CN101019829A

CN101019829A - Slow releasing anticancer prepn containing vasoinhibitor

Info

Publication number: CN101019829A
Application number: CNA2007102003199A
Authority: CN
Inventors: 刘玉燕; 张红军; 俞建江
Original assignee: Jinan Shuaihua Pharmaceutical Technology Co Ltd
Current assignee: Jinan Shuaihua Pharmaceutical Technology Co Ltd
Priority date: 2007-03-23
Filing date: 2007-03-23
Publication date: 2007-08-22

Abstract

The slow released anticancer preparation containing vasoinhibitor consists of slow released microsphere and solvent. The slow released microsphere includes effective anticancer component and slow releasing supplementary material, and the solvent is common solvent or special solvent containing suspending agent. The effective anticancer component is the composition of vasoinhibitor selected from lapatinib, erotinib and gefitinib, and/or alkylating agent. The slow releasing supplementary material is selected from polylactic acid, lactic acid copolymer, polifeprosan, etc. The suspending agent is carboxymethyl cellulose, etc. and has viscosity of 80-3000 cp at 20-30 deg.c. The slow released microsphere may be also prepared into slow released implanting agent for use alone or together with chemotherapeutic and/or radiotherapeutic medicine to strengthen the treatment effect.

Description

A kind of anticancer sustained-release agent that contains vasoinhibitor

(1) technical field

The present invention relates to a kind of anticancer sustained-release agent that contains vasoinhibitor, belong to technical field of pharmaceuticals.Particularly, the invention provides the slow releasing injection or the sustained-release implant of a kind of carried with blood-vessel inhibiting and cancer therapy drug, cancer therapy drug wherein is an alkylating agent kind anti-cancer drugs thing.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 strengthen the effect of chemotherapy.

(2) background technology

Treatment for cancer 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 the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and infiltration and diffusion in the tumor tissues, " situation of extracellular matrix is to the influence of medicine running in the entity tumor " " cancer research " 60 phase 2497-503 page or leaf such as carry referring to the Buddhist nun, (Netti PA, Cancer Res.2000,60 (9): 2497-503) in 2000.

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 anticancer sustained-release agent that contains vasoinhibitor is provided, belong to technical field of pharmaceuticals.Particularly, the invention provides the slow releasing injection or the sustained-release implant of a kind of carried with blood-vessel inhibiting and cancer therapy drug, cancer therapy drug wherein is an alkylating agent kind anti-cancer drugs thing.

Vasoinhibitor and alkylating agent kind anti-cancer drugs thing all can suppress tumor growth when using separately, can also increase tumor cell during use in conjunction to mutual sensitivity.With regard to alkylating agent kind anti-cancer drugs thing, be widely used in the multiple entity tumor of treatment both at home and abroad.Yet in application process, its tangible general toxicity has greatly limited the application of this medicine.

In addition, vasoinhibitor and/or 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.

Controlled release formulation for anti entity tumour of the present invention comprises anticancer effective component and pharmaceutic adjuvant, vasoinhibitor in the anticancer effective component is that vasoinhibitor is except that having the effect that suppresses growth of tumour cell, the blood vessel that can suppress or destroy tumor effectively also can suppress the formation of the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, also can obviously promote chemotherapeutics to enter tumor and reach around tumor and infiltration and diffusion in the tumor tissues.

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.

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 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 0.1-70%

Slow-release auxiliary material 30-99.9%

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.

Solvent is divided into common solvent and special solvent.

Anticancer effective component is the combination of vasoinhibitor and cancer therapy drug, and cancer therapy drug is an alkylating agent kind anti-cancer drugs thing.

Wherein, common solvent comprises the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt; Special solvent is the common solvent that contains suspending agent, and 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 suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent.

