CN1969816A

CN1969816A - Anticancer sustained release agent containing epothilone

Info

Publication number: CN1969816A
Application number: CNA2006102012704A
Authority: CN
Inventors: 孙娟; 张婕; 邹会凤
Original assignee: Jinan Shuaihua Pharmaceutical Technology Co Ltd
Current assignee: Jinan Shuaihua Pharmaceutical Technology Co Ltd
Priority date: 2006-12-12
Filing date: 2006-12-12
Publication date: 2007-05-30

Abstract

Disclosed is an anti-cancer drugs slow release agent containing Epothilone which comprises slow release microspheres and dissolvent, wherein the slow release microballoons comprise anti-cancer active constituents and slow release auxiliary materials, the dissolvent being specific dissolvent containing suspension adjuvant. The anticancer active constituents include Epothilone, Epothilone derivatives, Epothilone B, Epothilone D and combination of anti-cancer drugs selected from phosphoinositide-3-kinase inhibitor, of pyrimidine analogues and/or DNA restoring enzyme inhibitor, the slow release auxiliary materials include polylactic acid and its copolymer, polyethylene glycol, PLA-COOH copolymer, di-aliphatic acid and sebacylic acid copolymer, poly(erucic aciddipolymer-sebacylic acid), poly(fumaric acid-sebacylic acid), Polifeprosan, polylactic acid and other biocompatible high polymers, the viscosity of the suspension adjuvant is 100-3000cp (at 20-30 deg C), and is selected from sodium carboxymethylcellulose. The anticancer active constituents and the slow release microspheres can also be prepared into slow release implanting agent for intra-tumor or around-tumor injection or placement for the effective suppression of tumor growth and for the appreciable enhancement for curative effects of non-operative treatments such as chemotherapy.

Description

A kind of anticancer sustained-release agent that contains Epothilones

(1) technical field

The present invention relates to a kind of anticancer sustained-release agent that contains Epothilones, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains Epothilones and synergist thereof.

(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).

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 in 2000, Cancer Res.2000,60 (9): 2497-503).

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.

Antitumor drug local injection or placement 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 etal., J Surg 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 single medicine chemotherapy often causes tumor cell that the toleration of cancer therapy drug is increased, consequently treatment failure.

(3) summary of the invention

The present invention is directed to the deficiencies in the prior art, a kind of new pharmaceutical composition is provided, contain epothilone derivate, share with cancer therapy drug and can make its potentiation.More specifically, this pharmaceutical composition is the slow releasing agent of anti entity tumour, is mainly sustained-release implant and slow releasing injection.Decapacitation suppresses can also increase the sensitivity of tumor cell to cancer therapy drug outside the tumor growth.

In addition, with Epothilones and or cancer therapy drug make 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, reduce the toxicity of medicine 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 Epothilones and derivant thereof outside the tumor growth.

Controlled release formulation for anti entity tumour of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is the combination of Epothilones and phosphoinositide 3-kinase (P13K) inhibitor, pyrimidine analogue and/or DNA repairase inhibitor.

Epothilone derivate is selected from one of following or combination: Epothilones (Epothilone) or epothilone derivate, epothilone derivate is selected from Epothilones A, epothilone B (Patupilone, EPO-906), Epothilone C (-)-Deoxyepothilone A (Epothilone C, desoxyepothilone), epothilone d (epothilone D (EpoD), 12,13-desoxyepothilone B, Epothilone C B, dEpoB, KOS-862 or NSC-703147), Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F. etc. and their derivant.

Wherein, the derivant of Epothilone C (-)-Deoxyepothilone A as, but be not limited to 4-demethyl-9-ketone-Epothilone C (-)-Deoxyepothilone A, 12,13-dihydro-13-oxygen Epothilone C (-)-Deoxyepothilone A (12,13-dihydro-13-oxoepothilone C);

