CN101396342A

CN101396342A - Anti-cancer sustained-released injection containing epothilone derivate

Info

Publication number: CN101396342A
Application number: CNA2008103046425A
Authority: CN
Inventors: 孙娟; 刘玉燕; 孔庆新
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: 2009-04-01

Abstract

The invention relates to an anti-cancer sustained release injection containing epothilone derivative, consisting of sustained microspheres and menstruum. The sustained microspheres comprise anti-cancer drugs selected from taxane, alkylating agent and/or plant alkaloid and the like, the epothilone derivative and sustained release auxiliary material. The menstruum is a special menstruum containing suspending agent. The epothilone derivative is selected from epothilone B, epothilone D, iso-epothilone D, BMS-247550, azaepothilone B, furan epothilone D or BMS-310705. The sustained release auxiliary material is selected from poly-dl-lactide, the glycolic acid copolymer of the poly-dl-lactide, polyethyleneglycol, the polylactide copolymer of the polyethyleneglycol, carboxyl terminated polylactide copolymer, fatty acid and decanedioic acid copolymer, etc. The suspending agent is selected from carboxymethyl cellulose and the like with the viscosity of 100cp to 3000cp (under the temperature of 25 DEG C to 30 DEG C). The sustained release microsphere can also be made into a sustained release implant. The sustained release injection is injected or arranged in or around the tumour and can release drug at partial position for 40 days approximately, therefore, the sustained release injection improves the local drug concentration selectively and enhances the treatment effect of non-operative treatments, such as radiotherapy, chemotherapy and the like at the same time.

Description

The slow-releasing anticarcinogen injection that contains epothilone derivate

(1) technical field

The present invention relates to a kind of slow releasing injection that contains epothilone derivate, belong to technical field of pharmaceuticals.Particularly, the invention provides a kind of slow releasing injection and sustained-release implant that contains epothilone derivate.

(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): 7682).

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.The above unexpected main contents of the present invention of finding to constitute.

Controlled release formulation for anti entity tumour of the present invention comprises anticancer effective component and pharmaceutic adjuvant, and anticancer effective component is selected from taxane, alkylating agent and/or plant alkaloid and epothilone derivate.

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

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

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

(A) sustained-release micro-spheres comprises:

Anticancer effective component 0.5-60%

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 epothilone derivate and cancer therapy drug, and cancer therapy drug is selected from taxane, alkylating agent and/or plant alkaloid; 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), poly-to dioxy cyclohexanone (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.

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-desoxyepothiloneB, 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 D11,12-dehydro-12,13-dihydro-13-oxoepothilone D, 12,13-dehydrogenation-13-Epothilone C D (12,13-dihydro-13-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.

Taxane in the anticancer effective component (Taxanes) kind anti-cancer drugs owner to be selected from paclitaxel (Taxol), Docetaxel (Docetaxel, taxotere, docetaxel), 2 '-hydroxyl paclitaxel (paclitaxel-2 '-hydroxy), 10-removes acetyl paclitaxel (10-deacetyl taxol), 7-table-paclitaxel (7-epi-taxol).With paclitaxel and docetaxel serves as preferred.

Alkylating agent comprises and selects alestramustine; atrimustine; ambamustine; carmustine; nimustine; ditiomustine; bofumustine; bendamustine; galamustine; Ranimustine; fotemustine; elmustine; ecomustine; estramustine; hemustine heCNU He; pentamustine; mannomustine; lomustine; methyl lomustine; prednimustine; uracil mustard; tauromustine; tallimustine; spiromustine; streptozocin; Sarmustine SarCNU; semustine; methyl lomustine; streptozocin; a kind of or its combination in the appropriate azoles amine of miaow.Above alkylating agent also comprises their salt, as, but be not limited to sulfate, phosphate, hydrochlorate, Lactobionate, acetate, aspat, nitrate, citrate, purine or pyrimidine salt, succinate and maleate etc.

The percentage by weight of above-mentioned alkylating agent in slow releasing agent is good from 0.01%-99.99% with 1%-50%, is best with 5%-30%.

Plant alkaloid mainly is selected from vincristine, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, monocrotaline or cephalotaxin.

Plant alkaloid shared ratio in compositions is decided because of concrete condition, and generally speaking, percentage by weight can be good with 1%-50% from 0.01%-99.99%, is best with 5%-30%.

