CN1861047A

CN1861047A - Slow-releasing injection contg. vasoinhibitor and potentiator type anticarcinogen

Info

Publication number: CN1861047A
Application number: CNA2006102001964A
Authority: CN
Inventors: 孙中先
Original assignee: Jinan Shuaihua Pharmaceutical Technology Co Ltd
Current assignee: Jinan Shuaihua Pharmaceutical Technology Co Ltd
Priority date: 2006-03-06
Filing date: 2006-03-06
Publication date: 2006-11-15

Abstract

A slow-release anticancer injection contains the slow-release microspheres and solvent. Said slow-release microsphere contains the active anticancer component chosen from 16 vascula inhibitors including gefitinib, angiostatin, etc and 3 cytotoxins including phosphoinositide 3-kinase inhibitor, pyrimidine analog or DNA repairase inhibitor, and the slow-release auxiliary.

Description

The anti-cancer medicine sustained-release injection of carried with blood-vessel inhibiting and synergist thereof

(1) technical field

The present invention relates to a kind of compound anti-cancer medicament slow release injection, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of compound anti-cancer medicinal slow release agent that contains vasoinhibitor and/or its synergist, be mainly slow releasing injection and sustained-release implant.

(2) background technology

Treatment for cancer still mainly comprises methods such as operation, radiotherapy and chemotherapy at present.Therefore wherein operative treatment can not be removed the oncocyte that is dispersed in, and often recurs or causes tumor cell to stimulate diffusion transfer because of operation; Radiotherapy and traditional chemotherapy are not had a selectivity, and be difficult to tumor by local and form effective drug level or therapeutic dose, weak effect, toxicity is big, improves the restriction that medicine or radiological dose are subjected to general toxic reaction again merely.Referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82).

The local placement of chemotherapeutics can overcome above defective preferably, not only can obviously improve the drug level of tumor by local, and can significantly reduce general toxic reaction.A large amount of internal and external tests have demonstrated the therapeutic effect to entity tumor, referring to " placing cisplatin adding system carmustine treatment rat brain tumor in the tumor " " surgery tumor magazine " 69 phase 76-82 pages or leaves (1998) (Kong Q et al., J Surg Oncol.1998 Oct such as Kong Qingzhongs; 69 (2): 76-82) and Kong Qingzhong etc. " place cisplatin in the tumor and cure the former carbuncle in the occipital region tumor of rat " " surgery tumor magazine " 64 phase 268-273 pages or leaves (1997) (Kong Q et al., JSurg Oncol.1997 Oct; 64:268-273).Also can be referring to Chinese patent (ZL00111093.4; ZL96115937.5; Application number 001111264,001111272) and U.S.'s patent of invention (patent No. 6,376,525B1; 5,651,986; 5,626,862).

Yet, entity tumor is made up of tumor cell and mesenchyma stroma of tumors, wherein the blood vessel in the mesenchyma stroma of tumors not only provides support and requisite nutrient substance for the growth of tumor cell, also influenced chemotherapeutics around tumor and the infiltration in the tumor tissues and diffusion (carry and to wait " situation of extracellular matrix to entity tumor in the medicine influence of turning round " " cancer research " 60 phase 2497-503 page or leaf (2000) (Netti PA referring to the Buddhist nun, Cancer Res.2000,60 (9): 2497-503)).Moreover, the blood vessel in the mesenchyma stroma of tumors often causes the enhancing of tumor cell to the toleration of cancer therapy drug to conventional chemotherapy medicine and insensitive, consequently treatment failure.

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

Therefore, develop a kind of effective cancer therapy drug or Therapeutic Method and just become a current important topic.The present invention provides a kind of new anticancer pharmaceutical composition just at the deficiencies in the prior art, can suppress growth of tumour cell effectively, and can strengthen the treatment tumor effect of other medicines, reduces recurrence.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of compound recipe vasoinhibitor slow releasing agent is provided.Particularly, the invention provides a kind of anticancer medicine slow-release preparation containing that contains vasoinhibitor and/or its synergist, be mainly slow releasing injection and sustained-release implant.

Vasoinhibitor is mainly used in entity tumors such as treatment ovarian cancer, pulmonary carcinoma abroad as a kind of new cancer therapy drug.Yet in application process, still show tangible general toxicity, thereby greatly limited the application of such medicine.

The present invention finds that cancer therapy drug that has and vasoinhibitor share its antitumaous effect is strengthened mutually, below the vasoinhibitor antitumaous effect will be increased mutually medicine be referred to as the vasoinhibitor synergist, be mainly cell toxicity medicament; In addition, vasoinhibitor or vasoinhibitor synergist are made drug level that anticancer medicine slow-release preparation containing (being mainly slow releasing injection and sustained-release implant) not only can greatly improve tumor by local, 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.Vasoinhibitor can suppress or destroy the blood vessel of tumor effectively and can suppress the formation of the new vessels of tumor, and then not only make tumor cell lose the required support of growth and the source of nutrient substance, also promoted chemotherapeutics around tumor, to reach infiltration and the diffusion in the tumor tissues.The above unexpected main contents of the present invention of finding to constitute.

