CN101548948A - Anti-cancer medicine sustained-release agent containing 5-FU potentiating agent - Google Patents

Abstract

An anti-cancer medicine sustained-release agent containing 5-FU potentiating is sustained-release injection, which is made up of sustained-release micro-balloons and solvent. The sustained-release micro-balloons includes anticancer effective ingredient and sustained-release adjuvant, the solvent is common solvent or special solvent containing suspending agent. The anticancer effective ingredient contains 5-FU or the combination of 5-FU with the potentiating agent of 5-FU chosen from hormones anti-cancer drugs and/or blood vessel inhibitor. The sustained-release adjuvant is chosen from polylactic acid, polyglycolic acid, glycolic acid co-polymer, and one or the combination of ethylene acetic acid ethyenyl ester co-polymer, polifeprosan, FAD and sebacic acid co-polymer. The suspending agent is chosen from sodium carboxymethylcellulose, etc. The sustained-release micro balloons can also be produced into sustained-release implantation agent which is implanted into knub or injected around tumour or deposited around tumour. The sustained-release agent can be used alone or used with chemotherapy medicament and non-operative treatment such as radiotherapy.

Description

The anticancer medicine slow-release preparation containing that contains the 5-FU synergist

(1) technical field

The present invention relates to a kind of anticancer medicine slow-release preparation containing of the 5-FU of containing synergist, belong to technical field of pharmaceuticals.Particularly, the invention provides the anticancer medicine slow-release preparation containing of a kind of 5-FU of containing synergist or 5-FU and its synergist combination, 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 not only 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.1998Oct 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, provide a kind of 5-FU of containing anticancer medicine slow-release preparation containing, particularly, be the synergic anticancer medicine slow-release preparation containing of a kind of 5-FU of containing and/or 5-FU, be mainly slow releasing injection and sustained-release implant.

5-FU is mainly used in the treatment hematological system tumor abroad as a kind of new cancer therapy drug, as, Lymphocytic leukemia etc.In application process, its tangible general toxicity has greatly limited the application of this medicine.

The present invention finds that many entity tumors have higher sensitivity (seeing embodiment) to this medical instrument; Moreover, the present invention finds that also medicine that has and 5-FU share its antitumaous effect is strengthened mutually, below the 5-FU antitumaous effect will be increased mutually medicine be referred to as the 5-FU synergist; In addition, the combination of 5-FU or 5-FU 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.

A kind of form of 5-FU slow releasing agent of the present invention is a slow releasing injection, is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.5-60%

Slow-release auxiliary material 40-99%

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 the combination of 5-FU synergist or 5-FU and its synergist, and the 5-FU synergist is selected from steroids anti-cancer drugs and/or vasoinhibitor; Slow-release auxiliary material is selected from copolymer (PLGA), ethylene vinyl acetate copolymer (EVAc), polifeprosan, the FAD of polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid: one of certain herbaceous plants with big flowers diacid (SA) copolymer, xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera 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.

5-FU in the anticancer effective component can be its various salt, serves as preferred with its hydrochlorate wherein.