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

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

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

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

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

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

Anticancer effective component epothilone derivate and/or the cancer therapy drug percentage by weight in medicament slow-release microsphere is 0.5%-60%, is good with 2%-40%, is best with 5%-30%.The weight ratio of epothilone derivate and cancer therapy drug is 1-20:1 and 1:1-20, serves as preferred with 1-9:1 to 1:1-9, serves as preferred with 1-2:1 to 1:1-2.

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

(a) paclitaxel of the Epothilones of 2-40%, 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 or BMS-310705 and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel;

(b) Epothilones of 2-40%, 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 alestramustine of furan epothilone d or BMS-310705 and 2-40%, atrimustine, ambamustine, carmustine, nimustine, ditiomustine, bofumustine, bendamustine, galamustine, Ranimustine, fotemustine, elmustine, ecomustine, estramustine, hemustine heCNU He, pentamustine, mannomustine, lomustine, methyl lomustine, prednimustine, uracil mustard, tauromustine, tallimustine, spiromustine, streptozocin, Sarmustine SarCNU, semustine, methyl lomustine, the combination of the appropriate azoles amine of streptozocin or miaow; Or

(c) Epothilones of 2-40%, 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 vincristine of furan epothilone d or BMS-310705 and 2-40%, vincaleucoblastine, vinorelbine, vindesine, Vinmegallate, vinleurosine, vinleucinol, vinglycinate, vinfosiltine, vinformide, vinflunine, vinepidine, vinzolidine, vintriptol, vinrosidine, the combination of monocrotaline or cephalotaxin.

Slow-release auxiliary material is selected from 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, one of gelatin and albumin glue or its combination.

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

(1) PLA of 55-90%;

(2) PLGA of 50-90%

(3) polifeprosan of 50-85%;

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

(5) combination of the PLGA of the PLA of the polifeprosan of 35-60% and 35-60% or 35-60%;

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

(7) poly-dl-lactide of 40-95%, poly-dl-lactide/ethanol copolymer, monomethyl polyethylene glycol, monomethyl polyethylene glycol copolymer, polyethylene glycol, polyethylene glycol copolymer, end carboxyl polylactic acid or end carboxyl polylactic acid/ethanol copolymer.

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

The molecular weight peak value of polylactic acid can be, but is not limited to, 5000-100, and 000, but with 20,000-60,000 is preferred, with 5,000-30,000 for most preferably; The molecular weight of polyglycolic acid can be, but is not limited to, 5000-100, and 000, but with 5,000-50,000 is preferred, with 10,000-30,000 for most preferably; Above polyhydroxy acid can singly select or multiselect.When singly selecting, serve as preferred with the copolymer (PLGA) of polylactic acid (PLA) or hydroxy carboxylic acid and glycolic, the molecular weight of copolymer can be, but is not limited to, 5000-100,000, but with 20,000-60,000 be preferably, with 30,000-50,000 for most preferably; When multiselect, compound polymer or the copolymer formed with macromolecule polymer or different macromolecule polymer serve as preferred, with the compound polymer that contains different molecular weight polylactic acid or decanedioic acid or copolymer for most preferably, as, but be not limited to, molecular weight is 1000 to 30000 polylactic acid with molecular weight is that 20000 to 50000 polylactic acid mixes, molecular weight is 10000 to 30000 polylactic acid with molecular weight is that 30000 to 80000 PLGA mixes, molecular weight is that 20000 to 30000 polylactic acid mixes with decanedioic acid, molecular weight is that 30000 to 80000 PLGA mixes with decanedioic acid.Used polylactic acid serves as preferred with Poly-L-lactic acid (L-PLA).Poly-L-lactic acid (L-PLA) range of viscosities IV (dl/g) is 0.2～0.8, and glass transition temperature range is 55～65 ℃, 175～185 ℃ of fusing points.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Main Ingredients and Appearance of sustained-release implant can be made into multiple dosage form.As, but be not limited to capsule, slow releasing agent, implant, slow releasing agent implant etc.; Be multiple shape, as, but be not limited to granule, pill, tablet, powder, sphere, bulk, needle-like, bar-shaped, column and membranaceous.In various dosage forms, serve as preferred slowly to discharge implant in the body.Can be the bar-shaped of 0.1-5mm (slightly) * 1-10mm (length), also can be other shapes such as lamellar.