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

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.5-60%

Slow-release auxiliary material 40-99%

Suspending agent 0.0-30%

More than be weight percentage

With

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

Wherein,

Anticancer effective component is vasoinhibitor and/or its synergist, and the vasoinhibitor synergist is selected from phosphoinositide 3-kinase (PI3K) inhibitor, pyrimidine analogue and/or DNA repairase inhibitor; Slow-release auxiliary material is selected from one of copolymer (PLGA), xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin and white tempera of 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), polyglycolic acid and hydroxyacetic acid or its combination; Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

Vasoinhibitor mainly is selected from vasoinhibitor with gefitinib; Erlotinib; Lapatinib; votaranib; WAY-EKB 569; NSC 609974; thalidomide; LS-2616; angiostatin; Endostatin; the blood vessel endothelium chalone; imatinib mesylate; 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the aniline mesylate; 5-[5-fluoro-2-oxygen-1; the 2-indoline-(3Z)-methylene]-2; 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-diethylaminoethyl) amide; 3; 3-two chloro-5-(4-sulfonyloxy methyl yl pyridines)-2-dihydroindole ketone; 3-[1-(the 3H-imidazoles-4-yl)-first-(Z)-Ya Neiweng-5-methoxy-1; 3-dihydro-indole-2-dihydroindole ketone; 1H-pyrroles-3-propanoic acid; 2-[(1; 2-dihydro-2-oxygen-3H-indole-3-subunit) methyl]-the 4-methyl; 2H-indole-2-dihydroindole ketone; Sugen 5416; pyrroles's lactone dihydroindole ketone; the lactams dihydroindole ketone; 3-(4-dimethylamino-naphthal-1-methylene)-1; 3-dihydro-indole-2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone; 3-[5-methyl-2-(2-oxygen-1; 2-dihydro-indol-3-yl)-1H-pyrroles-3-methyl]-propanoic acid; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-methylene) methyl]-N-(2-(diethylin) ethyl-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-fluoro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 5-[(Z)-(5-chloro-2-oxygen-1; 2-dihydro-3H-indole-3-subunit) methyl]-2; 4-dimethyl-N-(2-pyrrolidinyl-1-ethyl)-1H-pyrroles-3-carboxylic acid amides; 3-[[3-phenyl-4 (3H)-quinazolinone-2-methyl] TGA] hydrazono-]-the 1H-2-dihydroindole ketone; 3-two (4-anisyl) methylene-2-dihydroindole ketone; 3-[4-formyl piperazine-4yl]-benzal]-the 2-dihydroindole ketone; 3-([5-imidazoles] 2; 1-methylene thiazole)-the 2-dihydroindole ketone; 3-1 (2; 6-methylimidazole [2; 1-Bj-thiazole-5-yl] methylene-5-methoxyl group-2-dihydroindole ketone; imidazoles [2; 1-b] methylene thiazole-2-dihydroindole ketone; methylene indole-2-dihydroindole ketone; (2-chloro-indole) methylene-2-dihydroindole ketone; arlydene 2-dihydroindole ketone; 1; 3-dihydro-5; 6-dimethoxy-3-[(4-hydroxyphenyl) methylene]-2H-indole-2-dihydroindole ketone; 3-(4-dimethylamino-benzal)-2-dihydroindole ketone; 5-chloro-3-methylene pyridine-2-dihydroindole ketone; 3; 3-lutidines-1-phenyl-2-dihydroindole ketone or E-3-(2-chloro-3-methylene indole) 1,3-indoline-2-dihydroindole ketone; BMS 354825; Avastin; Cl 1033; Sorafenib; Sutent; TLK286; ABX-EGF is preferred.

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

Above-mentioned vasoinhibitor shared ratio in slow releasing agent is decided because of concrete condition, can be 0.1%-50%, is good with 1%-40%, and 2%-30% is best.

Phosphoinositide 3-kinase (phosphoinositide 3-kinase, being called for short PI3K) inhibitor is selected from one of following or combination: 7-(hydroxy-star shaped spore native (7-hydroxyl-staurosporine, UCN-01), 7-O-alkyl-star shaped spore native (UCN-02), the beta-methoxy-star shaped spore native, alkyl phosphate choline (alkylphosphocholines), hexa-decyl choline phosphate (hexadecyl phosphocholine, MIL, HPC, Miltefosine), octadecyl-(1, the 1-dimethyl-4-piperidine) (Octadecyl-(1 for phosphate, 1-dimethyl-4-piperidylio) phosphate, perifosine, D-21266), 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine (AMG-PC, 1-O-hexadecyl-2-O-methyl-rac-glycero-3-phosphocholine, ET-16-OCH3), 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine (1-O-Octadecyl-2-O-methyl-rac-glycerophosphocholine, ET-18-OCH3, edelfosine), 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine, ilmofosine, L-ET-18-OCH (3)), inositolpolyphosphates (inositol polyphosphates), the basic phosphocholine of 14 (alkane) (Tetradecyl phosphocholine, TPC), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine (hexadecylphospho (N-N-N-trimethyl) hexanolamine, HPC6), D 19391 (octadecylphosphocholine, OPC), octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate (octadecyl-[2-(N-methyl piperidinio) ethyl]-phosphate, D-20133 or OMPEP).

In the above phosphoinositide 3-kinase inhibitor, with 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391 or octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate.Serve as preferred wherein with 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate.

Pyrimidine analogue mainly is selected from O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, one or more of 4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine.

DNA repairase inhibitor can be kinases inhibitor and/or poly-(ADP-ribose) AG14361 that any DNA-relies on, but with imidazopyrazine, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, aminotriazole(ATA) (AT) and DL-Buthionine-(S,R)-sulfoximine BSO are preferred.