Steroids anti-cancer drugs is mainly steroid hormone and hormone antagonist; comprise; but be not limited to; Anastrozole (anastrozole); idoxifene (idoxifene); Miproxifene (Miproxifene); tamoxifen (tamoxifen; tamoxifen); 4-monohydroxy tamoxifen (trans-4-monohydroxytamoxifen; OH-TAM); former times sweet smell (keoxifene not; LY156758); ICI-M 164384 (ICI164384; the 7-alpha-alkyl amide analogue of estradiol); 7-α-[9-(4; 4; 5; 5; 5-five fluorine amyl group sulfinyls) nonyl] female steroid-1; 3; 5 (10)-triolefins-3; 17 β diphenol (anticancer steroid alkene phenol; fulvestrant; 7 alpha-[9-(4; 4; 5; 5; 5-pentafluoropentylsulfinyl) nonyl] estra-1; 3; 5 (10)-triene-3; 17 beta-diol; ICI182780); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); γ-linoleic acid (gamma-linolenicacid); 2-methoxyestradiol (2-methoxyestradiol); moxestrol (moxestrol); 4-trans-Hydroxytamoxifen (4-hydroxytamoxifen); benzene hexachloride (benzene hexachloride; Gamma Hexaochlorocyclohexane; beta-hexachlorocyclohexane; beta-HCH); raloxifene (raloxifene); diethylstilbestrol (diethylstilbestrol); estradiol (estradiol); 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-.beta.-resorcylic acid lactone (zearalenone); estrone (estrone); 17 alpha-estradiols (17alpha-estradiol); estradiol (estriol); 2-hydroxyestrone (2-hydroxyestrone); 5; 7; 4 trihydroxy-isoflavones (genistein); Progesterone; mepitiostane (Mepitiostane); androgen; (.+-.)-Pyridoglutethimide; rubitecan; Acapodene; Drogenil (Flutamide; flutamide); overstate single silicon indigo plant; bicalutamide (Casodex); aminoglutethimide (Aminoglutethimide, aminoglutethimidium); betamethasone benzoate; calusterone; triptorelin; goserelin; leuprorelin; megestrol; medroxyprogesterone; datiscoside; epitiostanol; the female sweet smell of bromine vinegar ethane; hisphen; clomifene; toremifene; letrozole; Anastrozole and exemestane or testolactone.

Above steroids anti-cancer drugs can singly select or multiselect, with triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or bicalutamide serve as preferred.

Above steroids anti-cancer drugs can be used for the tumor that various hormones rely on, but different pharmaceutical has relative tumor-selective, as, tamoxifen, (.+-.)-Pyridoglutethimide, rubitecan, Acapodene etc. mainly rely on estrogenic tumor in order to treatment, as breast carcinoma and carcinoma of endometrium; Drogenil, overstate that single silicon indigo plant and bicalutamide mainly rely on androgenic tumor in order to treatment, as carcinoma of prostate; Triptorelin, goserelin, leuprorelin, tamoxifen, raloxifene, aminoglutethimide, clomifene, toremifene, letrozole, Anastrozole and exemestane are then in order to treatment breast carcinoma, carcinoma of prostate and carcinoma of endometrium.

The content of steroids anti-cancer drugs in compositions is 0.01%-60%, is good with 1%-40%, is best with 2%-30%, more than all be weight percentage.

Vasoinhibitor can suppress or destroy the blood vessel of tumor effectively and can suppress the new vessels formation 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.

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; imatinib mesylate (Imatinib mesylate; have another name called imatinib mesylate, Glivec); 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate (4-((Methyl-1-piperazinyl) methyl)-N[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamidemethanesulfonate, STI 571; CGP-57148B, STI-571A, CGP 57148); 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide (5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2; 4-dimethyl-1H-pyrrole-3 carboxylic Acid (2-Diethylaminoethyl) amide, Sutent, SU11248; SU011248); 3, and 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone (3,3-Dichloro-5-(4-methylpiperidinosulfonyl)-2-indolinone; DCM); 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1,3-dihydro-indole-2-dihydroindole ketone (3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene] 5-methoxy-1,3-dihydro-indol-2-one; SU9516, SU 95 18); 1H-pyrroles-3-propanoic acid, 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-4-methyl (SU6663, SU-5402,1H-Pyrrole-3-propanoicacid; 2-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) methyl]-4-methyl); 2H-indole-2-dihydroindole ketone (2H-Indol-2-one); Sugen 5416 (3-((4,5-dimethyl-1H-pyrroles-2-yl) methylene)-1; (3-((4 for 3-dihydro-[CAS]; 5-dimethyl-1H-pyrrol-2-yl) methylene)-1,3-dihydro-[CAS], SU5614; semaxanib; SU-011271, SU-011606, SU-11612)); pyrroles's lactone dihydroindole ketone (pyrrolyllactoneindolinones; SU6577); 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-pyrrole3-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)-(5-chloro-2-oxo1; 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-5-methoxyl group-2-dihydroindole ketone (3-1 (2,6-dimethylimidazo[2; 1-bJ-thiazol-5-yl] methylenel-5-methoxy-2-indolinone; DMMI, SU9518]; imidazoles [2,1-b] methylene thiazole-2-dihydroindole ketone (Imidazo[2; 1-b] thiazolylmethylene-2-indolinones; ITI); methylene indole-2-dihydroindole ketone (indolylmethylene-2-indolinones, IMI); (2-chloro-indole) methylene-2-dihydroindole ketone (2-chloroindolyl) methylene-2-indolinone, CMI); arlydene 2-dihydroindole ketone (arylidene 2-indolinone; AI); 1; 3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone (1,3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indol-2-one); cpd 1); 3-(4-dimethylamino benzal)-2-dihydroindole ketone (3-(4-dimethylamino-benzylidenyl)-2-indolinone, DMBI); 5-chloro-3-methylene pyridine-2-dihydroindole ketone (5-chloro-3-pyridylmethylene-2-indolinone, cpMI); 3; 3-lutidines-1-phenyl-2-dihydroindole ketone (3; 3-dipyridylmethyl-1-phenyl-2-indolinone, DPMPI) and E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone (E-3-(2-chloro-3-indolyl methylene) 1; 3-dihydroindol2-indolinone, CIDI); BMS 354825 (dasatinib); Avastin (avastin); Cl 1033 (canertinib); Sorafenib (sorafenib); Sutent (sunitinib; sutent; SU11248); TLK286 (Telcyta); ABX-EGF (panitumumab).