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

The anticancer effective component of sustained-release implant can be with reference to slow releasing injection, but is preferably as follows, and all is weight percentage:

(a) paclitaxel of the epothilone B of 2-40%, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 2-40%, Docetaxel, 2 '-hydroxyl paclitaxel, the 10-combination of removing acetyl paclitaxel or 7-table-paclitaxel;

(b) combination of the appropriate azoles amine of carmustine, nimustine, bendamustine, fotemustine, estramustine, lomustine, spiromustine, streptozocin, Sarmustine SarCNU, semustine or miaow of the Epothilones of 2-40%, 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 and 2-40%; Or

(c) combination of vincristine, vincaleucoblastine, vinorelbine or the vindesine of the Epothilones of 2-40%, 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 or BMS-310705 and 2-40%.

Slow-release auxiliary material can be various water solublity or water-insoluble macromolecule polymer.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;

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 behind the epothilone derivate 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 2.5mg/kg epothilone derivate.Measure medicament contg (%) in the different time tumor, the result shows, the local drug concentration significant difference of epothilone derivate 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 derivate compares

With the rat is subjects, with 2 * 10 ⁵Individual pancreatic 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 derivate.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 epothilone derivate 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.

Tumor-inhibiting action in the body of test 3, epothilone derivate 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 following 10 groups (seeing Table 1).First group is contrast, and the 2nd to 10 group is the treatment group, and medicine is through intratumor injection.Epothilone B is 1.5mg/kg, and cancer therapy drug is 7.5mg/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	60±10
2(6)	Epothilone B	38±5.2	<0.05	1(6)	Contrast	60±10
2(6)	Epothilone B	38±5.2	<0.05	3(6)	Paclitaxel	30±6.0	<0.01
4(6)	Docetaxel	30±4.0	<0.01	3(6)	Paclitaxel	30±6.0	<0.01
4(6)	Docetaxel	30±4.0	<0.01	5(6)	The hydroxyl paclitaxel	34±6.0	<0.01
6(6)	7-table-paclitaxel	36±8.0	<0.01	5(6)	The hydroxyl paclitaxel	34±6.0	<0.01
6(6)	7-table-paclitaxel	36±8.0	<0.01	7(6)	Paclitaxel+epothilone B	18±4.2	<0.001
8(6)	Docetaxel+epothilone B	20±4.4	<0.001	7(6)	Paclitaxel+epothilone B	18±4.2	<0.001
8(6)	Docetaxel+epothilone B	20±4.4	<0.001	9(6)	Hydroxyl paclitaxel+epothilone B	16±3.0	<0.001
10(6)	7-table-paclitaxel+epothilone B	16±2.6	<0.001	9(6)	Hydroxyl paclitaxel+epothilone B	16±3.0	<0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for epothilone B and its synergist-taxanes cancer therapy drug (paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 7-table-paclitaxel), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 4, epothilone derivate and cancer therapy drug (slow releasing injection)

Used tumor cell comprises the cerebral tumor (CNS-1, C6), gastric gland epithelial cancer (SA), bone tumor (BC), breast carcinoma (BA), pulmonary carcinoma (LH), papillary adenocarcinoma of thyroid (PAT) etc.Epothilone d is 1.5mg/kg, and cancer therapy drug is 7.5mg/kg.The gross tumor volume size was measured on the 21st day in the treatment back, and its growth of tumour cell suppression ratio (%) is shown in Table 2.

Table 2

Oncocyte	Carmustine	Nimustine	Fotemustine	Epothilone d	Carmustine+epothilone d	Nimustine+epothilone d	Fotemustine+epothilone d
Oncocyte	Carmustine	Nimustine	Fotemustine	Epothilone d	Carmustine+epothilone d	Nimustine+epothilone d	Fotemustine+epothilone d	CNS	42％	48％	42％	46％	72％	76％	88％
C6	60％	52％	40％	24％	64％	76％	78％	CNS	42％	48％	42％	46％	72％	76％	88％
C6	60％	52％	40％	24％	64％	76％	78％	SA	48％	60％	26％	22％	68％	82％	60％
BC	52％	48％	34％	64％	64％	86％	80％	SA	48％	60％	26％	22％	68％	82％	60％
BC	52％	48％	34％	64％	64％	86％	80％	BA	54％	52％	52％	22％	68％	72％	78％
LH	52％	50％	22％	18％	60％	82％	82％	BA	54％	52％	52％	22％	68％	72％	78％
LH	52％	50％	22％	18％	60％	82％	82％	PAT	42％	50％	40％	58％	72％	84％	80％