Sustained-release microparticle of the present invention is made up of effective medicinal components and slow-release auxiliary material and/or suspending agent, and wherein, effective ingredient can be the combination of vasoinhibitor, alkylating agent, taxanes anticarcinogen or vasoinhibitor and alkylating agent or taxanes anticarcinogen

Above-mentioned vasoinhibitor is; but be not limited to; gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; the blood vessel endothelium chalone; imatinib mesylate; 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro 2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; Sugen 5416; pyrroles's lactone dihydroindole ketone; the lactams dihydroindole ketone; 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone; 1; 3 dihydros-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 two-picoline-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; Marimastat; SU5416; SU6668; Amebacilin and derivant thereof; TNP-470 is preferred.

Above-mentioned vasoinhibitor can singly select or multiselect, serves as preferred with gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin and derivant thereof, TNP-470.

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.

Alkylating agent is selected from one of following or combination: cyclophosphamide (CTX), melphalan (Melphalan), Chlorambucil (chlorambucil), 4H-peroxide cyclophosphamide (4H-CTX), ifosfamide (Ifosfamide, Isophosphamide), three mustard cyclophosphamide, sufosfamide (Sufosfamide), defosfamide (Defosfamide), Mafosfamide (Mafosfamide), perfosfamide (Perfosfamide), trofosfamide (Trofosfamide), thiocarzolamide, metamelfalan (Metamelfalan), formylmerphalan (Formylmerphalan), hexamethylmelamine (hexamethylmelamine), Ametantrone, Thymopentin, clomifene, letrozole, disodium cantharidinate, cantharidin (cantharidine), sodium cantharidinate, N-methylcantharidimide, N-hydroxycantharidin, norcantharidin (Norcantharidin), mannomustine (Mannosulfan), treosulfan (Treosulfan), ritrosulfan (Ritrosulfan), an improsulfan (Improsulfan), etoglucid (etoglucid, Ethoglucid, Etoglucid), pipobroman (pipobroman, Pipobroman), piposulfan (A-20968, Piposulfan), triethylenemelaine (triethylenemelamine), epoxypiperazine (epoxypiperazine), benzene assistant TEPA (Benzodepa), Phopurine (Pumitepa), meturedepa (Meturedepa), Ah bundle's TEPA (Aza-TEPA), the salt of urethimine (Uredepa) or said medicine.

Above-mentioned alkylating agent serves as preferred with cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.

The salt of above-mentioned alkylating agent comprises: sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate or maleate.

The percentage by weight of alkylating agent in slow releasing agent is good from 1%-60% with 2%-50%, is best with 5%-30%.

Available pharmaceutic adjuvant is a lot, the present invention is several slow-release auxiliary material of screening from hundreds of adjuvants, selected slow-release auxiliary material can discharge the selected medicine of the present invention tens of days in people and animal body, discharge since a few hours, continues 30-50 days (seeing the embodiment in the description).Resulting product is an anticancer sustained-release agent.The selection of slow-release auxiliary material particularly need could be determined through a large amount of creative works with the combination of different pharmaceutical, is not just can determine through limited experiment, thereby has unobviousness.

Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～1.0, 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.

Anticancer effective component in the slow-releasing anticarcinogen injection microsphere of the present invention is preferably as follows:

(1) gefitinib of 0.1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470;

(2) cyclophosphamide of 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA; Or

(3) gefitinib of 0.1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the cyclophosphamide of Amebacilin or TNP-470 and 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

Slow-release auxiliary material is a bio-capacitivity, can (or non-) degraded and absorbed polymer, preferred silicone rubber, poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, one of gelatin and albumin glue or its combination.

Slow-release auxiliary material and percentage by weight thereof are most preferably as follows in the sustained-release micro-spheres of the present invention:

(1) PLA of 55-90%;

(2) PLGA of 50-90%;

(3) polifeprosan of 50-85%;

(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;

(5) PLGA of the polifeprosan of 30-65% and 30-65% or PLA;

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

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

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).

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, good stability and higher viscosity.

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.