Other vasoinhibitor is referring to relevant international monopoly, application number: WO 97/22596, and WO 97/30035, WO97/32856 and WO 98/13354.

Above vasoinhibitor also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.

Preferred one of the following or combination of above-mentioned vasoinhibitor:

Gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; 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.

Above-mentioned vasoinhibitor can singly select or multiselect, with gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF for most preferably.

Anticancer effective component is the combination of 5-FU synergist or 5-FU and its synergist.When the cancer therapy drug in the medicament slow-release microsphere only was the 5-FU synergist, slow-releasing anticarcinogen injection was mainly used in the action effect that increases the 5-FU that other approach use or is used for potentiation to radiotherapy or other therapies.When being used to increase the action effect of the 5-FU that other approach use, 5-FU can be through tremulous pulse, vein or local injection, placement administration.

The percentage by weight of cancer therapy drug in sustained-release micro-spheres is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.During 5-FU and its synergist (steroids anti-cancer drugs and/or vasoinhibitor) use in conjunction, the weight ratio of 5-FU and steroids anti-cancer drugs and/or vasoinhibitor is that the weight ratio of 5-FU and 5-FU synergist is 1-9: 1 to 1: 1-9, with 1-2: 1 serves as preferred.

Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows, and all is weight percentage:

(a) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or bicalutamide; Or

(b) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or

(c) triptorelin of the 5-FU of 2-40% and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide; Or

(d) combination of the gefitinib of the 5-FU of 2-40% and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or

(e) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the gefitinib of exemestane or bicalutamide and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF; Or

(f) triptorelin of the 5-FU of 2-40% and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the gefitinib of exemestane or bicalutamide and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF.

Suspending agent be used for preparation and/or effectively suspend, stable and/or protect various medicines or sustained-release micro-spheres (or microcapsule), thereby make prepared injection injectivity good, be not easy obstruction, good stability, be difficult for layering, the viscosity height.

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), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).

Common solvent can be, but is not limited to, the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt, and pharmacopeia has respective specified; The special solvent of indication of the present invention is the common solvent that contains suspending agent, suspending agent can be, but be not limited to 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 is 0.1-30% volume weight percentage ratio in the special solvent, is preferably as follows:

A) 0.5-5% sodium carboxymethyl cellulose; Or

B) 0.5-5% sodium carboxymethyl cellulose and 0.1-0.5% Tween 80; Or

C) 5-20% mannitol; Or

D) 5-20% mannitol and 0.1-0.5% Tween 80; Or

E) 0.5-5% sodium carboxymethyl cellulose, 5-20% sorbitol and 0.1-0.5% Tween 80.

The above-mentioned volume weight percentage ratio that is contains the weight of suspending agent in the common solvent of unit volume, as g/ml, and kg/l.Down together.