The derivant of epothilone B as, but be not limited to, 21 and 26 difference or the epothilone B that is replaced by amino simultaneously, 9,10 dehydrogenation epothilone Bs, 10,11 dehydrogenation epothilone Bs, 26,27 epothilone Bs that replaced by halogen, 9,10,11,14,21,26 epothilone Bs that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone B, 21-hydroxyl-10,11 dehydrogenation epothilone Bs, 4-demethyl-9-ketone-epothilone B, 4-demethyl-9,10-two dehydrogenation epothilone Bs, 4-demethyl-10,11-two dehydrogenation epothilone Bs, 6-demethyl-10,11-two dehydrogenation epothilone Bs, the amino epothilone B of 21-, 21-hydroxyl epothilone B, 26-hydroxyl epothilone B, 26-fluorine epothilone B, the amino epothilone B of 26-, 12,13 cyclopropyl epothilone Bs, 12,13 cyclobutyl epothilone Bs, ixabepilone (BMS-247550), Azaepothilone B (Azaepothilone B, oxygen in the lactone ring is replaced by nitrogen), 26-three fluoro-(E)-9,10-dehydrogenation-12,13-Epothilone C B (26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B[Fludelone (Flu)]); The derivant of epothilone d as, but be not limited to, 21 and 26 difference or the epothilone d that is replaced by amino simultaneously, 9 and 10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, 26,27 epothilone ds that replaced by halogen, 9,10,11,14,21,26 epothilone ds that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone d, 21-hydroxyl-10,11 dehydrogenation epothilone ds, 4-demethyl-9-ketone-epothilone d, 4-demethyl-9,10-two dehydrogenation epothilone ds, 4-demethyl-10,11-two dehydrogenation epothilone ds, 6-demethyl-10,11-two dehydrogenation epothilone ds, 21-hydroxyl epothilone d, the amino epothilone d of 21-, 26-hydroxyl epothilone d, the amino epothilone d of 26-, 26-fluorine epothilone d, the 6-ethyl, the 16-fluorine, 17-pyridine Epothilones (or isoesperamicin), isoesperamicin D, 9,10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, furan epothilone d (furano-epothilone D), (E)-9,10-dehydrogenation-12,13-Epothilone C D (E)-9,10-dehydro-12,13-desoxyepothiloneD), BMS-310705, the 6-ethyl, the 16-fluorine, 17-pyridine Epothilones (ZK-EPO), 11,12-dehydrogenation-12,13-dehydrogenation-13-Epothilone C D 11,12-dehydro-12,13-dihydro13-oxoepothilone D, 12,13-dehydrogenation-13-Epothilone C D (12,13-dihydro13-oxoepothilone D), 9-oxygen base epothilone d (9-oxoepothilone D), 8-table-9-oxygen base epothilone d (8-epi-9-oxoepothilone D).

A kind of or its combination among the preferred Epothilones of above-mentioned Epothilones and epothilone derivate, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, furan epothilone d, the BMS-310705.

Epothilones and epothilone derivate shared ratio in compositions is decided because of concrete condition, can be 0.1%-50%, is good with 1%-30%, and 5%-20% is best.

Phosphoinositide 3-kinase (phosphoinositide 3-kinase, being called for short P13K) inhibitor is selected from one of following or combination: 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.

Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, be selected from poly-dl-lactide (D, L-PLA), poly-dl-lactide/ethanol copolymer (D, L-PLGA), monomethyl polyethylene glycol (MPEG-PLA), monomethyl polyethylene glycol copolymer (MPEG-PLGA), polyethylene glycol (PLA-PEG-PLA), polyethylene glycol copolymer (PLGA-PEG-PLGA), end carboxyl polylactic acid (PLA-COOH), end carboxyl polylactic acid/ethanol copolymer (PLGA-COOH), polifeprosan, bis-fatty acid and decanedioic acid copolymer (PFAD-SA), poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)], poly-(fumaric acid decanedioic acid) [P (FA-SA)], ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), the copolymer of polyglycolic acid and hydroxyacetic acid (PLGA), PPDO (PDO), PTMC (PTMC), xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer, 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.

Pharmaceutic adjuvant have hundreds of more than, pharmaceutic adjuvant with slow releasing function, it is not apparent particularly selected active ingredient among the present invention slowly being discharged in the regular hour in human body or animal body, but specific slow-release auxiliary material need could be determined through a large amount of creative works with the selection of slow releasing pharmaceutical combination.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.

Compositions of the present invention can prepare medicine by known method, for example, draws, makes dragee, levigate, emulsifying, glue capsule, embedding or cryodesiccated method by mixing, dissolving, the system of routine.Carrier wherein comprises various excipient and adjuvant.Can make appropriate formulation according to selected route of administration.As prepare dosage forms such as injection, oral, suction, bolt, subsides, implantation.For through mucous membrane and administration percutaneous, using the penetrating agent that is suitable for permeability barrier in preparation is that this area is known usually.

Be used for oral formulations and can become tablet, pill, disintegrating agent, dragee, capsule, the capsule of slippaging, sealing soft capsule, liquid, gel, syrup, mud agent, suspension etc.

In various preparations, serve as preferred with long-lasting preparation, with the topical application durative action preparation for most preferably.The latter can pass through implantation (injection rectum, through mucous membrane, percutaneous, enteral, intramuscular, subcutaneous, that marrow is interior, and in the sheath, the directly injection of intraventricular, intravenous, endoperitoneal, intranasal or ophthalmic) be applied to tumor by local, its general toxicity that when effectively obtaining and keeping local drug concentration, obviously falls.

The local mode administration, for example, by direct injection to particular organization, usually to store or the form of extended release preparation.

Principal mode of the present invention is a slow releasing agent, comprises sustained-release implant and slow releasing injection.

A kind of principal mode 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 the combination of P13K inhibitor, pyrimidine analogue and/or DNA repairase inhibitor and epothilone derivate;

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

A) polylactic acid (PLA);

B) copolymer of polyglycolic acid and hydroxyacetic acid (PLGA);

C) polifeprosan;

D) combination of polifeprosan and PLA or PLGA;

E) bis-fatty acid and decanedioic acid copolymer;

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

G) poly-(fumaric acid decanedioic acid) copolymer.