The content of suspending agent is decided because of the medicine that solvent suspended, composition, character and the requirement thereof of sustained-release micro-spheres (or microcapsule), the preparation method of injection and the kind and the composition thereof of suspending agent, as, sodium carboxymethyl cellulose can be 0.5-5%, but with 1-3% is preferred, mannitol and/or sorbitol are 5-30%, but is preferred with 10-20%, and soil temperature 20, soil temperature 40 or soil temperature 80 are 0.05-2%, but are preferred with 0.10-0.5%.In most cases, sustained-release microparticle is made up of effective ingredient and slow-release auxiliary material, and solvent is special solvent.When solvent was common solvent, medicine that is suspended or sustained-release micro-spheres (or microcapsule) then were made up of effective ingredient, slow-release auxiliary material and/or suspending agent.In other words, when the suspending agent in the sustained-release microparticle (A) was " 0 ", solvent (B) was special solvent, and when the suspending agent in the sustained-release microparticle (A) was not " 0 ", solvent (B) can be common solvent or special solvent.The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), preferred 1000cp-3000cp (20 ℃-30 ℃ time), most preferably 1500cp-3000cp (20 ℃-30 ℃ time).

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 sodium carboxymethyl cellulose (1.5%)+mannitol and/or sorbitol (15%) and/or soil temperature 80 (0.1%) are dissolved in the normal saline mutually deserved solvent, viscosity is at 10cp-650cp (20 ℃-30 ℃ time).

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

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

The route of administration of injection depends on multiple factor.Can be in vein, lymphatic vessel, subcutaneous, muscle, intracavity (in as abdominal cavity, thoracic cavity, articular cavity and in the canalis spinalis), tissue, tumor in, reach in the bone marrow in all, the selective arterial injection of tumor, lymph node and inject.For entity tumor, though can be through above-mentioned 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.

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

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.

Anticancer effective component is mainly vasoinhibitor and cancer therapy drug.When the cancer therapy drug in the medicament slow-release microsphere only was vasoinhibitor or cancer therapy drug, slow-releasing anticarcinogen injection was mainly used in the cancer therapy drug of other approach application of increase or the action effect of vasoinhibitor, 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) local injection contains the slow releasing injection of vasoinhibitor and the cancer therapy drug associating that other approach are used;

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

(3) local injection contains the associating of the slow releasing injection that contains vasoinhibitor of the slow releasing injection of cancer therapy drug and topical application.

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.

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%.When vasoinhibitor and cancer therapy drug use in conjunction, the weight ratio of vasoinhibitor and kind anti-cancer drugs is for for 1-19: 1 to 1: 1-19, and with 1-9: serve as preferred at 1 to 1-9: 1, with 1-5: 1 arrives 1-5: 1 for most preferably.

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 (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 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.

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, in various high molecular polymers, be main separation, as polifeprosan with the high molecular weight water soluble polymer, 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), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, one of gelatin and white tempera or its combination.

Preferred slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer.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, but are preferably as follows:

(1) PLA of 55-90%;

(2) PLGA of 50-90%;

(3) polifeprosan of 50-85%;

(4) bis-fatty acid of 55-90% and decanedioic acid copolymer;

(5) mixture of the PLGA of the polifeprosan of 30-60% and 30-60% or PLA;

(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, chitosan, poloxamer, hyaluronic acid, collagen protein, gelatin or albumin glue; Or

Therefore, 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, 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.

The most preferred dosage form of sustained-release implant is the slow releasing agent implant that biocompatibility, degradable absorb, and can make different shape and various dosage form because of the clinical needs of difference.The packing method of its Main Ingredients and Appearance and step in United States Patent (USP) (US5651986) have a detailed description, comprise the some kinds of methods that prepare slow releasing preparation: as, but be not limited to, (i) carrier holder powder and medicament mixed be pressed into implant then, promptly so-called mixing method; (ii) carrier holder fusing, mix solid cooled then, promptly so-called fusion method mutually with medicine to be packaged; (iii) the carrier holder is dissolved in the solvent, medicine dissolution to be packaged or be scattered in the polymer solution, evaporating solvent then, drying, promptly so-called dissolution method; (iv) spray drying method; And (v) freeze-drying etc.