One of the copolymer (PLGA) of the preferred polylactic acid of slow-release auxiliary material (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc), FAD:SA copolymer and polifeprosan or its combination.

When selecting the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content, percentage by weight are respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, 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, 5000-100, 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, 5000-100,000, 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.

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 Rising-moon A)], poly-(erucic acid dimer one decanedioic acid) [P (EAD Rising-moon A)] and poly-(fumaric acid-decanedioic acid) [P (FA Rising-moon A)] 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.

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.

The preparation of injection comprises that the preparation of preparation, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend, and make injection at last in solvent.

Wherein, sustained-release micro-spheres or drug microparticles can prepare with some kinds of methods: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are in conjunction with freezing (drying) comminuting method, liposome bag medicine method and emulsion process etc.Serve as preferred wherein with dissolution method (being the solvent volatility process), freezing (drying) comminuting method, seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection.The particle diameter of suspended drug or sustained-release micro-spheres (or microcapsule) decide because of specifically needing, and can be, but be not limited to, 1-300um, but be that preferably 30-150um most preferably with 20-200um.Medicine or sustained-release micro-spheres can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller.Slow-release auxiliary material is above-mentioned bio-capacitivity, biodegradable or non-biodegradation polymer.

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 with sodium carboxymethyl cellulose (1.5%)+mannitol with or sorbitol (15%) and/or soil temperature 80 (0.1%) be 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 sustained-release microparticle is directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that sustained-release microparticle is mixed in special solvent or common solvent, obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle 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 application of injection comprises the application of the injection of making after the application of application, solvent of sustained-release micro-spheres or drug microparticles and sustained-release micro-spheres or drug microparticles suspend in solvent.

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.

Microsphere is used to prepare slow releasing injection, as suspension type slow releasing injection, gel injection, block copolymer micelle injection.In various injections, serve as preferred with the suspension type slow releasing injection.The suspension type slow releasing injection is to contain the medicament slow-release microsphere of effective composition or the preparation that drug microparticles is suspended in gained in the solvent, and 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; 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 is (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000) hydrophobic block as the micelle copolymer.The particle size range of block copolymer micelle can be at 1-300um, but is preferred with 20-200um, and 30-150um most preferably; 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.

The application of solvent refers to that mainly the application of special solvent is effective suspension, stablizes and/or protects various medicines or sustained-release micro-spheres (or microcapsule), thereby prepares corresponding injection.The application of special solvent can make prepared injection have better injectivity, stability and higher viscosity.

The application of injection be with full-bodied special solvent with pastille microgranule, particularly sustained-release microparticle, make corresponding slow releasing injection, thus make corresponding medicine can with the injection mode import in the patient or mammalian body of required medicine.The medicine that is injected can be, but is not limited to, said medicine micropowder or medicament slow release microgranule.

The route of administration of injection depends on multiple factor.Though can be through the number of ways administration, with in selective arterial, intracavity, the tumor, the injection of tumor week serves as preferred.

For obtaining valid density in former or position, metastatic tumour place, also can unite and give through number of ways, in the time of as vein, lymphatic vessel, subcutaneous, muscle, intracavity (as in abdominal cavity, thoracic cavity, the articular cavity and in the canalis spinalis) or selective arterial injection in conjunction with local injection.So administering drug combinations is specially adapted to entity tumor.As in the tumor, tumor week injection time is in conjunction with systemic injection.

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, FAD:SA copolymer, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.

Except that above-mentioned adjuvant, also can select for use other materials to see United States Patent (USP) (4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.

The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.In addition, the effective ingredient of anti-cancer sustained-released implantation agent also can be packaged in the liposome equably, or makes microsphere with art methods.

Anticancer implant is multiple shape, as, but be not limited to granule, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.Its most preferred dosage form is the implantation slow release agent that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference, as, but be not limited to slow releasing agent implant, granule, capsule, ball, ball, diffusing, excellent.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.

Anti-cancer sustained-released implantation agent of the present invention can give through number of ways, in number of ways, with topical, as with in selective arterial, intracavity, the tumor, tumor week be placed as the master, with in the tumor, the form that slowly discharges of tumor week or tumor chamber serve as preferably, directly to be placed as the best in the tumor body.