Above result shows that growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used cancer therapy drug (carmustine, nimustine, fotemustine) and epothilone d, can show significant potentiation when use in conjunction.Same effect also sees the other types tumor, as esophageal carcinoma, ovarian cancer, cancer of pancreas, hepatocarcinoma, intestinal cancer etc.

The tumor-inhibiting action of test 5, epothilone derivate 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 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.Epothilone derivate is 7.5mg/kg, and cancer therapy drug is 2.5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 3) on the 20th 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	60±10
2(6)	Epothilone derivate	53±4.0	<0.05	1(6)	Contrast	60±10
2(6)	Epothilone derivate	53±4.0	<0.05	3(6)	Nimustine	40±4.0	<0.01
4(6)	Epothilone derivate+nimustine	18±6.2	<0.001	3(6)	Nimustine	40±4.0	<0.01
4(6)	Epothilone derivate+nimustine	18±6.2	<0.001	5(6)	Carmustine	38±3.2	<0.01
6(6)	Epothilone derivate+carmustine	18±1.8	<0.001	5(6)	Carmustine	38±3.2	<0.01
6(6)	Epothilone derivate+carmustine	18±1.8	<0.001	7(6)	Fotemustine	38±2.8	<0.01
8(6)	Epothilone derivate+fotemustine	22±2.6	<0.001	7(6)	Fotemustine	38±2.8	<0.01
8(6)	Epothilone derivate+fotemustine	22±2.6	<0.001	9(6)	Sarmustine SarCNU	36±4.0	<0.01
10(6)	Epothilone derivate+Sarmustine SarCNU	14±2.2	<0.001	9(6)	Sarmustine SarCNU	36±4.0	<0.01

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used epothilone derivate (isoesperamicin D) and cancer therapy drug-alkylating agent (nimustine, carmustine, fotemustine, Sarmustine SarCNU), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 6, epothilone derivate and cancer therapy drug (slow releasing injection)

With the rat is subjects, with 2 * 10 ⁵Individual pancreatic tumor cell subcutaneous injection is in its hypochondrium, treats that tumor growth after 14 days is divided into it negative control (blank), single therapy group (epothilone derivate or cancer therapy drug) and therapeutic alliance group (epothilone derivate and cancer therapy drug).Medicine is through intratumor injection.Epothilone derivate is 2.5mg/kg, and cancer therapy drug is 5mg/kg.The treatment back was measured gross tumor volume size, relatively therapeutic effect (seeing Table 4) on the 20th day.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 derivate	48	<0.05	1(6)	Contrast	-
2(6)	Epothilone derivate	48	<0.05	3(6)	Semustine	46	<0.01
4(6)	Lomustine	42	<0.01	3(6)	Semustine	46	<0.01
4(6)	Lomustine	42	<0.01	5(6)	Estramustine	50	<0.01
6(6)	Streptozocin	42	<0.01	5(6)	Estramustine	50	<0.01
6(6)	Streptozocin	42	<0.01	7(6)	Epothilone derivate+semustine	76	<0.001
8(6)	Epothilone derivate+lomustine	74	<0.001	7(6)	Epothilone derivate+semustine	76	<0.001
8(6)	Epothilone derivate+lomustine	74	<0.001	9(6)	Epothilone derivate+estramustine	82	<0.001
10(6)	Epothilone derivate+streptozocin	86	<0.001	9(6)	Epothilone derivate+estramustine	82	<0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used epothilone derivate (BMS-247550) and cancer therapy drug-alkylating agent (semustine, lomustine, estramustine, streptozocin), can show significant potentiation when use in conjunction.

