CN100998868A - Antientity tumour composition - Google Patents

Abstract

An antineoplostic composition for treating solid tumor is a slow-release injection, which is composed of the slow-release microballs consisting of the active anticancer component prepared from vascular depressant and anticancer medicine and the slow-release auxiliary and the special solvent containing suspending aid.

Description

A kind of composition for treating solid tumor

(1) technical field

The present invention relates to a kind of composition for treating solid tumor, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains vasoinhibitor.This anticancer sustained-release agent can suppress or destroy matter and tumor vessel between entity tumor effectively, and can suppress the new vessels of tumor, helps medicine and enters entity tumor and the effective diffusion in tumor, and can increase the sensitivity of medicine.

(2) background technology

The treatment of entity tumor mainly comprises methods such as operation, radiotherapy and chemotherapy.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 such as hole, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 69 (2): 76-82).

The cancer drug therapy of low dosage not only can increase the Drug tolerance of cancerous cell, but also can promote its infiltrative growth "; referring to beam etc. " increased the Drug tolerance of human lung carcinoma cell and external wetting capacity after the cancer therapy drug pulse screening and with the change of gene expression " " international journal of cancer " 111 phase 484-93 page or leaf; 2004 (Liang Y; et al., Int JCancer.2004; 111 (4): 484-93).

The local placement of antitumor drug can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves such as Kong Qingzhongs, (Kong Q et al., J Surg Oncol.1998 Oct in 1998; 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 tumor asks that the blood vessel in the matter not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf such as carry referring to the Buddhist nun, (Netti PA, Cancer Res.2000,60 (9): 2497-503) in 2000.

The tumor cell of composition such as the blood vessel in the mesenchyma stroma of tumors and fibrin in the connective tissue and collagen protein and hyperplasia cause entity tumor between matter pressure (interstitial pressure) high, a matter viscosity (interstitialviscosity) is big, tissue tension coefficient (tissue tensile modulus) is big, (hydraulicconductance) is low for the interstitial fluid conductance.Above factors have limited medicine greatly and have entered entity tumor and the effective diffusion in tumor, therefore constitute the major obstacle of chemotherapy of tumors.

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.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of new pharmaceutical composition is provided, contain vasoinhibitor and/or cancer therapy drug.More specifically, be the slow releasing agent of anti entity tumour, be mainly sustained-release implant and slow releasing injection.Topical application can suppress or destroy the blood vessel of tumor effectively and can suppress the new vessels of tumor; Decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth; This controlled release formulation for anti entity tumour also effectively reduces tension force, a matter pressure, the matter viscosity in the tumor, and then improves its interstitial fluid conductance, helps medicine and enters entity tumor and the effective diffusion in tumor.

In addition, vasoinhibitor and cancer therapy drug are made drug level that slow releasing agent (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, reduce the drug level of medicine in blood circulation, are 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 cancer therapy drug decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.The above unexpected main contents of the present invention of finding to constitute.

Controlled release formulation for anti entity tumour of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is selected from the cancer therapy drug and the vasoinhibitor of topoenzyme inhibitor and/or tetrazine class medicine.

Compound medicament composition of the present invention can be made into any dosage form, as, but be not limited to capsule, slow releasing agent, granule, pill, tablet, powder, injection, ointment, patch, implant, slow releasing agent implant, slow releasing agent injection etc.Wherein be preferred with the slow releasing agent, with slow releasing agent implant and slow releasing agent injection for most preferably.

The present invention is directed to the deficiencies in the prior art, a kind of new slow releasing injection that contains vasoinhibitor and cancer therapy drug is provided.

Vasoinhibitor slow releasing injection of the present invention is made up of sustained-release micro-spheres and solvent.Particularly, this slow-releasing anticarcinogen injection is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.01-60%

Slow-release auxiliary material 40-99%

Suspending agent 0.0-30%

More than be weight percentage

With

(B) solvent is for common solvent or contain the special solvent of suspending agent.

Solvent is divided into common solvent and special solvent.

Anticancer effective component is the combination of vasoinhibitor and topoenzyme inhibitor and/or tetrazine class medicine.

Administering mode of the present invention is the local sustained release administration, obviously reduces the toxic action of its whole body in the therapeutic effect that significantly strengthens medicine.With regard to vasoinhibitor, be not the slow release effect that all slow-release auxiliary material all can reach effective release with active anticancer.Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, particularly the pharmaceutic adjuvant that selected vasoinhibitor among the present invention slowly can be discharged in the regular hour in human body or animal body must could obtain through a large amount of creationary experiments, specific slow-release auxiliary material and can need be passed through a large amount of creative works by the selection of the combination of slow releasing pharmaceutical and could determine.Discharged and be not enough to obtain active drug concentration slowly, thereby effective kill tumor cell; Cause prominent releasing if discharge too fast meeting, then cause general toxic reaction as conventional injection easily.The data of release characteristics need could obtain through a large amount of creationary experiments in inside and outside in the related data, particularly animal body, are not just can determine to have unobviousness through limited experiment.

Vasoinhibitor is selected from one of following or combination: ZD6474 (Vandetinib, ZD6474, Zactima), Zarnestra (tipifarnib), sirolimus (temsirolimus), sirolimus, tacrolimus, lenalidomide (lenalidomide), Ai Sha for health (exatecan, DX-8951f).

Above-mentioned vasoinhibitor serves as preferred with ZD6474, Zarnestra, sirolimus, lenalidomide and Ai Sha for health.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 neovascularization inhibitor shared ratio in slow releasing agent is decided because of concrete condition, can be 0.01%-50%, is good with 0.1%-40%, and 1%-30% is best.