The same slow releasing injection of application formula of anti-cancer sustained-released implantation agent, sustained-release implant anticancer effective component and percentage by weight thereof can be referring to slow releasing injection.

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, 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.

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 anti-cancer sustained-released implantation agent of the present invention and percentage by weight can be with reference to slow releasing injection.When the cancer therapy drug in the medicament slow-release microsphere only is vasoinhibitor or cancer therapy drug, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.

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, vasoinhibitor and cancer therapy drug 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 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.

Route of administration depends on multiple factor, for obtain valid density in former or position, metastatic tumour place, medicine can give through number of ways, as in subcutaneous, intracavity (in abdominal cavity, thoracic cavity and canalis spinalis), the tumor, in all injections of tumor or placement, selective arterial injection, the lymph node and injection in the bone marrow.With in selective arterial injection, intracavity, the tumor, tumor week injection or be placed as preferred.When the cancer therapy drug in the medicament slow-release microsphere only is vasoinhibitor or cancer therapy drug, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.

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

The tumor of above-mentioned internal organs can be different histological type, and why the tumor of the lymph node of lymph node divides outstanding golden lymphoma and non_hodgkin lymphoma, and pulmonary carcinoma comprises small cell lung cancer and nonsmall-cell lung cancer etc., and the cerebral tumor comprises glioma etc.Yet common tumor comprises entity tumors such as the retinoblastoma, nasopharyngeal carcinoma, ovarian cancer, carcinoma of endometrium, cervical cancer, carcinoma of prostate, bladder cancer, colon cancer, rectal cancer, carcinoma of testis of the cerebral tumor, 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, 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.As medicine is mixed and made into the sustained-release micro-spheres that contains different pharmaceutical with different adjuvant, this sustained-release micro-spheres is packing and storing separately, when using simultaneously or successively be injected in the body; Sustained-release micro-spheres also can be realized the packing of of the same race or multiple ingredient by the way of delamination packing clothes, and this sustained-release micro-spheres also can further be shaped by several different methods, makes the sustained-release implant of different shape, contains one or more effective ingredient.

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 technical method of the present invention is further described:

The local drug concentration that test 1, different modes are used alkylating agent (melphalan) compares

With the rat is subjects, with 2 * 10 ⁵Individual mammary gland adenoncus oncocyte subcutaneous injection is in its hypochondrium, treats behind tumor growth to 1 cm diameter its grouping.Every group of dosage is the 2.5mg/kg melphalan.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of melphalan after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.This discovery constitutes key character of the present invention.Following relevant inhibition test has further confirmed this point.

Tumor-inhibiting action relatively in the body of the medicine (norcantharidin) that test 2, different modes are used

With the rat is subjects, with 2 * 10 ⁵Individual ovarian cancer cell subcutaneous injection is in its hypochondrium, treats behind tumor growth to 0.5 cm diameter its grouping.Every group of dosage is the 5mg/kg norcantharidin.The treatment back was measured gross tumor volume size, relatively therapeutic effect on the 20th day.The result shows, the tumor-inhibiting action significant difference of paclitaxel after different modes is used, topical can obviously improve and effectively keep the active drug concentration at position, tumor place, and is wherein best with the effect of placing sustained-release implant and intratumor injection slow releasing injection in the tumor.Yet, intratumor injection slow releasing injection operation most convenient, easy.Good effect not only, toxic and side effects is also little.Make repeated experiments with vasoinhibitor, get same experimental result.

The tumor-inhibiting action of test 3, vasoinhibitor (Lapatinib) and cancer therapy drug (sustained-release implant)

With the rat is subjects, with 2 * 10 ⁵Individual pulmonary carcinoma 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 15mg/kg except that Lapatinib is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 1) of index with inhibition rate of tumor growth.