When the cancer therapy drug in the medicament slow-release microsphere only was vasoinhibitor or its synergist, the application of slow-releasing anticarcinogen injection and potentiation mode were:

(1) contain the slow releasing injection local injection of vasoinhibitor, other approach of vasoinhibitor synergist are used;

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

(3) local injection contains the slow releasing injection and the slow releasing injection that contains the vasoinhibitor synergist of vasoinhibitor; Or

(4) local injection contains the slow releasing injection of vasoinhibitor and synergist.

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

The percentage by weight of vasoinhibitor synergist in medicament slow-release microsphere is 0.5%-60%, is good with 1%-40%, is best with 5%-30%.The weight ratio of vasoinhibitor and vasoinhibitor synergist is 1-9: 1 to 1: 1-9.With 1-2: 1 serves as preferred.

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

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

(b) 7-hydroxy-star shaped spore native of 1-40%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;

(c) the O4-benzyl folic acid, 2 of 1-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine;

(d) imidazopyrazine of 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO;

(e) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, 7-hydroxy-star shaped spore native of TLK286 or ABX-EGF and 1-40%, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, the combination of alkyl phosphate choline or hexa-decyl choline phosphate;

(f) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the O4-benzyl folic acid of TLK286 or ABX-EGF and 1-40%, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine;

(j) gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the imidazopyrazine of TLK286 or ABX-EGF and 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 6-aromatic radical-2-morphol-4-base-pyrans-4-base, 2-(4-Lin Ji)-8-phenylchromone, 7-ethyl-10-hydroxycamptothecine, 3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1, phenylbutyric acid, methoxamine, hydroxylamine, inositolpolyphosphates, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.

One of the copolymer (PLGA) of the preferred polifeprosan of slow-release auxiliary material, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid) copolymer, poly-(fumaric acid-decanedioic acid) copolymer, polylactic acid (PLA), polyglycolic acid and hydroxyacetic acid, ethylene vinyl acetate copolymer (EVAc) or its combination.

When selecting the copolymer (PLGA) of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid (PLA) and mixture, glycolic and the hydroxy carboxylic acid of polyglycolic acid for use, PLA and PLGA content percentage by weight are respectively 0.1-99.9% and 99.9-0.1%.The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 30,000-50,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.

In various high molecular polymers, with polylactic acid, decanedioic acid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, glycolic and hydroxy carboxylic acid, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.The blend ratio of glycolic and hydroxy carboxylic acid is 10/90-90/10 (weight), preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and hydroxy carboxylic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is polifeprosan [poly-(1,3-two (to the carboxyl phenoxy group) propane-decanedioic acid) (p (CPP-SA)), bis-fatty acid-decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] and poly-(fumaric acid-decanedioic acid) [P (FA-SA)] etc.Content during to carboxylic phenoxypropane (p-CPP) and decanedioic acid copolymerization is respectively percentage by weight 10-60% and 20-90%, and the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.

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

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

In the slow releasing injection, drug sustained release system can be made into microsphere, sub-micro ball, microemulsion, nanosphere, granule or spherical piller, makes the injection use then with after the injection solvent mixes.In various slow releasing injection, serve as preferred with the suspension type slow releasing injection, the suspension type slow releasing injection is the preparation that the drug sustained release system that will contain anticancer component is suspended in gained in the injection, used adjuvant is a kind of or its combination in the above-mentioned slow-release auxiliary material, and used solvent is common solvent or the special solvent that contains suspending agent.Common solvent is, but is not limited to the buffer that distilled water, water for injection, physiology are prepared towards liquid, dehydrated alcohol or various salt.The purpose of suspending agent is the pastille microsphere that effectively suspends, thereby is beneficial to the usefulness of injection.

Suspending agent is selected from one of sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

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

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

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

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

The 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 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).So 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, certain herbaceous plants with big flowers diacid, the mixture or the copolymer that contain the macromolecule polymer of polylactic acid or certain herbaceous plants with big flowers diacid is first-selection, mixture and copolymer can be selected from, but be not limited to the mixture or the copolymer of the mixture of PLA, PLGA, PLA and PLGA, certain herbaceous plants with big flowers diacid and fragrant polyanhydride or aliphatic polyanhydride.Polylactic acid (PLA) is 10/90-90/10 (weight) with the blend ratio of polyglycolic acid, preferably 25/75-75/25 (weight).The method of blend is arbitrarily.Content when glycolic and lactic acid copolymerization is respectively percentage by weight 10-90% and 90-10%.The representative of fragrance polyanhydride is to carboxy phenyl propane (p-CPP), content during to carboxy phenyl propane (p-CPP) and the copolymerization of certain herbaceous plants with big flowers diacid is respectively percentage by weight 10-60% and 20-90%, the blend weight ratio is 10-40: 50-90, preferably weight ratio 15-30: 65-85.

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

The 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 pill, tablet, powder, granule, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.

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

Anticancer effective component and percentage by weight in the sustained-release implant are preferably as follows:

When the cancer therapy drug in the medicament slow-release microsphere only is vasoinhibitor or its synergist, the application of anti-cancer sustained-released implantation agent and the same slow releasing injection of potentiation mode.

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.

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.

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 after the vasoinhibitor (gefitinib) compares

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

The interior tumor-inhibiting action of body that test 2, different modes are used after the vasoinhibitor (Erlotinib) compares

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

Test 3, contain tumor-inhibiting action in the body of vasoinhibitor and vasoinhibitor synergist (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is all through intratumor injection.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 10th day.