Topoenzyme inhibitor is selected from one of following or combination: Camptothecin (camptothecin, CPT), the derivant of Camptothecin, lurtotecan (Lurtotecan), topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin, topotecan), irinotecan (irinotecan, IRT), 9-nitro Camptothecin (9-nitrocamptothecin, 9NC), 7-ethyl-10-hydroxyl-Camptothecin (7-ethyl-10-hydroxy-camptothecin, SN-38), 7-ethyl-10-[4-(1-piperidino)-1-piperidino] and the carbonyl Camptothecin (7-ethyl-10[4-(1-pyperidino)-1-piperidino] carbonyloxycamptothecin, CPT-11), 10-hydroxyl-Camptothecin (10-Hydroxycamptothecin, HCPT), Homocamptothecins (Homocamptothecins), MD-CPT (10,11-methylenedioxy, MD-CPT), (RS)-MD-CPT (10,11-MD-20 (RS) CPT), (S)-MD-CPT glycinate (10,11-MD-20 (s)-cpT-glycinate ester (Gly) .HCl), 9-amino-(S)-MD-CPT glycinate (9-amino-10,11-MD-20 (S)-CPT-Gly), N-[2-(dimethylamino) ethyl] and pyridine-4-carboxylic acid amides (N-[2-(dimethylamino) ethyl] acridine-4-carboxamide, DACA) and the derivant of 5 or 7 replacements, podophyllotoxin (podophyllotoxin), etoposide (Etoposide, epipodophyllotoxins, etoposide, etoposide, VP-16), teniposide (Teniposide, teniposide, vM-26), Podophyllinic acid, podophyllotoxin, trihydroxy-isoflavone (Genistein), the 14-doxorubicin, amrubicin (Amrubicin), Ai Rou is than star (4 '-(acridinylamino) methansulfon-m-anisidide (amsacrine, m-AMSA)), the nor-oxygen daunorubicin of 4-(4-demeth oxydaunorubicin), detorubicin, 7-0-methyl Nuo Jia-4 '-epirubicin (7-o-methylnogallol-4 '-epiadriamycin), esorubicin (Esorubicin), carubicin, idarubicin (idarubicin, IDA), rodorubicin, leurubicin (Leurubicin), medorubicin, Nemorubicin (Nemorubicin), doxorubicin, valrubicin (N-trifluoro toxin-14-valerate, N-trifluoroacetyladriamycin-14-valerate, AD 32, valrubicin), 2-[4-(7-chloro-2-quinoxalinyl phenoxy base]-propanoic acid ((2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid, XK469), zorubicin (Zorubicin), N-(2-ethyl chloride)-N-nitroso-group urea groups daunorubicin (N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin, AD312), pyrazoles [1,5-a] indole derivatives, as, but be not limited to, GS-2,-3,-4, GS-5; The dioxy piperazine oxazine derivatives, as, but be not limited to, (+)-1, two (3, the 5-dioxo piperazinyl) propane ((+)-1 of 2-, 2-bis (3,5-dioxopiperazinyl-1-yl) propane, ICRF-187) ,-2,3-two (3,5-dioxo piperazine-1-yl) butane (meso-2,3-bis (3,5-dioxopiperazine-1-yl) butane, ICRF-193), two dioxo piperazine (bisdioxopiperazine); Suramin (Suramin), deoxyguanosine (Deoxyguanosine), lithocholic acid (lithocholic acid, LCA) or Hydrazoic acid,sodium salt (sodium azide).

In the above topology enzyme inhibitor, serve as preferred than star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin with Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou.

Topoenzyme inhibitor shared ratio in compositions is decided because of concrete condition, generally speaking, can be good with 1%-40% from 0.01%-50%, is best with 5%-30%.All be weight percentage.

Tetrazine kind compound is selected from one of following or combination: imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine (procarbazine, PCB), mitozolomide (mitozolomide, MTZ), temozolomide (Temozolomide orNSC 362856)), 4-carboxyl temozolomide, 3-N-methyl temozolomide [3-N-methyl] temozolomide).Serve as preferred wherein with procarbazine, mitozolomide, 4-carboxyl temozolomide or temozolomide.Above tetrazine kind compound 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.

Tetrazine kind compound shared ratio in slow releasing agent is decided because of concrete condition, generally speaking, can be from 0.1%-50%, be preferred with 1%-40%, with 5%-30% for most preferably.All be weight percentage.

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), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, 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.

When the anticancer effective component in the medicament slow-release microsphere only was vasoinhibitor or cancer therapy drug, slow-releasing anticarcinogen injection was mainly used in the vasoinhibitor of other approach application of increase or the action effect of cancer therapy drug, or was used for the potentiation to radiotherapy or other therapies.When the cancer therapy drug in the medicament slow-release microsphere only was vasoinhibitor or cancer therapy drug, the application of slow-releasing anticarcinogen injection and potentiation mode were:

(1) contain the slow releasing injection local injection of vasoinhibitor, and cancer therapy drug is used through other approach;

(2) local injection contains the slow releasing injection of cancer therapy drug, and other approach are used vasoinhibitor;

(3) local injection contains the slow releasing injection and the slow releasing injection that contains cancer therapy drug of vasoinhibitor; Or

(4) local injection contains the slow releasing injection of vasoinhibitor and cancer therapy drug.

The slow-releasing anticarcinogen injection of topical application also is used for the potentiation to radiotherapy or other therapies.Other approach refer to, but, be not limited to tremulous pulse, vein, abdominal cavity, subcutaneous, intracavitary administration.

Anticancer effective component vasoinhibitor and/or the cancer therapy drug percentage by weight in medicament slow-release microsphere is 0.1%-60%, is good with 1%-40%, and 2%-30% is best.The weight ratio of vasoinhibitor and cancer therapy drug is 1-49: 1 to 1: 1-49, and with 1-19: 1 to 1: 1-19 serves as preferred, with 1-5: 1 to 1: 1-5 is for most preferably.

Anticancer effective component is a kind of or the combination of several vasoinhibitors and/or a kind of or several anticarcinogens in the anticancer pharmaceutical composition of the present invention, and the anticancer effective component preferred compositions is as follows:

(1) ZD6474 of 0.1-40%, Zarnestra, sirolimus, sirolimus, tacrolimus, lenalidomide or Ai Sha are for the combination than star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin of the Camptothecin of health and 1-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou; Or

(2) ZD6474 of 0.1-40%, Zarnestra, sirolimus, sirolimus, tacrolimus, lenalidomide or Ai Sha are for imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide or the 3-N-methyl temozolomide's of health and 1-40% combination.