The consumption of cancer therapy drug depends on several factors, as, but be not limited to gross tumor volume, patient body weight, administering mode, disease progression situation and therapeutic response.Generally speaking, bendamustine and vasoinhibitor can be 0.01-1000 milligram/kg body weight, with 1-800 milligram/kg body weight is ideal, with 5-80 milligram/kg body weight for the most desirable, hormone anti-cancer medicine can be 0.01-500 milligram/kg body weight, with 1-100 milligram/kg body weight is ideal, with 5-50 milligram/kg body weight for the most desirable.

The present invention can be used for preparation treatment people, the pharmaceutical preparation of the various entity tumors of house pet and animal, be mainly sustained-release implant and slow releasing injection, entity tumor comprises the tumor that originates from brain and central nervous system, also comprises originating from 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.

Also can add other medicinal ingredient in anti-cancer sustained-released implantation agent of the present invention and the slow releasing injection, as, but be not limited to antibiotics, antalgica, anticoagulant medicine, hemorrhage etc.Above medicinal ingredient can singly select or multiselect, can join the compositions that contains or do not contain additive, and its content is because of specifically deciding.

Above-mentioned effective ingredient is packaged in the pharmaceutic adjuvant, then topical application optionally.Good as injecting or be placed as in selective arterial injection and the direct tumor body, be the best with part placement or injection again wherein.When used the part, anti-cancer sustained-released implantation agent of the present invention can directly place around former or the entity tumor that shifts or in the tumor body, also can directly place or be injected in former or all or part of excision of entity tumor shifted formed intracavity afterwards.

Main Ingredients and Appearance of the present invention is holder with the biocompatible substance, so do not cause foreign body reaction.Support to place in the object back degradable and absorb, so no longer operation is taken out, because of at tumor by local release contained drug, thereby optionally improve and prolong local drug concentration, the while can be reduced the general toxic reaction that is caused by the conventional route administration.

Above cancer therapy drug local injection or placement not only can overcome the toxic reaction that the whole body administration brings, and solved the tumor by local drug level and cross the low and cell sensitive question to medicine.Effective killing tumor cell, and can suppress tumor vessel simultaneously, therefore, have unique advantages.

By following test and embodiment technology of the present invention is further described:

The local drug concentration that test 1, different modes are used behind the 5-FU compares

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection treats that in its hypochondrium tumor growth is divided into following 8 groups (seeing Table 1) with it to the 1cm diameter.Every group of dosage is 5mg/kg.Measure medicament contg (%) in the different time tumor.

Table 1

Test group (n)	Administering mode	Medication amount in the 1st day tumor	Medicament contg in the 3rd day tumor	Medicament contg in the 7th day tumor
					1 (3)	The agent of tail vein injection normal injection	0.65	0.35	0.12
2 (3)	The agent of lumbar injection normal injection	0.58	0.3	0.08
					3 (3)	The agent of tumor week injection normal injection	2.8	1.2	0.3
4 (3)	Tumor week injection slow releasing injection	10	18	20
					5 (3)	Tumor week is placed sustained-release implant	20	30	32
6 (3)	The agent of intratumor injection normal injection	4	2	1
					7 (3)	The intratumor injection slow releasing injection	90	80	60
8 (3)	Place sustained-release implant in the tumor	94	90	84

Above result shows, the local drug concentration significant difference of 5-FU after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant in the tumor, secondly is the intratumor injection slow releasing injection.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.

The interior tumor-inhibiting action of body that test 2, different modes are used behind the 5-FU compares

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is treated behind tumor growth to 0.5 cm diameter it to be divided into following 9 groups (seeing Table 2) in its hypochondrium.Every group of dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 10th day.