Table 1

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1 (6)	Contrast	-
2 (6)	Vasoinhibitor	50	＜0.05	1 (6)	Contrast	-
2 (6)	Vasoinhibitor	50	＜0.05	3 (6)	Defosfamide	48	＜0.05
4 (6)	Mafosfamide	38	＜0.05	3 (6)	Defosfamide	48	＜0.05
4 (6)	Mafosfamide	38	＜0.05	5 (6)	Perfosfamide	40	＜0.05
6 (6)	Hexamethylmelamine	36	＜0.01	5 (6)	Perfosfamide	40	＜0.05
6 (6)	Hexamethylmelamine	36	＜0.01	7 (6)	Vasoinhibitor+defosfamide	72	＜0.01
8 (6)	Vasoinhibitor+Mafosfamide	66	＜0.01	7 (6)	Vasoinhibitor+defosfamide	72	＜0.01
8 (6)	Vasoinhibitor+Mafosfamide	66	＜0.01	9 (6)	Vasoinhibitor+perfosfamide	74	＜0.01
10 (6)	Vasoinhibitor+hexamethylmelamine	68	＜0.001	9 (6)	Vasoinhibitor+perfosfamide	74	＜0.01

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used vasoinhibitor and cancer therapy drug (defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 4, vasoinhibitor (Erlotinib) and cancer therapy drug (sustained-release implant)

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, therapeutic alliance group.Sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 2) of index with inhibition rate of tumor growth.

Table 2

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1 (6)	Contrast	-
2 (6)	Vasoinhibitor	38	＜0.05	1 (6)	Contrast	-
2 (6)	Vasoinhibitor	38	＜0.05	3 (6)	Cyclophosphamide	46	＜0.05
4 (6)	Ifosfamide	36	＜0.05	3 (6)	Cyclophosphamide	46	＜0.05
4 (6)	Ifosfamide	36	＜0.05	5 (6)	4H peroxide cyclophosphamide	42	＜0.05
6 (6)	Melphalan	38	＜0.01	5 (6)	4H peroxide cyclophosphamide	42	＜0.05
6 (6)	Melphalan	38	＜0.01	7 (6)	Vasoinhibitor+cyclophosphamide	76	＜0.01
8 (6)	Vasoinhibitor+ifosfamide	78	＜0.01	7 (6)	Vasoinhibitor+cyclophosphamide	76	＜0.01
8 (6)	Vasoinhibitor+ifosfamide	78	＜0.01	9 (6)	Vasoinhibitor+4H peroxide cyclophosphamide	84	＜0.01
10 (6)	Vasoinhibitor+melphalan	84	＜0.001	9 (6)	Vasoinhibitor+4H peroxide cyclophosphamide	84	＜0.01

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used vasoinhibitor and cancer therapy drug (cyclophosphamide, ifosfamide, 4H-peroxide cyclophosphamide, melphalan), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 5, vasoinhibitor (gefitinib) and cancer therapy drug (sustained-release implant)

With the rat is subjects, with 2 * 10 ⁵Individual hepatocarcinoma 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 25mg/kg except that gefitinib is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (seeing Table 3) of index with inhibition rate of tumor growth.

Table 3

The tumor-inhibiting action of test 6, vasoinhibitor (votaranib) and cancer therapy drug (sustained-release implant)

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 negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is placed in tumor.Dosage is 25mg/kg except that votaranib is 2.5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.The result shows, growth all has the obvious suppression effect to kinds of tumor cells when using separately for used vasoinhibitor (votaranib) and cancer therapy drug (defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 7, vasoinhibitor and cancer therapy drug (slow releasing injection)

According to the tumor-inhibiting action of test 3 described methods mensuration WAY-EKB 569 and anti-cancer medicine sustained-release 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) etc.The dosage of vasoinhibitor (WAY-EKB 569) and cancer therapy drug is 10mg/kg, treats 30 days.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumors when using separately for used vasoinhibitor and cancer therapy drug (Chlorambucil, cantharidin, norcantharidin, mannomustine), can show significant potentiation (P＜0.01) when use in conjunction.Further test shows, so obvious synergistic effect also sees the potentiation of vasoinhibitors such as NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone or grace degree to treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.