Slow-release auxiliary material of the present invention can be through enzyme, soda acid or tissue fluid hydrolysis or degraded, comprises one of following or its combination:

(1) biocompatibility polymer comprises biodegradable or biological nondegradable polymer and composition thereof or copolymer;

(2) water-soluble low-molecular chemical compound; Or/and

(3) be used to realize the suitable additive and the excipient of pharmaceutical dosage forms such as injection and slow releasing agent.

Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer, preferred one of following or its combination of slow-release auxiliary material and percentage by weight thereof in the sustained-release micro-spheres of the present invention:

(1) PLA of 55-98%;

(2) PLGA of 50-99%;

(3) polifeprosan of 50-95%;

(4) bis-fatty acid of 55-96% and decanedioic acid copolymer;

(5) PLA of the polifeprosan of 30-70% and 30-70% or PLGA;

(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, 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 slow-release auxiliary material, also can select for use other materials to see the United States Patent (USP) (patent No. 4757128; 4857311; 4888176; 4789724) and in " pharmaceutic adjuvant complete works " (the 123rd page, Sichuan science tech publishing house published in 1993, Luo Mingsheng and Gao Tianhui chief editor) have a detailed description.In addition, Chinese patent (application number 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S.'s patent of invention (patent No. 5,651,986) also enumerated some pharmaceutic adjuvant, comprise filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.

For regulating drug releasing rate or changing other characteristic of the present invention, can change the composition and the proportioning of monomer component or molecular weight, interpolation or the adjusting pharmaceutic adjuvant of polymer, add the water-soluble low-molecular chemical compound, as, but be not limited to various sugar or salt etc.Wherein sugar can be, but is not limited to, xylitol, oligosaccharide, (sulphuric acid) chrondroitin and chitin, chitosan, poloxamer etc., and wherein salt can be, but is not limited to, potassium salt and sodium salt etc.; Also can add other pharmaceutic adjuvant, as but be not limited to filler, solubilizing agent, absorption enhancer, film former, gellant, system (or causing) hole agent, excipient or blocker etc.

In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used slow-release auxiliary material is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.Be convenient injection, the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

The content of suspending agent in common solvent is decided because of its characteristic, can be 0.1-30% and decides because of concrete condition.Consisting of of preferred suspending agent:

A) 0.5-5% sodium carboxymethyl cellulose+0.1-0.5% soil temperature 80; Or

B) 5-20% mannitol+0.1-0.5% soil temperature 80; Or

C) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.

The kind of solvent is then depended in the preparation of solvent, and common solvent has commercially available, also can make by oneself, and as distilled water, water for injection, physiology buffer towards liquid, dehydrated alcohol or the preparation of various salt, but must be in strict accordance with related standards.Special solvent need be considered the kind of suspending agent and the medicine that composition, solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule) and the preparation method of injection, as sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or Tween 80 (0.1%) are dissolved in the normal saline corresponding solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).

The present invention finds to influence medicine and/or sustained-release micro-spheres suspends and/or the key factor of injection is the viscosity of solvent, and viscosity is big more, and suspension effect is good more, and syringeability is strong more.This unexpected one of main index characteristic of the present invention of finding to have constituted.The viscosity of solvent depends on the viscosity of suspending agent, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).According to the viscosity of the prepared solvent of this condition is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).

The preparation of injection has several different methods, and a kind of is that the sustained-release microparticle (A) of suspending agent for " 0 " directly mixed in special solvent, obtains corresponding sustained-release microparticle injection; Another kind is that suspending agent is not mixed in special solvent or common solvent for the sustained-release microparticle (A) of " 0 ", obtains corresponding sustained-release microparticle injection; Another is that sustained-release microparticle (A) is mixed in common solvent, adds the suspending agent mixing then, obtains corresponding sustained-release microparticle injection.Except, also can earlier sustained-release microparticle (A) be mixed and in special solvent, make corresponding suspension, with the moisture in ways such as the vacuum drying removal suspension, special solvent of reuse or common solvent suspendible obtain corresponding sustained-release microparticle injection afterwards then.Above method just is illustrative rather than definitive thereof the present invention.It should be noted that suspended drug or sustained-release micro-spheres (or microcapsule) concentration in injection decide because of specifically needing, can be, but be not limited to, 10-400mg/ml, but be preferably with 30-300mg/ml, with 50-200mg/ml most preferably.The viscosity of injection is 50cp-1000cp (20 ℃-30 ℃ time), preferred 100cp-1000cp (20 ℃-30 ℃ time), most preferably 200cp-650cp (20 ℃-30 ℃ time).This viscosity is applicable to 18-22 injection needle and special bigger (to 3 millimeters) injection needle of internal diameter.

The preparation method of slow releasing injection is arbitrarily, available some kinds of methods preparation: as, but be not limited to, mixing method, fusion method, dissolution method, spray drying method for preparation microsphere, dissolution method are made micropowder, liposome bag medicine method and emulsion process etc. in conjunction with freezing (drying) comminuting method.Serve as preferred wherein with dissolution method (being the solvent volatility process), seasoning, spray drying method and emulsion process.Microsphere then can be used for preparing above-mentioned various slow releasing injection, and its method is arbitrarily.The particle size range of used microsphere can be between 5-400um, serving as preferred between the 10-300um, with between the 20-200um for most preferably.