The tumor-inhibiting action of test 7, epothilone derivate 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.Medicine is through intratumor injection.Dosage is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th day, made relatively therapeutic effect (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 derivate	30	<0.05	1(6)	Contrast	-
2(6)	Epothilone derivate	30	<0.05	3(6)	Galamustine	54	<0.01
4(6)	Ranimustine	46	<0.01	3(6)	Galamustine	54	<0.01
4(6)	Ranimustine	46	<0.01	5(6)	Fotemustine	32	<0.01
6(6)	Tallimustine	44	<0.01	5(6)	Fotemustine	32	<0.01
6(6)	Tallimustine	44	<0.01	7(6)	Epothilone derivate+galamustine	74	<0.001
8(6)	Epothilone derivate+Ranimustine	82	<0.001	7(6)	Epothilone derivate+galamustine	74	<0.001
8(6)	Epothilone derivate+Ranimustine	82	<0.001	9(6)	Epothilone derivate+fotemustine	84	<0.001
10(6)	Epothilone derivate+tallimustine	76	<0.001	9(6)	Epothilone derivate+fotemustine	84	<0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used epothilone derivate (Azaepothilone B) and cancer therapy drug-alkylating agent (galamustine, Ranimustine, fotemustine, tallimustine), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 8, epothilone derivate 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.Sustained-release implant is placed in tumor.Epothilone derivate is 2.5mg/kg, and cancer therapy drug is 5mg/kg.The treatment back was measured the gross tumor volume size on the 20th 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 derivate	36	<0.05	1(6)	Contrast	-
2(6)	Epothilone derivate	36	<0.05	3(6)	Vincristine	58	<0.01
4(6)	Vincaleucoblastine	52	<0.01	3(6)	Vincristine	58	<0.01
4(6)	Vincaleucoblastine	52	<0.01	5(6)	Vinorelbine	68	<0.01
6(6)	Vindesine	46	<0.01	5(6)	Vinorelbine	68	<0.01
6(6)	Vindesine	46	<0.01	7(6)	Epothilone derivate+vincristine	82	<0.001
8(6)	Epothilone derivate+vincaleucoblastine	84	<0.001	7(6)	Epothilone derivate+vincristine	82	<0.001
8(6)	Epothilone derivate+vincaleucoblastine	84	<0.001	9(6)	Epothilone derivate+vinorelbine	82	<0.001
10(6)	Epothilone derivate+vindesine	86	<0.001	9(6)	Epothilone derivate+vinorelbine	82	<0.001

Above result shows, growth all has the obvious suppression effect to kinds of tumor cells when this concentration is used separately for used epothilone derivate (furan epothilone d) and cancer therapy drug-plant alkaloid (vincristine, vincaleucoblastine, vinorelbine, vindesine), can show significant potentiation when use in conjunction.This discovery constitutes the another key character of the present invention.

The tumor-inhibiting action of test 9, epothilone derivate and cancer therapy drug (slow releasing injection)

Measure the tumor-inhibiting action of epothilone derivate and cancer therapy drug (slow releasing injection) by test 7 described methods, the result shows that BMS-310705 can significantly strengthen the tumor killing effect of alkylating agents such as the appropriate azoles amine of carmustine, nimustine, bendamustine, galamustine, Ranimustine, fotemustine, lomustine, tallimustine, spiromustine, streptozocin, Sarmustine SarCNU, semustine, methyl lomustine, streptozocin or miaow to breast carcinoma and carcinoma of prostate, and potentiation is in 38-70% (P＜0.01).

The tumor-inhibiting action of test 10, epothilone derivate and cancer therapy drug (slow releasing injection)

Measure the tumor-inhibiting action of BMS-310705 and cancer therapy drug (slow releasing injection) by test 7 described methods, the result shows that can significantly strengthen paclitaxel, Docetaxel, 2 '-hydroxyl paclitaxel, 10-removes the tumor killing effect of taxanes anticarcinogens such as acetyl paclitaxel or 7-table-paclitaxel to pulmonary carcinoma and cancer of pancreas, and potentiation is in 40-80% (P＜0.01).

The tumor-inhibiting action of test 11, cancer therapy drug (slow releasing injection)

Measure the tumor-inhibiting action of epothilone derivate (BMS-310705) and cancer therapy drug (slow releasing injection) by test 7 described methods, the result shows that epothilone derivate can significantly strengthen vincristine, vincaleucoblastine, vinorelbine, the vindesine tumor killing effect to gastric cancer and colon cancer, and potentiation is in 60-80% (P＜0.01).

