with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 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 gefitinib of 10-20%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the ifosfamide of TLK286 or ABX-EGF and 10-20%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.
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 votaranib and 15mg nocodazole, shake up the back contains 15% votaranib and 15% with spray drying method for preparation nocodazole injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.
Embodiment 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 cytochalasin, acodazole, procodazole, arsenicum, giracodazole or the nocodazole of 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%.
Embodiment 11
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 meturedepa and 20mg WAY-EKB 569, shake up the back contains 10% meturedepa and 20% WAY-EKB 569 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 ifosfamide of 10-20%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the gefitinib of urethimine or Ah bundle's TEPA and 10-20%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF.
Embodiment 13
With 70mg molecular weight peak value 45000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg NSC 609974 and 20mg4H-peroxide cyclophosphamide, shake up the back contains 10% NSC 609974 and 20%4H-peroxide cyclophosphamide with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 15-25 days, is about 35-50 days at the subcutaneous drug release time of mice.
Embodiment 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 and percentage by weight are:
(a) gefitinib of 2-30%, 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;
(b) colchicine of 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole;
(c) ifosfamide of 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA;
(d) gefitinib of 2-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the colchicine of TLK286 or ABX-EGF and 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, the combination of giracodazole or nocodazole;
(e) gefitinib of 2-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the ifosfamide of TLK286 or ABX-EGF and 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA; Or
(f) combination of the ifosfamide of the colchicine of 2-30%, B cytochalasin B, alpha-Naphthol, betanaphthol, acodazole, procodazole, arsenicum, giracodazole or nocodazole and 2-30%, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, etoglucid, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.
Embodiment 15
The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:
A) the molecular weight peak value is the polylactic acid (PLA) of 10000-30000,30000-60000,60000-100000 or 100000-150000;
B) the molecular weight peak value is the polyglycolic acid of 10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), and wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;
C) ethylene vinyl acetate copolymer (EVAc);
D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);
E) bis-fatty acid and decanedioic acid copolymer;
F) poly-(erucic acid dimer-decanedioic acid) copolymer;
G) poly-(fumaric acid-decanedioic acid) copolymer;
H) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera;
I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.
Embodiment 16
The method step that is processed into slow releasing injection is identical with embodiment 1-10, 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;
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.
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 (1)
1. the anticancer sustained-release agent of carried with blood-vessel inhibiting and synergist thereof is slow releasing injection, is grouped into by following one-tenth:
(A) sustained-release micro-spheres comprises:
Anticancer effective component
Slow-release auxiliary material
With
(B) solvent is for common solvent or contain the special solvent of suspending agent;
Wherein,
Anticancer effective component is vasoinhibitor and the vasoinhibitor synergist that is selected from alkylating agent;
The component of described slow releasing injection is one of following combination:
(1) anticancer effective component is 15% Erlotinib and 15% ifosfamide, and slow-release auxiliary material is 65000 polylactic acid for the molecular weight peak value, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose;
(2) anticancer effective component is 20% Lapatinib and 10% etoglucid, and slow-release auxiliary material is to carboxy phenyl propane: decanedioic acid is 20: 80 a polifeprosan, and solvent is the normal saline of 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80;
Below all be weight percentage.
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Open date: 20090107 |