Microsphere also can be used for preparing other slow releasing injection, as gel injection, block copolymer micelle injection.Wherein, block copolymer micelle is formed in aqueous solution by hydrophobic-hydrophilic block copolymers, has spherical inner core-shell mechanism, and hydrophobic block forms kernel, and hydrophilic block forms shell.The carrier micelle injection enters the purpose that reaches control drug release or targeted therapy in the body.Used pharmaceutical carrier is above-mentioned any one or its combination.Wherein preferred molecular weight is the hydrophilic block of the Polyethylene Glycol (PEG) of 1000-15000 as the micelle copolymer, and preferred biological degradation polyalcohol (as PLA, polylactide, polycaprolactone and copolymer thereof (molecular weight 1500-25000)) is as the hydrophobic block of micelle copolymer.The particle size range of block copolymer micelle can be between 10-300um, between the 20-200um serving as preferred.Gel injection system is dissolved in some amphipathic solvent with biological degradation polyalcohol (as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer), adds medicine miscible with it (or suspendible) back again and forms flowability gel preferably, can be through tumor week or intratumor injection.In case inject, amphipathic solvent diffuses to body fluid very soon, the moisture in the body fluid then infiltrates gel, makes polymer cure, slowly discharges medicine.

Sustained-release micro-spheres also can be used for preparing sustained-release implant, used pharmaceutic adjuvant can be any or multiple material in the above-mentioned pharmaceutic adjuvant, but with the high molecular weight water soluble polymer is main separation, in various high molecular polymers, with polylactic acid, the certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid are first-selection, mixture and copolymer can be selected from, but be not limited to PLA, PLGA, the mixture of PLA and PLGA, the mixture or the copolymer of certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid-decanedioic acid) [P (FA-SA)].Polylactic acid (PLA) and polyglycolic acid the blend ratio be 10/90-90/10 (weight), 25/75-75/25 (weight) preferably.The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.

Another form of anticancer medicine slow-release preparation containing of the present invention is that anticancer medicine slow-release preparation containing is a sustained-release implant.The effective ingredient of anticancer implant can be packaged in the whole pharmaceutic adjuvant equably, also can be packaged in carrier holder center or its surface; Can effective ingredient be discharged by direct diffusion and/or the mode of degrading through polymer.

The characteristics of sustained-release implant are that used slow-release auxiliary material removes the high molecular polymerization beyond the region of objective existence, also contain above-mentioned any one or multiple other adjuvant.The pharmaceutic adjuvant that adds is referred to as additive.Additive can be divided into filler, porogen, excipient, dispersant, isotonic agent, preservative agent, blocker, solubilizing agent, absorption enhancer, film former, gellant etc. according to its function.

The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, 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.

Used organic solvent is known in the preparation process, as, but be not limited to dichloromethane, chloroform, dehydrated alcohol, acetone, glacial acetic acid, chloroform etc.

The anticancer effective component of sustained-release implant is preferably as follows, and all is weight percentage:

(1) ZD6474 of 1-30%, Zarnestra, sirolimus, sirolimus, tacrolimus, lenalidomide or Ai Sha are for the combination than star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin of the Camptothecin of health and 1-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou; Or

(2) ZD6474 of the 1%-40% of 1-30%, Zarnestra, sirolimus, sirolimus, tacrolimus, lenalidomide or Ai Sha are for imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide or the 3-N-methyl temozolomide's of health and 1-40% combination.

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 can be with reference to slow releasing injection in the sustained-release implant of the present invention.

The route of administration of slow releasing agent 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.

The present invention can be used to prepare the pharmaceutical preparation of the various tumors for the treatment of people and animal, be mainly slow releasing injection or sustained-release implant, the indication tumor comprises former or cancer or sarcoma or the carcinosarcoma that shifts that originates from brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon, rectum.

The tumor of above-mentioned internal organs can be different histological type, and why the tumor of the lymph node of lymph node divides outstanding golden lymphoma and non_hodgkin lymphoma, and pulmonary carcinoma comprises small cell lung cancer and nonsmall-cell lung cancer etc., and the cerebral tumor comprises glioma etc.Yet common tumor comprises entity tumors such as the retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis of the cerebral tumor, cerebral glioma, renal carcinoma, hepatocarcinoma, carcinoma of gallbladder, tumor of head and neck, oral cancer, thyroid carcinoma, skin carcinoma, hemangioma, osteosarcoma, lymphoma, pulmonary carcinoma, thymic carcinoma, the esophageal carcinoma, gastric cancer, breast carcinoma, cancer of pancreas, eyes.

The application of sustained-release implant and the same slow-releasing anticarcinogen injection of potentiation mode, the cancer therapy drug that place the associating of the chemical-therapy synergistic agent of the associating of the cancer therapy drug of the promptly local chemical-therapy synergistic agent of placing and other administration, the local cancer therapy drug of placing and other administration, part and the associating of the local chemical-therapy synergistic agent of placing.Wherein the cancer therapy drug of topical application and chemical-therapy synergistic agent can be separately or Joint Production, packing, sale, use.Packing refers to medicine carrying process and pastille slow-release agent the exterior and interior packing for transport and/or store of medicine for adjuvant.The medicine carrying process includes, but not limited to weighing, dissolving, mixing, drying, shaping, coating, spraying, granulation etc.

The clinical practice dosage of effective ingredient depends on patient's concrete condition, can be from 0.01 to 1000mg/kg body weight, and 0.1 to 800mg/kg is preferred, 1 to 500mg/kg for there being most choosing.

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 the technology of composition for treating solid tumor of the present invention is further described:

Tumor-inhibiting action in the body of test one, vasoinhibitor (ZD6474) and cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual colon cancer 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 wherein, the 2nd group is vasoinhibitor, and the 3rd to 6 group is respectively Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan.The the 7th to 10 group of associating that is respectively ZD6474 and Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan.Except that ZD6474 was placed in tumor, Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan were intraperitoneal administration.Except that being 2.5mg/kg, ZD6474 is 15mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 30th day.