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).

Anticancer effective component in the slow releasing injection microsphere is preferably as follows, and all is weight percentage:

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

(1) combination of 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or the hexa-decyl choline phosphate of the Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, furan epothilone d, BMS-310705 and 1-40%;

(2) Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, the furan epothilone d, the O4-benzyl folic acid of BMS-310705 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; Or

(3) Epothilones of the 1-40% of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, the furan epothilone d, the imidazopyrazine of BMS-310705 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; Or

(4) Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705.

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) combination of the PLGA of the PLA of the polifeprosan of 25-60% and 25-60% or 25-60%;

(6) xylitol of 40-95%, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer 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.

More than the combination in, the total amount of various adjuvants be no more than preparation heavy 98%.

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 10ep-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 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 volume size depends on factors such as the position, size of focus.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.

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

Anticancer effective component in the sustained-release implant and percentage by weight can be with reference to its slow releasing injection, but are preferably as follows:

(3) Epothilones of the 1-40% of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, the furan epothilone d, the imidazopyrazine of BMS-310705 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; Or

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

(1) PLA of 55-90%;

(2) PLGA of 50-90%;

(3) polifeprosan of 50-85%;

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

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

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.

The anticarcinogen amount of clinical practice depends on patient's concrete condition, can be from 0.1 to 3000mg/kg body weight, and 0.5 to 2000mg/kg is preferred, 0.8 to 1000mg/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 behind the Epothilones 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 is the 2.5mg/kg epothilone B.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of epothilone B 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 behind the epothilone d compares

With the rat is subjects, with 2 * 10 ⁵Individual breast tumor 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 epothilone d.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 epothilone d 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 Epothilones 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 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.Epothilone B is 2.5mg/kg, and cancer therapy drug is 10mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 1) on the 21st 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	64±10
2(6)	Epothilone B	46±5.0	＜0.05	1(6)	Contrast	64±10
2(6)	Epothilone B	46±5.0	＜0.05	3(6)	UCN-01	44±2.2	＜0.01
4(6)	UCN-02	32±2.4	＜0.01	3(6)	UCN-01	44±2.2	＜0.01
4(6)	UCN-02	32±2.4	＜0.01	5(6)	MIL	44±5.0	＜0.01
6(6)	D-21266	42±3.0	＜0.01	5(6)	MIL	44±5.0	＜0.01
6(6)	D-21266	42±3.0	＜0.01	7(6)	Epothilone B+UCN-01	20±2.2	＜0.001
8(6)	Epothilone B+UCN-02	30±3.4	＜0.001	7(6)	Epothilone B+UCN-01	20±2.2	＜0.001
8(6)	Epothilone B+UCN-02	30±3.4	＜0.001	9(6)	Epothilone B+MIL	22±3.2	＜0.001
10(6)	Epothilone B+D-21266	18±2.0	＜0.001	9(6)	Epothilone B+MIL	22±3.2	＜0.001

Above result shows, epothilone B and used cancer therapy drug-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, epothilone B and cancer therapy drug (slow releasing injection)

Used tumor cell comprises CNS-1, C6, gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT) etc.Medicine is through intratumor injection.Therapeutic effect (seeing Table 2).Epothilone B is 7.5mg/kg, and cancer therapy drug is 2.5mg/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

Oncocyte	Epothilone d	O4-BA	UCN-01	UCN-02	Epothilone d+O4-BA	Epothilone d+UCN-01	Epothilone d+UCN-02
Oncocyte	Epothilone d	O4-BA	UCN-01	UCN-02	Epothilone d+O4-BA	Epothilone d+UCN-01	Epothilone d+UCN-02	CNS	34％	52％	62％	62％	86％	84％	80％
C6	34％	64％	60％	64％	74％	80％	90％	CNS	34％	52％	62％	62％	86％	84％	80％
C6	34％	64％	60％	64％	74％	80％	90％	SA	28％	60％	50％	62％	86％	82％	82％
BC	38％	62％	54％	66％	74％	82％	82％	SA	28％	60％	50％	62％	86％	82％	82％
BC	38％	62％	54％	66％	74％	82％	82％	BA	28％	60％	62％	60％	92％	90％	82％
LH	42％	56％	62％	58％	80％	86％	80％	BA	28％	60％	62％	60％	92％	90％	82％
LH	42％	56％	62％	58％	80％	86％	80％	PAT	40％	52％	66％	52％	90％	84％	82％

Above result shows, used epothilone d and cancer therapy drug (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, isoesperamicin D and cancer therapy drug (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.Isoesperamicin D is 2.5mg/kg, and cancer therapy drug is 15mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, did relatively therapeutic effect treatment (seeing Table 3) of index with inhibition rate of tumor growth (%).