Table 2

Test group (n)	Administering mode	Gross tumor volume (cm 3)	The P value
				1 (6)	-	70
2 (6)	The agent of tail vein injection normal injection	65	0.06
				3 (6)	The agent of lumbar injection normal injection	66	0.06
4 (6)	The agent of tumor week injection normal injection	58	0.03
				5 (6)	Tumor week injection slow releasing injection	32	＜0.01
6 (6)	Tumor week is placed sustained-release implant	22	＜0.01
				7 (6)	The agent of intratumor injection normal injection	54	0.04
8 (6)	The intratumor injection slow releasing injection	22	＜0.001
				9 (6)	Place sustained-release implant in the tumor	16	＜0.001

Above result shows, the tumor-inhibiting action significant difference of 5-FU after different modes is used, and topical can obviously improve its tumor-inhibiting action, and is wherein best with the effect of placing sustained-release implant in the tumor, secondly is the intratumor injection slow releasing injection.Good effect not only, toxic and side effects is also little.

Test 3, contain the tumor-inhibiting action of 5-FU and 5-FU synergist

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 matched group and treatment group (1-11).The treatment component is 5-FU group, 5-FU synergist group, 5-FU and 5-FU synergist group.Drug dose is 5mg/kg, through intratumor injection.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.

Table 3

Group	5-FU	Synergist	Tumor control rate (%)	The P value
					1	+	-	60	*
2	-	Triptorelin	46	*
					3	-	Goserelin	42	*
4	-	Leuprorelin	38	*
					5	-	Anastrozole	48	*
6	-	Idoxifene	36	*
					7	+	Triptorelin	80	**
8	+	Goserelin	82	**
					9	+	Leuprorelin	88	**
10	+	Anastrozole	88	**
					11	+	Idoxifene	90	**

Above result shows, 5-FU and used 5-FU synergist (triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene) all have significant inhibitory effect (*: the P value is less than 0.05) to tumor growth when this concentration is used separately, can show the potentiation (* *: the P value is less than 0.001) of highly significant when use in conjunction.

The tumor-inhibiting action of test 4,5-FU and 5-FU synergist (slow releasing injection)

Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.5-FU and 5-FU synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect (%) and is shown in Table 4.

Table 4

Oncocyte	Benzene	A	B	C	D	E	Benzene+A	Benzene+B	Benzene+C	Benzene+D	Benzene+E
												CNS	62	50	48	38	58	42	84	78	92	88	86
C6	64	52	46	36	64	40	90	84	94	84	94
												SA	58	58	36	42	62	48	86	82	88	92	92
BC	54	54	40	42	64	54	84	84	94	84	82
												BA	58	46	38	48	60	56	82	90	98	92	90
LH	60	56	40	52	58	60	92	88	90	88	84
												PAT	64	48	46	50	54	68	92	78	92	88	90

Above result shows, used benzene (5-FU) and 5-FU synergist (A wherein: Miproxifene, B: tamoxifen, C: not former times sweet smell, D: raloxifene, E: ICI-M 164384) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 5,5-FU and 5-FU synergist (slow releasing injection)

Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.5-FU and 5-FU synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect (%) and is shown in Table 5.

Table 5

Oncocyte	Benzene	A	B	C	D	E	Benzene+A	Benzene+B	Benzene+C	Benzene+D	Benzene+E
												CNS	62				58		84	78	92	88	86
C6	64				64		90	84	94	84	94
												SA	58				62		86	82	88	92	92
BC	54				64		84	84	94	84	82
												BA	58				60		82	90	98	92	90
LH	60				58		92	88	90	88	84
												PAT	64				54		92	78	92	88	90

Above result shows, used benzene (5-FU) and 5-FU synergist (A wherein: anticancer steroid alkene phenol; B: Drogenil; C: aminoglutethimide; D: (.+-.)-Pyridoglutethimide; E: megestrol) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 6,5-FU and 5-FU synergist (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (5-FU or 5-FU synergist) and therapeutic alliance group (5-FU and 5-FU synergist).Medicine is through intratumor injection.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)	5-FU	42	＜0.05
				3 (6)	Medroxyprogesterone	36	＜0.01
4 (6)	Toremifene	40	＜0.01
				5 (6)	Anastrozole	44	＜0.01
6 (6)	Exemestane	46	＜0.01
				7 (6)	The 5-FU+ medroxyprogesterone	86	＜0.001
8 (6)	The 5-FU+ toremifene	80	＜0.001
				9 (6)	The 5-FU+ Anastrozole	82	＜0.001
10 (6)	The 5-FU+ exemestane	92	＜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 5-FU and 5-FU synergist (medroxyprogesterone, toremifene, Anastrozole, exemestane), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 7,5-FU and 5-FU synergist (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 7) of index with inhibition rate of tumor growth.