Table 1

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	50±14
2 (6)	Vasoinhibitor	42±10	＜0.05
				3 (6)	Camptothecin	40±8	＜0.05
4 (6)	Hydroxy-camptothecin alkali	46±10	＜0.05
				5 (6)	Lurtotecan	40±10	＜0.01
6 (6)	Topotecan	38±6	＜0.01
				7 (6)	Vasoinhibitor+Camptothecin	26±4	＜0.001
8 (6)	Vasoinhibitor+hydroxy-camptothecin alkali	22±6	＜0.001
				9 (6)	Vasoinhibitor+lurtotecan	14±4	＜0.001
10 (6)	Vasoinhibitor+topotecan	18±4	＜0.001

Annotate: Camptothecin, hydroxy-camptothecin alkali, lurtotecan, topotecan are topoenzyme inhibitor.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and topoenzyme inhibitor (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05), particularly topical.And use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

Tumor-inhibiting action in the body of test two, vasoinhibitor (Zarnestra) and cancer therapy drug.

According to test one described method measure vasoinhibitor and cancer therapy drug to tumor-inhibiting action in the pancreas corpus carcinosus, the result shows, Zarnestra or Ai Sha can obviously strengthen irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, the Ai Rou tumor-inhibiting action (P＜0.05) than star, detorubicin, esorubicin, rodorubicin, leurubicin for vasoinhibitors such as health.The two uses separately particularly that topical all has certain tumor-inhibiting action (P＜0.05) to cancer of pancreas, and use in conjunction has obvious synergistic effect (P＜0.001).

The tumor-inhibiting action of test three, topical application cancer therapy drug and vasoinhibitor (Ai Sha is for health).

With the rat is subjects, with 2 * 10 ⁵Individual breast cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 2).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor, and the 3rd to 6 group is respectively.The the 7th to 10 group of associating that is respectively vasoinhibitor and irinotecan, etoposide, teniposide, amrubicin.All medicines are placed in being tumor, except that Ai Sha is to be 15mg/kg the 5mg/kg for health.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 2) on the 30th day.

Table 2

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	58±12
2 (6)	Vasoinhibitor	42±10	＜0.05
				3 (6)	Irinotecan	38±10	＜0.01
4 (6)	Etoposide	42±8	＜0.01
				5 (6)	Teniposide	38±8	＜0.01
6 (6)	Amrubicin	36±8	＜0.01
				7 (6)	Vasoinhibitor+irinotecan	26±4.6	＜0.001
8 (6)	Vasoinhibitor+etoposide	22±4.2	＜0.001
				9 (6)	Vasoinhibitor+teniposide	24±4	＜0.001
10 (6)	Vasoinhibitor+amrubicin	24±3	＜0.001

Annotate: irinotecan, etoposide, teniposide, amrubicin are topoenzyme inhibitor.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and topoenzyme inhibitor (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

Tumor-inhibiting action in the body of test four, vasoinhibitor (lenalidomide) and topoenzyme inhibitor.

Detected tumor-inhibiting action in the body of lenalidomide and topoenzyme inhibitor according to test three method.The result shows lenalidomide and is selected from Ai Rou all has obvious tumor-inhibiting action (P＜0.05) than independent application of the cancer therapy drug of star, detorubicin, esorubicin, rodorubicin to colon cancer.And use in conjunction has obvious synergistic effect (P＜0.001).

Tumor-inhibiting action in the body of test five, vasoinhibitor (lenalidomide) and cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual ovarian cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor; The the 3rd to 6 group is respectively etoposide, rodorubicin, leurubicin, zorubicin.The the 7th to 10 group of associating that is respectively vasoinhibitor and different cancer therapy drugs.Except that the blood vessel inhibitor is placed, be intraperitoneal administration in tumor.Except that being 10mg/kg, the blood vessel inhibitor is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 30th day.

Table 3

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	54±10
2 (6)	Vasoinhibitor	40±8	＜0.05
				3 (6)	Etoposide	44±10	＜0.01
4 (6)	Rodorubicin	42±8	＜0.01
				5 (6)	Leurubicin	46±9	＜0.01
6 (6)	Zorubicin	42±6	＜0.01
				7 (6)	Vasoinhibitor+etoposide	26±4	＜0.001
8 (6)	Vasoinhibitor+rodorubicin	22±3.6	＜0.001
				9 (6)	Vasoinhibitor+leurubicin	24±3.8	＜0.001
10 (6)	Vasoinhibitor+zorubicin	18±2.8	＜0.001

Annotate: etoposide, rodorubicin, leurubicin, zorubicin are topoenzyme inhibitor.

Tumor-inhibiting action in the body of test six, vasoinhibitor (ZD6474) and cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual lung carcinoma cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 4).The 1st group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor; The the 3rd to 6 group is respectively topoenzyme inhibitor.The the 7th to 10 group of associating that is respectively vasoinhibitor and different cancer therapy drugs.Except that the blood vessel inhibitor was placed in tumor, topotecan, irinotecan, mitozolomide, temozolomide were intraperitoneal administration.Except that being 1mg/kg, the blood vessel inhibitor is 16mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 30th day.

Table 4

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	62±14
2 (6)	Vasoinhibitor	46±10	＜0.05
				3 (6)	Topotecan	46±8.3	＜0.05
4 (6)	Irinotecan	48±6.8	＜0.05
				5 (6)	Mitozolomide	42±8.4	＜0.05
6 (6)	The temozolomide	40±6.8	＜0.05
				7 (6)	Vasoinhibitor+topotecan	24±4.8	＜0.001
8 (6)	Vasoinhibitor+irinotecan	22±4.6	＜0.001
				9 (6)	Vasoinhibitor+mitozolomide	18±4.2	＜0.001
10 (6)	Vasoinhibitor+temozolomide	14±2.8	＜0.001

Annotate: topotecan, irinotecan, mitozolomide, temozolomide are cancer therapy drug.

Tumor-inhibiting action in the body of test seven, vasoinhibitor (sirolimus) and cancer therapy drug.

With the rat is subjects, with 2 * 10 ⁵Individual gastric cancer tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 5).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor, and the 3rd to 6 group is respectively procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide.The the 7th to 10 group of associating that is respectively vasoinhibitor and procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide.Except that the blood vessel inhibitor was placed in tumor, procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide were intraperitoneal administration.Except that being 15mg/kg, the blood vessel inhibitor is 2.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 5) on the 30th day.