Table 1

Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value
Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value	1(6)	Contrast	68±10
2(6	Vasoinhibitor	50±5.0	＜0.05	1(6)	Contrast	68±10
2(6	Vasoinhibitor	50±5.0	＜0.05	3(6)	UCN-01	52±2.0	＜0.01
4(6)	UCN-02	48±2.2	＜0.01	3(6)	UCN-01	52±2.0	＜0.01
4(6)	UCN-02	48±2.2	＜0.01	5(6)	MIL	58±5.2	＜0.01
6(6)	D-21266	40±3.0	＜0.01	5(6)	MIL	58±5.2	＜0.01
6(6)	D-21266	40±3.0	＜0.01	7(6)	Vasoinhibitor+UCN-01	20±2.0	＜0.001
8(6)	Vasoinhibitor+UCN-02	32±3.6	＜0.001	7(6)	Vasoinhibitor+UCN-01	20±2.0	＜0.001
8(6)	Vasoinhibitor+UCN-02	32±3.6	＜0.001	9(6)	Vasoinhibitor+MIL	30±3.2	＜0.001
10(6)	Vasoinhibitor+D-21266	18±2.2	＜0.001	9(6)	Vasoinhibitor+MIL	30±3.2	＜0.001

Above result shows, vasoinhibitor (gefitinib) and used vasoinhibitor synergist-phosphoinositide 3-kinase (PI3K) inhibitor (UCN-01:7-hydroxy-star shaped spore native wherein; UCN-02:7-O-alkyl-star shaped spore native; MIL:Miltefosine; D-21266: octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate or perifosine) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

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

Used tumor cell comprises CNS-1, C6,9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT), hepatocarcinoma etc.Vasoinhibitor and vasoinhibitor synergist are added in 24 hours the various tumor cells of In vitro culture by 10ug/ml concentration, continue to cultivate counting cells sum after 48 hours.Its growth of tumour cell suppresses effect and is shown in Table 2.

Table 2

Oncocyte	Erlotinib	O4-BA	UCN-01	UCN-02	Erlotinib+O4-BA	Erlotinib+UCN-1	Erlotinib+UCN-2
Oncocyte	Erlotinib	O4-BA	UCN-01	UCN-02	Erlotinib+O4-BA	Erlotinib+UCN-1	Erlotinib+UCN-2	CNS	30％	50％	62％	62％	88％	86％	80％
C6	34％	64％	60％	64％	94％	80％	94％	CNS	30％	50％	62％	62％	88％	86％	80％
C6	34％	64％	60％	64％	94％	80％	94％	SA	38％	60％	50％	62％	86％	92％	92％
BC	36％	62％	54％	64％	94％	82％	82％	SA	38％	60％	50％	62％	86％	92％	92％
BC	36％	62％	54％	64％	94％	82％	82％	BA	38％	60％	62％	60％	92％	92％	92％
LH	42％	56％	62％	58％	90％	86％	84％	BA	38％	60％	62％	60％	92％	92％	92％
LH	42％	56％	62％	58％	90％	86％	84％	PAT	44％	50％	66％	52％	90％	82％	82％

Above result shows, used vasoinhibitor (valrubicin) and vasoinhibitor synergist (O4-BA:O4-benzyl uric acid; UCN-01:7-hydroxy-star shaped spore native; UCN-02:7-O-alkyl-star shaped spore native) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

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

With the rat is subjects, with 2 * 10 ⁵Individual tumor cell of liver subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it following 10 groups (seeing Table 3).First group is contrast, and the 2nd to 10 group is the treatment group, and sustained-release implant is placed in tumor.Dosage is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 10th day.

Table 3

Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value
Test group (n)	Suffered treatment	Gross tumor volume (cm ³)	The P value	1(6)	Contrast	72±10
2(6)	ilmofosine	46±5.0	＜0.05	1(6)	Contrast	72±10
2(6)	ilmofosine	46±5.0	＜0.05	3(6)	Vasoinhibitor	50±2.2	＜0.01
4(6)	The ilmofosine+ vasoinhibitor	32±2.6	＜0.001	3(6)	Vasoinhibitor	50±2.2	＜0.01
4(6)	The ilmofosine+ vasoinhibitor	32±2.6	＜0.001	5(6)	AMG-PC	48±3.2	＜0.01
6(6)	The AMG-PC+ vasoinhibitor	22±3.0	＜0.001	5(6)	AMG-PC	48±3.2	＜0.01
6(6)	The AMG-PC+ vasoinhibitor	22±3.0	＜0.001	7(6)	edelfosine	32±2.6	＜0.01
8(6)	The Edelfosine+ vasoinhibitor	22±2.4	＜0.001	7(6)	edelfosine	32±2.6	＜0.01
8(6)	The Edelfosine+ vasoinhibitor	22±2.4	＜0.001	9(6)	IDOU	32±3.4	＜0.01
10(6)	The IDOU+ vasoinhibitor	18±2.2	＜0.001	9(6)	IDOU	32±3.4	＜0.01

Above result shows, used vasoinhibitor (Lapatinib) and vasoinhibitor synergist-PI3K inhibitor (wherein, AMG-PC:1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine; Edelfosine:1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine; Ilmofosine:1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine; IDOU:5-iodo-2 '-deoxyguanosine) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

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

With the rat is subjects, with 2 * 10 ⁵Individual prostate tumor cells subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (vasoinhibitor or vasoinhibitor synergist) and therapeutic alliance group (vasoinhibitor and vasoinhibitor synergist).Vasoinhibitor is through intratumor injection, and the vasoinhibitor synergist is through lumbar injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 4) of index with inhibition rate of tumor growth.