Release ratio in the body of the epothilone derivate sustained-release implant that test 12, different molecular weight polylactic acid are made

With the rat is subjects, grouping (3/group) and the equivalent epothilone B sustained-release implant that carries in the subcutaneous polylactic acid (PLA) that contains different molecular weight (MW).Survey the surplus of medicine in implant respectively at 1,3,7,14,21,28 and 35 day then, and then draw rate of release (%) in its body.The result shows, molecular weight is 20000 is released to: 1 day (8%), 3 (28%), 7 (56%), 14 (82%), 21 (90), 28 (94) and 35 (98%).Discharge in the body of the epothilone B 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 66% (MW:5000), 62% (MW:15000), 54% (MW:25000), 50% (MW:40000) and 46 (MW:60000).

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 to want characteristic different with 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.The slow releasing preparation that above-mentioned slow-release auxiliary material is made does not have the prominent phenomenon of releasing of tangible medicine; 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 epothilone derivate and any 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 paclitaxel and 10mg epothilone B, shake up the back contains 10% paclitaxel and 10% epothilone B with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the normal saline that contains 15% mannitol, makes corresponding suspension type slow releasing injection, viscosity is 220cp-460cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 2.

The method step that is processed into slow releasing injection is identical with embodiment 1, but different is that polifeprosan is 20:80, and contained anticancer effective component and percentage by weight thereof are:

(a) paclitaxel of 5% Epothilones, 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 and 25% or the combination of Docetaxel;

(b) 20% Epothilones, 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 and 10% carmustine, nimustine, bendamustine, galamustine, Ranimustine, fotemustine, hemustine heCNU He, lomustine, methyl lomustine, uracil mustard, Sarmustine SarCNU, semustine, the combination of the appropriate azoles amine of streptozocin or miaow; Or

(c) combination of vincristine, vincaleucoblastine, vinorelbine or the vindesine of 20% Epothilones, 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 and 20%.The viscosity of slow releasing injection is 200cp-450cp (20 ℃-30 ℃ time).

Embodiment 3.

With 70mg molecular weight peak value is that (PLGA 75:25) puts into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg epothilone d and 15mg nimustine, shakes up the dry organic solvent of removing of final vacuum again for the polylactic acid of 40000-65000.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% epothilone d and 15% nimustine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 300cp-400cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 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 PLGA (50:50) of 20000-40000, and contained anticancer effective component and percentage by weight thereof are: the combination of the appropriate azoles amine of carmustine, nimustine, bendamustine, fotemustine, lomustine, tallimustine, spiromustine, Sarmustine SarCNU or miaow of the epothilone B of 2-40%, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 2-40%.

Embodiment 5.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 40000-65000 is put into container, after adding 100 milliliters of dichloromethane dissolving mixings, add 20 milligrams of vincristine and 10 milligrams of isoesperamicin D, shake up the back contains 20% vincristine and 10% isoesperamicin D with spray drying method for preparation injectable microsphere again.Then microsphere is suspended in the injection that contains the 5-15% sorbitol, makes corresponding suspension type slow releasing injection, viscosity is 100cp-200cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 6.

The method step that is processed into slow releasing injection is identical with embodiment 5, but different is that the molecular weight peak value is the polylactic acid (PLA) of 20000-45000, and contained anticancer effective component is: the combination of vincristine, vincaleucoblastine, vinorelbine or the vindesine of 10% epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 20%.

Embodiment 7.

With 40mg polifeprosan (20:80) and 30mg molecular weight peak value is that the polylactic acid (PLA) of 20000-45000 is put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg paclitaxel and 10mg BMS-247550, shake up the back contains 20% paclitaxel and 10% BMS-247550 with spray drying method for preparation injectable microsphere again.Microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 0.5% Tween 80 then, makes corresponding suspension type slow releasing injection, viscosity is 80cp-150cp (20 ℃-25 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 8.

The method step that is processed into slow releasing injection is identical with embodiment 7, but different is that used slow-release auxiliary material is that 30mg polifeprosan (30:70) and 40mg molecular weight peak value are the polylactic acid (PLA) of 10000-20000, and contained anticancer effective component is: the combination of 20% paclitaxel or docetaxel and 10% epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705.