Table 5

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	56±12
2 (6)	Vasoinhibitor	46±10	＜0.05
				3 (6)	Procarbazine	42±8	＜0.05
4 (6)	Mitozolomide	50±10	＜0.05
				5 (6)	The temozolomide	44±10	＜0.01
6 (6)	4-carboxyl temozolomide	38±6	＜0.01
				7 (6)	Vasoinhibitor+procarbazine	26±4	＜0.001
8 (6)	Vasoinhibitor+mitozolomide	14±4	＜0.001
				9 (6)	Vasoinhibitor+temozolomide	20±4	＜0.001
10 (6)	Vasoinhibitor+4-carboxyl temozolomide	16±4	＜0.001

Annotate: procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide are cancer therapy drug.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05), particularly topical.And use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

The tumor-inhibiting action of test eight, topical application cancer therapy drug and vasoinhibitor (sirolimus).

With the rat is subjects, with 2 * 10 ⁵Individual hepatoma carcinoma cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 6).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor, and the 3rd to 6 group is respectively mitozolomide, temozolomide, 4-carboxyl temozolomide, 3-N-methyl temozolomide.The the 7th to 10 group of associating that is respectively vasoinhibitor and mitozolomide, temozolomide, 4-carboxyl temozolomide, 3-N-methyl temozolomide.All medicines are placed in being tumor, and equal except that the blood vessel inhibitor is 2.5mg/kg, cancer therapy drug is 17.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 6) on the 30th day.

Table 6

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	58±12
2 (6)	Vasoinhibitor	48±10	＜0.05
				3 (6)	Mitozolomide	34±8	＜0.01
4 (6)	The temozolomide	40±10	＜0.01
				5 (6)	4-carboxyl temozolomide	34±6	＜0.01
6 (6)	3-N-methyl temozolomide	36±8	＜0.01
				7 (6)	Vasoinhibitor+mitozolomide	24±5.6	＜0.001
8 (6)	Vasoinhibitor+temozolomide	18±4.2	＜0.001
				9 (6)	Vasoinhibitor+4-carboxyl temozolomide	24±6	＜0.001
10 (6)	Vasoinhibitor+3-N-methyl temozolomide	18±3	＜0.001

Annotate: mitozolomide, temozolomide, 4-carboxyl temozolomide, 3-N-methyl temozolomide are cancer therapy drug.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

Similar potentiation also sees the associating of other vasoinhibitor and other cancer therapy drug, as the combination of mitozolomide or temozolomide and sirolimus or ZD6474, and Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, lurtotecan, topotecan, irinotecan, etoposide or teniposide and ZD6474, Zarnestra, sirolimus, sirolimus, tacrolimus, lenalidomide or Ai Sha are for the combination of health.The tumor cell that tries comprises the cerebral tumor (CNS-1, C6,9L), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma, cancer of pancreas, renal carcinoma and the esophageal carcinoma etc.

Release ratio in the body of the vasoinhibitor sustained-release implant that test nine, different molecular weight polylactic acid are made

With the rat is subjects, grouping (3/group) and the equivalent vasoinhibitor sustained-release implant that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, 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 vasoinhibitor (ZD6474) sustained-release implant 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, tumor control 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).

The tumor-inhibiting action of test ten, topical application cancer therapy drug and vasoinhibitor (ZD6474).

With the rat is subjects, with 2 * 10 ⁵Individual esophageal cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 7).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is vasoinhibitor, and the 3rd to 6 group is respectively Camptothecin, hydroxy-camptothecin alkali, topotecan, irinotecan.The the 7th to 10 group of associating that is respectively vasoinhibitor and Camptothecin, hydroxy-camptothecin alkali, topotecan, irinotecan.All medicines are placed in being tumor, and equal except that the blood vessel inhibitor is 2.5mg/kg, cancer therapy drug is 17.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 7) on the 30th day.

Table 7

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	56±12
2 (6)	Vasoinhibitor	48±10	＜0.05
				3 (6)	Camptothecin	38±10	＜0.01
4 (6)	Hydroxy-camptothecin alkali	32±6	＜0.01
				5 (6)	Topotecan	38±8	＜0.01
6 (6)	Irinotecan	36±8	＜0.01
				7 (6)	Vasoinhibitor+Camptothecin	22±4.6	＜0.001
8 (6)	Vasoinhibitor+hydroxy-camptothecin alkali	14±2.2	＜0.001
				9 (6)	Vasoinhibitor+topotecan	16±4	＜0.001
10 (6)	Vasoinhibitor+irinotecan	14±4	＜0.001

Annotate: Camptothecin, hydroxy-camptothecin alkali, topotecan, irinotecan are cancer therapy drug.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

Test 11, the tumor-inhibiting action of topical application cancer therapy drug and sirolimus.

With the rat is subjects, with 2 * 10 ⁵Individual esophageal cancer cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 8).First group is contrast, and the 2nd to 10 group is the treatment group, and wherein, the 2nd group is sirolimus, and the 3rd to 6 group is respectively.The the 7th to 10 group of associating that is respectively vasoinhibitor (sirolimus) and mitozolomide, temozolomide, Camptothecin, topotecan.All medicines are placed in being tumor, and equal except that the blood vessel inhibitor is 5mg/kg, cancer therapy drug is 15mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 8) on the 30th day.