Table 4

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Vasoinhibitor	60	＜0.05	1(6)	Contrast	-
2(6)	Vasoinhibitor	60	＜0.05	3(6)	Imidazopyrazine	28	＜0.01
4(6)	Imidazopyridine	38	＜0.01	3(6)	Imidazopyrazine	28	＜0.01
4(6)	Imidazopyridine	38	＜0.01	5(6)	Wortmannin	34	＜0.01
6(6)	.alpha.-5:6-benzopyran	30	＜0.01	5(6)	Wortmannin	34	＜0.01
6(6)	.alpha.-5:6-benzopyran	30	＜0.01	7(6)	Vasoinhibitor+imidazopyrazine	88	＜0.001
8(6)	Vasoinhibitor+imidazopyridine	80	＜0.001	7(6)	Vasoinhibitor+imidazopyrazine	88	＜0.001
8(6)	Vasoinhibitor+imidazopyridine	80	＜0.001	9(6)	Vasoinhibitor+wortmannin	82	＜0.001
10(6)	Vasoinhibitor+.alpha.-5:6-benzopyran	84	＜0.001	9(6)	Vasoinhibitor+wortmannin	82	＜0.001

Above result shows, the kinases inhibitor that used vasoinhibitor (votaranib) and vasoinhibitor synergist-DNA-relies on (wherein, imidazopyrazine, imidazopyridine, wortmannin .alpha.-5:6-benzopyran) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

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

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

Table 5

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Vasoinhibitor	48	＜0.05	1(6)	Contrast	-
2(6)	Vasoinhibitor	48	＜0.05	3(6)	LY294002	70	＜0.01
4(6)	SU11752	66	＜0.01	3(6)	LY294002	70	＜0.01
4(6)	SU11752	66	＜0.01	5(6)	SN-38	74	＜0.01
6(6)	OK-1035	66	＜0.01	5(6)	SN-38	74	＜0.01
6(6)	OK-1035	66	＜0.01	7(6)	Vasoinhibitor+LY294002	88	＜0.001
8(6)	Vasoinhibitor+SU11752	96	＜0.001	7(6)	Vasoinhibitor+LY294002	88	＜0.001
8(6)	Vasoinhibitor+SU11752	96	＜0.001	9(6)	Vasoinhibitor+SN-38	92	＜0.001
10(6)	Vasoinhibitor+OK-1035	92	＜0.001	9(6)	Vasoinhibitor+SN-38	92	＜0.001

Above result shows, kinases inhibitor (wherein, LY294002:2-(4-Lin Ji)-8-phenylchromone that used vasoinhibitor (WAY-EKB 569) and vasoinhibitor synergist-DNA-relies on; SU11752: inhibitors of kinases; SN-38:7-ethyl-10-hydroxycamptothecine; Growth all has the obvious suppression effect to OK-1035:3-cyano group-6-hydrazono-methyl-5-(4-pyridine radicals) pyridine-[1H]-2-1) to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

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

With the rat is subjects, with 2 * 10 ⁵Individual breast tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group, therapeutic alliance group.Sustained-release implant is all placed in tumor.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 10th day, made relatively therapeutic effect (seeing Table 6) of index with inhibition rate of tumor growth.

Table 6

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Vasoinhibitor	48	＜0.05	1(6)	Contrast	-
2(6)	Vasoinhibitor	48	＜0.05	3(6)	Methoxamine	30	＜0.05
4(6)	Minocycline	38	＜0.05	3(6)	Methoxamine	30	＜0.05
4(6)	Minocycline	38	＜0.05	5(6)	Hydroxylamine	32	＜0.05
6(6)	O-methyl hydroxylamine	30	＜0.01	5(6)	Hydroxylamine	32	＜0.05
6(6)	O-methyl hydroxylamine	30	＜0.01	7(6)	Vasoinhibitor+methoxamine	82	＜0.01
8(6)	Vasoinhibitor+minocycline	74	＜0.01	7(6)	Vasoinhibitor+methoxamine	82	＜0.01
8(6)	Vasoinhibitor+minocycline	74	＜0.01	9(6)	Vasoinhibitor+hydroxylamine	84	＜0.01
10(6)	Vasoinhibitor+O-methyl hydroxylamine	88	＜0.001	9(6)	Vasoinhibitor+hydroxylamine	84	＜0.01

Above result shows, growth all has the obvious suppression effect to the kinases inhibitor that used vasoinhibitor (imatinib mesylate) and vasoinhibitor synergist-DNA-relies on to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

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

By the tumor-inhibiting action of test 8 described methods mensuration vasoinhibitors and vasoinhibitor synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 7.