Table 7

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
				1 (6)	Contrast	-
2 (6)	5-FU	58	＜0.05
				3 (6)	Gefitinib	50	＜0.01
4 (6)	Erlotinib	40	＜0.01
				5 (6)	Lapatinib	36	＜0.01
6 (6)	Votaranib	36	＜0.01
				7 (6)	The 5-FU+ gefitinib	82	＜0.001
8 (6)	The 5-FU+ Erlotinib	84	＜0.001
				9 (6)	The 5-FU+ Lapatinib	92	＜0.001
10 (6)	The 5-FU+ votaranib	94	＜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 5-FU and 5-FU synergist-vasoinhibitor (gefitinib, Erlotinib, Lapatinib, votaranib), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 8,5-FU and 5-FU synergist (sustained-release implant)

With the rat is subjects, with 2 * 10 ⁵Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 8) of index with inhibition rate of tumor growth.

Table 8

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
				1 (6)	Contrast	-
2 (6)	5-FU	54	＜0.05
				3 (6)	WAY-EKB 569	58	＜0.05
4 (6)	Thalidomide	36	＜0.05
				5 (6)	LS-2616	46	＜0.05
6 (6)	Angiostatin	36	＜0.01
				7 (6)	The 5-FU+ WAY-EKB 569	80	＜0.01
8 (6)	The 5-FU+ thalidomide	82	＜0.01
				9 (6)	The 5-FU+ LS-2616	90	＜0.01
10 (6)	The 5-FU+ 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 5-FU and 5-FU synergist-vasoinhibitor (WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 9,5-FU and 5-FU synergist (sustained-release implant)

By the tumor-inhibiting action of test 8 described methods mensuration 5-FU and 5-FU synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 9.

Table 9

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
				1 (6)	Contrast	-
2 (6)	5-FU	58	＜0.05
				3 (6)	Endostatin	40	＜0.01
4 (6)	The methanesulfonic acid methanesulfonic acid	50	＜0.01
				5 (6)	Sugen 5416	40	＜0.01
6 (6)	BMS 354825	42	＜0.01
				7 (6)	The 5-FU+ Endostatin	86	＜0.001
8 (6)	5-FU+ methanesulfonic acid methanesulfonic acid	88	＜0.001
				9 (6)	The 5-FU+ Sugen 5416	92	＜0.001
10 (6)	The 5-FU+ BMS 354825	94	＜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 5-FU and 5-FU synergist-vasoinhibitor (Endostatin, imatinib mesylate, Sugen 5416, BMS 354825), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 10,5-FU and 5-FU synergist (slow releasing injection)

By the tumor-inhibiting action of test 8 described methods mensuration 5-FU and 5-FU synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 10.

Table 10

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
				1 (6)	Contrast	-
2 (6)	5-FU	52	＜0.05
				3 (6)	Avastin	48	＜0.01
4 (6)	Cl 1033	38	＜0.01
				5 (6)	Sorafenib	40	＜0.01
6 (6)	Sutent	50	＜0.01
				7 (6)	The 5-FU+ Avastin	80	＜0.001
8 (6)	The 5-FU+ Cl 1033	78	＜0.001
				9 (6)	The 5-FU+ Sorafenib	86	＜0.001
10 (6)	The 5-FU+ Sutent	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 5-FU and 5-FU synergist-vasoinhibitor (Avastin, Cl 1033, Sorafenib, Sutent), can show significant potentiation when use in conjunction.

In a word, growth all had the obvious suppression effect to kinds of tumor cells when used 5-FU and various 5-FU synergist were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of 5-FU and any one 5-FU synergist.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then makes slow releasing injection and implant, serves as preferred with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent wherein.