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	60±12
2(6)	ilmofosine	48±5.0	＜0.05	1(6)	Contrast	60±12
2(6)	ilmofosine	48±5.0	＜0.05	3(6)	Isoesperamicin D	40±2.2	＜0.01
4(6)	Ilmofosine+ isoesperamicin D	30±2.6	＜0.001	3(6)	Isoesperamicin D	40±2.2	＜0.01
4(6)	Ilmofosine+ isoesperamicin D	30±2.6	＜0.001	5(6)	AMG-PC	46±3.2	＜0.01
6(6)	AMG-PC+ isoesperamicin D	20±3.0	＜0.001	5(6)	AMG-PC	46±3.2	＜0.01
6(6)	AMG-PC+ isoesperamicin D	20±3.0	＜0.001	7(6)	edelfosine	30±2.6	＜0.01
8(6)	Edelfosine+ isoesperamicin D	18±2.4	＜0.001	7(6)	edelfosine	30±2.6	＜0.01
8(6)	Edelfosine+ isoesperamicin D	18±2.4	＜0.001	9(6)	IDOU	32±3.4	＜0.01
10(6)	IDOU+ isoesperamicin D	18±2.2	＜0.001	9(6)	IDOU	32±3.4	＜0.01

Above result shows, used Epothilones (hyaluronidase) and cancer therapy drug-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, epothilone d and cancer therapy drug (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 (epothilone d or cancer therapy drug) and therapeutic alliance group (epothilone d and cancer therapy drug).Epothilone d (2mg/kg) is through intratumor injection, and cancer therapy drug (18mg/kg) is through lumbar injection.The treatment back was measured the gross tumor volume size on the 20th 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)	Epothilone d	58	＜0.05	1(6)	Contrast	-
2(6)	Epothilone d	58	＜0.05	3(6)	Imidazopyrazine	26	＜0.01
4(6)	Imidazopyridine	38	＜0.01	3(6)	Imidazopyrazine	26	＜0.01
4(6)	Imidazopyridine	38	＜0.01	5(6)	Wortmannin	32	＜0.01
6(6)	.alpha.-5:6-benzopyran	30	＜0.01	5(6)	Wortmannin	32	＜0.01
6(6)	.alpha.-5:6-benzopyran	30	＜0.01	7(6)	Epothilone d+imidazopyrazine	82	＜0.001
8(6)	Epothilone d+imidazopyridine	86	＜0.001	7(6)	Epothilone d+imidazopyrazine	82	＜0.001
8(6)	Epothilone d+imidazopyridine	86	＜0.001	9(6)	Epothilone d+wortmannin	86	＜0.001
10(6)	Epothilone d+.alpha.-5:6-benzopyran	84	＜0.001	9(6)	Epothilone d+wortmannin	86	＜0.001

Above result shows, the kinases inhibitor that used epothilone d and cancer therapy drug-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, epothilone B and cancer therapy drug (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.Epothilone B (18mg/kg) is through lumbar injection, and cancer therapy drug (2mg/kg) is through the injection of tumor week.The treatment back was measured the gross tumor volume size on the 21st 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)	Epothilone B	40	＜0.05	1(6)	Contrast	-
2(6)	Epothilone B	40	＜0.05	3(6)	LY294002	50	＜0.01
4(6)	SU11752	42	＜0.01	3(6)	LY294002	50	＜0.01
4(6)	SU11752	42	＜0.01	5(6)	SN-38	52	＜0.01
6(6)	OK-1035	46	＜0.01	5(6)	SN-38	52	＜0.01
6(6)	OK-1035	46	＜0.01	7(6)	Epothilone B+LY294002	76	＜0.001
8(6)	Epothilone B+SU11752	76	＜0.001	7(6)	Epothilone B+LY294002	76	＜0.001
8(6)	Epothilone B+SU11752	76	＜0.001	9(6)	Epothilone B+SN-38	70	＜0.001
10(6)	Epothilone B+OK-1035	80	＜0.001	9(6)	Epothilone B+SN-38	70	＜0.001

Above result shows, kinases inhibitor (wherein, LY294002:2-(4-Lin Ji)-8-phenylchromone that used epothilone B and cancer therapy drug-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, Epothilone C (-)-Deoxyepothilone A and cancer therapy drug (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.Epothilone C (-)-Deoxyepothilone A (5mg/kg) is through lumbar injection, and cancer therapy drug (10mg/kg) is through the injection of tumor week.The treatment back was measured the gross tumor volume size on the 21st 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)	Epothilone C (-)-Deoxyepothilone A	46	＜0.05	1(6)	Contrast	-
2(6)	Epothilone C (-)-Deoxyepothilone A	46	＜0.05	3(6)	Methoxamine	30	＜0.05
4(6)	Minocycline	32	＜0.05	3(6)	Methoxamine	30	＜0.05
4(6)	Minocycline	32	＜0.05	5(6)	Hydroxylamine	34	＜0.05
6(6)	O-methyl hydroxylamine	36	＜0.01	5(6)	Hydroxylamine	34	＜0.05
6(6)	O-methyl hydroxylamine	36	＜0.01	7(6)	Epothilone C (-)-Deoxyepothilone A+methoxamine	80	＜0.01
8(6)	Epothilone C (-)-Deoxyepothilone A+minocycline	88	＜0.01	7(6)	Epothilone C (-)-Deoxyepothilone A+methoxamine	80	＜0.01
8(6)	Epothilone C (-)-Deoxyepothilone A+minocycline	88	＜0.01	9(6)	Epothilone C (-)-Deoxyepothilone A+hydroxylamine	84	＜0.01
10(6)	Epothilone C (-)-Deoxyepothilone A+O-methyl hydroxylamine	78	＜0.001	9(6)	Epothilone C (-)-Deoxyepothilone A+hydroxylamine	84	＜0.01