Embodiment 9

With 40mg polifeprosan (20:80) and 30mg molecular weight peak value is the polylactic acid (PLGA of 20000-45000,50:50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 20mg Docetaxel and 10mg furan epothilone d, shake up the back again and contain 20% Docetaxel and 10% furan epothilone d injectable microsphere with spray drying method for preparation.Then microsphere is suspended in the normal saline that contains 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.2% Tween 80, makes corresponding suspension type slow releasing injection, viscosity is 560cp-640cp (20 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 10

The method step that is processed into slow releasing injection is identical with embodiment 9, but different is that contained anticancer effective component is: the combination of 10% paclitaxel or Docetaxel and 10% furan epothilone d.

Embodiment 11

With 40mg polifeprosan (30:70) and 30mg molecular weight peak value is the polylactic acid (PLGA of 10000-25000,50:50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg carmustine and 20mg BMS-310705, shake up the back contains 10% carmustine and 20% BMS-310705 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 used slow-release auxiliary material that different is is 30mg polifeprosan (40:60) and 40mg molecular weight peak value is that polylactic acid (PLA) slow-release auxiliary material of 15000-30000 is 35000 polylactic acid (PLA) for the molecular weight peak value, and contained anticancer effective component is 15% epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 10% nimustine, bendamustine, carmustine, galamustine, fotemustine, lomustine, Ranimustine, Sarmustine SarCNU, the combination of the appropriate azoles amine of spiromustine or miaow.

Embodiment 13

With 70mg molecular weight peak value is the polylactic acid (PLGA of 15000-35000,50:50) put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 10mg epothilone d and 20mg vinorelbine, shake up the back contains 10% epothilone d and 20% vinorelbine with spray drying method for preparation injectable microsphere again.Then microsphere is made corresponding sustained-release implant through pressed disc method.The drug release time of this sustained-release implant in external normal saline is 10-15 days, is about 35-50 days at the subcutaneous drug release time of mice.

Embodiment 14

The method step that is processed into sustained-release implant is identical with embodiment 11,13, but different is that contained anticancer effective component is:

(a) paclitaxel of the epothilone B of 5-15%, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 10-35% or the combination of docetaxel;

(b) nimustine of the epothilone B of 5-15%, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 5-20%, carmustine, fotemustine, estramustine, lomustine, methyl lomustine, bendamustine or, the combination of Ranimustine or the appropriate azoles amine of miaow; Or

(c) combination of vincristine, vincaleucoblastine, vinorelbine, vindesine or the vinrosidine of the epothilone B of 5-15%, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 15-25%.

Embodiment 15.

With 70mg molecular weight peak value is that the polylactic acid (PLA) of 10000-35000 is put into container, adds 100 milliliters of dichloromethane, behind the dissolving mixing, adds 15mg isoesperamicin D and 15mg vincaleucoblastine, shakes up the dry organic solvent of removing of final vacuum again.Dried pastille solid composite freezing and pulverizing is made the micropowder that contains 15% isoesperamicin D and 15% vincaleucoblastine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 220cp-260cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 16

The method step that is processed into slow releasing injection is identical with embodiment 15, but different is that contained anticancer effective component and percentage by weight thereof are:

The combination of vincristine, vincaleucoblastine, vinorelbine or the vindesine of 10% epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B or furan epothilone d and 10%.

Embodiment 17.

With 80mg molecular weight peak value is that bis-fatty acid and certain herbaceous plants with big flowers diacid (SA) copolymer (bis-fatty acid: the certain herbaceous plants with big flowers diacid is 20:80) of 20000-30000 put into container, add 100 milliliters of dichloromethane, behind the dissolving mixing, add 5mg Azaepothilone B and 15mg vincristine, 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 5% Azaepothilone B and 15% vincristine, be suspended in then in the normal saline that contains 1.5% sodium carboxymethyl cellulose, make corresponding suspension type slow releasing injection, viscosity is 380cp-460cp (25 ℃-30 ℃ time).The drug release time of this slow releasing injection in external normal saline is 10-15 days, is about 20-30 days at the subcutaneous drug release time of mice.

Embodiment 18.

The method step that is processed into slow releasing injection is identical with embodiment 17, but different is used slow-release auxiliary material is that the bis-fatty acid of 30000-50000 and certain herbaceous plants with big flowers diacid (SA) copolymer (bis-fatty acid: the certain herbaceous plants with big flowers diacid is 50:50) contained anticancer effective component and percentage by weight thereof are for the molecular weight peak value:

The combination of new alkali of spring, vincaleucoblastine, vinorelbine, vindesine or the vinleurosine of 15% epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B or furan epothilone d and 15%.