The tumor-inhibiting action of test 8, vasoinhibitor (thalidomide) and cancer therapy drug (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (vasoinhibitor or cancer therapy drug) and therapeutic alliance group (vasoinhibitor and cancer therapy drug).Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect of index with inhibition rate of tumor growth.The result shows, growth all has obvious suppression effect (P＜0.05) to kinds of tumor cells when using separately for used vasoinhibitor and cancer therapy drug (etoglucid, pipobroman, piposulfan, triethylenemelaine), can show significant potentiation (P＜0.01) when use in conjunction.Further test shows, so obvious synergistic effect also sees the combination that Endostatin and epoxypiperazine, benzene are helped TEPA, Phopurine, meturedepa.

The tumor-inhibiting action of test 9, vasoinhibitor (Sugen 5416) and cancer therapy drug (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual rectal neoplasm 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.Cancer therapy drug is through intratumor injection, and vasoinhibitor is through lumbar injection.Dosage is 25mg/kg except that Sugen 5416 is 2.5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.

Table 4

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1 (6)	Contrast	-
2 (6)	Vasoinhibitor	58	＜0.05	1 (6)	Contrast	-
2 (6)	Vasoinhibitor	58	＜0.05	3 (6)	Chlorambucil	54	＜0.01
4 (6)	Norcantharidin	42	＜0.01	3 (6)	Chlorambucil	54	＜0.01
4 (6)	Norcantharidin	42	＜0.01	5 (6)	Mannomustine	54	＜0.01
6 (6)	Treosulfan	50	＜0.01	5 (6)	Mannomustine	54	＜0.01
6 (6)	Treosulfan	50	＜0.01	7 (6)	Vasoinhibitor+Chlorambucil	72	＜0.001
8 (6)	Vasoinhibitor+norcantharidin	74	＜0.001	7 (6)	Vasoinhibitor+Chlorambucil	72	＜0.001
8 (6)	Vasoinhibitor+norcantharidin	74	＜0.001	9 (6)	Vasoinhibitor+mannomustine	78	＜0.001
10 (6)	Vasoinhibitor+treosulfan	80	＜0.001	9 (6)	Vasoinhibitor+mannomustine	78	＜0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used vasoinhibitor (Sugen 5416) and cancer therapy drug (Chlorambucil, norcantharidin, mannomustine, treosulfan), can show significant potentiation when use in conjunction.

Same potentiation also sees the combination of BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin or norcantharidin.

In a word, growth all had the obvious suppression effect to kinds of tumor cells when used vasoinhibitor and various cancer therapy drug were used separately, can show significant potentiation when use in conjunction.Therefore, effective ingredient of the present invention is the combination of vasoinhibitor and/or any one cancer therapy drug.The medicine that contains above effective ingredient can be made into sustained-release micro-spheres, and then make slow releasing injection and implant, serve as preferred wherein with the suspensoid injectio that is combined to form with the special solvent that contains suspending agent, the viscosity of the solvent of suspensoid injectio is 10cp-650cp (20 ℃-30 ℃ time), preferred 20cp-650cp (20 ℃-30 ℃ time), most preferably 60cp-650cp (20 ℃-30 ℃ time).

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): decanedioic acid (SA) is 20: 80) copolymer is put into container, add the 100ml dichloromethane, behind the dissolving mixing, add 10mg Erlotinib and 10mg melphalan, shake up the back contains 10% Erlotinib and 10% melphalan 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 20-25 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 p-CPP in the polifeprosan: SA is 50: 50, contained anticancer effective component and percentage by weight thereof are: the combination of the cyclophosphamide of the Erlotinib of 1-5% or gefitinib and 5-25%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA, the viscosity of slow releasing injection are 100cp-260cp (20 ℃-30 ℃ time).

Embodiment 3.