Table 7

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
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)	3-AB	46	＜0.01
4(6)	Benzoylamide	46	＜0.01	3(6)	3-AB	46	＜0.01
4(6)	Benzoylamide	46	＜0.01	5(6)	PD128763	42	＜0.01
6(6)	AG14361	38	＜0.01	5(6)	PD128763	42	＜0.01
6(6)	AG14361	38	＜0.01	7(6)	Vasoinhibitor+3-AB	78	＜0.001
8(6)	Vasoinhibitor+Benzoylamide	76	＜0.001	7(6)	Vasoinhibitor+3-AB	78	＜0.001
8(6)	Vasoinhibitor+Benzoylamide	76	＜0.001	9(6)	Vasoinhibitor+PD128763	84	＜0.001
10(6)	Vasoinhibitor+AG14361	80	＜0.001	9(6)	Vasoinhibitor+PD128763	84	＜0.001

Above result shows, used vasoinhibitor (thalidomide) and vasoinhibitor synergist-poly-(ADP-ribose) AG14361 (wherein, 3-AB:3-aminobenzamide; Benzoylamide; PD 128763:3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide; AG14361: AG14361) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

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

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

Table 8

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)	BZ1-6	52	＜0.01
4(6)	TI1-5	38	＜0.01	3(6)	BZ1-6	52	＜0.01
4(6)	TI1-5	38	＜0.01	5(6)	TBC	44	＜0.01
6(6)	Benzimidazole	48	＜0.01	5(6)	TBC	44	＜0.01
6(6)	Benzimidazole	48	＜0.01	7(6)	Vasoinhibitor+BZ1-6	78	＜0.001
8(6)	Vasoinhibitor+TI1-5	80	＜0.001	7(6)	Vasoinhibitor+BZ1-6	78	＜0.001
8(6)	Vasoinhibitor+TI1-5	80	＜0.001	9(6)	Vasoinhibitor+TBC	76	＜0.001
10(6)	Vasoinhibitor+benzimidazole	90	＜0.001	9(6)	Vasoinhibitor+TBC	76	＜0.001

Above result shows, used vasoinhibitor (Sugen 5416) and vasoinhibitor synergist-poly-(ADP-ribose) AG14361 (wherein, BZ1-6: benzimidazole-4-carboxamides BZ1-6; TI1-5: tricyclic lactam hydrogen sulfide; TBC: three ring benzimidazole carboxylic acid amides, benzimidazole) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 11, vasoinhibitor and/or vasoinhibitor synergist (sustained-release implant)

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

Table 9

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Vasoinhibitor	40	＜0.05	1(6)	Contrast	-
2(6)	Vasoinhibitor	40	＜0.05	3(6)	NU1025	56	＜0.01
4(6)	PBC	42	＜0.01	3(6)	NU1025	56	＜0.01
4(6)	PBC	42	＜0.01	5(6)	MPBC	40	＜0.01
6(6)	NU1085	46	＜0.01	5(6)	MPBC	40	＜0.01
6(6)	NU1085	46	＜0.01	7(6)	Vasoinhibitor+NU1025	88	＜0.001
8(6)	Vasoinhibitor+PBC	82	＜0.001	7(6)	Vasoinhibitor+NU1025	88	＜0.001
8(6)	Vasoinhibitor+PBC	82	＜0.001	9(6)	Vasoinhibitor+MPBC	78	＜0.001
10(6)	Vasoinhibitor+NU1085	90	＜0.001	9(6)	Vasoinhibitor+MPBC	78	＜0.001

Above result shows, used vasoinhibitor (BMS 354825) and vasoinhibitor synergist-poly-(ADP-ribose) AG14361 (wherein, PBC:2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6; MPBC:2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6 (2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide); NU1025:8-hydroxy-2-methyl quinazolinone; NU1085:2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 12, vasoinhibitor and/or vasoinhibitor synergist (sustained-release implant)

By the tumor-inhibiting action of test 6 described methods mensuration vasoinhibitors and/or vasoinhibitor synergist (sustained-release implant), its inhibition rate of tumor growth sees Table 10.

Table 10

Test group (n)	Suffered treatment	Tumor control rate (%)	The P value
Test group (n)	Suffered treatment	Tumor control rate (%)	The P value	1(6)	Contrast	-
2(6)	Vasoinhibitor	62	＜0.05	1(6)	Contrast	-
2(6)	Vasoinhibitor	62	＜0.05	3(6)	BSO	56	＜0.01
4(6)	Aminotriazole(ATA)	34	＜0.01	3(6)	BSO	56	＜0.01
4(6)	Aminotriazole(ATA)	34	＜0.01	5(6)	Cavatic acid	42	＜0.01
6(6)	New podophyllotoxin	40	＜0.01	5(6)	Cavatic acid	42	＜0.01
6(6)	New podophyllotoxin	40	＜0.01	7(6)	Vasoinhibitor+BSO	84	＜0.001
8(6)	Vasoinhibitor+aminotriazole(ATA)	84	＜0.001	7(6)	Vasoinhibitor+BSO	84	＜0.001
8(6)	Vasoinhibitor+aminotriazole(ATA)	84	＜0.001	9(6)	Vasoinhibitor+cavatic acid	78	＜0.001
10(6)	Vasoinhibitor+new podophyllotoxin	88	＜0.001	9(6)	Vasoinhibitor+cavatic acid	78	＜0.001

Above result shows, used vasoinhibitor (Cl 1033) and vasoinhibitor synergist-poly-(ADP-ribose) AG14361 (wherein, BSO is a DL-Buthionine-(S,R)-sulfoximine BSO) growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately, can show significant potentiation when use in conjunction.

Further test shows that gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF can strengthen the action effect of poly-(ADP-ribose) AG14361 and other vasoinhibitor synergist to some extent.

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

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

(4) specific embodiment

Embodiment 1.

80mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg gefitinib and 7-hydroxy-star shaped spore native, shake up the back contains 10% gefitinib and 10%7-hydroxy-star shaped spore native with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 2.