Embodiment 19

The method step that is processed into slow releasing agent is identical with embodiment 1-18, but different is used slow-release auxiliary material is one of following or its combination:

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

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

C) combination of polifeprosan and PLA or PLGA;

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

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

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

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

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

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

Embodiment 20

The method step that is processed into slow releasing injection is identical with embodiment 1-19, 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 21

The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is that contained anticancer effective component is: the combination of the appropriate azoles amine of paclitaxel, docetaxel, nimustine, carmustine, fotemustine, lomustine, the miaow of 15% epothilone B, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B or furan epothilone d and 5-25%, vincristine, vincaleucoblastine or vinorelbine.

Embodiment 22

The method step that is processed into slow releasing injection is identical with embodiment 1-20, but different is that contained anticancer effective component is:

(b) combination of nimustine, carmustine, fotemustine, bendamustine or the Ranimustine of the epothilone B of 5-15%, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 5-20% or the appropriate azoles amine of miaow; Or

(c) combination of vincristine, vincaleucoblastine, vinorelbine or the vindesine of the epothilone B of 5-15%, epothilone d, isoesperamicin D, BMS-247550, Azaepothilone B, furan epothilone d or BMS-310705 and 15-25%.

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

Claims

[claim 1] a kind of slow-releasing anticarcinogen injection that contains epothilone derivate 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 the cancer therapy drug of epothilone derivate and taxane;

Described epothilone derivate 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-diaminourea epothilone B, 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, grand according to husky, 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, the amino epothilone B of C21-, 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, 9-oxygen base epothilone d or 8-table-9-oxygen base epothilone d;

Described alkylating agent is selected from alestramustine, atrimustine, ambamustine, nimustine, bendamustine, ditiomustine, bofumustine, carmustine, elmustine, ecomustine, CNCC, galamustine, fotemustine, estramustine, hemustine heCNU He, pentamustine, mannomustine, lomustine, methyl lomustine, semustine, Ranimustine, prednimustine, uracil mustard, Sarmustine SarCNU, tauromustine, streptozocin, tallimustine, spiromustine, one of appropriate azoles amine of miaow or its combination;

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

A) polylactic acid, its molecular weight peak value is 10000-30000,30000-60000,60000-100000 or 100000-150000;

B) copolymer of polyglycolic acid and hydroxyacetic acid, wherein, the weight ratio of polyglycolic acid and hydroxyacetic acid is 50-95:50-5, the molecular weight peak value is 10000-30000,30000-60000,60000-100000 or 100000-150000;

C) polifeprosan, wherein, to carboxy phenyl propane: the decanedioic acid weight ratio is 10: 90,20: 80,30: 70,40: 60,50: 50 or 60: 40;

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

Used suspending agent is respectively one of following or its combination:
A) 0.5-3.0% sodium carboxymethyl cellulose;

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% Tween 80;

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

I) 0.5-5% sodium carboxymethyl cellulose+5-20% sorbitol+0.1-0.5% Tween 80;

In the time of 20 ℃-30 ℃, the viscosity of suspending agent is 100cp-3000cp.
The slow-releasing anticarcinogen injection that [claim 2] is according to claim 1 is characterized in that in the slow-releasing anticarcinogen injection, and the percentage by weight of epothilone derivate and cancer therapy drug is 1-20:1 and 1:1-20.
The slow-releasing anticarcinogen injection that [claim 3] is according to claim 1, it is characterized in that sustained-release micro-spheres in the slow-releasing anticarcinogen injection also 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 sustained-release implant of sarcoma or carcinosarcoma is in tumor or tumor week injection or place administration.
It is one of following that the anti-cancer sustained-released implantation agent that [claim 4] is according to claim 3, the anticancer effective component that it is characterized in that sustained-release implant are mainly:

The combination of the appropriate azoles amine of carmustine, nimustine, bendamustine, fotemustine, estramustine, lomustine, spiromustine, streptozocin, Sarmustine SarCNU, semustine or miaow of the Epothilones of 2-40%, 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 and 2-40%; Or;

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