Table 8

Test group (n)	Suffered treatment	Gross tumor volume (cm 3)	The P value
				1 (6)	Contrast	54±10
2 (6)	Vasoinhibitor	46±8	＜0.05
				3 (6)	Mitozolomide	38±10	＜0.01
4 (6)	The temozolomide	44±8	＜0.01
				5 (6)	Camptothecin	34±8	＜0.01
6 (6)	Topotecan	34±8	＜0.01
				7 (6)	Vasoinhibitor+mitozolomide	24±4.6	＜0.001
8 (6)	Vasoinhibitor+temozolomide	18±4.2	＜0.001
				9 (6)	Vasoinhibitor+Camptothecin	20±4.4	＜0.001
10 (6)	Vasoinhibitor+topotecan	16±4	＜0.001

Annotate: mitozolomide, temozolomide, Camptothecin, topotecan are cancer therapy drug.The result shows, compares with matched group, and vasoinhibitor (the 2nd group) and cancer therapy drug (the 3rd to 6 group) application separately all have certain tumor-inhibiting action (P＜0.05).Yet use in conjunction (the 7th to 10 group) has obvious synergistic effect (P＜0.001).

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 different with the drug release feature of 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), polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, gelatin or albumin glue; 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, experimental result shows that vasoinhibitor among the present invention is to the potentiation of listed topoenzyme inhibitor or tetrazine kind anti-cancer drugs thing.Therefore, the effective ingredient of anticancer compound of the present invention is the associating of vasoinhibitor and any one (or multiple) topoenzyme inhibitor or tetrazine kind anti-cancer drugs thing or packs separately.Above effective ingredient can be made into any dosage form or shape, but serves as preferred with the agent for slow releasing type, is mainly slow releasing injection or sustained-release implant.

(4) specific embodiment

Embodiment 1.

With 80mg molecular weight peak value is that the polylactic acid (PLGA, 50: 50) of 25000-40000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 10mg ZD6474 and 10mg Camptothecin, shakes up the dry organic solvent of removing of final vacuum again.Dried solid composite is shaped immediately, and ray sterilizing after the packing must contain the anticancer slow-release of 10% ZD6474 and 10% Camptothecin.All be weight percentage.The drug release time of this entity-tumor-resistant medicine composition in external normal saline is 15-25 days, is 25-50 days at the subcutaneous drug release time of mice.

Embodiment 2.

As described in embodiment 1, the molecular weight peak value of different is polylactic acid is 10000-25000 (PLGA, 75: 25), and anticancer effective component and percentage by weight are one of following:

The combination of (1) 5% lenalidomide and 20% hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide or teniposide; Or

The combination of (2) 1% ZD6474 and 10% Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide or teniposide.

Embodiment 3.

80mg polifeprosan (to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg Zarnestra and 10mg mitozolomide, shake up the back contains 10% Zarnestra and 10% mitozolomide with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 20cp-300cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 15-25 days, is about 30-40 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 polifeprosan is 50: 50, contained anticancer effective component and percentage by weight thereof are: the combination of the mitozolomide of the lenalidomide of 2.5-20% or ZD6474 and 5-25%, the viscosity of slow releasing injection are 300cp-600cp (20 ℃-30 ℃ time).

Embodiment 5.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 30000-60000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 25mg temozolomide and 5mg Zarnestra, 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 25% temozolomide and 5% Zarnestra, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-340cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days, is about 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 the molecular weight peak value of different is polylactic acid is 10000-30000, and contained anticancer effective component and percentage by weight thereof are:

The combination of (1) 25% imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide or 3-N-methyl temozolomide and 10% ZD6474;

The combination of the Zarnestra of (2) 10% procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide or 3-N-methyl temozolomide and 10%;

The combination of the lenalidomide of (3) 15% mitozolomide, temozolomide, 4-carboxyl temozolomide or 3-N-methyl temozolomide and 10%;

The Ai Sha of (4) 25% procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide or 3-N-methyl temozolomide and 10% is for the combination of health or sirolimus.

The viscosity of injection is 100cp-650cp (20 ℃-30 ℃ time).

Embodiment 7.

With 30mg polifeprosan (20: 80) and 40mg molecular weight peak value is that the polylactic acid (PLA) of 30000-60000 is put into container, add 20mg procarbazine and 10mg lenalidomide after adding an amount of dichloromethane dissolving mixing, shake up the back contains 20% procarbazine and 10% lenalidomide with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection, viscosity is 180cp-260cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 21-25 days, is about 30-35 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 polifeprosan is 50: 50, the molecular weight peak value of polylactic acid is 10000-30000, and contained anticancer effective component is: the procarbazine of the Zarnestra of 5-25%, lenalidomide, ZD6474 or sirolimus and 5-25%, mitozolomide, temozolomide, 4-carboxyl temozolomide or 3-N-methyl temozolomide's combination; The slow releasing injection viscosity is 440cp-650cp (25 ℃-30 ℃ time).

Embodiment 9

With 40mg polifeprosan (20: 80) and 30mg molecular weight peak value is the polylactic acid (PLGA of 30000-60000,50: 50) put into container, add and add 20mg Camptothecin and 10mg Ai Sha behind an amount of dichloromethane dissolving mixing, shake up the back again and contain 20% Camptothecin and 10% Ai Sha injectable microsphere for health with spray drying method for preparation for health.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection, viscosity is 120cp-180cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days, is about 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 polifeprosan is 50: 50, the molecular weight peak value of polylactic acid (75: 25) is 10000-30000, and contained anticancer effective component is: 15% Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, lurtotecan, topotecan, irinotecan, etoposide, teniposide, amrubicin, Ai Rou replace the combination of health or sirolimus than the Ai Sha of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin and 5%; Viscosity is 560cp-640cp (25 ℃-30 ℃ time).

Embodiment 11

70mg bis-fatty acid and decanedioic acid copolymer (PFAD-SA) (30: 70) copolymer are put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg etoposide and 20mg sirolimus, shake up the back contains 10% etoposide and 20% sirolimus 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 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 used slow-release auxiliary material is: poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] of 60-95% or poly-(fumaric acid decanedioic acid) [P (FA-SA)], and contained anticancer effective component is: 20% Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, the 14-doxorubicin, amrubicin, Ai Rou compares star, detorubicin, esorubicin, rodorubicin, the combination of leurubicin or zorubicin and 5-20% Zarnestra.