Above result shows that growth all has the obvious suppression effect to the kinases inhibitor that used Epothilone C (-)-Deoxyepothilone A and cancer therapy drug-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, Epothilones and cancer therapy drug (sustained-release implant)

By the tumor-inhibiting action of test 8 described methods mensuration Epothilones and cancer therapy drug (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)	Epothilones	46	＜0.05	1(6)	Contrast	-
2(6)	Epothilones	46	＜0.05	3(6)	3-AB	40	＜0.01
4(6)	Benzoylamide	36	＜0.01	3(6)	3-AB	40	＜0.01
4(6)	Benzoylamide	36	＜0.01	5(6)	PD128763	30	＜0.01
6(6)	AG14361	26	＜0.01	5(6)	PD128763	30	＜0.01
6(6)	AG14361	26	＜0.01	7(6)	Epothilones+3-AB	70	＜0.001
8(6)	Epothilones+Benzoylamide	78	＜0.001	7(6)	Epothilones+3-AB	70	＜0.001
8(6)	Epothilones+Benzoylamide	78	＜0.001	9(6)	Epothilones+PD128763	74	＜0.001
10(6)	Epothilones+AG14361	82	＜0.001	9(6)	Epothilones+PD128763	74	＜0.001

Above result shows, used Epothilones and cancer therapy drug-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, Epothilone E (-)-Epothilone E. and cancer therapy drug (slow releasing injection)

By the tumor-inhibiting action of test 8 described methods mensuration Epothilones and cancer therapy drug (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)	Epothilone E (-)-Epothilone E.	48	＜0.05	1(6)	Contrast	-
2(6)	Epothilone E (-)-Epothilone E.	48	＜0.05	3(6)	BZ1-6	50	＜0.01
4(6)	TI1-5	30	＜0.01	3(6)	BZ1-6	50	＜0.01
4(6)	TI1-5	30	＜0.01	5(6)	TBC	36	＜0.01
6(6)	Benzimidazole	42	＜0.01	5(6)	TBC	36	＜0.01
6(6)	Benzimidazole	42	＜0.01	7(6)	Epothilone E (-)-Epothilone E .+BZ1-6	86	＜0.001
8(6)	Epothilone E (-)-Epothilone E .+TI1-5	82	＜0.001	7(6)	Epothilone E (-)-Epothilone E .+BZ1-6	86	＜0.001
8(6)	Epothilone E (-)-Epothilone E .+TI1-5	82	＜0.001	9(6)	Epothilone E (-)-Epothilone E .+TBC	78	＜0.001
10(6)	Epothilone E (-)-Epothilone E .+benzimidazole	78	＜0.001	9(6)	Epothilone E (-)-Epothilone E .+TBC	78	＜0.001

Above result shows, used Epothilone E (-)-Epothilone E. and cancer therapy drug-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, Azaepothilone B and/or cancer therapy drug (sustained-release implant)

By the tumor-inhibiting action of test 8 described methods mensuration Epothilones and/or cancer therapy drug (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)	Azaepothilone B	36	＜0.05	1(6)	Contrast	-
2(6)	Azaepothilone B	36	＜0.05	3(6)	NU1025	36	＜0.01
4(6)	PBC	40	＜0.01	3(6)	NU1025	36	＜0.01
4(6)	PBC	40	＜0.01	5(6)	MPBC	48	＜0.01
6(6)	NU1085	48	＜0.01	5(6)	MPBC	48	＜0.01
6(6)	NU1085	48	＜0.01	7(6)	Azaepothilone B+NU1025	86	＜0.001
8(6)	Azaepothilone B+PBC	76	＜0.001	7(6)	Azaepothilone B+NU1025	86	＜0.001
8(6)	Azaepothilone B+PBC	76	＜0.001	9(6)	Azaepothilone B+MPBC	88	＜0.001
10(6)	Azaepothilone B+NU1085	78	＜0.001	9(6)	Azaepothilone B+MPBC	88	＜0.001

Above result shows, used Azaepothilone B and cancer therapy drug-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, Ixabepilone and/or cancer therapy drug (sustained-release implant)