With 70mg molecular weight peak value is that the polylactic acid (PLGA, 75: 25) of 20000-40000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg gefitinib and 15mg norcantharidin, 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 15% gefitinib and 15% norcantharidin, 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 4

The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that used adjuvant is the polylactic acid (PLGA of 40000-60000 for the molecular weight peak value, 50: 50), contained anticancer effective component and percentage by weight thereof are: the combination of the Erlotinib of 10-20% or gefitinib and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide or norcantharidin; 100cp-690cp (20 ℃-30 ℃ time).

Embodiment 5.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 20000-40000 is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of Lapatinibs and 10 milligrams of ifosfamides, shake up the back contains 20% Lapatinib and 10% ifosfamide with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection, viscosity is 100cp-160cp (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 6.

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: the combination of the melphalan of the BMS 354825 of 0.5-10%, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and 10-30%, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA; The viscosity of slow releasing injection is 10cp-650cp (20 ℃-30 ℃ time).

Embodiment 7.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 20000-40000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg BMS 354825 and 10mg ifosfamide, shake up the back contains 20% BMS 354825 and 10% ifosfamide 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 160cp-240cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 30-35 days.

Embodiment 8.

The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that the molecular weight peak value is the polylactic acid (PLA) of 10000-20000, and contained anticancer effective component and percentage by weight thereof are: the combination of the Erlotinib of 1-5% or BMS 354825 and 15% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA; Viscosity is 200cp-560cp (25 ℃-30 ℃ time).

Embodiment 9

With 40mg polifeprosan (20: 80) 40mg molecular weight peak value is that the polylactic acid (PLA) of 20000-40000 is put into container, add an amount of dichloromethane, behind the dissolving mixing, add 10mg Avastin and 10mg 4H-peroxide cyclophosphamide, shake up the back contains 10% Avastin and 10%4H-peroxide cyclophosphamide 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, viscosity is 100cp-160cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 20-25 days, is about 25 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 20: 80, polylactic acid molecule amount peak value is 10000-20000, and contained anticancer effective component and percentage by weight thereof are: the combination of 20% Lapatinib, Erlotinib or gefitinib and 10%4H-peroxide cyclophosphamide; Viscosity is 560cp-640cp (25 ℃-30 ℃ time).

Embodiment 11

The method step that is processed into slow releasing injection is identical with embodiment 9 and 10, but different contained anticancer effective component and percentage by weights thereof be: the combination of 5-15% Lapatinib, Erlotinib or gefitinib and 15% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, norcantharidin, meturedepa, urethimine or Ah bundle's TEPA, viscosity are 260cp-680cp (25 ℃-30 ℃ time).

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:

(1) bis-fatty acid of 60-95% and decanedioic acid copolymer (PFAD-SA);

(2) poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] of 75-95%; Or

(3) poly-(fumaric acid-decanedioic acid) [P (FA-SA)] of 70-95%.

Embodiment 13

With 30mg molecular weight peak value is the polylactic acid (PLGA of 25000-45000,50: 50) and 50mg polifeprosan (20: 80) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 5mg Lapatinib and 15mg melphalan, shake up the back contains 5% Lapatinib and 15% melphalan 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 and percentage by weight are:

(1) gefitinib of 0.1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470; Or

(2) cyclophosphamide of 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA.

Embodiment 15

The method step that is processed into slow releasing agent is identical with embodiment 1-14, but different is used slow-release auxiliary material is one of following or its combination:

A) 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) polyethylene glycol, polyethylene glycol copolymer;

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, 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

The method step that is processed into slow releasing injection is identical with embodiment 1-10, and that effective ingredient is is one of following but different is:

(1) gefitinib of 0.1-10%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the cyclophosphamide of Amebacilin or TNP-470 and 20-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA;

(2) gefitinib of 10-20%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the cyclophosphamide of Amebacilin or TNP-470 and 1-20%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA; Or

(3) 10% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, Amebacilin or TNP-470 and 10% cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

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

1. anticancer sustained-release agent that contains vasoinhibitor, it is characterized in that this anticancer sustained-release agent is made up of slow-release auxiliary material and anticancer effective component, anticancer effective component be neovascularization inhibitor and or alkylating agent, wherein, neovascularization inhibitor and the alkylating agent weight ratio in anticancer sustained-release agent is 1-19: 1 to 1: 1-19.