The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that contained anticancer effective component and percentage by weight thereof are:

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

(2) 7-hydroxy-star shaped spore native of 1-40%, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine, inositolpolyphosphates, cyclosporin A, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391 or octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate; Or

(3) 1-40% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, 7-hydroxy-star shaped spore native of TLK286 or ABX-EGF and 2-40%, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine, inositolpolyphosphates, cyclosporin A, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391 or octadecyl-[2-(N-methyl piperidine) ethyl]-phosphatic combination.

Embodiment 3.

With 70mg molecular weight peak value 65000 polylactic acid (PLGA, 75: 25) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 15mg Erlotinib and 15mg7-ethyl-10-hydroxycamptothecine, shake up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% Erlotinib and 15%7-ethyl-10-hydroxycamptothecine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 20-35 days, is about 35-50 days at the subcutaneous drug release time of mice.

Embodiment 4

The method step that is processed into slow releasing injection is identical with embodiment 3, but different is that contained anticancer effective component and percentage by weight thereof are:

(1) imidazopyrazine of 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 2-(morphol-4-yl)-.alpha.-5:6-benzopyran-4-base, 2-(4-Lin Ji)-8-phenylchromone, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-, inhibitors of kinases, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, phenylbutyric acid salt, methylamine, methoxamine, hydroxylamine, minocycline, the O-hydroxylamine, O-methyl hydroxylamine or O-δ-ammonia oxygen-butyl hydroxylamine; Or

(2) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the imidazopyrazine of TLK286 or ABX-EGF and 1-40%, imidazopyridine, wortmannin, .alpha.-5:6-benzopyran, 2-(morphol-4-yl)-.alpha.-5:6-benzopyran-4-base, 2-(4-Lin Ji)-8-phenylchromone, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-, inhibitors of kinases, vanillin, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, phenylbutyric acid salt, methylamine, methoxamine, hydroxylamine, minocycline, the O-hydroxylamine, the combination of O-methyl hydroxylamine or O-δ-ammonia oxygen-butyl hydroxylamine.

Embodiment 5.

(EVAc) puts into container with the 70mg ethylene vinyl acetate copolymer, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of Lapatinibs and 10 milligrams of benzimidazoles, shake up the back contains 20% Lapatinib and 10% benzimidazole with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 6.

The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that contained anticancer effective component is:

(1) the 3-aminobenzamide of 1-40%, Benzoylamide, 3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, the poly polymerase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide, three ring benzimidazole carboxylic acid amides, benzimidazole, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6,8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6; Or

(2) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the 3-aminobenzamide of TLK286 or ABX-EGF and 1-40%, Benzoylamide, 3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, the poly polymerase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide, three ring benzimidazole carboxylic acid amides, benzimidazole, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6, the combination of 8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6.

Embodiment 7.

70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg votaranib and 10mg DL-Buthionine-(S,R)-sulfoximine BSO, shake up the back contains 20% votaranib and 10% DL-Buthionine-(S,R)-sulfoximine BSO with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 8.

The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is:

(1) glutathione bisulphide of 1-40%, tetramethylthiuram disulfide, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin; Or

(2) gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the glutathione bisulphide of TLK286 or ABX-EGF and 2-40%, tetramethylthiuram disulfide, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin, the combination of Exatecan mesylate or TAN-1518.

Embodiment 9

70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg WAY-EKB 569 and 10mgO4-benzyl folic acid, shake up the back contains 20% WAY-EKB 569 and 10%O4-benzyl folic acid with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection.The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 10

The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is:

(1) the O4-benzyl folic acid, 2 of 10-40%, 4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2,4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine; Or

(2) gefitinib of 10-30%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, the O4-benzyl folic acid of TLK286 or ABX-EGF and 10-40%, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine.

Embodiment 11

70mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 20: 80) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg7-hydroxy-star shaped spore native and 20mg BMS 354825, shake up the back contains 10%7-hydroxy-star shaped spore native and 20% BMS 354825 with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 30-40 days at the subcutaneous drug release time of mice.

Embodiment 12

The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is:

20% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 7-hydroxy-star shaped spore native of 10%, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, the combination of alkyl phosphate choline or hexa-decyl choline phosphate.

Embodiment 13

With 70mg molecular weight peak value 80000 polylactic acid (PLGA, 50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg Avastin and the new podophyllotoxin of 20mg, shake up the back contains 10% Avastin and 20% new podophyllotoxin with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 25-30 days, is about 35-50 days at the subcutaneous drug release time of mice.

Embodiment 14

Be processed into the method step and the embodiment 11 of sustained-release implant, 13 is identical, but different is that contained anticancer effective component is: 10% gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, the blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 20% aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin, the combination of Exatecan mesylate or TAN-1518.

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, molecular weight peak value are 10000-30000,300000-60000,60000-100000 or 100000-150000;

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

C) ethylene vinyl acetate copolymer;

D) polifeprosan, to carboxy phenyl propane: the certain herbaceous plants with big flowers diacid is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;

E) bis-fatty acid and decanedioic acid copolymer;

F) poly-(erucic acid dimer-decanedioic acid);

G) poly-(fumaric acid-decanedioic acid);

H) xylitol, oligosaccharide, chrondroitin, chitin, hyaluronic acid, collagen protein, gelatin or white tempera.

Embodiment 16

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

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

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20.

Embodiment 17

The method step that is processed into slow releasing injection is identical with embodiment 11-15, but different is that contained anticancer effective component is:

(c) the O4-benzyl folic acid of 1-40%;

(d) methoxamine of 1-40%, hydroxylamine, inositolpolyphosphates, aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO;

(f) combination of the O4-benzyl folic acid of the gefitinib of 1-40%, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 1-40%;

(j) combination of methoxamine, hydroxylamine, aminotriazole(ATA) or the DL-Buthionine-(S,R)-sulfoximine BSO of gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF and 1-40%.