By the tumor-inhibiting action of test 6 described methods mensuration Ixabepi lone and/or cancer therapy drug (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)	Ixabepilone	48	＜0.05	1(6)	Contrast	-
2(6)	Ixabepilone	48	＜0.05	3(6)	BSO	46	＜0.01
4(6)	Aminotriazole(ATA)	36	＜0.01	3(6)	BSO	46	＜0.01
4(6)	Aminotriazole(ATA)	36	＜0.01	5(6)	Cavatic acid	42	＜0.01
6(6)	New podophyllotoxin	30	＜0.01	5(6)	Cavatic acid	42	＜0.01
6(6)	New podophyllotoxin	30	＜0.01	7(6)	Ixabepilone+BSO	78	＜0.001
8(6)	The Ixabepilone+ aminotriazole(ATA)	88	＜0.001	7(6)	Ixabepilone+BSO	78	＜0.001
8(6)	The Ixabepilone+ aminotriazole(ATA)	88	＜0.001	9(6)	The Ixabepilone+ cavatic acid	82	＜0.001
10(6)	The new podophyllotoxin of Ixabepilone+	86	＜0.001	9(6)	The Ixabepilone+ cavatic acid	82	＜0.001

Above result shows, AG14361 (wherein for used Ixabepilone and cancer therapy drug poly-(ADP-ribose), 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.

Release ratio in the body of the furan epothilone d sustained-release implant that test 13, different molecular weight polylactic acid are made

With the rat is subjects, grouping (3/group) and the equivalent furan epothilone d sustained-release implant that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (12%), 3 (26%), 7 (56%), 14 (80%), 21 (86%), 28 (92%) and 35 (94%).Discharge in the body of the sustained-release implant that comparison different molecular weight polylactic acid is made and find, slack-off with the molecular weight increase, with the 7th day was example, compare with whole body administration group, tumor control rate increases with the polylactic acid molecule amount and improves, and is followed successively by 68% (MW:5000), 62% (MW:15000), 54% (MW:25000), 52% (MW:40000) and 46 (MW:60000).

It is the slow releasing agent that contains BMS-310705 and anticarcinogen that adjuvant is made that same result also sees with polylactic acid.

That pays special attention to is simple to operation, the good reproducibility of slow releasing agent of the present invention, particularly slow releasing injection.Good effect not only, toxic and side effects is little.

Different drug packages is different with the drug release feature of different Biodegradable high moleculars.Discover that further the slow-release auxiliary material that is most appropriate to medicament slow release of the present invention is a poly-dl-lactide, poly-dl-lactide/ethanol copolymer, the monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, the polyethylene glycol copolymer, end carboxyl polylactic acid, end carboxyl polylactic acid/ethanol copolymer, polifeprosan, bis-fatty acid and decanedioic acid copolymer, poly-(erucic acid dimer-decanedioic acid), poly-(fumaric acid-decanedioic acid), ethylene vinyl acetate copolymer, polylactic acid, the copolymer of polyglycolic acid and hydroxyacetic acid, xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer, one of albumin glue or its combination; Optimum suspending agent is one of methylcellulose, hydroxy methocel, sodium carboxymethyl cellulose, (iodine) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40, soil temperature 80 or its combination.

In a word, growth all had the obvious suppression effect to kinds of tumor cells when used epothilone derivate 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 epothilone derivate and any one (or more than one) cancer therapy drug.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 epothilone B and 10mg7-hydroxy-star shaped spore native, shake up the back contains 10% epothilone B 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 viscosity of injection is 200cp-400cp (20 ℃-30 ℃ time), and the drug release time of this slow releasing injection in external normal saline is 18-25 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 polifeprosan is 50: 50, contained anticancer effective component and percentage by weight thereof are: 5% Epothilones, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, furan epothilone d or BMS-310705 and 7-hydroxy-star shaped spore native of 15%, 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

The viscosity of injection is 200cp-400cp (20 ℃-30 ℃ time).

Embodiment 3.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 10000-20000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 20mg epothilone d and 10mg7-ethyl-10-hydroxycamptothecine, 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 20% epothilone d and 10%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 viscosity of injection is 240cp-420ep (20 ℃-30 ℃ time), and 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 the molecular weight peak value is the polylactic acid (PLA) of 40000-60000, and contained anticancer effective component and percentage by weight thereof are:

15% Epothilones, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, furan epothilone d or BMS-310705 and 20% 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, the combination of aminotriazole(ATA) or DL-Buthionine-(S,R)-sulfoximine BSO.

Embodiment 5.

With 70mg molecular weight peak value is the polylactic acid (PLGA of 10000-20000,50: 50) put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of isoesperamicin D and 10 milligrams of benzimidazoles, shake up the back contains 20% isoesperamicin D 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 viscosity of injection is 260cp-480cp (20 ℃-30 ℃ time), and 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: 10% Epothilones, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone, Azaepothilone B, furan epothilone d or BMS-310705 and 10% 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, the combination of 4-diaminourea-6-benzyloxy-s-triazine or 2-amino-O4-benzyl pteridine.