Slow releasing injection or sustained-release implant also can be further specified by following embodiment.Just the invention will be further described for the foregoing description and following examples, is not its content and use are imposed any restrictions.

(4) specific embodiment

Embodiment 1.

80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg5-FU and leuprorelin, shake up the back contains 10%5-FU and 10% leuprorelin 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 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: the 5-FU of 2-40% and the triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide.

Embodiment 3.

With 70mg molecular weight peak value is that 25000 polylactic acid (PLGA, 75: 25) is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg5-FU and 15mg gefitinib, 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%5-FU and 10% gefitinib, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make 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 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: the combination of the 5-FU of 2-40% and the gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF.

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 5-FU and 10 milligrams of tamoxifens, shake up the back contains 20%5-FU and 10% tamoxifen 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 5-FU of 10-20% and the triptorelin of 10-20%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide.

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 20mg5-FU and 10mg DL-Buthionine-(S,R)-sulfoximine BSO, shake up the back contains 20%5-FU and 10% DL-Buthionine-(S,R)-sulfoximine BSO 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 combination of the 5-FU of 5-20% and the gefitinib of 10-20%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF.

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 20mg5-FU and 10mg Erlotinib, shake up the back contains 20%5-FU and 10% Erlotinib with spray drying method for preparation 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 20%5-FU and 10% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF.

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 Anastrozole and 20mg5-FU, shake up the back contains 10% Anastrozole and 20%5-FU with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.

Embodiment 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: 20% 5-FU and 10% triptorelin, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the combination of exemestane or bicalutamide.

Embodiment 13

With 70mg molecular weight peak value 35000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg5-FU and the new podophyllotoxin of 20mg, shake up the back contains 10%5-FU and 20% new podophyllotoxin 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:

(1) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or bicalutamide; Or

(2) gefitinib of 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or

(3) triptorelin of the 5-FU of 2-40% and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, exemestane or the combination of bicalutamide; Or

(4) combination of the gefitinib of the 5-FU of 2-40% and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF; Or

(5) triptorelin of 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the gefitinib of exemestane or bicalutamide and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF; Or

(6) triptorelin of the 5-FU of 2-40% and 5-30%, goserelin, leuprorelin, Anastrozole, idoxifene, Miproxifene, tamoxifen, 4-monohydroxy tamoxifen (OH-TAM), not former times sweet smell, raloxifene, ICI-M 164384, anticancer steroid alkene phenol, the 4-trans-Hydroxytamoxifen, Drogenil, aminoglutethimide, (.+-.)-Pyridoglutethimide, megestrol, medroxyprogesterone, clomifene, toremifene, letrozole, Anastrozole, the gefitinib of exemestane or bicalutamide and 5-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the combination of TLK286 or ABX-EGF.

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) molecular weight is the polylactic acid (PLA) of 5000-15000,10000-20000,20000-35000 or 30000-50000;

B) molecular weight is the polyglycolic acid of 5000-15000,10000-20000,20000-35000 or 30000-50000 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);

D) FAD and certain herbaceous plants with big flowers diacid (SA) copolymer;

E) xylitol, oligosaccharide, chrondroitin, chitin, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin or white tempera.

Embodiment 16

The method step that is processed into slow releasing injection is identical with embodiment 1-15, but different is used suspending agent is respectively one of following or its combination:

A) 0.5-3.0% carboxymethyl cellulose (sodium):

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20.

Above embodiment only is used for explanation, and is not limitation application of the present invention.

The present invention disclosed and the protection the content see claim.

Claims (2)

1. an anticancer medicine slow-release preparation containing that contains 5-FU is a 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;

Wherein,

Anticancer effective component is 5-FU and the combination that is selected from the 5-FU synergist of vasoinhibitor;

The component of described slow-releasing anticarcinogen injection is following combination:

Anticancer effective component is 20%5-FU and 10% Erlotinib, and slow-release auxiliary material is to carboxy phenyl propane: decanedioic acid is 20: 80 a polifeprosan, and solvent is the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80;

The percentage by weight of anticancer effective component is based on microsphere, and the envelope-bulk to weight ratio of suspending agent is based on solvent.

2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that being sustained-release implant