2. the anticancer sustained-release agent according to claim 1 is characterized in that this anticancer sustained-release agent is slow releasing injection or 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:

Biological effective components 0.1-70%

Slow-release auxiliary material 30-99.9%

Suspending agent 0.0-30%

More than be weight percentage

With

Wherein,

Anticancer effective component be effective anticancer vasoinhibitor and or alkylating agent;

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.

4. the anticancer sustained-release agent according to claim 1 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;

I) poly-dl-lactide, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.

5. the anticancer sustained-release agent according to claim 1 is characterized in that alkylating agent is selected from one of cyclophosphamide, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, urethimine or Ah bundle's TEPA or its combination.

6. the anticancer sustained-release agent according to claim 1; it is characterized in that vasoinhibitor is selected from gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; the blood vessel endothelium chalone; imatinib mesylate; 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; Sugen 5416; pyrroles's lactone dihydroindole ketone; the lactams dihydroindole ketone; 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone; 3-[5-methyl-2-(2-oxygen-1; 2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-fluoro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 3-[[3-phenyl-4 (3H) quinazolinone-2-methyl] TGA] hydrazono-]-the 1H-2-dihydroindole ketone; 3-two (4-anisyl) methylene-2-dihydroindole ketone; 3-[4-formyl piperazine-4yl]-benzal]-the 2-dihydroindole ketone; 3-([5-imidazoles] 2; 1-methylene thiazole)-the 2-dihydroindole ketone; 3-1 (2; 6-methylimidazole [2; 1-Bj-thiazole-5-yl] methylene-5-methoxyl group-2-dihydroindole ketone; imidazoles [2; 1-b] methylene thiazole-2-dihydroindole ketone; methylene indole-2-dihydroindole ketone; (2-chloro-indole) methylene-2-dihydroindole ketone; arlydene 2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone; 3-(4-dimethylamino-benzal)-2-dihydroindole ketone; 5-chloro-3-methylene pyridine-2-dihydroindole ketone; 3; 3-lutidines-1-phenyl-2-dihydroindole ketone or E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone; BMS 354825; Avastin; Cl 1033; Sorafenib; Sutent; TLK286; ABX-EGF; Marimastat; SU5416; SU6668; Amebacilin and derivant thereof; a kind of or its combination among the TNP-470.

7. according to claim 2 and 3 described slow-releasing anticarcinogen injections, it is characterized in that suspending agent is selected from one of following or its combination:

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

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20;

F) (iodine) glycerol, simethicone, propylene glycol or carbomer;

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

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

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

8. the anticancer sustained-release agent according to claim 1 is characterized in that contained anticancer effective component is:

9. the anticancer sustained-release agent according to claim 1 is characterized in that contained anticancer effective component and percentage by weight are:

The gefitinib of 0.1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, the grace degree, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286, ABX-EGF, Marimastat, SU5416, SU6668, the cyclophosphamide of Amebacilin or TNP-470 and 1-40%, melphalan, Chlorambucil, ifosfamide, 4H-peroxide cyclophosphamide, defosfamide, Mafosfamide, perfosfamide, hexamethylmelamine, cantharidin, norcantharidin, mannomustine, treosulfan, ritrosulfan, an improsulfan, etoglucid, pipobroman, piposulfan, triethylenemelaine, epoxypiperazine, benzene assistant TEPA, Phopurine, meturedepa, the combination of urethimine or Ah bundle's TEPA.

10. the anticancer sustained-release agent according to claim 1 is characterized in that described slow releasing agent is used to prepare the medicine that treatment originates from cancer, sarcoma or the carcinosarcoma of people and animal brain, central nervous system, kidney, liver, gallbladder, incidence, oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, uterus, ovary, endometrium, cervix uteri, prostate, bladder, colon or rectum former or secondary.