Embodiment 7.

With 70mg molecular weight peak value is the polylactic acid (PLGA of 20000-40000,50: 50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg BMS-247550 and 10mg DL-Buthionine-(S,R)-sulfoximine BSO, shake up the back contains 20%BMS-247550 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 viscosity of injection is 300cp-480cp (20 ℃-30 ℃ time), and the drug release time of this slow releasing injection in external normal saline is 18-25 days, is about 25-35 days at the subcutaneous drug release time of mice.

Embodiment 8.

The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that contained anticancer effective component is to the polylactic acid (PLGA, 75: 25) of different the is molecular weight peak value is 40000-60000: the combination of the O4-benzyl folic acid of 10% Epothilones, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone, Azaepothilone B, furan epothilone d or BMS-310705 and 15%.

Embodiment 9

With 40mg polifeprosan (to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) is 50: 50) copolymer and 30mg molecular weight peak value is that the polylactic acid (PLA) of 10000-20000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Azaepothilone B and 10mgO4-benzyl folic acid, shake up the back contains 20% Azaepothilone B 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 24-35 days, is about 28-40 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 used slow-release auxiliary material is that 40mg polifeprosan (50: 50) copolymer and 30mg molecular weight peak value are the PLGA (50: 50) of 20000-40000, contained anticancer effective component is: the epothilone B of 10-30%, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone, Azaepothilone B, the O4-benzyl folic acid of furan epothilone d or BMS-310705 and 10-40%, 2,4,5 triamidos-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 30: 70) copolymer is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg7-hydroxy-star shaped spore native and 20mg furan epothilone d, shake up the back contains 10%7-hydroxy-star shaped spore native and 20% furan epothilone d with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 21-25 days, is about 30-40 days at the subcutaneous drug release time of mice.

Embodiment 12

The method step that is processed into sustained-release implant is identical with embodiment 11, but different is that contained anticancer effective component is: the combination of 20% BMS-310705 and 10% 7-hydroxy-star shaped spore native, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate.

Embodiment 13

With 70mg molecular weight peak value is that the PLGA (50: 50) of 60000-80000 puts into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg BMS-310705 and the new podophyllotoxin of 20mg, shake up the back contains 10%BMS-310705 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

The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that the molecular weight peak value is 40000 PLGA (70: 25), and contained anticancer effective component is:

The combination of 10% BMS-310705 and 20% aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin, 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) the molecular weight peak value is the polylactic acid (PLA) of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000;

B) the molecular weight peak value is the polyglycolic acid of 5000-10000,10000-30000,30000-60000,60000-100000 or 100000-150000 and the copolymer of hydroxyacetic acid (PLGA), wherein, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50;

C) ethylene vinyl acetate copolymer (EVAc);

D) 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40 to carboxy phenyl propane (p-CPP): certain herbaceous plants with big flowers diacid (SA) copolymer (polifeprosan);

E) bis-fatty acid and decanedioic acid copolymer;

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

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

H) xylitol, oligosaccharide, chrondroitin, chitin, chitosan, potassium salt, sodium salt, hyaluronic acid, collagen protein, gelatin, poloxamer or albumin glue;

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

Embodiment 16

The method step that is processed into slow releasing injection is identical with embodiment 1-15, 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:

(1) combination of 7-hydroxy-star shaped spore native of the epothilone B of 5-30%, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone, Azaepothilone B, furan epothilone d or BMS-310705 and 5-30%, 7-O-alkyl-star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;

(2) epothilone B of 5-30%, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone, Azaepothilone B, the O4-benzyl folic acid of furan epothilone d or BMS-310705 and 5-30%, 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; Or

(3) epothilone B of 5-30%, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone, Azaepothilone B, the imidazopyrazine of furan epothilone d or BMS-310705 and 5-30%, 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.

In the embodiment scope that the present invention is not limited to be given an example, this embodiment is intended to illustrate as the present invention is discrete.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.

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. anticancer sustained-release agent that contains Epothilones is characterized in that anticancer sustained-release agent is a slow releasing 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 epothilone derivate or epothilone derivate and the cancer therapy drug that 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;

Slow-release auxiliary material range of viscosities IV (dl/g) is 0.1～0.8, is selected from one of following or its combination:

A) polylactic acid;

B) copolymer of polyglycolic acid and hydroxyacetic acid;

C) polifeprosan;

D) combination of polifeprosan and polylactic acid or polyglycolic acid and co-glycolic acid;

E) bis-fatty acid and decanedioic acid copolymer;

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

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

H) xylitol, oligosaccharide, chrondroitin, chitin, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer or albumin glue;

The viscosity of suspending agent is 100cp-3000cp (20 ℃-30 ℃ time), is selected from one of sodium carboxymethyl cellulose, hydroxy methocel, iodine glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, soil temperature 20, soil temperature 40 and soil temperature 80 or its combination.