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

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

Claims

1. anti-cancer medicine sustained-release injection is grouped into by following one-tenth:

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.5-60%

Slow-release auxiliary material 40-99%

Suspending agent 0.0-30%

More than be weight percentage

With

Wherein,

Anticancer effective component is vasoinhibitor and/or its synergist, and the vasoinhibitor synergist is selected from phosphoinositide 3-kinase inhibitor, pyrimidine analogue and/or DNA repairase inhibitor;

Suspending agent is selected from one of sodium carboxymethyl cellulose, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination;

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

2. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that vasoinhibitor is selected from gefitinib, Erlotinib, Lapatinib, votaranib, WAY-EKB 569, NSC 609974, thalidomide, LS-2616, angiostatin, Endostatin, blood vessel endothelium chalone, imatinib mesylate, NSC 609974, thalidomide, LS-2616, Sugen 5416, BMS 354825, Avastin, Cl 1033, Sorafenib, Sutent, TLK286 or ABX-EGF.

3. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that phosphoinositide 3-kinase inhibitor is selected from 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, the beta-methoxy-star shaped spore native, alkyl phosphate choline, hexa-decyl choline phosphate, octadecyl-(1, the 1-dimethyl-4-piperidine) phosphate, 1-O-six decyls-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-glyceryl-3-phosphocholine, inositolpolyphosphates, cyclosporin A, the basic phosphocholine of 14 (alkane), six certain herbaceous plants with big flowers base phosphoric acid (N-N-N-trimethyl) hexanol amine, D 19391, one of octadecyl-[2-(N-methyl piperidine) ethyl]-phosphate or its combination.

4. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that pyrimidine analogue is selected from O4-benzyl folic acid, 2,4,5-triamido-6-benzyloxy pyrimidine, 2,4-diaminourea-6-benzyloxy-5-nitroso-group pyrimidine, 2,4-diaminourea-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitro-pyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitro pyrimidine, 2, one of 4-diaminourea-6-benzyloxy-s-triazine, 2-amino-O4-benzyl pteridine or its combination.

5. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that DNA repairase inhibitor is selected from one of following or its combination:

(a) 2-(morphol-4-yl)-.alpha.-5:6-benzopyran-4-base, 2-(4-Lin Ji)-8-phenylchromone, 1-(2-hydroxyl-4-morphol-4-base-phenyl)-ethano-, inhibitors of kinases, 2-aminopurine, 7-ethyl-10-hydroxycamptothecine, phenylbutyric acid salt, methylamine, methoxamine, hydroxylamine, minocycline, O-hydroxylamine, O-methyl hydroxylamine or O-δ-ammonia oxygen-butyl hydroxylamine;

(b) 3-aminobenzamide, Benzoylamide, 3,4-dihydro methoxy isoquinolin-1 (2H)-Benzoylamide, AG14361, the poly synthase inhibitor, the amino 2-aromatic radical benzimidazole-4-carboxamides BZ1-6 that replaces, benzimidazole-4-carboxamides BZ1-6, tricyclic lactam hydrogen sulfide, three ring benzimidazole carboxylic acid amides, benzimidazole, 1H-three ring benzimidazole carboxylic acid amides, 2-aromatic radical-1H-benzimidazole-4-carboxamides BZ1-6,2-phenyl-1H-benzimidazole-4-carboxamides BZ1-6,2-(4-hydroxymethyl phenyl)-1H-benzimidazole-4-carboxamides BZ1-6,2-(3-anisyl)-1H-benzimidazole-4-carboxamides BZ1-6,8-hydroxy-2-methyl quinazolinone or 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6;

(c) aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin, Exatecan mesylate or TAN-1518.

6. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that the anticancer effective component of slow-releasing anticarcinogen injection and percentage by weight are:

7. the slow-releasing anticarcinogen injection according to claim 6 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) ethylene vinyl acetate copolymer;

E) bis-fatty acid and decanedioic acid copolymer;

F) poly-(erucic acid dimer-decanedioic acid);

G) poly-(fumaric acid-decanedioic acid);

8. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that used suspending agent is respectively one of following or its combination:

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

B) 5-15% mannitol;

C) 5-15% sorbitol;

D) 0.1-1.5% surfactant;

E) 0.1-0.5% polysorbas20;

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

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

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

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

9. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that slow-releasing anticarcinogen injection is used for the preparation treatment and originates from people and animal brain, the central nervous system, kidney, liver, gallbladder, incidence, the oral cavity, thyroid, skin, mucosa, body of gland, blood vessel, osseous tissue, lymph node, lungs, esophagus, stomach, mammary gland, pancreas, eyes, nasopharynx part, the uterus, ovary, endometrium, cervix uteri, prostate, bladder, former or the cancer of secondary of colon or rectum, the suspensoid injectio of sarcoma or carcinosarcoma or sustained-release implant are in tumor or tumor week injection or place administration.

10. the slow-releasing anticarcinogen injection according to claim 9 is characterized in that the anticancer effective component of described anti-cancer sustained-released implantation agent is:

Slow-release auxiliary material is one of following or its combination:

C) ethylene vinyl acetate copolymer;

E) bis-fatty acid and decanedioic acid copolymer;

F) poly-(erucic acid dimer-decanedioic acid);

G) poly-(fumaric acid-decanedioic acid);