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 15mg mitozolomide and 5mg ZD6474, shake up the back contains 15% mitozolomide and 5% ZD6474 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 21-24 days, is about 30 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:

(1) Camptothecin of the Zarnestra of 1-20% or ZD6474 and 10-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou are than the combination of star, detorubicin, esorubicin, rodorubicin, leurubicin or zorubicin; Or

(2) the imidazo tetrazine of the sirolimus of 10-30% or lenalidomide and 1-40%, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide or 3-N-methyl temozolomide's combination.

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) polylactic acid (PLA), the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;

B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, the molecular weight peak value is 10000-30000,300000-60000,60000-100000 or 100000-150000;

C) polifeprosan and polylactic acid or PLGA;

D) polifeprosan, to carboxy phenyl propane (p-CPP): decanedioic acid (SA) is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;

E) bis-fatty acid and decanedioic acid copolymer (PFAD-SA);

F) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)];

G) poly-(fumaric acid-decanedioic acid) [P (FA-SA)];

H) xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, 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.

Embodiment 17.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 20000-40000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 25mg mitozolomide and 5mg sirolimus, 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 25% mitozolomide and 5% sirolimus, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-340cp (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 18

The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component and percentage by weight thereof are:

(1) Camptothecin of 20-40%, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, procarbazine, mitozolomide or the ZD6474 of temozolomide and 5-10% or the combination of sirolimus;

(2) 40% mitozolomide or temozolomide and 10% Zarnestra or the combination of lenalidomide;

The combination of (3) 30% mitozolomide or temozolomide and 10% Zarnestra;

(4) 20% mitozolomide or temozolomide and 15% ZD6474 or the combination of sirolimus;

The combination of (5) 10% mitozolomide or temozolomide and 20% Zarnestra, lenalidomide, ZD6474 or sirolimus.

The viscosity of injection is 100cp-650cp (20 ℃-30 ℃ time).

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.

Above result shows that the vasoinhibitor that the present invention is used and the combination and the consequent anticancer synergia effect of its cancer therapy drug are of universal significance.Dosage when therefore, vasoinhibitor and its cancer therapy drug are united is selected and can be had day data to release according to of the present invention.

The foregoing description has been done further description to technical method of the present invention.Be to illustrate for example rather than will limit scope of the present invention.In fact, except that shown in this paper and the of the present invention various changes described, to those skilled in the art all can be from description and chart apparent.Certainly these changes should be in the scope of appended claim.Therefore, to disclose some specific implementations of the present invention emphatically and its being equal to of making is changed or replaces all be in described design of appended claims and scope to the description that should be realized that the front.

Claims (10)

1. composition for treating solid tumor, the anticancer effective component that it is characterized in that anti-group of entities compound is neovascularization inhibitor and the combination that is selected from the cancer therapy drug of topoenzyme inhibitor and/or tetrazine class medicine, wherein, the weight ratio of neovascularization inhibitor and cancer therapy drug is 1-49: 1 to 1: 1-49.

2. the compositions according to claim 1 is characterized in that this anti-compositions is a slow releasing agent, is selected from slow releasing injection and sustained-release implant.

3. the slow-releasing anticarcinogen injection according to claim 2 is characterized in that this slow-releasing anticarcinogen injection is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.1-60%

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 cancer therapy drug, and described cancer therapy drug is selected from topoenzyme inhibitor and/or tetrazine class medicine;

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, and the viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time).

4. the composition for treating solid tumor according to claim 1 is characterized in that vasoinhibitor one of is selected from or its combination.

5. the composition for treating solid tumor according to claim 1 is characterized in that described tetrazine class medicine is selected from one of imidazo tetrazine, imidazopyrazine, imidazopyridine, procarbazine, mitozolomide, temozolomide, 4-carboxyl temozolomide, 3-N-methyl temozolomide or its combination.

6. the composition for treating solid tumor according to claim 1 is characterized in that described topoenzyme inhibitor is selected from Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, podophyllotoxin, trihydroxy-isoflavone, lurtotecan, topotecan, irinotecan, etoposide, teniposide, 14-doxorubicin, amrubicin, Ai Rou than one of star, detorubicin, esorubicin, rodorubicin, leurubicin, zorubicin or its combination.

7. the composition for treating solid tumor according to claim 1 is characterized in that anticancer effective component is one of following:

(1) lenalidomide of 1-40%, lenalidomide activator, ZD6474, lenalidomide, Ai Sha replace the combination of Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, lurtotecan, topotecan, irinotecan, etoposide or the teniposide of health, Cervilaxin, brinase, sirolimus or sirolimus and 1-40%; Or

(2) lenalidomide of 1-40%, lenalidomide activator, ZD6474, lenalidomide, Ai Sha are for health, Cervilaxin, brinase, sirolimus or the mitozolomide of sirolimus and 1-40% or temozolomide's combination.

8. the slow releasing agent according to claim 2 is characterized in that slow-release auxiliary material is selected from one of following or its combination:

A) polylactic acid;

B) copolymer of polyglycolic acid and hydroxyacetic acid;

C) polifeprosan;

D) polyethylene glycol;

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, chitosan, poloxamer, 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.

9. according to claim 2 and 3 described slow releasing injection, it is characterized in that used suspending agent is one of following:

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;

I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% soil temperature 80.

10. the sustained-release implant according to claim 2 is characterized in that described anticancer effective component and percentage by weight thereof are:

(1) lenalidomide of 1-40%, lenalidomide activator, ZD6474, lenalidomide, Ai Sha replace the combination of Camptothecin, hydroxy-camptothecin alkali, 9-nitro Camptothecin, lurtotecan, topotecan, irinotecan, etoposide or the teniposide of health, Cervilaxin, brinase, sirolimus or sirolimus and 1-40%; Or

(2) lenalidomide of 1-40%, lenalidomide activator, ZD6474, lenalidomide, Ai Sha are for health, Cervilaxin, brinase, sirolimus or the mitozolomide of sirolimus and 1-40% or temozolomide's combination.