2. 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.

3. 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.

4. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that DNA repairase inhibitor is selected from 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, the O-hydroxylamine, O-methyl hydroxylamine, O-δ-ammonia oxygen-butyl hydroxylamine, the 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, 2-(4-hydroxyphenyl) benzimidazole-4-carboxamides BZ1-6, aminotriazole(ATA), DL-Buthionine-(S,R)-sulfoximine BSO, cavatic acid, S-hexyl glutathion, new podophyllotoxin, Exatecan mesylate or TAN-1518.

5. the slow-releasing anticarcinogen injection according to claim 1, it is characterized in that Epothilones is selected from Epothilones, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., 4-demethyl-9-ketone Epothilone C (-)-Deoxyepothilone A, 12,13-dihydro-13-oxygen Epothilone C (-)-Deoxyepothilone A, the amino epothilone B of 21-, the amino epothilone B of 26-, 21,26 Shao are by F Lv Gu Xia, 9,10-dehydrogenation epothilone B, 10,11-hydrogen epothilone B, 26,27-halogen epothilone B, 9,10,11,14,21,26 epothilone Bs that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone B, 21-hydroxyl-10,11 dehydrogenation epothilone Bs, 4-demethyl-9-ketone-epothilone B, 4-demethyl-9,10-two dehydrogenation epothilone Bs, 4-demethyl-10,11-two dehydrogenation epothilone Bs, 6-demethyl-10,11-two dehydrogenation epothilone Bs, the amino epothilone B of 21-, 21-hydroxyl epothilone B, 26-hydroxyl epothilone B, 26-fluorine epothilone B, the amino epothilone B of 26-, 12,13 cyclopropyl epothilone Bs, 12,13 cyclobutyl epothilone Bs, ixabepilone, Azaepothilone B, 26-three fluoro-(E)-9,10-dehydrogenation-12,13-Epothilone C B, 21 and 26 difference or the epothilone d that is replaced by amino simultaneously, 9 and 10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, 26,27 epothilone ds that replaced by halogen, 9,10,11,14,21,26 epothilone ds that replaced by hydroxyl respectively, 21,26-dihydroxy epothilone d, 21-hydroxyl-10,11 dehydrogenation epothilone ds, 4-demethyl-9-ketone epothilone d, 4-demethyl-9,10-two dehydrogenation epothilone ds, 4-demethyl-10,11-two dehydrogenation epothilone ds, 6-demethyl-10,11-two dehydrogenation epothilone ds, 21-hydroxyl epothilone d, the amino epothilone d of 21-, 26-hydroxyl epothilone d, the amino epothilone d of 26-, 26-fluorine epothilone d, isoesperamicin, isoesperamicin D, 9,10 dehydrogenation epothilone ds, 10,11 dehydrogenation epothilone ds, the furan epothilone d, (E)-9,10-dehydrogenation-12,13-Epothilone C D, BMS-310705, the 6-ethyl, the 16-fluorine, 17-pyridine Epothilones, 11,12-dehydrogenation-12,13-dehydrogenation-13-Epothilone C D, 12,13-dehydrogenation-13-Epothilone C D, a kind of or its combination in 9-oxygen base epothilone d or the 8-table-9-oxygen base epothilone d.

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:

(1) combination of the 7 hydroxy star shaped spore natives of the Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., ixabepilone (BMS-247550), Azaepothilone B, furan epothilone d, BMS-310705 and 1-40%, 7-O-alkyl star shaped spore native, beta-methoxy-star shaped spore native, alkyl phosphate choline or hexa-decyl choline phosphate;

(3) Epothilones of the 1-40% of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, the furan epothilone d, the imidazopyrazine of BMS-310705 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;

(4) Epothilones of 1-40%, Epothilones A, epothilone B, Epothilone C (-)-Deoxyepothilone A, epothilone d, isoesperamicin D, Epothilone E (-)-Epothilone E., Epothilone F (-)-Epothilone F., BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705

7. the slow-releasing anticarcinogen injection according to claim 1 is characterized in that in the selected slow-release auxiliary material,

(1) the molecular weight peak value of polylactic acid is selected from 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;

(2) in the copolymer of polyglycolic acid and hydroxyacetic acid, the ratio of polyglycolic acid and hydroxyacetic acid is 50-95: 50-50, and the molecular weight peak value is 5000-10000,10000-30000,300000-60000,60000-100000 or 100000-150000;

(3) in the 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.

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 is characterized in that anticancer effective component is used to prepare former or cancer, sarcoma or the carcinosarcoma sustained-release implant of secondary that treatment originates from 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.

10. the anticancer sustained-release agent according to claim 9 is characterized in that the weight ratio of epothilone derivate and cancer therapy drug is 1-9 in the anticancer effective component of described anti-cancer sustained-released implantation agent: 1 to 1: 1-9.

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, chitosan, hyaluronic acid, collagen protein, gelatin, poloxamer or white tempera;